Stability and iron coordination in DNA adducts of Anthracycline based anti-cancer drugs

There is evidence that the interaction of the α-ketol group of the Doxorubicin and Epirubicin anti-cancer drugs with Fe(iii) generates hydroxyl radicals under aerobic conditions, causing cardiotoxicity in patients. Considering that the formation of DNA adducts is one of the main targets of Anthracycline drugs, we have in the present study characterized several [Anthracycline-DNA]Fe(iii) complexes with respect to their stability and Fe(iii) coordination, by means of MD simulations. Iron is found to coordinate well to the drugs containing an α-ketol group, this being the only group of the drug that binds to the metal. The complexes containing an α-ketol group, [Doxorubicin-DNA]Fe(iii) and [Epirubicin-DNA]Fe(iii), thus show greater stability than those not containing it, i.e., [Daunorubicin-DNA]Fe(iii), [Idarubicin-DNA]Fe(iii) and [5-Imino-Daunorubicin]Fe(iii). Metal attachment to the α-ketol group is furthermore facilitated by the phosphate groups of DNA. The coordination to iron in the [Doxorubicin-DNA]Fe(iii) system is smaller than that found for the [Epirubicin-DNA]Fe(iii) system, and the corresponding number of coordinating waters in the former is larger than in the latter. This may in turn result in higher hydroxyl radical production, thus explaining the increased cardiotoxicity noted for Doxorubicin.     

Identifying the sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA) as a potential target for hypericin - a theoretical study

The exact cellular target for the potent anti-cancer agent hypericin has not yet been determined; this thus encourages the application of computational chemistry tools to be employed in order to provide insights that can be employed in further drug development studies. In the present study computational docking and molecular dynamics simulations are applied to investigate possible interactions between hypericin and the Ca(2+) pump SERCA as proposed in the literature. Hypericin was found to bind strongly both in pockets within the transmembrane region and in the cytosolic region of the protein, although the two studied isoforms of SERCA differ slightly in their preferred binding sites. The calculated binding energies for hypericin in the four investigated sites were of the same magnitude as for thapsigargin (TG), the most potent SERCA inhibitor, or in the range between TG and di-tert-butylhydroquinone (BHQ), which is also known to possess inhibitory activity. The hydrophobic character of hypericin indicates that the molecule initially binds in the ER membrane from which it diffuses into the transmembrane region of the protein and to binding pockets therein. The transmembrane TG and BHQ binding pockets provide suitable locations for hypericin as they allow for favourable interactions with the lipid tails that surround these. High binding energies were noted for hypericin in these pockets and are expected to constitute highly possible binding sites due to their accessibility from the ER membrane. Hypericin most likely binds to both isoforms of SERCA and acts as an inhibitor or, under light irradiation, as a singlet oxygen generator that in turn degrades the protein or induces lipid peroxidation.     

Microprobe sampling—Photo ionization-time-of-flight mass spectrometry for in situ chemical analysis of pyrolysis and combustion gases: Examination of the thermo-chemical processes within a burning cigarette

A microprobe sampling device (μ-probe) has been developed for in situ on-line photo ionization mass spectrometric analysis of volatile chemical species formed within objects consisting of organic matter during thermal processing. With this approach the chemical signature occurring during heating, pyrolysis, combustion, roasting and charring of organic material within burning objects such as burning fuel particles (e.g., biomass or coal pieces), lit cigarettes or thermally processed food products (e.g., roasting of coffee beans) can be investigated. Due to its dynamic changes between combustion and pyrolysis phases the cigarette smoking process is particularly interesting and has been chosen as first application. For this investigation the tip of the μ-probe is inserted directly into the tobacco rod and volatile organic compounds from inside the burning cigarette are extracted and real-time analyzed as the glowing front (or coal) approaches and passes the μ-probe sampling position. The combination of micro-sampling with photo ionization time-of-flight mass spectrometry (PI-TOFMS) allows on-line intrapuff-resolved analysis of species formation inside a burning cigarette. Monitoring volatile smoke compounds during cigarette puffing and smoldering cycles in this way provides unparalleled insights into formation mechanisms and their time-dependent change. Using this technique the changes from pyrolysis conditions to combustion conditions inside the coal of a cigarette could be observed directly. A comparative analysis of species formation within a burning Kentucky 2R4F reference cigarette with μ-probe analysis reveals different patterns and behaviors for nicotine, and a range of semi-volatile aromatic and aliphatic species.     

Synthesis and characterization of a ferrocene-linked bis-fullerene[60] dumbbell

A new [60]fullerene dumbbell consisting of two fulleropyrrolidines connected to a central ferrocene unit by amide linkages has been prepared and fully characterized by elemental analysis, (1)H NMR, UV/Vis, fluorescence and mass spectrometry. The electrochemical properties as determined by cyclic voltammetry show ground state electronic communication between the ferrocene and the fullerene units. In addition, the preparaton of a ferrocene building block for an alternative linking approach is presented.     

