Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

O ⁶-methylguanine-DNA methyltransferase (MGMT) repairs the cancer chemotherapy-relevant DNA adducts, O ⁶-methylguanine and O ⁶-chloroethylguanine, induced by methylating and chloroethylating anticancer drugs, respectively. These adducts are cytotoxic, and given the overwhelming evidence that MGMT is a key factor in resistance, strategies for inactivating MGMT have been pursued. A number of drugs have been shown to inactivate MGMT in cells, human tumour models and cancer patients, and O ⁶-benzylguanine and O ⁶-[4-bromothenyl]guanine have been used in clinical trials. While these agents show no side effects per se, they also inactivate MGMT in normal tissues and hence exacerbate the toxic side effects of the alkylating drugs, requiring dose reduction. This might explain why, in any of the reported trials, the outcome has not been improved by their inclusion. It is, however, anticipated that, with the availability of tumour targeting strategies and hematopoetic stem cell protection, MGMT inactivators hold promise for enhancing the effectiveness of alkylating agent chemotherapy.     

Liquid marbles.

The transport of a small amount of liquid on a solid is not a simple process, owing to the nature of the contact between the two phases. Setting a liquid droplet in motion requires non-negligible forces (because the contact-angle hysteresis generates a force opposing the motion), and often results in the deposition of liquid behind the drop. Different methods of levitation-electrostatic, electromagnetic, acoustic, or even simpler aerodynamic techniques-have been proposed to avoid this wetting problem, but all have proved to be rather cumbersome. Here we propose a simple alternative, which consists of encapsulating an aqueous liquid droplet with a hydrophobic powder. The resulting 'liquid marbles' are found to behave like a soft solid, and show dramatically reduced adhesion to a solid surface. As a result, motion can be generated using gravitational, electrical and magnetic fields. Moreover, because the viscous friction associated with motion is very small, we can achieve quick displacements of the droplets without any leaks. All of these features are of potential benefit in microfluidic applications, and also permit the study of a drop in a non-wetting situation-an issue of renewed interest following the recent achievement of super-hydrophobic substrates.     

How 'spin ice' freezes.

The large degeneracy of states resulting from the geometrical frustration of competing interactions is an essential ingredient of important problems in fields as diverse as magnetism, protein folding and neural networks. As first explained by Pauling, geometrical frustration of proton positions is also responsible for the unusual low-temperature thermodynamics of ice and its measured 'ground state' entropy. Recent work has shown that the geometrical frustration of ice is mimicked by Dy2Ti2O7, a site-ordered magnetic material in which the spins reside on a lattice of corner-sharing tetrahedra where they form an unusual magnetic ground state known as 'spin ice'. Here we identify a cooperative spin-freezing transition leading to the spin-ice ground state in Dy2Ti2O7. This transition is associated with a very narrow range of relaxation times, and represents a new form of spin-freezing. The dynamics are analogous to those associated with the freezing of protons in ice, and they provide a means through which to study glass-like behaviour and the consequences of frustration in the limit of low disorder.     

New cooperative frequency domain differential modulation and demodulation

An innovative method of cooperative frequency domain differential modulation and demodulation is presented.This method applies the prior knowledge of channel propagation to selecting the variable differential length and carrying out frequency domain modulation.This strategy optimizes the design of system parameters to effectively improve the anti-interference ability of the differential system in time-varied multipath channel circumstance without making the execution more complicating.The simulations and comparisons demonstrate the proposed method is effective,and the results show that it is especially suitable for the fading channel with strong propagation and fast time-variation.     

Playing Dissymmetry in Action Research: The Role of Power and Differences in Promoting Participative Knowledge and Change

This article explores the importance of power and dissymmetry in promoting participative knowledge and change in action research. Based on the analysis of two action research cases, the paper builds its argument by analyzing two key aspects: the construction of the action research setting and its maintenance during the process. It does so by highlighting the decisions assumed with respect to the relationship between researchers and participants and with respect to power issues. The findings indicate that promoting a functional dissymmetry in internal relationships allows distribution of the necessary types of power that make the participants use their authority and knowledge to invest in change. Thus, the distributed leadership is essential every time an organization needs to create a realistic and workable change of roles and responsibilities inside its boundaries. The article discusses some key factors in employing dissymmetry for sustained learning and knowledge-sharing.     

