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Chemistry
Potassium complexes supported by monoanionic tetradentate amino-phenolate ligands: synthesis, structure and catalysis in the ring-opening polymerization of rac-lactide
Apr 21, 2017   Dalton Transactions (Cambridge, England : 2003)
Yao C, Yang Y, Xu S, Ma H
Potassium complexes supported by monoanionic tetradentate amino-phenolate ligands: synthesis, structure and catalysis in the ring-opening polymerization of rac-lactide
Apr 21, 2017
Dalton Transactions (Cambridge, England : 2003)
A series of potassium complexes bearing monoanionic tetradentate amino-phenolate ligands, [LK]2 (L = {(2-R1)C6H4CH2N[(CH2)2R2]CH2(4-R4-6-R3)C6H2O-}, R1 = NMe2, R2 = NEt2, R3 = CPh3, R4 = Me (1); R1 = R2 = NEt2, R3 = CPh3, R4 = Me (2); R1 = NMe2, R2 = NEt2, R3 = R4 = cumyl (4); R1 = R2 = OMe, R3 = tBu, R4 = Me (6); L = (2-NMe2)C6H4CH2N[[CH2-(S)-1-butylpyrrolidinyl]CH2(4-Me-6-CPh3)C6H2O-] (3)), have been synthesized via reactions of KN(SiMe3)2 and 1 equiv. of the corresponding aminophenols. The solid-state structures of typical complexes 4 and 6 are determined via X-ray diffraction studies, which reveal the dinuclear nature of these complexes. By contrast, DOSY measurements of 1, 4 and 6 suggest that these complexes are monomeric in solution. It is noteworthy that the coordination chemistry of these potassium complexes is versatile, which is closely related to the nature of the ortho-substituent of the phenolate ring, as indicated by the results of the corresponding spectroscopic studies. In the presence of iPrOH, 1-4 and 6 could initiate the polymerization of 500 equiv. of rac-lactide to achieve high monomer conversions within several minutes but afford atactic PLAs with slightly isotactic-enriched microstructures (Pm = 0.58-0.60). Experimental results also demonstrated that a bulky trityl substituent at the ortho-position of the phenolate ring of the ligand framework is beneficial for the enhancement of the activities of these potassium complexes.
ADP-Ribosylation Goes Normal: Serine as the Major Site of the Modification
Apr 21, 2017   Cell Chemical Biology
Liu Q, Florea BI, Filippov DV
ADP-Ribosylation Goes Normal: Serine as the Major Site of the Modification
Apr 21, 2017
Cell Chemical Biology
Proteins containing adenosine diphosphate ribosylserine as a posttranslational modification are widespread and formed via HPF1-assisted, PARP-1-mediated PARylation as Bonfiglio et al. (2017) report in a recent issue of Molecular Cell. Copyright © 2017 Elsevier Ltd. All rights reserved.
A quinoline-based Cu2+ ion complex fluorescence probe for selective detection of inorganic phosphate anion in aqueous solution and its application to living cells
Apr 22, 2017   Spectrochimica Acta. Part A, Molecular And Biomolecular Spectroscopy
Dai Y, Wang P, Fu J, Yao K, Xu K, Pang X
A quinoline-based Cu2+ ion complex fluorescence probe for selective detection of inorganic phosphate anion in aqueous solution and its application to living cells
Apr 22, 2017
Spectrochimica Acta. Part A, Molecular And Biomolecular Spectroscopy
A quinaldine functionalized probe QP has been designed and synthesized. It exhibited selective turn-off fluorescence response toward Cu2+ ion over most of the biologically important ions at physiological pH. The binding ratio of the probe QP and Cu2+ ion was determined to be 1:1 through fluorescence titration, Job's plot and ESI-MS. The binding constant (K) of Cu2+ to probe QP was found to be 2.12×104M-1. Further, the Cu2+ ensemble of probe QP was found to respond H2PO4- and HPO42- among other important biological anions via fluorescence turn-on response at physiological pH. Fluorescence microscopy imaging using living Hela cells showed that probe QP could be used as an effective fluorescent probe for detecting Cu2+ cation and H2PO4- and HPO42- anions in living cells. Copyright © 2017 Elsevier B.V. All rights reserved.
