Biomimetic modeling of the nitrogen-centered radical postulated to occur during the inhibition of ribonucleotide reductases by 2'-azido-2'-deoxynucleotides

Ribonucleotide reductases (RNR) are essential enzymes that catalyze the reduction of ribonucleotides to 2'-deoxyribonucleotides, which is a critical step that produces precursors for DNA replication and repair. The inactivation of RNR, logically, would discontinue producing the precursors of the DNA of viral or cancer cells, which then would consequently end the cycle of DNA replication. Among different compounds that were found to be inhibitors of RNR, 2'-azido-2'-deoxynucleotide diphosphates (N3NDPs) have been investigated in depth as potent inhibitors of RNR. Decades of investigation has suggested that the inactivation of RNR by N3NDPs is a result of the formation of a nitrogen-centered radical (N·) that is covalently attached to the nucleotide at C3' and cysteine molecule C225 [3'-C(R-S-N·-C-OH)]. Biomimetic simulation reactions for the generation of the nitrogen-centered radicals similar to the one observed during the inactivation of the RNR by azionuclotides was investigated. The study included several modes: (i) theoretical calculation that showed the feasibility of the ring closure reaction between thiyl radicals and azido group; (ii) synthesis of the model azido nucleosides with a linker attached to C3' or C5' having a thiol or vicinal dithiol functionality; (iii) generation of the thiyl radical under both physiological and radiolysis conditions whose role is important in the initiation on RNR cascades; and (iv) analysis of the nitrogen-centered radical species formed during interaction between the thiyl radical and azido group by electron paramagnetic resonance spectroscopy (EPR). Characterization of the aminyl radical species formed during one electron attachment to the azido group of 2'-azido-2'-deoxyuridine and its stereospecifically labelled 1'-, 2'-, 3'-, 4'- or 5,6-[2H 2]-analogues was also examined. This dissertation gave insight toward understanding the mechanism of the formation of the nitrogen-centered radical during the inactivation of RNRs by azidonucleotides as well as the mechanism of action of RNRs that might provide key information necessary for the development of the next generation of antiviral and anticancer drugs.

Ab initio quantum chemical studies on neutral-radical reactions of ethynyl (C2H) and cyano (CN) with unsaturated hydrocarbons

An Ab Initio/RRKM study of the reaction mechanism and product branching ratios of neutral-radical ethynyl (C2H) and cyano (CN) radical species with unsaturated hydrocarbons is performed. The reactions studied apply to cold conditions such as planetary atmospheres including Titan, the Interstellar Medium (ISM), icy bodies and molecular clouds. The reactions of C2H and CN additions to gaseous unsaturated hydrocarbons are an active area of study. NASA's Cassini/Huygens mission found a high concentration of C2H and CN from photolysis of ethyne (C2H2) and hydrogen cyanide (HCN), respectively, in the organic haze layers of the atmosphere of Titan. The reactions involved in the atmospheric chemistry of Titan lead to a vast array of larger, more complex intermediates and products and may also serve as a chemical model of Earth's primordial atmospheric conditions. The C2H and CN additions are rapid and exothermic, and often occur barrierlessly to various carbon sites of unsaturated hydrocarbons. The reaction mechanism is proposed on the basis of the resulting potential energy surface (PES) that includes all the possible intermediates and transition states that can occur, and all the products that lie on the surface. The B3LYP/6-311g(d,p) level of theory is employed to determine optimized electronic structures, moments of inertia, vibrational frequencies, and zero-point energy. They are followed by single point higher-level CCSD(T)/cc-vtz calculations, including extrapolations to complete basis sets (CBS) of the reactants and products. A microcanonical RRKM study predicts single-collision (zero-pressure limit) rate constants of all reaction paths on the potential energy surface, which is then used to compute the branching ratios of the products that result. These theoretical calculations are conducted either jointly or in parallel to experimental work to elucidate the chemical composition of Titan's atmosphere, the ISM, and cold celestial bodies.<.

Formation of Polycyclic Aromatic Hydrocarbons and Nitrogen Containing Polycyclic Aromatic Compounds in Titan's Atmosphere, the Interstellar Medium and Combustion

