The influence of magnetised electron transport on thermal self-focusing and channelling of nanosecond laser beams

The propagation of a nanosecond IR laser pulse through an under-dense (0.01 — 0.1ncr) magnetised laser-plasma is considered. The interplay between magnetised transport, B-field evolution and plasma hydrodynamics in the presence of a dynamically evolving beam are investigated by means of a paraxial wave solving module coupled to CTC, a 2D MHD code including Braginskii electron transport and IMPACT, a 2D implicit Vlasov-Fokker-Planck (VFP) code with magnetic fields. Magnetic fields have previously been shown to improve density channel formation for plasma waveguides however fluid simulations presented here indicate that Nernst advection can result in the rapid cavitation of magnetic field in the laser-heated region resulting in beam defocusing. Kinetic simulations indicate that strong non-local transport is present leading to the fluid code overestimating heat-flow and magnetic field advection and resulting in the recovery of beam channelling for the conditions considered

How serpins transport hormones and regulate their release

The adaptation of the serpin framework and its mechanism to perform diverse functions is epitomised in the hormone carriers of the blood. Thyroxine and the corticosteroids are transported bound in a 1:1 ratio on almost identical sites in the two homologous binding-globulins, TBG and CBG. Recent structural findings show an equilibrated, rather than on-and-off, release of the hormones from the carriers, reflecting small reversible movements of the hinge region of the reactive loop that modify the conformational flexibility of the underlying hormone-binding site. Consequently, contrary to previous concepts, the binding affinities of TBG and CBG are not fixed but can be allosterically modified to allow differential hormone delivery. Notably, the two carriers function like protein thermocouples with a surge in hormone release as body temperatures rise in fevers, and conversely a large diminution in free hormone levels at hibernation temperatures. By comparison angiotensinogen, the source of the angiotensin peptides that control blood pressure, does not appear to utilise the serpin mechanism. It has instead evolved a 63 residue terminal extension containing the buried angiotensin cleavage site, which on interaction moves into the active cleft of the renin. The conformational shift involved is critically linked by a labile disulphide bridge. The observation of changes in the redox status of this S-S bridge, in the hypertensive complication of pregnancy, pre-eclampsia, has opened an unexpected level of regulation at what is the initial stage in the control of blood pressure.This research was supported by the Wellcome Trust (Principal Research Fellowship to RJR, grant 082961/Z/07/Z) and by the British Heart Foundation grant 12/41/29679. The research was facilitated by a Wellcome Trust Strategic Award (100140) to the Cambridge Institute for Medical Research

A log-likelihood-gain intensity target for crystallographic phasing that accounts for experimental error

The crystallographic diffraction experiment measures Bragg intensities; crystallographic electron-density maps and other crystallographic calculations in phasing require structure-factor amplitudes. If data were measured with no errors, the structure-factor amplitudes would be trivially proportional to the square roots of the intensities. When the experimental errors are large, and especially when random errors yield negative net intensities, the conversion of intensities and their error estimates into amplitudes and associated error estimates becomes nontrivial. Although this problem has been addressed intermittently in the history of crystallographic phasing, current approaches to accounting for experimental errors in macromolecular crystallography have numerous significant defects. These have been addressed with the formulation of LLGI, a log-likelihood-gain function in terms of the Bragg intensities and their associated experimental error estimates. LLGI has the correct asymptotic behaviour for data with large experimental error, appropriately downweighting these reflections without introducing bias. LLGI abrogates the need for the conversion of intensity data to amplitudes, which is usually performed with the French and Wilson method [French & Wilson (1978), Acta Cryst. A35, 517-525], wherever likelihood target functions are required. It has general applicability for a wide variety of algorithms in macromolecular crystallography, including scaling, characterizing anisotropy and translational noncrystallographic symmetry, detecting outliers, experimental phasing, molecular replacement and refinement. Because it is impossible to reliably recover the original intensity data from amplitudes, it is suggested that crystallographers should always deposit the intensity data in the Protein Data Bank.This research was supported by the Wellcome Trust (Principal Research Fellowship to RJR, grant 082961/Z/07/Z). The Cambridge Institute for Medical Research is supported by a Wellcome Trust Strategic Award (100140)