Comparison of pneumatic tube system with manual transport for routine chemistry, hematology, coagulation and blood gas tests
Apr 22, 2017   Clinical Chemistry And Laboratory Medicine
Pupek A, Matthewson B, Whitman E, Fullarton R, Chen Y
Comparison of pneumatic tube system with manual transport for routine chemistry, hematology, coagulation and blood gas tests
Apr 22, 2017
Clinical Chemistry And Laboratory Medicine
The pneumatic tube system (PTS) is commonly used in modern clinical laboratories to provide quick specimen delivery. However, its impact on sample integrity and laboratory testing results are still debatable. In addition, each PTS installation and configuration is unique to its institution. We sought to validate our Swisslog PTS by comparing routine chemistry, hematology, coagulation and blood gas test results and sample integrity indices between duplicate samples transported either manually or by PTS. Duplicate samples were delivered to the core laboratory manually by human courier or via the Swisslog PTS. Head-to-head comparisons of 48 routine chemistry, hematology, coagulation and blood gas laboratory tests, and three sample integrity indices were conducted on 41 healthy volunteers and 61 adult patients. The PTS showed no impact on sample hemolysis, lipemia, or icterus indices (all p
An integrated microsystem with dielectrophoresis enrichment and impedance detection for detection of Escherichia coli
Apr 22, 2017   Biomedical Microdevices
Wang R, Xu Y, Liu H, Peng J, Irudayaraj J, Cui F
An integrated microsystem with dielectrophoresis enrichment and impedance detection for detection of Escherichia coli
Apr 22, 2017
Biomedical Microdevices
An integrated microsystem device with matched interdigitated microelectrode chip was fabricated for enrichment and detection of Escherichia coli O157:H7. The microsystem has integrated with positive dielectrophoresis (pDEP) enrichment and in situ impedance detection, whose total volume is only 3.0 × 10-3 m3, and could provide impedance testing voltages of 0 ~ 10 V, detection frequencies of 1 KHz ~ 1 MHz, DEP excitation signals with amplitude of 0 ~ 10 Vpp and frequencies of 1KHz ~ 1 MHz, which fully meets the demands of pDEP enrichment and impedance detection for bacteria. The microfluidic chip with interdigitated microelectrodes was manufactured by microfabrication methods. The interdigital microelectrode array has sufficient contact area with a bacterial suspension to improve enrichment efficiency and detection sensitivity. Bacteria in the interdigital microelectrode area of the microfluidic chip were firstly captured and enriched by pDEP. Then, in situ impedance detection of the enriched bacteria was realized by switching test conditions. Using the self-assembly microsystem, a novel quantitative detection method was established and demonstrated to detect Escherichia coli O157:H7. Experimental results showed that the detection limits of Escherichia coli O157:H7 was 5 × 104 cfu mL-1, and testing time was only 6 min under the optimized detection voltage of 100 mV and frequency of 500 KHz. The method was successfully used to detect Escherichia coli O157:H7 in synthetic chicken synthetic samples.
Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating
Apr 22, 2017   Scientific Reports
Yelshanskaya MV, Mesbahi-Vasey S, Kurnikova MG, Sobolevsky AI
Role of the Ion Channel Extracellular Collar in AMPA Receptor Gating
Apr 22, 2017
Scientific Reports
AMPA subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission and are implicated in numerous neurological diseases. Ionic currents through AMPA receptor channels can be allosterically regulated via different sites on the receptor protein. We used site-directed mutagenesis and patch-clamp recordings to probe the ion channel extracellular collar, the binding region for noncompetitive allosteric inhibitors. We found position and substitution-dependent effects for introduced mutations at this region on AMPA receptor gating. The results of mutagenesis suggested that the transmembrane domains M1, M3 and M4, which contribute to the ion channel extracellular collar, undergo significant relative displacement during gating. We used molecular dynamics simulations to predict an AMPA receptor open state structure and rationalize the results of mutagenesis. We conclude that the ion channel extracellular collar plays a distinct role in gating and represents a hub for powerful allosteric modulation of AMPA receptor function that can be used for developing novel therapeutics.
