Reactions of One-Electron-Oxidized Methionine with Oxygen: An ab initio study

A one-electron oxidation of a methionine residue is thought to be a key step in the neurotoxicity of the beta amyloid peptide of Alzheimer's disease. The chemistry of the radical cation of N-formylmethioninamide (11+) and two model systems, dimethyl sulfide (1+) and ethyl methyl sulfide (6+), in the presence of oxygen have been studied by B3LYP/6-31G(d) and CBS-RAD calculations. The stable form of 11+ has a three-electron bond between the sulfur radical cation and the carbonyl oxygen atom of the i - 1 residue. The radical cation may lose a proton from the methyl or methylene groups flanking the oxidized sulfur. Both 11+ and the resultant C-centered radicals may add oxygen to form peroxy radicals. The calculations indicate that unlike C-centered radicals the sulfur radical cation does not form a covalent bond to oxygen but rather forms a loose ion-induced dipole complex with an S-O separation of about 2.7 Å, and is bound by about 13 kJ mol-1 (on the basis of 1+ + O2). Direct intramolecular abstraction of an H atom from the C site is unlikely. It is endothermic by more than 20 kJ mol-1 and involves a high barrier (G = 79 kJ mol-1). The -to-S C-centered radicals will add oxygen to form peroxy radicals. The OH BDEs of the parent hydroperoxides are in the range of 352-355 kJ mol-1, similar to SH BDEs (360 kJ mol-1) and C-H BDEs (345-350 kJ mol-1). Thus, the peroxy radicals are oxidizing species comparable in strength to thiyl radicals and peptide backbone C-centered radicals. Each peroxy radical can abstract a hydrogen atom from the backbone C site of the Met residue to yield the corresponding C-centered radical/hydroperoxide in a weakly exothermic process with modest barriers in the range of 64-92 kJ mol-1.

Dysregulated apoptosis and NFkappaB expression in COPD subjects.

Background
The abnormal regulation of neutrophil apoptosis may contribute to the ineffective resolution of inflammation in chronic lung diseases. Multiple signalling pathways are implicated in regulating granulocyte apoptosis, in particular, NF?B (nuclear factor-kappa B) signalling which delays constitutive neutrophil apoptosis. Although some studies have suggested a dysregulation in the apoptosis of airway cells in chronic obstructive pulmonary disease (COPD), no studies to date have directly investigated if NF?B is associated with apoptosis of airway neutrophils from COPD patients. The objectives of this study were to examine spontaneous neutrophil apoptosis in stable COPD subjects (n = 13), healthy smoking controls (n = 9) and non-smoking controls (n = 9) and to investigate whether the neutrophil apoptotic process in inflammatory conditions is associated with NF?B activation.

Methods
Analysis of apoptosis in induced sputum was carried out by 3 methods; light microscopy, Annexin V/Propidium iodide and the terminal transferase-mediated dUTP nick end-labeling (TUNEL) method. Activation of NF?B was assessed using a flow cytometric method and the phosphorylation state of I?Ba was carried out using the Bio-Rad Bio-Plex phosphoprotein I?Ba assay.

Results
Flow cytometric analysis showed a significant reduction in the percentage of sputum neutrophils undergoing spontaneous apoptosis in healthy smokers and subjects with COPD compared to non-smokers (p < 0.001). Similar findings were demonstrated using the Tunel assay and in the morphological identification of apoptotic neutrophils. A significant increase was observed in the expression of both the p50 (p = 0.006) and p65 (p = 0.006) subunits of NF?B in neutrophils from COPD subjects compared to non-smokers.

Conclusion
These results demonstrate that apoptosis is reduced in the sputum of COPD subjects and in healthy control smokers and may be regulated by an associated activation of NF?B.

Dose, dose-rate and field size effects on cell survival following exposure to non-uniform radiation fields

For the delivery of intensity-modulated radiation therapy (IMRT), highly modulated fields are used to achieve dose conformity across a target tumour volume. Recent in vitro evidence has demonstrated significant alterations in cell survival occurring out-of-field which cannot be accounted for on the basis of scattered dose. The radiobiological effect of area, dose and dose-rate on out-of-field cell survival responses following exposure to intensity-modulated radiation fields is presented in this study. Cell survival was determined by clonogenic assay in human prostate cancer (DU-145) and primary fibroblast (AG0-1522) cells following exposure to different modulated field configurations delivered using a X-Rad 225 kVp x-ray source. Uniform survival responses were compared to in- and out-of-field responses in which 25-99% of the cell population was shielded. Dose delivered to the out-of-field region was varied from 1.6-37.2% of that delivered to the in-field region using different levels of brass shielding. Dose rate effects were determined for 0.2-4 Gy min⁻¹ for uniform and modulated exposures with no effect seen in- or out-of-field. Survival responses showed little dependence on dose rate and area in- and out-of-field with a trend towards increased survival with decreased in-field area. Out-of-field survival responses were shown to scale in proportion to dose delivered to the in-field region and also local dose delivered out-of-field. Mathematical modelling of these findings has shown survival response to be highly dependent on dose delivered in- and out-of-field but not on area or dose rate. These data provide further insight into the radiobiological parameters impacting on cell survival following exposure to modulated irradiation fields highlighting the need for refinement of existing radiobiological models to incorporate non-targeted effects and modulated dose distributions.

