Formation of tricyclic [4.3.3.0] adducts between 8-oxoguanosine and tyrosine under conditions of oxidative DNA-protein cross-linking

8-Oxo-7,8-dihydro-2'-deoxyguanosine (OG), a prevalent product of oxidative stress on cellular DNA, is readily further oxidized forming adducts with nucleophiles. In the presence of tyrosine or p-cresol, an unusual tricyclo[4.3.3.0] adduct has been characterized in both nucleoside and oligodeoxynucleotide studies. The adduct is more stable in oligomers than nucleosides and undergoes slow reversion and hydration to spiroiminodihydantoin.     

An exploration of mechanisms for the transformation of 8-oxoguanine to guanidinohydantoin and spiroiminodihydantoin by density functional theory

The potential energy surface for formation of 2-amino-5-hydroxy-7,9-dihydropurine-6,8-dione (5-OH-OG), guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp) from 8-oxoguanine (8-oxoG) has been mapped out using B3LYP density functional theory, the aug-cc-pVTZ and 6-31+G(d,p) basis sets and the IEF-polarizable continuum model (PCM) solvation model. Three pathways for formation of 5-OH-OG from 8-oxoG were evaluated: (A) stepwise loss of two electrons and two protons to form the quinonoid intermediate 2-amino-7,9-dihydro-purine-6,8-dione (8-oxoG(ox)) followed by hydration; (B) stepwise loss of two electrons and one proton and net addition of hydroxide, in which the key step is nucleophilic addition to the 8-oxoG radical cation; and (C) stepwise loss of one electron and one proton and addition of hydroxyl radical to the 8-oxoG radical cation. The data suggest that all three pathways are energetically feasible mechanisms for the formation of 5-OH-OG, however, Pathway A may be kinetically favored over Pathway B. Although lower in energy, Pathway C may be of limited biological significance since it depends on the local concentration of hydroxyl radical. Pathways for hydrolysis and decarboxylation of 5-OH-OG to form Gh via either a carboxylic acid or substituted carbamic acid intermediate have been evaluated with the result that cleavage of the N1-C6 bond is clearly favored over that of the C5-C6 bond. Formation of Sp from 5-OH-OG via stepwise proton transfer and acyl migration or ring opening followed by proton transfer and ring closure have also been explored and suggest that deprotonation of the hydroxyl group facilitates a 1,2 acyl shift. Results of the calculations are consistent with experimental studies showing dependence of the Gh/Sp product ratio on pH. Under neutral and basic conditions, the data predict that formation of Sp is kinetically favored over the pathways for formation of Gh. Under acidic conditions, Gh is predicted to be the kinetically favored product.     

Connecting a population dynamic model with a multi-period location-allocation problem for post-disaster relief operations

In this study, we propose a mathematical model and heuristics for solving a multi-period location-allocation problem in post-disaster operations, which takes into account the impact of distribution over the population. Logistics restrictions such as human and financial resources are considered. In addition, a brief review on resilience system models is provided, as well as their connection with quantitative models for post-disaster relief operations. In particular, we highlight how one can improve resilience by means of OR/MS strategies. Then, a simpler resilience schema is proposed, which better reflects an active system for providing humanitarian aid in post-disaster operations, similar to the model focused in this work. The proposed model is non-linear and solved by a decomposition approach: the master level problem is addressed by a non-linear solver, while the slave subproblem is treated as a black-box coupling heuristics and a Variable Neighborhood Descent local search. Computational experiments have been done using several scenarios, and real data from Belo Horizonte city in Brazil.     

A note on the square root law for urban police travel times

The classical Square Root Law formula for emergency travel times consists of one observable component, the density of patrol coverage, and one unknown component that must be estimated empirically, the effective travel speed. The effective travel speed is typically assumed to be an empirical constant. We test whether this simplifying assumption is justified empirically. We propose a modern machine-learning approach and a Least Absolute Shrinkage and Selection Operator regression to incorporate into a travel speed model various exogenous factors such as call type, incident location, weather conditions and traffic congestion. The value of the proposed analytical approach and some practical implications are demonstrated using operational data from a large urban police jurisdiction based in British Columbia, Canada. Although the analysis is framed within the context of urban emergency police operations, the proposed approach has the potential to be useful for other emergency services or roving business units that deal with unscheduled service calls.     