Structure-function analysis of the DNA-binding domain of a transmembrane transcriptional activator
Apr 22, 2017   Scientific Reports
Schlundt A, Buchner S, Janowski R, Heydenreich T, Heermann R, Lassak J, Geerlof A, Stehle R, Niessing D, Jung K, Sattler M
Structure-function analysis of the DNA-binding domain of a transmembrane transcriptional activator
Apr 22, 2017
Scientific Reports
The transmembrane DNA-binding protein CadC of E. coli, a representative of the ToxR-like receptor family, combines input and effector domains for signal sensing and transcriptional activation, respectively, in a single protein, thus representing one of the simplest signalling systems. At acidic pH in a lysine-rich environment, CadC activates the transcription of the cadBA operon through recruitment of the RNA polymerase (RNAP) to the two cadBA promoter sites, Cad1 and Cad2, which are directly bound by CadC. However, the molecular details for its interaction with DNA have remained elusive. Here, we present the crystal structure of the CadC DNA-binding domain (DBD) and show that it adopts a winged helix-turn-helix fold. The interaction with the cadBA promoter site Cad1 is studied by using nuclear magnetic resonance (NMR) spectroscopy, biophysical methods and functional assays and reveals a preference for AT-rich regions. By mutational analysis we identify amino acids within the CadC DBD that are crucial for DNA-binding and functional activity. Experimentally derived structural models of the CadC-DNA complex indicate that the CadC DBD employs mainly non-sequence-specific over a few specific contacts. Our data provide molecular insights into the CadC-DNA interaction and suggest how CadC dimerization may provide high-affinity binding to the Cad1 promoter.
Enhanced Response of Metformin towards the Cancer Cells due to Synergism with Multi-walled Carbon Nanotubes in Photothermal Therapy
Apr 22, 2017   Scientific Reports
Yoo S, Hou J, Yi W, Li Y, Chen W, Meng L, Si J, Hou X
Enhanced Response of Metformin towards the Cancer Cells due to Synergism with Multi-walled Carbon Nanotubes in Photothermal Therapy
Apr 22, 2017
Scientific Reports
Converging evidence from laboratory models pointed that the widely used antidiabetic drug metformin has direct effects on cancer cells. Thus far, relatively little attention has been addressed to the drug exposures used experimentally relative to those achievable clinically. Here, we demonstrated that metformin loaded on carbon nanotubes under near-infrared (NIR) irradiation led to the remarkably enhancement in response towards cancer cells. The dose of metformin has reduced to only 1/280 of typical doses in monotherapy (35: 10 000-30 000 µM) where the realization of metformin in conventional antidiabetic doses for cancer therapies becomes possible. The heat generated from carbon nanotubes upon NIR irradiation has mediated a strong and highly localized hyperthermia-like condition that facilitated the enhancement. Our work highlight the promise of using highly localized heating from carbon nanotubes to intensify the efficacy of metformin for potential cancer therapies.
Entropic uncertainty relations for Markovian and non-Markovian processes under a structured bosonic reservoir
Apr 22, 2017   Scientific Reports
Wang D, Huang AJ, Hoehn RD, Ming F, Sun WY, Shi JD, Ye L, Kais S
Entropic uncertainty relations for Markovian and non-Markovian processes under a structured bosonic reservoir
Apr 22, 2017
Scientific Reports
The uncertainty relation is a fundamental limit in quantum mechanics and is of great importance to quantum information processing as it relates to quantum precision measurement. Due to interactions with the surrounding environment, a quantum system will unavoidably suffer from decoherence. Here, we investigate the dynamic behaviors of the entropic uncertainty relation of an atom-cavity interacting system under a bosonic reservoir during the crossover between Markovian and non-Markovian regimes. Specifically, we explore the dynamic behavior of the entropic uncertainty relation for a pair of incompatible observables under the reservoir-induced atomic decay effect both with and without quantum memory. We find that the uncertainty dramatically depends on both the atom-cavity and the cavity-reservoir interactions, as well as the correlation time, τ, of the structured reservoir. Furthermore, we verify that the uncertainty is anti-correlated with the purity of the state of the observed qubit-system. We also propose a remarkably simple and efficient way to reduce the uncertainty by utilizing quantum weak measurement reversal. Therefore our work offers a new insight into the uncertainty dynamics for multi-component measurements within an open system, and is thus important for quantum precision measurements.
