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DNA damaging agents have been a cornerstone of cancer therapy for nearly a century. The discovery of many of these chemicals, particularly the alkylating agents, are deeply entwined with the development of poisonous materials originally intended for use in warfare. Over the last decades, their anti-proliferative effects have focused on the specific mechanisms by which they damage DNA, and the factors involved in the repair of such damage. Due to the variety of aberrant adducts created even for the simplest alkylating agents, numerous pathways of repair are engaged as a defense against this damage. More recent work has underscored the role of RNA damage in the cellular response to these agents, although the understanding of their role in relation to established DNA repair pathways is still in its infancy. In this review, we discuss the chemistry of alkylating agents, the numerous ways in which they damage nucleic acids, as well as the specific DNA and RNA repair pathways which are engaged to counter their effects. [ABSTRACT FROM AUTHOR]

Promutagenic O6-alkylguanine adducts in DNA are repaired in humans by O6-methylguanine-DNA-methyltransferase (MGMT) in an irreversible reaction. Here we describe the synthesis of a phosphoramidite that allows the preparation of oligodeoxyribonucleotides (ODNs) containing a novel tricyclic thio analogue of O6-methylguanine in which the third ring bridges the 6-thio group and C7 of a 7-deazapurine. These ODNs are very poor substrates for MGMT and poorly recognised by the alkyltransferase-like protein, Atl1. Examination of the active sites of both MGMT and Atl1 suggest large steric clashes hindering binding of the analogue. Such analogues, if mutagenic, are likely to be highly toxic. [ABSTRACT FROM AUTHOR]

For modern munitions, high energy explosives are expected to reduce vulnerability and improve safety. In this study, based on the formulation of PAX-11 (94 wt% HNIW, 2.4 wt% CAB, 3.6 wt% BDNPA/F), FOX-7 is used as a portion replacement for HNIW to decrease vulnerability. To further decrease mechanical sensitivities and prevent static electricity, 0.5 wt% graphite is added to the surface of PBXs. A series of HNIW/FOX-7 based polymer bonded explosives (PBXs) with different formulations are prepared and mechanical sensitivities, thermal stabilities, detonation velocities, and slow cook-offs are studied to evaluate the energy and hazard of these PBXs. Additionally, finite element numerical simulations are utilized to study the transient temperature distributions, ignition time and ignition locations of the PBX cylinders during slow cook-off. Based on the results of this study, we obtain a high energetic low vulnerable PBX formulation (54 wt% HNIW, 40 wt% FOX-7, 2.4 wt% CAB, 3.6 wt% BDNPA/F, 0.5 wt% additional graphite) that balances energy and vulnerability. This formulation passes the slow cook-off test and detonation velocity reaches 8776 m·s−1, which can be used in the warhead of the high explosive anti-tank cartridge. [ABSTRACT FROM AUTHOR]

O 6-(carboxymethyl)guanine (O 6-CMG) and O 6-(4-oxo-4-(3-pyridyl)butyl)guanine (O 6-pobG) are toxic lesions formed in DNA following exposure to alkylating agents. O 6-CMG results from exposure to nitrosated glycine or nitrosated bile acid conjugates and may be associated with diets rich in red meat. O 6-pobG lesions are derived from alkylating agents found in tobacco smoke. Efficient syntheses of oligodeoxyribonucleotides (ODNs) containing O 6-CMG and O 6-pobG are described that involve nucleophilic displacement by the appropriate alcohol on a common synthetic ODN containing the reactive base 2-amino-6-methylsulfonylpurine. ODNs containing O 6-pobG and O 6-CMG were found to be good substrates for the S. pombe alkyltransferase-like protein Atl1. [Supplemental materials are available for this article. Go to the publisher's online edition of Nucleosides, Nucleotides & Nucleic Acids to view the free supplemental file.] [ABSTRACT FROM PUBLISHER]

Daemon-stimulated proton decay is capable of providing an appreciable part of the Sun luminosity L[this character cannot be converted into ASCII text] as well as non-electron flavour component in the solar neutrino flux. This follows, firstly, from our experiments on detection of negative daemons in Earth-crossing orbits, which give Δτex &assymp; 1 μs for the decay time of a daemon-containing proton, and, secondly, from an estimate of the total number of daemons which could be captured by the Sun from the Galactic disc (up to about 2.4 × 1030). Because of their huge mass (about 3 × 10-5 g), the captured daemons settle down to the Sun's centre to form there a kernel a few centimetres in size. The outside protons diffuse gradually into the kernel to decay there with a release of energy. If this process generates a noticeable part of L[this character cannot be converted into ASCII text], physically sound estimates of the parameters of an isothermal kernel can be obtained under the assumption that it consists mainly of negative daemons. Proton decay maintains a high temperature of the daemon gas (up to about 1011–1012 K), which makes it physically collisionless and prevents kernel collapse into a black hole. [ABSTRACT FROM AUTHOR]

The paper considers the fate of the electrically charged ( Z e ≈ 10 e ) Planckian elementary black holes, namely, daemons, making up the dark matter of the Galactic disc, which, as follows from our measurements, were trapped by the Earth during 4.5 Gyears in an amount equal to approximately 10 24 . Owing to their huge mass (about 2 × 10 -8  kg), these particles settle down to the Earth's centre to form a kernel. Assuming that the excess flux of 10-20 TW over the heat flux level produced by known sources, which is quoted by many researchers, is due to the energy liberated in the outer kernel layers in daemon-stimulated proton decay of Fe nuclei, we have come to the conclusion that the Earth's kernel is at present a fraction of a metre in size. The observed mantle flux of 3 He (and the limiting 3 He to 4 He ratio of about 10 -4 itself) can be provided if at least one 3 He (or 3 T) nucleus is emitted in a daemon-stimulated decay of 10 2 -10 3 Fe nuclei. This could actually remove the only objection to the hot origin of the Earth and to its original melting. The high energy liberation at the centre of the Earth drives two-phase two-dimensional convection in its inner core (IC), with rolls oriented along the rotation axis. This provides an explanation for the numerous features in the IC structure revealed in recent years (anisotropy in the seismic wave propagation, the existence of small irregularities, the strong damping of the P and S waves, ambiguities in the measurements of the IC rotation rate, etc.). The energy release in the kernel grows continuously as the number of daemons in it increases. Therefore the global tectonic activity, which had died out after the initial differentiation and cooling off of the Earth was reanimated 2 Gyears ago by the rearrangement and enhancement of convection in the mantle as a result of the increasing outward energy flow. It is pointed out that, as the kernel continues to grow, the tectonic activity will become intensified rather than die out, as was believed before. [ABSTRACT FROM AUTHOR]