Diffraction study of actinides under pressure

Abstract

Uranium and thorium have sufficiently low radioactive dose rates to allow their study at synchrotrons and neutron facilities. Correspondingly, numerous compounds of these two actinides have been studied under pressure by synchrotron x-ray diffraction. The maximum pressures reached were on the order of 60-80 GPa, and 300 GPa in one case.

The situation is much more difficult for all other actinides. Their high level of radioactivity has up to now prevented their study at synchrotrons, except in a few special cases. In contrast, all actinide metals available in sufficient quantities, and a large number of compounds of highly radioactive actinides, have been studied in highpressure laboratory facilities.

Recent examples of in situ high pressure x-ray diffraction work will be described.     

A maximum entropy approach to the newsvendor problem with partial information

In this paper, we consider the newsvendor model under partial information, i.e., where the demand distribution D is partly unknown. We focus on the classical case where the retailer only knows the expectation and variance of D. The standard approach is then to determine the order quantity using conservative rules such as minimax regret or Scarf’s rule. We compute instead the most likely demand distribution in the sense of maximum entropy. We then compare the performance of the maximum entropy approach with minimax regret and Scarf’s rule on large samples of randomly drawn demand distributions. We show that the average performance of the maximum entropy approach is considerably better than either alternative, and more surprisingly, that it is in most cases a better hedge against bad results.     

Volatility skews and extensions of the Libor market model

The paper considers extensions of the Libor market model to markets with volatility skews in observable option prices. The family of forward rate processes is expanded to include diffusions with non-linear forward rate dependence, and efficient techniques for calibration to quoted prices of caps and swaptions are discussed. Special emphasis is put on generalized CEV processes for which closed-form expressions for cap and swaption prices are derived. Modifications of the CEV process which exhibit more appealing growth and boundary characteristics are also discussed. The proposed models are investigated numerically through Crank–Nicholson finite difference schemes and Monte Carlo simulations.     

Dissociation of the K-Ras4B/PDEδ complex upon contact with lipid membranes: membrane delivery instead of extraction

K-Ras4B is a small GTPase whose selective membrane localization and clustering into microdomains are mediated by its polybasic farnesylated C-terminus. The importance of the subcellular distribution for the signaling activity of K-Ras4B became apparent from recent in vivo studies, showing that the delta subunit of cGMP phosphodiesterase (PDEδ), which possesses a hydrophobic prenyl-binding pocket, is able to function as a potential binding partner for farnesylated proteins, thereby leading to a modulation of the spatiotemporal organization of K-Ras. Even though PDEδ has been suggested to serve as a cytosolic carrier for Ras, the functional transport mechanism still remains largely elusive. In this study, the effect of PDEδ on the interaction of GDP- and GTP-loaded K-Ras4B with neutral and anionic model biomembranes has been investigated by a combination of different spectroscopic and imaging techniques. The results show that PDEδ is not able to extract K-Ras4B from membranes. Rather, the K-Ras4B/PDEδ complex formed in bulk solution turned out to be unstable in the presence of heterogeneous membranes, resulting in a release of farnesylated K-Ras4B upon membrane contact. With the additional observation of enhanced membrane affinity for the K-Ras4B/PDEδ complex, a molecular mechanism for the PDEδ-K-Ras4B-membrane interaction could be proposed. This includes an effective delivery of PDEδ-solubilized K-Ras4B to the plasma membrane, probably through cytoplasmic diffusion, the dissociation of the K-Ras4B/PDEδ complex upon plasma membrane contact, and finally the membrane binding of released farnesylated K-Ras4B that leads to K-Ras4B-enriched microdomain formation.     

Behavior of a free surface of a magnetic fluid containing a magnetizable cylinder

The deformation of the free surface of a magnetic fluid containing a cylinder made of a magnetizable material subjected to a uniform applied magnetic field is analyzed. The statics and dynamics of a magnetic fluid free surface is studied theoretically and experimentally. A discontinuous (jump-like) change of the surface shape is shown to occur when the applied magnetic field gradually increases or decreases. If the applied magnetic field increases and then decreases, a hysteresis of the shape is observed.     

Mixed-integer linear programming for resource leveling problems

We consider project scheduling problems subject to general temporal constraints, where the utilization of a set of renewable resources has to be smoothed over a prescribed planning horizon. In particular, we consider the classical resource leveling problem, where the variation in resource utilization during project execution is to be minimized, and the so-called “overload problem”, where costs are incurred if a given resource-utilization threshold is exceeded. For both problems, we present new mixed-integer linear model formulations and domain-reducing preprocessing techniques. In order to strengthen the models, lower and upper bounds for resource requirements at particular points in time, as well as effective cutting planes, are outlined. We use CPLEX 12.1 to solve medium-scale instances, as well as instances of the well-known test set devised by Kolisch et al. (1999). Instances with up to 50 activities and tight project deadlines are solved to optimality for the first time.