The internal structure of asteroid (25143) Itokawa as revealed by detection of YORP spin-up *’**

Context. Near-Earth asteroid (25143) Itokawa was visited by the Hayabusa spacecraft in 2005, resulting in a highly detailed shape and surface topography model. This model has led to several predictions for the expected radiative torques on this asteroid, suggesting that its spin rate should be decelerating. Aims. To detect changes in rotation rate that may be due to YORP-induced radiative torques, which in turn may be used to investigate the interior structure of the asteroid. Methods. Through an observational survey spanning 2001 to 2013 we obtained rotational lightcurve data at various times over the last five close Earth-approaches of the asteroid. We applied a polyhedron-shape-modelling technique to assess the spin-state of the asteroid and its long term evolution. We also applied a detailed thermophysical analysis to the shape model determined from the Hayabusa spacecraft. Results. We have successfully measured an acceleration in Itokawa's spin rate of dω/dt = (3.54 ± 0.38) × 10 rad day, equivalent to a decrease of its rotation period of ~45 ms year. From the thermophysical analysis we find that the centre-of-mass for Itokawa must be shifted by ~21 m along the long-axis of the asteroid to reconcile the observed YORP strength with theory. Conclusions. This can be explained if Itokawa is composed of two separate bodies with very different bulk densities of 1750 ± 110 kg m and 2850 ± 500 kg m, and was formed from the merger of two separate bodies, either in the aftermath of a catastrophic disruption of a larger differentiated body, or from the collapse of a binary system. We therefore demonstrate that an observational measurement of radiative torques, when combined with a detailed shape model, can provide insight into the interior structure of an asteroid. Futhermore, this is the first measurement of density inhomogeneity within an asteroidal body, that reveals significant internal structure variation. A specialised spacecraft is normally required for this.

Direct Detection of YORP Spin-up on Asteroid (25143) Itokawa and Implications for its Internal Structure

Near-Earth asteroid (25143) Itokawa was visited by the Hayabusa spacecraft in 2005, resulting in a highly detailed surface shape and topography model. This model has led to several predictions for the expected radiative torques on this asteroid, suggesting that its spin rate should be decelerating. Through an observational survey spanning 2001 to 2013 we have successfully measured an acceleration in its spin rate of dω/dt = 3.54 (± 0.38) × 10^(-8) rad day^(-2), equivalent to a decrease of its rotation period of ~ 45 ms year^(-1). Using the shape model determined from the Hayabusa spacecraft, we applied a detailed thermophysical analysis, to reconcile the predicted YORP strength with that observed. We find that the center-of-mass for Itokawa must be shifted by ~20 m along the long-axis of the asteroid to reconcile observations with theory. This can be explained if Itokawa is composed of two separate bodies with very different bulk densities of 1740 ± 110 kg m^(-3) and 2730 ± 440 kg m^(-3), and was formed from the merger of two separate bodies, consistent with the collapse of a binary system or the re-accumulation of material from a catastrophic collisional disruption. We demonstrate that an observational measurement of radiative torques, when combined with a detailed shape model, can provide insight into the interior structure of an asteroid.

Radiative hydrodynamic modelling and observations of the X-class solar flare on 2011 March 9

Aims. We investigated the response of the solar atmosphere to non-thermal electron beam heating using the radiative transfer and hydrodynamics modelling code RADYN. The temporal evolution of the parameters that describe the non-thermal electron energy distribution were derived from hard X-ray observations of a particular flare, and we compared the modelled and observed parameters.

Methods. The evolution of the non-thermal electron beam parameters during the X1.5 solar flare on 2011 March 9 were obtained from analysis of RHESSI X-ray spectra. The RADYN flare model was allowed to evolve for 110 s, after which the electron beam heating was ended, and was then allowed to continue evolving for a further 300 s. The modelled flare parameters were compared to the observed parameters determined from extreme-ultraviolet spectroscopy.

Results. The model produced a hotter and denser flare loop than that observed and also cooled more rapidly, suggesting that additional energy input in the decay phase of the flare is required. In the explosive evaporation phase a region of high-density cool material propagated upward through the corona. This material underwent a rapid increase in temperature as it was unable to radiate away all of the energy deposited across it by the non-thermal electron beam and via thermal conduction. A narrow and high-density (ne ≤ 1015 cm-3) region at the base of the flare transition region was the source of optical line emission in the model atmosphere. The collision-stopping depth of electrons was calculated throughout the evolution of the flare, and it was found that the compression of the lower atmosphere may permit electrons to penetrate farther into a flaring atmosphere compared to a quiet Sun atmosphere.