A very faint core-collapse supernova in M85

An anomalous transient in the early Hubble-type (S0) galaxy Messier 85 (M85) in the Virgo cluster was discovered by Kulkarni et al. on 7 January 2006 that had very low luminosity (peak absolute R-band magnitude M(R) of about -12) that was constant over more than 80 days, red colour and narrow spectral lines, which seem inconsistent with those observed in any known class of transient events. Kulkarni et al. suggest an exotic stellar merger as the possible origin. An alternative explanation is that the transient in M85 was a type II-plateau supernova of extremely low luminosity, exploding in a lenticular galaxy with residual star-forming activity. This intriguing transient might be the faintest supernova that has ever been discovered.     

Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo

In Parkinson's disease, brain dopamine neurons degenerate most prominently in the substantia nigra. Neurotrophic factors promote survival, differentiation and maintenance of neurons in developing and adult vertebrate nervous system. The most potent neurotrophic factor for dopamine neurons described so far is the glial-cell-line-derived neurotrophic factor (GDNF). Here we have identified a conserved dopamine neurotrophic factor (CDNF) as a trophic factor for dopamine neurons. CDNF, together with its previously described vertebrate and invertebrate homologue the mesencephalic-astrocyte-derived neurotrophic factor, is a secreted protein with eight conserved cysteine residues, predicting a unique protein fold and defining a new, evolutionarily conserved protein family. CDNF (Armetl1) is expressed in several tissues of mouse and human, including the mouse embryonic and postnatal brain. In vivo, CDNF prevented the 6-hydroxydopamine (6-OHDA)-induced degeneration of dopaminergic neurons in a rat experimental model of Parkinson's disease. A single injection of CDNF before 6-OHDA delivery into the striatum significantly reduced amphetamine-induced ipsilateral turning behaviour and almost completely rescued dopaminergic tyrosine-hydroxylase-positive cells in the substantia nigra. When administered four weeks after 6-OHDA, intrastriatal injection of CDNF was able to restore the dopaminergic function and prevent the degeneration of dopaminergic neurons in substantia nigra. Thus, CDNF was at least as efficient as GDNF in both experimental settings. Our results suggest that CDNF might be beneficial for the treatment of Parkinson's disease.     

Recognition of DNA damage by the Rad4 nucleotide excision repair protein

Mutations in the nucleotide excision repair (NER) pathway can cause the xeroderma pigmentosum skin cancer predisposition syndrome. NER lesions are limited to one DNA strand, but otherwise they are chemically and structurally diverse, being caused by a wide variety of genotoxic chemicals and ultraviolet radiation. The xeroderma pigmentosum C (XPC) protein has a central role in initiating global-genome NER by recognizing the lesion and recruiting downstream factors. Here we present the crystal structure of the yeast XPC orthologue Rad4 bound to DNA containing a cyclobutane pyrimidine dimer (CPD) lesion. The structure shows that Rad4 inserts a beta-hairpin through the DNA duplex, causing the two damaged base pairs to flip out of the double helix. The expelled nucleotides of the undamaged strand are recognized by Rad4, whereas the two CPD-linked nucleotides become disordered. These findings indicate that the lesions recognized by Rad4/XPC thermodynamically destabilize the Watson-Crick double helix in a manner that facilitates the flipping-out of two base pairs.     

Chiral magnetic order at surfaces driven by inversion asymmetry

Chirality is a fascinating phenomenon that can manifest itself in subtle ways, for example in biochemistry (in the observed single-handedness of biomolecules) and in particle physics (in the charge-parity violation of electroweak interactions). In condensed matter, magnetic materials can also display single-handed, or homochiral, spin structures. This may be caused by the Dzyaloshinskii-Moriya interaction, which arises from spin-orbit scattering of electrons in an inversion-asymmetric crystal field. This effect is typically irrelevant in bulk metals as their crystals are inversion symmetric. However, low-dimensional systems lack structural inversion symmetry, so that homochiral spin structures may occur. Here we report the observation of magnetic order of a specific chirality in a single atomic layer of manganese on a tungsten (110) substrate. Spin-polarized scanning tunnelling microscopy reveals that adjacent spins are not perfectly antiferromagnetic but slightly canted, resulting in a spin spiral structure with a period of about 12 nm. We show by quantitative theory that this chiral order is caused by the Dzyaloshinskii-Moriya interaction and leads to a left-rotating spin cycloid. Our findings confirm the significance of this interaction for magnets in reduced dimensions. Chirality in nanoscale magnets may play a crucial role in spintronic devices, where the spin rather than the charge of an electron is used for data transmission and manipulation. For instance, a spin-polarized current flowing through chiral magnetic structures will exert a spin-torque on the magnetic structure, causing a variety of excitations or manipulations of the magnetization and giving rise to microwave emission, magnetization switching, or magnetic motors.