In vitro fermentation behaviors of fucosylated chondroitin sulfate from Pearsonothuria graeffei by human gut microflora
Apr 22, 2017   International Journal Of Biological Macromolecules
Wei CY, Liao NB, Zhang Y, Ye XQ, Li S, Hu YQ, Liu DH, Linhardt RJ, Wang X, Chen SG
In vitro fermentation behaviors of fucosylated chondroitin sulfate from Pearsonothuria graeffei by human gut microflora
Apr 22, 2017
International Journal Of Biological Macromolecules
A fucosylated chondroitin sulfate (FCS-pg) with highly repeated structure from Pearsonothuria graeffei was subjected to a in vitro fermentation model to investigate its fermentability and effects on human gut microflora. High performance liquid chromatography (HPLC) measurement found FCS-pg can be fermented to short chain fatty acids (SCFAs) by gut microflora from partial human fecal samples. 16S rRNA gene-based polymerase chain reaction-based denaturing gradient gel electrophoresis (PCR-DGGE) profiling and real-time quantitative PCR analysis showed that FCS-pg mainly increased the proportions of Clostridium cluster XI, Bacteriodes prevotella group, Bifidobacterium genus, Clostridium cluster I and Clostridium cluster XIVab, whereas the numbers of the Enterobacteriaceae and Lactobacillus decreased. These results indicated that FCS-pg is mainly fermented by Bacteroides, Bifidobacterium and Clostridium. It increased the content of probiotics bacteria in achieving health-enhancing effect, was slightly different than most sulfated polysaccharides from marine animals. The current study provides useful new information on the mechanism of absorption and functional activity on FCS-pg within the gastrointestinal tract of the human body. Copyright © 2017. Published by Elsevier B.V.
Structural and Functional Analysis of a β2-Adrenergic Receptor Complex with GRK5
Apr 21, 2017   Cell
Komolov KE, Du Y, Duc NM, Betz RM, Rodrigues JPGLM, Leib RD, Patra D, Skiniotis G, Adams CM, Dror RO, Chung KY, Kobilka BK, Benovic JL
Structural and Functional Analysis of a β2-Adrenergic Receptor Complex with GRK5
Apr 21, 2017
Cell
The phosphorylation of agonist-occupied G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) functions to turn off G-protein signaling and turn on arrestin-mediated signaling. While a structural understanding of GPCR/G-protein and GPCR/arrestin complexes has emerged in recent years, the molecular architecture of a GPCR/GRK complex remains poorly defined. We used a comprehensive integrated approach of cross-linking, hydrogen-deuterium exchange mass spectrometry (MS), electron microscopy, mutagenesis, molecular dynamics simulations, and computational docking to analyze GRK5 interaction with the β2-adrenergic receptor (β2AR). These studies revealed a dynamic mechanism of complex formation that involves large conformational changes in the GRK5 RH/catalytic domain interface upon receptor binding. These changes facilitate contacts between intracellular loops 2 and 3 and the C terminus of the β2AR with the GRK5 RH bundle subdomain, membrane-binding surface, and kinase catalytic cleft, respectively. These studies significantly contribute to our understanding of the mechanism by which GRKs regulate the function of activated GPCRs. PAPERCLIP. Copyright © 2017 Elsevier Inc. All rights reserved.
A Compendium of RNA-Binding Proteins that Regulate MicroRNA Biogenesis
Apr 21, 2017   Molecular Cell
Treiber T, Treiber N, Plessmann U, Harlander S, Daiß JL, Eichner N, Lehmann G, Schall K, Urlaub H, Meister G
A Compendium of RNA-Binding Proteins that Regulate MicroRNA Biogenesis
Apr 21, 2017
Molecular Cell
During microRNA (miRNA) biogenesis, two endonucleolytic reactions convert stem-loop-structured precursors into mature miRNAs. These processing steps can be posttranscriptionally regulated by RNA-binding proteins (RBPs). Here, we have used a proteomics-based pull-down approach to map and characterize the interactome of a multitude of pre-miRNAs. We identify ∼180 RBPs that interact specifically with distinct pre-miRNAs. For functional validation, we combined RNAi and CRISPR/Cas-mediated knockout experiments to analyze RBP-dependent changes in miRNA levels. Indeed, a large number of the investigated candidates, including splicing factors and other mRNA processing proteins, have effects on miRNA processing. As an example, we show that TRIM71/LIN41 is a potent regulator of miR-29a processing and its inactivation directly affects miR-29a targets. We provide an extended database of RBPs that interact with pre-miRNAs in extracts of different cell types, highlighting a widespread layer of co- and posttranscriptional regulation of miRNA biogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.
