A Selective Small Molecule DNA2 Inhibitor for Sensitization of Human Cancer Cells to Chemotherapy

Cancer cells frequently up-regulate DNA replication and repair proteins such as the multifunctional DNA2 nuclease/helicase, counteracting DNA damage due to replication stress and promoting survival. Therefore, we hypothesized that blocking both DNA replication and repair by inhibiting the bifunctional DNA2 could be a potent strategy to sensitize cancer cells to stresses from radiation or chemotherapeutic agents. We show that homozygous deletion of DNA2 sensitizes cells to ionizing radiation and camptothecin (CPT). Using a virtual high throughput screen, we identify 4-hydroxy-8-nitroquinoline-3-carboxylic acid (C5) as an effective and selective inhibitor of DNA2. Mutagenesis and biochemical analysis define the C5 binding pocket at a DNA-binding motif that is shared by the nuclease and helicase activities, consistent with structural studies that suggest that DNA binding to the helicase domain is necessary for nuclease activity. C5 targets the known functions of DNA2 in vivo: C5 inhibits resection at stalled forks as well as reducing recombination. C5 is an even more potent inhibitor of restart of stalled DNA replication forks and over-resection of nascent DNA in cells defective in replication fork protection, including BRCA2 and BOD1L. C5 sensitizes cells to CPT and synergizes with PARP inhibitors

Biosorption of Heavy Metal Ions from Aqueous Solution on Chinese Fir Bark Modified by Sodium Hypochlorite

The oxidation conditions and adsorption ability of Cu (II), Cd (II), and Pb (II) from an aqueous solution of sodium hypochlorite-oxidized fir bark powder were investigated. The optimum amount of NaClO was 9.6%, the pH was 9, and the oxidation time was 120 min. Batch adsorption experiments were carried out with various times, pH values, and initial metal ion concentrations. The adsorption isotherms and kinetics of adsorption were also studied. The maximum adsorption capacity of oxidized fir bark was 0.983, 1.223, and 0.966 mmol/g for Cu (II), Cd (II), and Pb (II), respectively, within 30 min at pH 5, higher adsorption capacity than that of unoxidized fir bark. The isothermal adsorption of heavy metal ions in aqueous solution was a good fit to the Langmuir equation, with a coefficient of determination, R2, above 0.99. The adsorption of fir bark on metal ions can be appropriately approximated by a pseudo-second order adsorption kinetics model. Results indicate that the fir bark powder modified with sodium hypochlorite can adsorb large amounts of metal ions and could be a good adsorbent for the removal of Cu(II), Cd(II), and Pb(II) from aqueous solution

Fouling Characteristics of Dissolved Organic Matter in Papermaking Process Water on Polyethersulfone Ultrafiltration Membranes

In the papermaking industry, closure of process water (whitewater) circuits has been used to reduce fresh water consumption. Membrane separation technology has potential for use in treating process water for recirculation. The purpose of this study was to reveal the fouling characteristics of a polyethersulfone (PES) ultrafiltration membrane caused by dissolved organic matter (DOM) in process water. Ultrafiltration membranes (UF) and DAX ion exchange resins were applied to characterize the molecular weight (MW) and hydrophilicity distribution of DOM. The interactions between various fractions of DOM and a PES ultrafiltration membrane were investigated. The membrane fouling characteristics were elucidated by examining the filtration resistances and linearized Herman’s blocking models. The results demonstrated that the membrane was fouled significantly by much of the MW distribution. The membrane was fouled more significantly by the low MW fraction rather than the high MW fraction. The filtration resistances and the fitted equation of Hermia’s laws indicated that hydrophilic organics were the main foulants. The hydrophilic organics partially block the membrane pores and form intermediate blocking, reducing the effective filtration area, while the hydrophobic organics form a gel layer or cake on the surface of the membrane

Transcriptome Dynamics of Double Recessive Mutant, <i>o2o2o16o16</i>, Reveals the Transcriptional Mechanisms in the Increase of Its Lysine and Tryptophan Content in Maize

In maize, pyramiding of o2 and o16 alleles can greatly improve the nutritional quality of grains. To dissect its molecular mechanism, we created a double recessive mutant line, o2o2o16o16, by introgression of the o2 and o16 alleles into the wild-type maize inbred line, by molecular marker-assisted backcross selection. The kernels (18 day after pollination (DAP), 28 DAP, and 38 DAP) of the o2o2o16o16 mutant and its parent lines were subject to RNA sequencing (RNA-Seq). The RNA-Seq analysis revealed that 59 differentially expressed genes (DEGs) were involved in lysine metabolism and 43 DEGs were involved in tryptophan metabolism. Among them, the genes encoding AK, ASADH, and Dap-F in the lysine synthesis pathway were upregulated at different stages of endosperm development, promoting the synthesis of lysine. Meanwhile, the genes encoding LKR/SDH and L-PO in the lysine degradation pathway were downregulated, inhibiting the degradation of lysine. Moreover, the genes encoding TAA and YUC in the tryptophan metabolic pathway were downregulated, restraining the degradation of tryptophan. Thus, pyramiding o2 and o16 alleles could increase the lysine and tryptophan content in maize. These above results would help to uncover the molecular mechanisms involved in the increase in lysine and the tryptophan content, through the introgression of o2 and o16 alleles into the wild-type maize

