Chemistry of the 2-deoxyribonolactone lesion in oligonucleotides: cleavage kinetics and products analysis

Deoxyribonolactone in DNA is an oxidized abasic site damage that is produced by a variety of physical and chemical agents such as gamma-irradiation and ene-diyne antibiotics. The extent and biological significance of the lesion are poorly documented due to the high lability of the damaged DNA. The chemistry of degradation of deoxyribonolactone-containing DNA was investigated using oligonucleotides of different length (5-, 11-, 23-, 34-mers) in which the lactone was photochemically generated, as already reported, from oligonucleotide precursors containing a photoactive nitroindole residue. The procedure was successfully extended to double-strand synthesis by irradiation of the preformed duplex in which one strand contained the nitroindole residue. The degradation kinetics were investigated as a function of pH, temperature, length, and ionic strength. The cleavage fragments resulting from beta- and delta-eliminations were isolated and identified by (1)H NMR. It was found that the lesion is extremely sensitive to pH and temperature while slightly dependent upon ionic strength, length, and sequence. The cleavage rates for the beta- and delta-elimination steps are of the same order of magnitude. The deoxyribonolactone site leads to greater instability of DNA than the "regular" deoxyribose abasic site.     

Thresholds and optimal binary comparison search trees

We present an O(n⁴)-time algorithm for the following problem: Given a set of items with known access frequencies, find the optimal binary search tree under the realistic assumption that each comparison can only result in a two-way decision: either an equality comparison or a less-than comparisons. This improves the best known result of O(n⁵) time, which is based on split tree algorithms. Our algorithm relies on establishing thresholds on the frequency of an item that can occur as an equality comparison at the root of an optimal tree.     

Wettability alteration of sandstones by silica nanoparticle dispersions in light and heavy crude oil

Unlike conventional oil production methods, enhanced oil recovery (EOR) processes can recover most oil products from the reservoir. One method, known as wettability alteration, changes the hydrophilicity of the reservoir rock via decreased surface interactions with crude oils. The mitigation of these attractive forces enhances petroleum extraction and increases the accessibility of previously inaccessible rock deposits. In this work, silica nanoparticles (NPs) have been used to alter the wettability of two sandstone surfaces, Berea and Boise. Changes in wettability were assessed by measuring the contact angle and interfacial tension of different systems. The silica NPs were suspended in brine and a combined solution of brine and the Tween®20 nonionic surfactant at concentrations of 0, 0.001, and 0.01 wt% NP with both light and heavy crude oil. The stability of the different nanofluids was characterized by the size, zeta potential, and sedimentation of the particles in suspension. Unlike the NPs, the surfactant had a greater effect on the interfacial tension by influencing the liquid-liquid interactions. The introduction of the surfactant decreased the interfacial tension by 57 and 43% for light and heavy crude oil samples, respectively. Imaging and measurements of the contact angle were used to assess the surface-liquid interactions and to characterize the wettability of the different systems. The images reflect that the contact angle increased with the addition of NPs for both sandstone and oil types. The contact angle in the light crude oil sample was most affected by the addition of 0.001 wt% NP, which altered both sandstones’ wettability. Increases in contact angle approached 101.6% between 0 and 0.001 wt% NPs with light oil on the Berea sandstone. The contact angle however remained relatively unaffected by addition of higher NP concentrations, thus indicating that low NP concentrations can effectively be used for enhancing crude oil recovery. While the contact angle of the light crude oil plateaued, the heavy crude oil continued to increase with an increase in NP concentration; therefore indicating that a maximum contact angle in heavy crude oil was not yet achieved. The introduction of NPs in light and heavy crude oil samples altered both the Berea and Boise sandstone systems’ wettability, which in turn indicated the efficacy of the silica NPs and surfactants in generating a more water-wet reservoir. Consequently, silica NPs and surfactants are most promising for EOR across the range of oil types.     