Thermal degradation in a trimodal poly(dimethylsiloxane) network studied by (1)H multiple quantum NMR

Thermal degradation of a filled, cross-linked siloxane material synthesized from poly(dimethylsiloxane) chains of three different average molecular weights and with two different cross-linking species has been studied by (1)H multiple quantum (MQ) NMR methods. Multiple domains of polymer chains were detected by MQ NMR exhibiting residual dipolar coupling () values of 200 and 600 Hz, corresponding to chains with high average molecular weight between cross-links and chains with low average molecular weight between cross-links or near the multifunctional cross-linking sites. Characterization of the values and changes in distributions present in the material were studied as a function of time at 250 degrees C and indicate significant time-dependent degradation. For the domains with low , a broadening in the distribution was observed with aging time. For the domain with high , increases in both the mean and the width in were observed with increasing aging time. Isothermal thermal gravimetric analysis reveals a 3% decrease in weight over 20 h of aging at 250 degrees C. Degraded samples also were analyzed by traditional solid-state (1)H NMR techniques, and off-gassing products were identified by solid-phase microextraction followed by gas chromatography-mass spectrometry. The results, which will be discussed here, suggest that thermal degradation proceeds by complex competition between oxidative chain scissioning and postcuring cross-linking that both contribute to embrittlement.     

A two-step procedure for the preparation of mono-protected bis-N-heterocyclic alkyl ether systems

A two-step convenient sequence for the synthesis of previously inaccessible mono-Boc-protected bis-N-heterocyclic alkyl substituted ether derivatives 4 is described. Mitsunobu protocol was applied to the preparation of pyridinyl ether precursor 5. The reduction of the electron rich pyridinyl system 5 has been achieved catalytically using the combination of PtO₂-H₂SO₄ or PtO₂-pTsOH under a hydrogen atmosphere maintained by a gas balloon at ambient temperature.     

Mono and dinuclear arene ruthenium complexes containing 6,7-dimethyl-2,3-di(pyridine-2-yl)quinoxaline as chelating ligand: Synthesis and molecular structure

The mononuclear cations of the general formula [(η⁶-arene)RuCl(dpqMe₂)]⁺ (dpqMe₂ = 6,7-dimethyl-2,3-di(pyridine-2-yl)quinoxaline; arene = C₆H₆, 1; C₆H₅Me, 2; p-PrⁱC₆H₄Me, 3; C₆Me₆, 4) as well as the dinuclear dications [(η⁶-arene)₂Ru₂Cl₂(μ-dpqMe₂)]²⁺ (arene = C₆H₆, 5; C₆H₅Me, 6; p-PrⁱC₆H₄Me, 7; C₆Me₆, 8) have been synthesised from 6,7-dimethyl-2,3-di(pyridine-2-yl)quinoxaline (dpqMe₂) and the corresponding chloro complexes [(η⁶-C₆H₆)Ru(μ-Cl)Cl]₂, [(η⁶-C₆H₅Me)Ru(μ-Cl)Cl]₂, [(η⁶-p-PrⁱC₆H₄Me)Ru(μ-Cl)Cl]₂ and [(η⁶-C₆Me₆)Ru(μ-Cl)Cl]₂, respectively. The X-ray crystal structure analyses of [1][PF₆], [3][PF₆] and [6][PF₆]₂ reveal a typical piano-stool geometry around the metal centre; in the dinuclear complexes the two chloro ligands, with respect to each other, are found to be trans oriented.     

Reactions of CF3CH2I+O(3P): competing mechanisms of HF elimination

Ab initio density functional and molecular orbital calculations provide singlet and triplet electronic potential energy surfaces for the reactions of CF3CH2I+O(3P) leading to OI and HF eliminations, reactions which have been the subject of recent experimental studies. A barrier to OI formation occurs on the triplet potential energy surface; there is no reverse barrier to OI formation on the singlet pathway. Findings suggest that two competing pathways may form HF. One is an addition-insertion-elimination process involving insertion of O into the C-I bond. The alternate path involves OI elimination, addition of an O atom to CF3CH2, and subsequent HF elimination. The computed reactant pathways and energetics are discussed in relation to recent experiments.