Several different mechanisms leading to the formation of (substituted) naphthalene and azanaphthalenes were examined using theoretical quantum chemical calculations. As a result, a series of novel synthetic routes to Polycyclic Aromatic Hydrocarbons (PAHs) and Nitrogen Containing Polycyclic Aromatic Compounds (N-PACs) have been proposed. On Earth, these aromatic compounds originate from incomplete combustion and are released into our environment, where they are known to be major pollutants, often with carcinogenic properties. In the atmosphere of a Saturn's moon Titan, these PAH and N-PACs are believed to play a critical role in organic haze formation, as well as acting as chemical precursors to biologically relevant molecules. The theoretical calculations were performed by employing the ab initio G3(MP2,CC)/B3LYP/6-311G** method to effectively probe the Potential Energy Surfaces (PES) relevant to the PAH and N-PAC formation. Following the construction of the PES, Rice-Ramsperger-Kassel-Markus (RRKM) theory was used to evaluate all unimolecular rate constants as a function of collision energy under single-collision conditions. Branching ratios were then evaluated by solving phenomenological rate expressions for the various product concentrations. The most viable pathways to PAH and N-PAC formation were found to be those where the initial attack by the ethynyl (C2H) or cyano (CN) radical toward a unsaturated hydrocarbon molecule led to the formation of an intermediate which could not effectively lose a hydrogen atom. It is not until ring cyclization has occurred, that hydrogen elimination leads to a closed shell product. By quenching the possibility of the initial hydrogen atom elimination, one of the most competitive processes preventing the PAH or N-PAC formation was avoided, and the PAH or N-PAC formation was allowed to proceed. It is concluded that these considerations should be taken into account when attempting to explore any other potential routes towards aromatic compounds in cold environments, such as on Titan or in the interstellar medium.

Ballots for Equality: An Approach to the Radical Tradition in U.S. Electoral Politics

Posing radical challenges to structural inequality is the defining quality of the Left. What role electoral politics might play in such processes is a dilemma of radical politics, the contours of which vary by historical and national contexts. For the U.S. Left there is a distinctive aspect of the dilemma directly related to the failure of a "Left" party of even the most moderate social democratic type to take root, creating a seemingly never ending debate over the value if any of "third party" progressive organizing. This debate is current, as illustrated by three divergent approaches; independent left electoral politics (Socialist Alternative), organizing within the less conservative of the dominant parties (Progressive Democrats of America), and a social movement focus outside the electoral process (Occupy Movement). The present day examples of alternative Left strategies noted here in passing are but three of many such specific organizational options for progressive politics. This article does not seek to advocate for any one of these options to the exclusion of the others but rather seeks to provide historical perspective.

The effects of biofeedback on the occurrence of urinary incontinence in patients following radical retropubic prostatectomy

Postprostatectomy incontinence can create a significant barrier to the attainment of optimal social and physical functioning postoperatively. The objective of this retrospective, descriptive study was to determine the effect of biofeedback on the incidence of urinary incontinence in men status post radical retropubic prostatectomy (RRP). All patients of a urologic practice who had a biofeedback session preoperatively, and two sessions postoperatively, were sent a survey to complete. Correlational analysis concluded that there was no significance (p > .05) between a subject's age, educational level, or adherence to biofeedback therapy, and their level of postprostatectomy incontinence. Of those subjects who participated (n = 46), 35% reported their urinary control as excellent, 50% reported good results, and 15% reported fair results. No subjects reported poor urinary control. Ninety-five percent of subjects said they would recommend the biofeedback treatment to a friend, and 88% felt that biofeedback had helped them attain their present level of urinary control.

Ab Initio Quantum Chemical Studies on Neutral-Radical Reactions of Ethynyl (C2H) and Cyano (CN) with Unsaturated Hydrocarbons

An Ab Initio/RRKM study of the reaction mechanism and product branching ratios of neutral-radical ethynyl (C2H) and cyano (CN) radical species with unsaturated hydrocarbons is performed. The reactions studied apply to cold conditions such as planetary atmospheres including Titan, the Interstellar Medium (ISM), icy bodies and molecular clouds. The reactions of C2H and CN additions to gaseous unsaturated hydrocarbons are an active area of study. NASA’s Cassini/Huygens mission found a high concentration of C2H and CN from photolysis of ethyne (C2H2) and hydrogen cyanide (HCN), respectively, in the organic haze layers of the atmosphere of Titan. The reactions involved in the atmospheric chemistry of Titan lead to a vast array of larger, more complex intermediates and products and may also serve as a chemical model of Earth’s primordial atmospheric conditions. The C2H and CN additions are rapid and exothermic, and often occur barrierlessly to various carbon sites of unsaturated hydrocarbons. The reaction mechanism is proposed on the basis of the resulting potential energy surface (PES) that includes all the possible intermediates and transition states that can occur, and all the products that lie on the surface. The B3LYP/6-311g(d,p) level of theory is employed to determine optimized electronic structures, moments of inertia, vibrational frequencies, and zero-point energy. They are followed by single point higher-level CCSD(T)/cc-vtz calculations, including extrapolations to complete basis sets (CBS) of the reactants and products. A microcanonical RRKM study predicts single-collision (zero-pressure limit) rate constants of all reaction paths on the potential energy surface, which is then used to compute the branching ratios of the products that result. These theoretical calculations are conducted either jointly or in parallel to experimental work to elucidate the chemical composition of Titan’s atmosphere, the ISM, and cold celestial bodies.