Genome mining unearths a hybrid nonribosomal peptide synthetase-like-pteridine synthase biosynthetic gene cluster
Apr 21, 2017   ELife
Park HB, Perez CE, Barber KW, Rinehart J, Crawford JM
Genome mining unearths a hybrid nonribosomal peptide synthetase-like-pteridine synthase biosynthetic gene cluster
Apr 21, 2017
ELife
Nonribosomal peptides represent a large class of metabolites with pharmaceutical relevance. Pteridines, such as pterins, folates, and flavins, are heterocyclic metabolites that often serve as redox-active cofactors. The biosynthetic machineries for construction of these distinct classes of small molecules operate independently in the cell. Here, we discovered an unprecedented nonribosomal peptide synthetase-like-pteridine synthase hybrid biosynthetic gene cluster in Photorhabdus luminescens using genome synteny analysis. P. luminescens is a Gammaproteobacterium that undergoes phenotypic variation and can have both pathogenic and mutualistic roles. Through extensive gene deletion, pathway-targeted molecular networking, quantitative proteomic analysis, and NMR, we show that the genetic locus affects the regulation of quorum sensing and secondary metabolic enzymes and encodes new pteridine metabolites functionalized with cis-amide acyl-side chains, termed pepteridine A (1) and B (2). The pepteridines are produced in the pathogenic phenotypic variant and represent the first reported metabolites to be synthesized by a hybrid NRPS-pteridine pathway. These studies expand our view of the combinatorial biosynthetic potential available in bacteria.
Regioisomerically pure multiaryl coronene derivatives: highly efficient synthesis via bay-extended perylene tetrabutylester
Apr 21, 2017   Chemical Communications (Cambridge, England)
Mao W, Zhang J, Li X, Li C, Tian H
Regioisomerically pure multiaryl coronene derivatives: highly efficient synthesis via bay-extended perylene tetrabutylester
Apr 21, 2017
Chemical Communications (Cambridge, England)
By a facile strategy, we obtained three pure regioisomers of multiaryl coronene bisimide (CBI) derivatives via IBr-mediated annelation and subsequent Suzuki coupling reactions with high yields. A series of aromatic groups with different electron properties were efficiently introduced to obtain functional CBI derivatives under mild conditions with good yields. Furthermore, the annelation mechanism as well as the optical and electrochemical properties of CBI derivatives were further investigated.
Phase-Transfer Ligand Exchange of Lead Chalcogenide Quantum Dots for Direct Deposition of Thick, Highly Conductive Films
Apr 21, 2017   Journal Of The American Chemical Society
Lin Q, Yun HJ, Liu W, Song HJ, Makarov NS, Isaienko O, Nakotte T, Chen G, Luo H, Klimov VI, Pietryga JM
Phase-Transfer Ligand Exchange of Lead Chalcogenide Quantum Dots for Direct Deposition of Thick, Highly Conductive Films
Apr 21, 2017
Journal Of The American Chemical Society
The use of semiconductor nanocrystal quantum dots (QDs) in optoelectronic devices typically requires post-synthetic chemical surface treatments to enhance electronic coupling between QDs and allow for efficient charge transport in QD films. Despite their importance to solar cells, and infrared (IR) light-emitting diodes and photodetectors, advances in these chemical treatments for lead chalcogenide (PbE, E = S, Se, Te) QDs have lagged behind those of, for instance, II-VI semiconductor QDs. Here, we introduce a method for fast and effective ligand exchange for PbE QDs in solution, resulting in QDs completely passivated by a wide range of small anionic ligands. Due to electrostatic stabilization, these QDs are readily dispersible in polar solvents, in which they form highly concentrated solutions that remain stable for months. QDs of all three Pb chalcogenides retain their photoluminescence, allowing for a detailed study of the effect of the surface ionic double-layer on electronic passivation of QD surfaces, which we find can be explained using the hard/soft acid-base theory. Importantly, we prepare highly conductive films of PbS, PbSe and PbTe QDs by direct casting from solution without further chemical treatment, as determined by field-effect transistor measurements. This method allows for precise control over the surface chemistry, and therefore the transport properties of deposited films, and allows for the single-step deposition of films of unprecedented thickness via continuous processing techniques, as we demonstrate by preparing a dense, smooth 5.3 µm thick PbSe QD film via doctor blading. As such, it offers important advantages over laborious layer-by-layer methods for solar cells and photodetectors, while opening the door to new possibilities in ionizing radiation detectors.
