Charge localization in DNA fibers.

We study by first-principles molecular dynamics the mechanism of electron hole (positive charge) localization in a laboratory realizable radical cation Z DNA crystal. We find that at room temperature structural deformation does not provide an efficient localization mechanism. Instead, we find evidence for the importance of changes in the protonation state for stabilizing the radical defect

Genetic Basis of Virulence Attenuation Revealed by Comparative Genomic Analysis of Mycobacterium tuberculosis Strain H37Ra versus H37Rv

Tuberculosis, caused by Mycobacterium tuberculosis, remains a leading infectious disease despite the availability of chemotherapy and BCG vaccine. The commonly used avirulent M. tuberculosis strain H37Ra was derived from virulent strain H37 in 1935 but the basis of virulence attenuation has remained obscure despite numerous studies. We determined the complete genomic sequence of H37Ra ATCC25177 and compared that with its virulent counterpart H37Rv and a clinical isolate CDC1551. The H37Ra genome is highly similar to that of H37Rv with respect to gene content and order but is 8,445 bp larger as a result of 53 insertions and 21 deletions in H37Ra relative to H37Rv. Variations in repetitive sequences such as IS6110 and PE/PPE/PE-PGRS family genes are responsible for most of the gross genetic changes. A total of 198 single nucleotide variations (SNVs) that are different between H37Ra and H37Rv were identified, yet 119 of them are identical between H37Ra and CDC1551 and 3 are due to H37Rv strain variation, leaving only 76 H37Ra-specific SNVs that affect only 32 genes. The biological impact of missense mutations in protein coding sequences was analyzed in silico while nucleotide variations in potential promoter regions of several important genes were verified by quantitative RT-PCR. Mutations affecting transcription factors and/or global metabolic regulations related to in vitro survival under aging stress, and mutations affecting cell envelope, primary metabolism, in vivo growth as well as variations in the PE/PPE/PE-PGRS family genes, may underlie the basis of virulence attenuation. These findings have implications not only for improved understanding of pathogenesis of M. tuberculosis but also for development of new vaccines and new therapeutic agents

Combined quay crane assignment and quay crane scheduling with crane inter-vessel movement and non-interference constraints

Integrated models of the quay crane assignment problem (QCAP) and the quay crane scheduling problem (QCSP) exist. However, they have shortcomings in that some do not allow movement of quay cranes between vessels, others do not take into account precedence relationships between tasks, and yet others do not avoid interference between quay cranes. Here, an integrated and comprehensive optimization model that combines the two distinct QCAP and QCSP problems which deals with the issues raised is put forward. The model is of the mixed-integer programming type with the objective being to minimize the difference between tardiness cost and earliness income based on finishing time and requested departure time for a vessel. Because of the extent of the model and the potential for even small problems to lead to large instances, exact methods can be prohibitive in computational time. For this reason an adapted genetic algorithm (GA) is implemented to cope with this computational burden. Experimental results obtained with branch-and-cut as implemented in CPLEX and GA for small to large-scale problem instances are presented. The paper also includes a review of the relevant literature

An evolutionary approach to a combined mixed integer programming model of seaside operations as arise in container ports

This paper puts forward an integrated optimisation model that combines three distinct problems, namely berth allocation, quay crane assignment, and quay crane scheduling that arise in container ports. Each one of these problems is difficult to solve in its own right. However, solving them individually leads almost surely to sub-optimal solutions. Hence, it is desirable to solve them in a combined form. The model is of the mixed-integer programming type with the objective being to minimize the tardiness of vessels and reduce the cost of berthing. Experimental results show that relatively small instances of the proposed model can be solved exactly using CPLEX. Large scale instances, however, can only be solved in reasonable times using heuristics. Here, an implementation of the genetic algorithm is considered. The effectiveness of this implementation is tested against CPLEX on small to medium size instances of the combined model. Larger size instances were also solved with the genetic algorithm, showing that this approach is capable of finding the optimal or near optimal solutions in realistic times

Solvent Effects on Ionization Potentials of Guanine Runs and Chemically Modified Guanine in Duplex DNA: Effect of Electrostatic Interaction and Its Reduction due to Solvent

We examined the ionization potential (IP) corresponding to the free energy of a hole on duplex DNA by semiempirical molecular orbital theory with a continuum solvent model. As for the contiguous guanines (a guanine run), we found that the IP in the gas phase significantly decreases with the increasing number of nucleotide pairs of the guanine run, whereas the IP in water (OP, oxidation potential) only slightly does. The latter result is consistent with the experimental result for DNA oligomers in water. This decrease in the IP is mainly due to the attractive electrostatic interaction between the hole and a nucleotide pair in the duplex DNA. This interaction is reduced in water, which results in the small decrease in the IP in water. This mechanism explains the discrepancy between the experimental result and the previous computational results obtained by neglecting the solvent. As for the chemically modified guanine, the previous work showed that the removal of some solvent (water) molecules due to the attachment of a neutral functional group to a guanine in a duplex DNA stabilizes the hole on the guanine. One might naively have expected the opposite case, since a polar solvent usually stabilizes ions. This mechanism also explains this unexpected stabilization of a hole as follows. When some water molecules are removed, the attractive electrostatic interaction stabilizing the hole increases, and thus, the hole is stabilized. In order to design the hole energetics by a chemical modification of DNA, this mechanism has to be taken into account and can be used. 1