Filtering Whitewater with an Ultrafiltration Membrane: Effects of the Interaction between Dissolved Organics and Metal Ions on Membrane Fouling

The mechanisms regarding the influence of dissolved organics in papermaking whitewater together with metal ions on the fouling of an ultrafiltration (UF) membrane were studied in this paper. A series of experiments were carried out to characterize the organic matters’ size and membrane flux. The associated fouling mechanism was investigated using the modified Hermia empirical model, resistance distribution, and specific resistance of the cake layer. The results indicated that the addition of metal ions aggravated membrane fouling. Increasing concentrations of metal ions resulted in the higher specific resistance of the cake layer and greater membrane fouling due to their chelation with dissolved organics. Increased pH values influenced the interaction between the metal ions and dissolved organics, resulting in a relatively slow membrane flux decline. Increasing concentrations of Na+ resulted in greater membrane fouling. Cake layer formation played a major role in treating the water samples with high-concentration metal ions, whereas intermediate blocking formation may be the dominant fouling mechanism when treating the solution without metal ions

Dynamics and Complexity Analysis of Fractional-Order Chaotic Systems with Line Equilibrium Based on Adomian Decomposition

In this paper, the Adomian decomposition method (ADM) is applied to solve the fractional-order system with line equilibrium. The dynamics of the system is analyzed by means of the Lyapunov exponent spectrum, bifurcations, chaotic attractor, and largest Lyapunov exponent diagram. At the same time, through the Lyapunov exponent spectrum and bifurcation graph of the system under the change of the initial value, the influence of fractional order q on the system state can be observed. That is, integer-order systems do not have the phenomenon of attractors coexistence, while fractional-order systems have it

Copper- and Nickel-Catalyzed Cross-Coupling Reaction of Monofluoroalkenes with Tertiary, Secondary, and Primary Alkyl and Aryl Grignard Reagents

A highly efficient cross-coupling reaction of monofluoroalkenes with tertiary, secondary, and primary alkyl and aryl Grignard reagents in the presence of a catalytic amount of copper or nickel catalyst, respectively, has been developed. The reactions proceeded smoothly at room temperature, providing (<i>E</i>)-alkene isomers in moderate to high yields. Plausible mechanisms of the Ni-catalyzed coupling reaction of monofluoroalkene with Grignard reagents are suggested

Copper-Catalyzed Coupling Cyclization of <i>gem</i>-Difluoroalkenes with Activated Methylene Carbonyl Compounds: Facile Domino Access to Polysubstituted Furans

A novel and efficient CuI-catalyzed synthesis of 2,3,5-trisubstituted furans was developed via coupling cyclization of <i>gem</i>-difluoroalkenes with active methylene carbonyl compounds such as 1,3-dicarbonyl compounds, acetoacetonitrile, and phenylsulfonylacetone with the assistance of a base. Commercial availability of substrates or reagents, good to high isolated yields, and excellent functional group compatibility make this transformation a powerful tool for the synthesis of various furans. A plausible mechanism involving the allenyl ketone is suggested

Copper-Free Direct C–H Trifluoromethylation of Acetanilides with Sodium Trifluoromethanesulfinate

A copper-free direct C–H ortho trifluoromethylation of electron-deficient 4-substituted acetanilides using Langlois reagent (NaSO₂CF₃) as the CF₃ source in the presence of <i>tert</i>-butyl hydroperoxide (<i>t</i>BuOOH, TBHP) was developed

Sterically Controlled Cu-Catalyzed or Transition-Metal-Free Cross-Coupling of <i>gem</i>-Difluoroalkenes with Tertiary, Secondary, and Primary Alkyl Grignard Reagents

A robust copper-catalyzed or transition-metal-free cross-coupling of <i>gem</i>-difluoroalkenes with tertiary, secondary, and primary alkyl Grignard reagents has been developed. Remarkably, the tertiary and secondary alkylation of <i>gem</i>-difluoroalkenes proceeded very smoothly in the presence of 25 mol % of CuCN or under transition-metal-free conditions, affording the tertiary and secondary alkyl-substituted fluoroalkenes in good to excellent yields with excellent <i>Z</i> stereoselectivity