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81.
Ladner RD 《Current protein & peptide science》2001,2(4):361-370
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. 相似文献
82.
Yoann Mery Sbastien Ducruix Philippe Scouflaire Sbastien Candel 《Comptes Rendus Mecanique》2009,337(6-7):426-437
High frequency combustion instabilities have technical importance in the design of liquid rocket engines. These phenomena involve a strong coupling between transverse acoustic modes and combustion. They are currently being investigated by combining experimentation and numerical simulations. On the experimental level, the coupling is examined in a model scale system featuring a multiple injector combustor (MIC) comprising five coaxial injectors fed with liquid oxygen and gaseous methane. This system is equipped with a novel VHAM actuator (Very High Amplitude Modulator) which comprises two nozzles and a rotating toothed wheel blocking the nozzles in an alternate fashion. This device was designed to obtain the highest possible levels of transverse oscillation in the MIC. After a brief review of the VHAM, this article reports cold flow experiments using this modulator. Velocity maps obtained under resonant conditions using the VHAM are examined at different instants during a cycle of oscillation. Experimental data are compared with numerical pressure and velocity fields obtained from an acoustic solver. The good agreement observed in the nozzle vicinity indicates that numerical simulations can be used to analyze the complex flow field generated by the VHAM. To cite this article: Y. Mery et al., C. R. Mecanique 337 (2009). 相似文献
83.
84.
Mohanan K Presset M Mailhol D Coquerel Y Rodriguez J 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(30):9217-9220
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. 相似文献
85.
This paper concerns the development of a new Cartesian grid/immersed boundary (IB) method for the computation of incompressible viscous flows in two-dimensional irregular geometries. In IB methods, the computational grid is not aligned with the irregular boundary, and of upmost importance for accuracy and stability is the discretization in cells which are cut by the boundary, the so-called “cut-cells”. In this paper, we present a new IB method, called the LS-STAG method, which is based on the MAC method for staggered Cartesian grids and where the irregular boundary is sharply represented by its level-set function. This implicit representation of the immersed boundary enables us to calculate efficiently the geometry parameters of the cut-cells. We have achieved a novel discretization of the fluxes in the cut-cells by enforcing the strict conservation of total mass, momentum and kinetic energy at the discrete level. Our discretization in the cut-cells is consistent with the MAC discretization used in Cartesian fluid cells, and has the ability to preserve the five-point Cartesian structure of the stencil, resulting in a highly computationally efficient method. The accuracy and robustness of our method is assessed on canonical flows at low to moderate Reynolds number: Taylor–Couette flow, flows past a circular cylinder, including the case where the cylinder has forced oscillatory rotations. Finally, we will extend the LS-STAG method to the handling of moving immersed boundaries and present some results for the transversely oscillating cylinder flow in a free-stream. 相似文献
86.
Dr. Myriam Roy Dr. Veronika Berezhnaia Dr. Marco Villa Dr. Nicolas Vanthuyne Dr. Michel Giorgi Dr. Jean-Valère Naubron Dr. Salomé Poyer Dr. Valérie Monnier Prof. Dr. Laurence Charles Dr. Yannick Carissan Dr. Denis Hagebaum-Reignier Prof. Dr. Jean Rodriguez Prof. Dr. Marc Gingras Dr. Yoann Coquerel 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(8):3290-3297
We report a molecular design and concept using π-system elongation and steric effects from helicenes surrounding a triphenylene core toward stable chiral polycyclic aromatic hydrocarbons (PAHs) with a maximal π-distortion to tackle their aromaticity, supramolecular and molecular properties. The selective syntheses, and the structural, conformational and chiroptical properties of two diastereomeric large multi-helicenes of formula C90H48 having a triphenylene core and embedding three [5]helicene units on their inner edges and three [7]helicene units at their periphery are reported based on diastereoselective and, when applicable, enantiospecific Yamamoto-type cyclotrimerizations of racemic or enantiopure 9,10-dibromo[7]helicene. Both molecules have an extremely distorted triphenylene core, and one of them exhibits the largest torsion angle recorded so far for a benzene ring (twist=36.9°). 相似文献
87.
Deceuninck Y Bichon E Monteau F Antignac JP Le Bizec B 《Analytica chimica acta》2011,700(1-2):137-143
Dexamethasone, betamethasone, prednisolone and methylprednisolone are corticosteroids widely used in animal husbandry. These compounds are licensed for therapy in veterinary practices while their use for growth promoting practices, mainly in combination with other growth promoters, is prohibited within the European Union. In order to protect the consumer, maximum residue limits (MRLs) have been set by the European Community in liver to 2.0 μg kg(-1) (dexamethasone and betamethasone) and 10.0 μg kg(-1) (prednisolone and methylprednisolone) for different species. The major challenges in the analysis of dexamethasone and betamethasone consist in performing an efficient separation of both isomers and in detecting and identifying all the molecules according to the regulatory requirements fixed in Commission Decision 2002/657/EC. In this context, an UHPLC-MS/MS method with a short runtime (7 min) and using the SRM acquisition mode was developed and validated. An efficient selectivity of the sample preparation combined with a high sensitivity of the measurement system allowed identifying and quantifying the four corticosteroids of interest in this complex biological matrix. Signals obtained were found very repeatable, even at very low concentration levels with an unambiguous identification of the compounds. The performance limits of the method have been validated according to the regulatory requirements and the method has been successfully applied to the confirmation of incurred liver samples. 相似文献
88.
Brégier F Aly SM Gros CP Barbe JM Rousselin Y Harvey PD 《Chemistry (Weinheim an der Bergstrasse, Germany)》2011,17(51):14643-14662
The click chemistry synthesis and photophysical properties, notably photo-induced energy and electron transfers between the central core and the peripheral chromophores of a series of artificial special pair-dendron systems (dendron = G1, G2, G3; Gx = zinc(II) tetra-meso-arylporphyrin-containing polyimides) built upon a central core of dimethylxanthenebis(metal(II) porphyrin) (metal = zinc, copper), are reported. The dendrons act as singlet and triplet energy acceptors or donors, depending on the dendrimeric systems. The presence of the paramagnetic d(9) copper(II) in the dendrimers promotes singlet-triplet energy transfer from the zinc(II) tetra-meso-arylporphyrin to the bis(copper(II) porphyrin) unit and slow triplet-triplet energy transfer from the central bis(copper(II) porphyrin) fragment to the peripheral zinc(II) tetra-meso-arylporphyrin. If bis(zinc(II) porphyrin) is the central core, evidence for chain folding is observed; this is unambiguously demonstrated by the presence of triplet-triplet energy transfer in the heterobimetallic systems, a process that can only occur at short distances. 相似文献
89.
Jan Voigt Dr. Myriam Roy Dr. Miloš Baljozović Dr. Christian Wäckerlin Dr. Yoann Coquerel Prof. Dr. Marc Gingras Prof. Dr. Karl-Heinz Ernst 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(40):10251-10254
The chiral self-assembly of trispentahelicene propellers on a gold surface has been investigated in ultrahigh vacuum by means of scanning tunneling microscopy and time-of-flight secondary ion mass spectrometry. The trispentahelicene propellers aggregate into mirror domains with an enantiomeric ratio of 2 : 1. Thermally induced cyclodehydrogenation leads to planarization into nanographenes, which self-assemble into closed-packed layers with two different azimuths. Further treatment induces in part dimerization and trimerization by intermolecular cyclodehydrogenation. 相似文献
90.
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. 相似文献