SPA-LN: a scoring function of ligand-nucleic acid interactions via optimizing both specificity and affinity
Apr 21, 2017   Nucleic Acids Research
Yan Z, Wang J
SPA-LN: a scoring function of ligand-nucleic acid interactions via optimizing both specificity and affinity
Apr 21, 2017
Nucleic Acids Research
Nucleic acids have been widely recognized as potential targets in drug discovery and aptamer selection. Quantifying the interactions between small molecules and nucleic acids is critical to discover lead compounds and design novel aptamers. Scoring function is normally employed to quantify the interactions in structure-based virtual screening. However, the predictive power of nucleic acid-ligand scoring functions is still a challenge compared to other types of biomolecular recognition. With the rapid growth of experimentally determined nucleic acid-ligand complex structures, in this work, we develop a knowledge-based scoring function of nucleic acid-ligand interactions, namely SPA-LN. SPA-LN is optimized by maximizing both the affinity and specificity of native complex structures. The development strategy is different from those of previous nucleic acid-ligand scoring functions which focus on the affinity only in the optimization. The native conformation is stabilized while non-native conformations are destabilized by our optimization, making the funnel-like binding energy landscape more biased toward the native state. The performance of SPA-LN validates the development strategy and provides a relatively more accurate way to score the nucleic acid-ligand interactions. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.
DNAproDB: an interactive tool for structural analysis of DNA-protein complexes
Apr 21, 2017   Nucleic Acids Research
Sagendorf JM, Berman HM, Rohs R
DNAproDB: an interactive tool for structural analysis of DNA-protein complexes
Apr 21, 2017
Nucleic Acids Research
Many biological processes are mediated by complex interactions between DNA and proteins. Transcription factors, various polymerases, nucleases and histones recognize and bind DNA with different levels of binding specificity. To understand the physical mechanisms that allow proteins to recognize DNA and achieve their biological functions, it is important to analyze structures of DNA-protein complexes in detail. DNAproDB is a web-based interactive tool designed to help researchers study these complexes. DNAproDB provides an automated structure-processing pipeline that extracts structural features from DNA-protein complexes. The extracted features are organized in structured data files, which are easily parsed with any programming language or viewed in a browser. We processed a large number of DNA-protein complexes retrieved from the Protein Data Bank and created the DNAproDB database to store this data. Users can search the database by combining features of the DNA, protein or DNA-protein interactions at the interface. Additionally, users can upload their own structures for processing privately and securely. DNAproDB provides several interactive and customizable tools for creating visualizations of the DNA-protein interface at different levels of abstraction that can be exported as high quality figures. All functionality is documented and freely accessible at http://dnaprodb.usc.edu. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.
Replication and repair of a reduced 2΄-deoxyguanosine-abasic site interstrand cross-link in human cells
Apr 21, 2017   Nucleic Acids Research
Price NE, Li L, Gates KS, Wang Y
Replication and repair of a reduced 2΄-deoxyguanosine-abasic site interstrand cross-link in human cells
Apr 21, 2017
Nucleic Acids Research
Apurinic/apyrimidinic (AP) sites, or abasic sites, which are a common type of endogenous DNA damage, can forge interstrand DNA-DNA cross-links via reaction with the exocyclic amino group on a nearby 2΄-deoxyguanosine or 2΄-deoxyadenosine in the opposite strand. Here, we utilized a shuttle vector method to examine the efficiency and fidelity with which a reduced dG-AP cross-link-containing plasmid was replicated in cultured human cells. Our results showed that the cross-link constituted strong impediments to DNA replication in HEK293T cells, with the bypass efficiencies for the dG- and AP-containing strands being 40% and 20%, respectively. While depletion of polymerase (Pol) η did not perturb the bypass efficiency of the lesion, the bypass efficiency was markedly reduced (to 1-10%) in the isogenic cells deficient in Pol κ, Pol ι or Pol ζ, suggesting the mutual involvement of multiple translesion synthesis polymerases in bypassing the lesion. Additionally, replication of the cross-linked AP residue in HEK293T cells was moderately error-prone, inducing a total of ∼26% single-nucleobase substitutions at the lesion site, whereas replication past the cross-linked dG component occurred at a mutation frequency of ∼8%. Together, our results provided important insights into the effects of an AP-derived interstrand cross-link on the efficiency and accuracy of DNA replication in human cells. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.