Time-resolved Kerr microscopy of coupled transverse domain walls in a pair of curved nanowires

This is the final version of the article. Available from the American Institute of Physics via the DOI in this record.Time-resolved scanning Kerr microscopy has been used to directly observe magnetostatically coupled transverse domain walls (TDWs) in a pair of closely spaced, curved nanowires (NWs). Kerr images of the precessional response of the magnetic domain to either side of the TDW revealed the TDW as a minimum in the Kerr signal in the region of closest NW separation. When the TDWs were ejected from the NW pair, the minimum in the Kerr signal was no longer observed. By imaging this transition, the static de-coupling field was estimated to be in the range from 38 to 48 Oe in good agreement with a simple micromagnetic model. This work provides a novel technique by which DC and microwave assisted decoupling fields of TDWs may be explored in NW pairs of different width, separation, and curvature.This work was supported by the EU Grant Master No. NMP-FP7-212257, the UK EPSRC Grant Ref. EP/I038470/1, and partially supported by the EU FP7 Project 3SPIN No. 247368, and the Marie Curie IOF Project No. 299376

Coping with strong translational noncrystallographic symmetry and extreme anisotropy in molecular replacement with Phaser: human Rab27a

Data pathologies caused by effects such as diffraction anisotropy and translational noncrystallographic symmetry (tNCS) can dramatically complicate the solution of the crystal structures of macromolecules. Such problems were encountered in determining the structure of a mutant form of Rab27a, a member of the Rab GTPases. Mutant Rab27a constructs that crystallize in the free form were designed for use in the discovery of drugs to reduce primary tumour invasiveness and metastasis. One construct, hRab27aMut, crystallized within 24 h and diffracted to 2.82 Å resolution, with a unit cell possessing room for a large number of protein copies. Initial efforts to solve the structure using molecular replacement by Phaser were not successful. Analysis of the data set revealed that the crystals suffered from both extreme anisotropy and strong tNCS. As a result, large numbers of reflections had estimated standard deviations that were much larger than their measured intensities and their expected intensities, revealing problems with the use of such data at the time in Phaser. By eliminating extremely weak reflections with the largest combined effects of anisotropy and tNCS, these problems could be avoided, allowing a molecular-replacement solution to be found. The lessons that were learned in solving this structure have guided improvements in the numerical analysis used in Phaser, particularly in identifying diffraction measurements that convey very little information content. The calculation of information content could also be applied as an alternative to ellipsoidal truncation. The post-mortem analysis also revealed an oversight in accounting for measurement errors in the fast rotation function. While the crystal of mutant Rab27a is not amenable to drug screening, the structure can guide new modifications to obtain more suitable crystal forms

Magnetically responsive layer-by-layer microcapsules can be retained in cells and under flow conditions to promote local drug release without triggering ROS production.

Nanoengineered vehicles have the potential to deliver cargo drugs directly to disease sites, but can potentially be cleared by immune system cells or lymphatic drainage. In this study we explore the use of magnetism to hold responsive particles at a delivery site, by incorporation of superparamagnetic iron oxide nanoparticles (SPIONs) into layer-by-layer (LbL) microcapsules. Microcapsules with SPIONs were rapidly phagocytosed by cells but did not trigger cellular ROS synthesis within 24 hours of delivery nor affect cell viability. In a non-directional cell migration assay, SPION containing microcapsules significantly inhibited movement of phagocytosing cells when placed in a magnetic field. Similarly, under flow conditions, a magnetic field retained SPION containing microcapsules at a physiologic wall shear stress of 0.751 dyne cm-2. Even when the SPION content was reduced to 20%, the majority of microcapsules were still retained. Dexamethasone microcrystals were synthesised by solvent evaporation and underwent LbL encapsulation with inclusion of a SPION layer. Despite a lower iron to volume content of these structures compared to microcapsules, they were also retained under shear stress conditions and displayed prolonged release of active drug, beyond 30 hours, measured using a glucocorticoid sensitive reporter cell line generated in this study. Our observations suggest use of SPIONs for magnetic retention of LbL structures is both feasible and biocompatible and has potential application for improved local drug delivery