WIFIP: a web‐based user interface for automated synchrotron beamlines

The beamline control software, through the associated graphical user interface (GUI), is the user access point to the experiment, interacting with synchrotron beamline components and providing automated routines. FIP, the French beamline for the Investigation of Proteins, is a highly automatized macromolecular crystallography (MX) beamline at the European Synchrotron Radiation Facility. On such a beamline, a significant number of users choose to control their experiment remotely. This is often performed with a limited bandwidth and from a large choice of computers and operating systems. Furthermore, this has to be possible in a rapidly evolving experimental environment, where new developments have to be easily integrated. To face these challenges, a light, platform‐independent, control software and associated GUI are required. Here, WIFIP, a web‐based user interface developed at FIP, is described. Further than being the present FIP control interface, WIFIP is also a proof of concept for future MX control software.     

The role of dUTPase and uracil-DNA repair in cancer chemotherapy

Thymidylate metabolism is an important target for chemotherapeutic agents that combat a variety of neoplastic diseases including head and neck, breast and gastrointestinal cancers. Therapeutic strategies applied to this pathway target the thymidylate synthase (TS) reaction that catalyzes the reductive methylation of deoxyuridylate (dUMP) to form thymidylate (TMP). This reaction represents the sole de novo source of TMP required for DNA replication and repair. Inhibitors of this pathway include the widely utilized fluoropyrimide and antifolate classes of anti-cancer agents. Studies attempting to elucidate the molecular mechanisms of cell killing mediated by inhibitors of the TS reaction suggest that cytotoxicity results from a process known as "thymineless death". This term describes the extreme TTP pool depletion observed following TS inhibition. Although depletion of TTP pools is clearly involved in this process, there is now considerable evidence implicating aberrant uracil-DNA metabolism as an important mechanism of toxicity. Upon TS inhibition, dUTP pools may accumulate, inducing repeated cycles of uracil misincorporation into DNA and repair-mediated DNA damage. Central to the uracil-misincorporation pathway are the enzymes deoxyuridine nucleotidohydrolase (dUTPase) (EC 3.6.1.23) and uracil-DNA glycoslyase (UDG) (EC 3.2.2.3). dUTPase catalyzes the hydrolysis of dUTP to form dUMP and pyrophosphate thereby eliminating dUTP and preventing its utilization by DNA polymerases during replication and repair. UDG initiates the base excision repair pathway effectively removing any uracil residues that may arise in DNA. Under normal conditions, uracil is precluded from DNA by the combined actions of dUTPase and UDG. However, during TS inhibition, dUTP pools may accumulate and overwhelm dUTPase, resulting in repeated cycles of uracil misincorporation and detrimental repair leading to strand breaks and cell death. Because dUTPase plays a pivotal role in regulating cellular dUTP pools, this enzyme could have profound effects on the efficacy of agents that target thymidylate biosynthesis. This article reviews our current understanding of the role of aberrant uracil-DNA metabolism as a contributing mechanism of cytotoxicity initiated by chemotherapeutic agents that target de novo thymidylate metabolism. The role of dUTPase expression in modulating therapeutic response is presented including evidence from yeast and mammalian cell culture models and clinical studies. The regulation of human dUTPase isoforms in normal and neoplastic tissues will be reviewed as well as the role of dUTPase expression as a prognostic marker for overall survival and response to therapy in colon cancer.     

Bis-phosphonates-ultra small superparamagnetic iron oxide nanoparticles: a platform towards diagnosis and therapy

A new type of multifunctional magnetic nano-platform for diagnosis and therapy applications was designed using bisphosphonate/carboxylic ligands.     

Glycomimetics and glycodendrimers as high affinity microbial anti-adhesins

Adhesion to epithelial surface is often the first step in bacterial and viral infection. In this process, the microbes use a variety of proteins for interaction with host carbohydrates presented as glycoconjugates on cell surfaces. Crystal structures of adhesin and lectin binding sites in complexes with oligosaccharide open the route for design and synthesis of glycomimetics, glycodendrimers, and glycopolymers that are able to block infection at an early stage.     

Catalyst- and halogen-free regioselective Friedel-Crafts α-ketoacylations

Fast, efficient and green! Highly regioselective and efficient catalyst- and halogen-free Friedel-Crafts α-ketoacylation reactions leading to heterocycles functionalized with a very versatile 1,3-diketone moiety are described. The reactions rely on microwave-assisted domino Wolff rearrangement/Friedel-Crafts sequences from 2-diazo-1,3-diketones via transient, highly reactive α-keto ketene intermediates.