524 research outputs found
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
Euthanasia and Physician-Assisted Suicide in People With an Accumulation of Health Problems Related to Old Age:A Cross-Sectional Questionnaire Study Among Physicians in the Netherlands
Objectives: We explored characteristics of people with an accumulation of health problems related to old age requesting euthanasia or physician-assisted suicide (EAS) and identified characteristics associated with granting EAS requests. Methods: We conducted a cross-sectional questionnaire study among Dutch physicians on characteristics of these people requesting EAS (n = 123). Associations between characteristics and granting a request were assessed using logistic regression analyses. Results: People requesting EAS were predominantly >80Â years old (82.4%), female (70.0%), widow/widower (71.7%), (partially) care-dependent (76.7%), and had a life expectancy >12Â months (68.6%). The most prevalent health problems were osteoarthritis (70.4%) and impaired vision and hearing (53.0% and 40.9%). The most cited reasons to request EAS were physical deterioration (68.6%) and dependence (61.2%). 44.7% of requests were granted. Granting a request was positively associated with care dependence, disability/immobility, impaired vision, osteoporosis, loss of control, suffering without prospect of improvement and a treatment relationship with the physician >12Â months. Conclusion: Enhanced understanding of people with an accumulation of health problems related to old age requesting EAS can contribute to the ongoing debate on the permissibility of EAS in people without life-threatening conditions.</p
The tectonic significance of K/Ar illite fine-fraction ages from the San Luis Formation (Eastern Sierras Pampeanas, Argentina)
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
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
Time constraints on the tectonic evolution of the Eastern Sierras Pampeanas (Central Argentina)
Green tea polyphenols and Tai Chi for bone health: Designing a placebo-controlled randomized trial
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
EspA Acts as a Critical Mediator of ESX1-Dependent Virulence in Mycobacterium tuberculosis by Affecting Bacterial Cell Wall Integrity
Mycobacterium tuberculosis (Mtb) requires the ESX1 specialized protein secretion system for virulence, for triggering cytosolic immune surveillance pathways, and for priming an optimal CD8+ T cell response. This suggests that ESX1 might act primarily by destabilizing the phagosomal membrane that surrounds the bacterium. However, identifying the primary function of the ESX1 system has been difficult because deletion of any substrate inhibits the secretion of all known substrates, thereby abolishing all ESX1 activity. Here we demonstrate that the ESX1 substrate EspA forms a disulfide bonded homodimer after secretion. By disrupting EspA disulfide bond formation, we have dissociated virulence from other known ESX1-mediated activities. Inhibition of EspA disulfide bond formation does not inhibit ESX1 secretion, ESX1-dependent stimulation of the cytosolic pattern receptors in the infected macrophage or the ability of Mtb to prime an adaptive immune response to ESX1 substrates. However, blocking EspA disulfide bond formation severely attenuates the ability of Mtb to survive and cause disease in mice. Strikingly, we show that inhibition of EspA disulfide bond formation also significantly compromises the stability of the mycobacterial cell wall, as does deletion of the ESX1 locus or individual components of the ESX1 system. Thus, we demonstrate that EspA is a major determinant of ESX1-mediated virulence independent of its function in ESX1 secretion. We propose that ESX1 and EspA play central roles in the virulence of Mtb in vivo because they alter the integrity of the mycobacterial cell wall
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