Coping with strong translational non-crystallographic symmetry and extreme anisotropy in molecular replacement with Phaser: human Rab27a

Data pathologies caused by effects such as diffraction anisotropy and translational non-crystallographic symmetry (tNCS) can dramatically complicate the solution of crystal structures of macromolecules. Such problems were encountered in determining the structure of a mutant form of Rab27a, a member of the Rab GTPases. Mutant Rab27a constructs that crystallise in the free form were designed for use in the discovery of drugs to reduce primary tumour invasiveness and metastasis. One construct, hRab27aMut, crystallised within 24 hours and diffracted to 2.82 Å with a unit cell possessing room for a large number of protein copies. Initial efforts to solve the structure using molecular replacement by Phaser were not successful. Analysis of the dataset revealed that the crystals suffered from both extreme anisotropy and strong tNCS. As a result, large numbers of reflections had estimated standard deviations much larger than their measured intensities and their expected intensities, revealing problems with the use of such data at the time in Phaser. By eliminating extremely weak reflections with the largest combined effects of anisotropy and tNCS, these problems could be avoided, allowing a molecular replacement solution to be found. Lessons learned in solving this structure have guided improvements in numerical analysis used in Phaser, particularly in identifying diffraction measurements conveying very little information content. The calculation of information content could also be applied as an alternative to ellipsoidal truncation. The post mortem analysis also revealed an oversight in accounting for measurement errors in the fast rotation function. While the crystal of mutant Rab27a is not amenable to drug screening, the structure can guide new modifications to obtain more suitable crystal forms

Phase diagram of a Bose gas near a wide Feshbach resonance

In this paper, we study the phase diagram of a homogeneous Bose gas with a repulsive interaction near a wide Feshbach resonance at zero temperature. The Bose-Einstein-condensation (BEC) state of atoms is a metastable state. When the scattering length $a$ exceeds a critical value depending on the atom density $n$, $na^3>0.035$, the molecular excitation energy is imaginary and the atomic BEC state is dynamically unstable against molecule formation. The BEC state of diatomic molecules has lower energy, where the atomic excitation is gapped and the molecular excitation is gapless. However when the scattering length is above another critical value, $na^3>0.0164$, the molecular BEC state becomes a unstable coherent mixture of atoms and molecules. In both BEC states, the binding energy of diatomic molecules is reduced due to the many-body effect.Comment: 5 pages, 4 figure

Assessing knowledge and attitudes about end of life: Evaluation of three instruments designed for adults with intellectual disability

Background This paper examines the development and psychometric characteristics of three instruments about end of life, designed for use with adults with intellectual disability (ID). Respectively, the instruments assess understanding of the concept of death, end‐of‐life planning, and fear of death. Methods Part 1: instruments were developed or adapted, and pilot tested with 11 adults with ID and 2 disability staff. Part 2: 39 adults with ID and 40 disability staff were assessed on all three instruments. Results We evaluated comprehensibility, internal consistency, inter‐rater reliability, subscale: total score correlations, missing data, and withdrawal. Psychometric findings were mostly good. Overall, 23% of participants with ID withdrew at some point. This outcome may have been as much due to assessment fatigue as to sensitive content. There were no adverse events. Conclusions People with ID can reliably complete assessments about end‐of‐life. Generally, each instrument was found to be comprehensible, reliable and valid

Correcting pervasive errors in RNA crystallography through enumerative structure prediction

Three-dimensional RNA models fitted into crystallographic density maps exhibit pervasive conformational ambiguities, geometric errors and steric clashes. To address these problems, we present enumerative real-space refinement assisted by electron density under Rosetta (ERRASER), coupled to Python-based hierarchical environment for integrated 'xtallography' (PHENIX) diffraction-based refinement. On 24 data sets, ERRASER automatically corrects the majority of MolProbity-assessed errors, improves the average Rfree factor, resolves functionally important discrepancies in noncanonical structure and refines low-resolution models to better match higher-resolution models