Control of P2X2 Channel Permeability by the Cytosolic Domain

ATP-gated P2X channels are the simplest of the three families of transmitter-gated ion channels. Some P2X channels display a time- and activation-dependent change in permeability as they undergo the transition from the relatively Na+-selective I1 state to the I2 state, which is also permeable to organic cations. We report that the previously reported permeability change of rat P2X2 (rP2X2) channels does not occur at mouse P2X2 (mP2X2) channels expressed in oocytes. Domain swaps, species chimeras, and point mutations were employed to determine that two specific amino acid residues in the cytosolic tail domain govern this difference in behavior between the two orthologous channels. The change in pore diameter was characterized using reversal potential measurements and excluded field theory for several organic ions; both rP2X2 and mP2X2 channels have a pore diameter of ~11 Å in the I1 state, but the transition to the I2 state increases the rP2X2 diameter by at least 3 Å. The I1 to I2 transition occurs with a rate constant of ~0.5 s^-1. The data focus attention on specific residues of P2X2 channel cytoplasmic domains as determinants of permeation in a state-specific manner

Grain Boundary Loops in Graphene

Topological defects can affect the physical properties of graphene in unexpected ways. Harnessing their influence may lead to enhanced control of both material strength and electrical properties. Here we present a new class of topological defects in graphene composed of a rotating sequence of dislocations that close on themselves, forming grain boundary loops that either conserve the number of atoms in the hexagonal lattice or accommodate vacancy/interstitial reconstruction, while leaving no unsatisfied bonds. One grain boundary loop is observed as a "flower" pattern in scanning tunneling microscopy (STM) studies of epitaxial graphene grown on SiC(0001). We show that the flower defect has the lowest energy per dislocation core of any known topological defect in graphene, providing a natural explanation for its growth via the coalescence of mobile dislocations.Comment: 23 pages, 7 figures. Revised title; expanded; updated reference

Building effective models from sparse but precise data

A common approach in computational science is to use a set of of highly precise but expensive calculations to parameterize a model that allows less precise, but more rapid calculations on larger scale systems. Least-squares fitting on a model that underfits the data is generally used for this purpose. For arbitrarily precise data free from statistic noise, e.g. ab initio calculations, we argue that it is more appropriate to begin with a ensemble of models that overfit the data. Within a Bayesian framework, a most likely model can be defined that incorporates physical knowledge, provides error estimates for systems not included in the fit, and reproduces the original data exactly. We apply this approach to obtain a cluster expansion model for the Ca[Zr,Ti]O3 solid solution.Comment: 10 pages, 3 figures, submitted to Physical Review Letter

Fourier Transform Scanning Tunneling Spectroscopy: the possibility to obtain constant energy maps and the band dispersion using a local measurement

We present here an overview of the Fourier Transform Scanning Tunneling spectroscopy technique (FT-STS). This technique allows one to probe the electronic properties of a two-dimensional system by analyzing the standing waves formed in the vicinity of defects. We review both the experimental and theoretical aspects of this approach, basing our analysis on some of our previous results, as well as on other results described in the literature. We explain how the topology of the constant energy maps can be deduced from the FT of dI/dV map images which exhibit standing waves patterns. We show that not only the position of the features observed in the FT maps, but also their shape can be explained using different theoretical models of different levels of approximation. Thus, starting with the classical and well known expression of the Lindhard susceptibility which describes the screening of electron in a free electron gas, we show that from the momentum dependence of the susceptibility we can deduce the topology of the constant energy maps in a joint density of states approximation (JDOS). We describe how some of the specific features predicted by the JDOS are (or are not) observed experimentally in the FT maps. The role of the phase factors which are neglected in the rough JDOS approximation is described using the stationary phase conditions. We present also the technique of the T-matrix approximation, which takes into account accurately these phase factors. This technique has been successfully applied to normal metals, as well as to systems with more complicated constant energy contours. We present results recently obtained on graphene systems which demonstrate the power of this technique, and the usefulness of local measurements for determining the band structure, the map of the Fermi energy and the constant-energy maps.Comment: 33 pages, 15 figures; invited review article, to appear in Journal of Physics D: Applied Physic

Rules for Computing Symmetry, Density and Stoichiometry in a Quasi-Unit-Cell Model of Quasicrystals

The quasi-unit cell picture describes the atomic structure of quasicrystals in terms of a single, repeating cluster which overlaps neighbors according to specific overlap rules. In this paper, we discuss the precise relationship between a general atomic decoration in the quasi-unit cell picture atomic decorations in the Penrose tiling and in related tiling pictures. Using these relations, we obtain a simple, practical method for determining the density, stoichiometry and symmetry of a quasicrystal based on the atomic decoration of the quasi-unit cell taking proper account of the sharing of atoms between clusters.Comment: 14 pages, 8 figure

Clinical trial management: a profession in crisis?