Growth-suppressive activity of raloxifene on liver cancer cells by targeting IL-6/GP130 signaling
Apr 21, 2017   Oncotarget
Wang Y, Ma H, Zhao C, Liu T, Yan D, Jou D, Li H, Zhang C, Lü J, Li C, Lin J, Li S, Lin L
Growth-suppressive activity of raloxifene on liver cancer cells by targeting IL-6/GP130 signaling
Apr 21, 2017
Oncotarget
Interleukin-6 (IL-6) is a multifunctional cytokine, which is involved in the regulation of differentiation and growth of certain types of tumor cells. Constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) induced by IL-6 is frequently detected in liver cancer and has emerged as a viable molecular target for liver cancer treatment. However, few inhibitors targeting up-streams of STAT3 are available for the therapy of liver cancer. We reported the discovery of EVISTA (Raloxifene HCl) as novel inhibitor of IL-6/GP130 protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning. The possible effect of Raloxifene in STAT3 signaling or liver cancer cells is still unclear. Raloxifene inhibited the P-STAT3 stimulated by IL-6, but not the induction of STAT1 and STAT6 phosphorylation by IFN-γ, IFN-α, and IL-4. Raloxifene inhibited STAT3 phosphorylation and resulted in the induction apoptosis on human liver cancer cell-lines. Raloxifene inhibited the targets of STAT3, such as Bcl-2, Bcl-xl and survivin and cell viability, cell migration, and colony formation in liver cancer cells. Further, daily administration of Raloxifene suppressed the Hep-G2 tumor growth in mice in vivo. The inhibitory effect on STAT3 phosphorylation and activity as well as cell viability, migration, and colony forming ability by Raloxifene was examined in human liver cancer cells. Tumor growth was detected via mouse xenograft tumor mode. Our results suggest that Raloxifene is a potent IL-6/GP130 inhibitor and may be a chemoprevention agent for liver cancer by targeting persistent STAT3 signaling.
Poly(adenosine diphosphate-ribose) polymerase as therapeutic target: lessons learned from its inhibitors
Apr 21, 2017   Oncotarget
Cseh AM, Fábián Z, Sümegi B, Scorrano L
Poly(adenosine diphosphate-ribose) polymerase as therapeutic target: lessons learned from its inhibitors
Apr 21, 2017
Oncotarget
Poly(ADP-ribose) polymerases are a family of DNA-dependent nuclear enzymes catalyzing the transfer of ADP-ribose moieties from cellular nicotinamide-adenine-dinucleotide to a variety of target proteins. Although they have been considered as resident nuclear elements of the DNA repair machinery, recent works revealed a more intricate physiologic role of poly(ADP-ribose) polymerases with numerous extranuclear activities. Indeed, poly(ADP-ribose) polymerases participate in fundamental cellular processes like chromatin remodelling, transcription or regulation of the cell-cycle. These new insight into the physiologic roles of poly(ADP-ribose) polymerases widens the range of human pathologies in which pharmacologic inhibition of these enzymes might have a therapeutic potential. Here, we overview our current knowledge on extranuclear functions of poly(ADP-ribose) polymerases with a particular focus on the mitochondrial ones and discuss potential fields of future clinical applications.
Ag-Initiated gem-Difluoromethylenation of the Nitrogen Center of Arenediazonium Salts to gem-Difluoromethylene Azo Compounds
Apr 21, 2017   Organic Letters
Jiang H, Chen Y, Chen B, Xu H, Wan W, Deng H, Ma K, Wu S, Hao J
Ag-Initiated gem-Difluoromethylenation of the Nitrogen Center of Arenediazonium Salts to gem-Difluoromethylene Azo Compounds
Apr 21, 2017
Organic Letters
An efficient method for the synthesis of the thermally stable and pharmaceutically important gem-difluoromethylene azo compounds is developed. This protocol achieved gem-difluoromethylenation of the nitrogen center of arenediazonium salts through in situ generated benzo-1,3-diazolic difluoromethylene radical addition to arenediazonium salts under mild Ag-initiated conditions.
A Thorium Chalcogenolate Series Generated by Atom Insertion into Thorium-Carbon Bonds
Apr 21, 2017   Journal Of The American Chemical Society
Settineri NS, Garner ME, Arnold J
A Thorium Chalcogenolate Series Generated by Atom Insertion into Thorium-Carbon Bonds
Apr 21, 2017
Journal Of The American Chemical Society
A new thorium monoalkyl complex, Th(CH2SiMe3)(L3) (L = MeC(NiPr)2) (2), undergoes insertion of chalcogen atoms resulting in a series of thorium chalcogenolate complexes, Th(ECH2SiMe3)(L3) (E = S, SS, Se, Te; 5-8). Complex 6 represents the first alkyl disulfide thorium species and illustrates the ability of 2 to undergo controllable, stoichiometric atom insertion. All complexes have been characterized by 1H and 13C NMR spectroscopy, FTIR, EA, and melting point, and in the case of 1, 2, and 4-8, X-ray crystallography. Insertion was achieved by balancing the thermodynamic driving force of chalcogenolate formation versus the BDE of the pnictogen-chalcogen bond in the transfer reagent. Utilizing Me3NO as an oxygen atom transfer reagent led to C-H activation and SiMe4 extrusion rather than oxygen atom insertion, resulting in the alkoxide complex Th(OCH2NMe2)(L3) (4).