Clinical trial managers play a vital role in the design and conduct of clinical trials in the UK. There is a current recruitment and retention crisis for this specialist role due to a complex set of factors, most likely to have come to a head due to the COVID-19 pandemic. Academic clinical trial units and departments are struggling to recruit trial managers to vacant positions, and multiple influences are affecting the retention of this highly skilled workforce. Without tackling this issue, we face major challenges in the delivery on the Department of Health and Social Care’s Future of UK Clinical Research Delivery implementation plan. This article, led by a leading network of and for UK Trial Managers, presents some of the issues and ways in which national stakeholders may be able to address this

EVerT: Cryotherapy versus salicylic acid for the treatment of verrucae - a randomised controlled trial

OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of cryotherapy using liquid nitrogen versus patient daily self-treatment with 50% salicylic acid for the treatment of verrucae (plantar warts). DESIGN: A multicentre, pragmatic, open, two-armed randomised controlled trial with an economic evaluation. Randomisation was simple, with the allocation sequence generated by a computer in a 1 : 1 ratio. SETTING: Podiatry clinics, university podiatry schools and primary care in England, Scotland and Ireland. PARTICIPANTS: Patients were eligible if they presented with a verruca which, in the opinion of the health-care professional, was suitable for treatment with both salicylic acid and cryotherapy, and were aged 12 years and over. INTERVENTIONS: Cryotherapy using liquid nitrogen delivered by a health-care professional compared with daily patient self-treatment with 50% salicylic acid (Verrugon, William Ransom & Son Plc, Hitchin, UK) for a maximum of 8 weeks. MAIN OUTCOME MEASURES: The primary outcome was complete clearance of all verrucae at 12 weeks. Secondary outcomes were complete clearance of all verrucae at 12 weeks, controlling for age, whether or not the verrucae had been previously treated and type of verrucae, with a second model to explore the effect of patient preferences, time to clearance of verrucae, clearance of verrucae at 6 months, number of verrucae at 12 weeks and patient satisfaction with the treatment RESULTS: In total, 240 eligible patients were recruited, with 117 patients allocated to the cryotherapy group and 123 to the salicylic acid group. There was no evidence of a difference in clearance rates between the treatment groups in the primary outcome [17/119 (14.3%) in the salicylic acid group vs 15/110 (13.6%) in the cryotherapy group; p = 0.89]. The results of the study did not change when controlled for age, whether or not the verrucae had been previously treated and type of verrucae, or when patient preferences were explored. There was no evidence of a difference in time to clearance of verrucae between the two groups [hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.51 to 1.25; p = 0.33] or in the clearance of verrucae at 6 months (33.7% cryotherapy vs 30.5% salicylic acid). There was no evidence of a difference in the number of verrucae at 12 weeks between the two groups (incidence rate ratio 1.08, 95% CI 0.81 to 1.43; p = 0.62). Nineteen participants reported 28 adverse events, 14 in each group, with two treatment-related non-serious adverse events in the cryotherapy group. Cryotherapy was also associated with higher mean costs per additional healed patient (£101.17, 95% bias-corrected and accelerated CI £85.09 to £117.26). The probability of cryotherapy being cost-effective is 40% for a range of willingness-to-pay thresholds of £15,000-30,000 per patient healed. CONCLUSIONS: There is no evidence for a difference in terms of clearance of verrucae between cryotherapy and salicylic acid (at both 12 weeks and 6 months), number of verrucae at 12 weeks and time to clearance of verrucae. Cryotherapy was associated with higher mean costs per additional healed patient compared with salicylic acid. TRIAL REGISTRATION:Current Controlled Trials ISRCTN18994246. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 15, No. 32. See the HTA programme website for further project information

Single and Paired Point Defects in a 2D Wigner Crystal

Using the path-integral Monte Carlo method, we calculate the energy to form single and pair vacancies and interstitials in a two-dimensional Wigner crystal of electrons. We confirm that the lowest-lying energy defects of a 2D electron Wigner crystal are interstitials, with a creation energy roughly 2/3 that of a vacancy. The formation energy of the defects goes to zero near melting, suggesting that point defects might mediate the melting process. In addition, we find that the interaction between defects is strongly attractive, so that most defects will exist as bound pairs.Comment: 4 pages, 5 encapsulated figure

Total-energy-based prediction of a quasicrystal structure

Quasicrystals are metal alloys whose noncrystallographic symmetry and lack of structural periodicity challenge methods of experimental structure determination. Here we employ quantum-based total-energy calculations to predict the structure of a decagonal quasicrystal from first principles considerations. We employ Monte Carlo simulations, taking as input the knowledge that a decagonal phase occurs in Al-Ni-Co near a given composition, and using a few features of the experimental Patterson function. The resulting structure obeys a nearly deterministic decoration of tiles on a hierarchy of length scales related by powers of $\tau$, the golden mean.Comment: 9 pages, 3 figure