A complimentary benzophenone cross-linking/mass spectrometry photochemistry
Apr 21, 2017   Analytical Chemistry
Belsom A, Mudd G, Giese SH, Auer M, Rappsilber J
A complimentary benzophenone cross-linking/mass spectrometry photochemistry
Apr 21, 2017
Analytical Chemistry
Use of a heterobifunctional photoactivatable cross-linker, sulfo-SDA (diazirine), has yielded high-density data that facilitated structure modelling of individual proteins. We expand the photoactivatable chemistry toolbox here with a second reagent, sulfo-SBP (benzophenone). This further increases the density of photo-cross-linking to a factor of 20x over conventional cross-linking. Importantly, the two different photoactivatable groups display orthogonal directionality, enabling access to different protein regions, unreachable with a single cross-linker.
Targeting Conformational Activation of CDK2 Kinase
Apr 21, 2017   Biotechnology Journal
Pellerano M, Tcherniuk S, Perals C, Ngoc Van TN, Garcin E, Mahuteau-Betzer F, Teulade-Fichou MP, Morris MC
Targeting Conformational Activation of CDK2 Kinase
Apr 21, 2017
Biotechnology Journal
Cyclin-dependent kinases constitute attractive pharmacological targets for cancer therapeutics, yet inhibitors in clinical trials target the ATP-binding pocket of the CDK and therefore suffer from limited selectivity and emergence of resistance. The more recent development of allosteric inhibitors targeting conformational plasticity of protein kinases offers promising perspectives for therapeutics. In particular tampering with T-loop dynamics of CDK2 kinase would provide a selective means of inhibiting this kinase, by preventing its conformational activation. To this aim we engineered a fluorescent biosensor that specifically reports on conformational changes of CDK2 activation loop and is insensitive to ATP or ATP-competitive inhibitors, which constitutes a highly sensitive probe for identification of selective T-loop modulators. This biosensor was successfully applied to screen a library of small chemical compounds leading to discovery of a family of quinacridine analogs, which potently inhibit cancer cell proliferation, and promote accumulation of cells in S phase and G2. These compounds bind CDK2/ Cyclin A, inhibit its kinase activity, compete with substrate binding, but not with ATP, and dock onto the T-loop of CDK2. The best compound also binds CDK4 and CDK4/Cyclin D1, but not CDK1. The strategy we describe opens new doors for the discovery of a new class of allosteric CDK inhibitors for cancer therapeutics. Copyright © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Removal of antibiotics from piggery wastewater by biological aerated filter system: Treatment efficiency and biodegradation kinetics
Apr 22, 2017   Bioresource Technology
Chen J, Liu YS, Zhang JN, Yang YQ, Hu LX, Yang YY, Zhao JL, Chen FR, Ying GG
Removal of antibiotics from piggery wastewater by biological aerated filter system: Treatment efficiency and biodegradation kinetics
Apr 22, 2017
Bioresource Technology
This study aimed to investigate the removal efficiency and mechanism for antibiotics in swine wastewater by a biological aerated filter system (BAF system) in combination with laboratory aerobic and anaerobic incubation experiments. Nine antibiotics including sulfamonomethoxine, sulfachloropyridazine, sulfamethazine, trimethoprim, norfloxacin, ofloxacin, lincomycin, leucomycin and oxytetracycline were detected in the wastewater with concentrations up to 192,000ng/L. The results from this pilot study showed efficient removals (>82%) of the conventional wastewater pollutants (BOD5, COD, TN and NH3-N) and the detected nine antibiotics by the BAF system. Laboratory simulation experiment showed first-order dissipation kinetics for the nine antibiotics in the wastewater under aerobic and anaerobic conditions. The biodegradation kinetic parameters successfully predicted the fate of the nine antibiotics in the BAF system. This suggests that biodegradation was the dominant process for antibiotic removal in the BAF system. Copyright © 2017 Elsevier Ltd. All rights reserved.

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