Calculation of Diamagnetic Susceptibility Tensors of Organic Crystals: From Coronene to Pharmaceutical Polymorphs

Understanding why crystallization in strong magnetic fields can lead to new polymorphs requires methods to calculate the diamagnetic response of organic molecular crystals. We develop the calculation of the macroscopic diamagnetic susceptibility tensor, χ^{cryst}, for organic molecular crystals using periodic density functional methods. The crystal magnetic susceptibility tensor, χ^{cryst}, for all experimentally known polymorphs, and its molecular counterpart, χ^{mol}, are calculated for flexible pharmaceuticals such as carbamazepine, flufenamic acid, and chalcones, and rigid molecules, such as benzene, pyridine, acridine, anthracene, and coronene, whose molecular magnetic properties have been traditionally studied. A tensor addition method is developed to approximate the crystal diamagnetic susceptibility tensor, χ^{cryst}, from the molecular one, χ^{mol}, giving good agreement with those calculated directly using the more costly periodic density functional method for χ^{cryst}. The response of pharmaceutical molecules and crystals to magnetic fields, as embodied by χ^{cryst}, is largely determined by the packing in the crystal, as well as the molecular conformation. The anisotropy of χ^{cryst} can vary considerably between polymorphs though the isotropic terms are fairly constant. The implications for developing a computational method for predicting whether crystallization in a magnetic field could produce a novel or different polymorph are discussed

Implementing telephone triage in general practice: a process evaluation of a cluster randomised controlled trial

Background: Telephone triage represents one strategy to manage demand for face-to-face GP appointments in primary care. However, limited evidence exists of the challenges GP practices face in implementing telephone triage. We conducted a qualitative process evaluation alongside a UK-based cluster randomised trial (ESTEEM) which compared the impact of GP-led and nurse-led telephone triage with usual care on primary care workload, cost, patient experience, and safety for patients requesting a same-day GP consultation. The aim of the process study was to provide insights into the observed effects of the ESTEEM trial from the perspectives of staff and patients, and to specify the circumstances under which triage is likely to be successfully implemented. Here we report perspectives of staff. Methods: The intervention comprised implementation of either GP-led or nurse-led telephone triage for a period of 2-3 months. A qualitative evaluation was conducted using staff interviews recruited from eight general practices (4 GP triage, 4 Nurse triage) in the UK, implementing triage as part of the ESTEEM trial. Qualitative interviews were undertaken with 44 staff members in GP triage and nurse triage practices (16 GPs, 8 nurses, 7 practice managers, 13 administrative staff). Results: Staff reported diverse experiences and perceptions regarding the implementation of telephone triage, its effects on workload, and on the benefits of triage. Such diversity were explained by the different ways triage was organised, the staffing models used to support triage, how the introduction of triage was communicated across practice staff, and by how staff roles were reconfigured as a result of implementing triage. Conclusion: The findings from the process evaluation offer insight into the range of ways GP practices participating in ESTEEM implemented telephone triage, and the circumstances under which telephone triage can be successfully implemented beyond the context of a clinical trial. Staff experiences and perceptions of telephone triage are shaped by the way practices communicate with staff, prepare for and sustain the changes required to implement triage effectively, as well as by existing practice culture, and staff and patient behaviour arising in response to the changes made. Trial registration: Current Controlled Trials ISRCTN20687662. Registered 28 May 2009

One Size Fits All? Development of the CPOSS209 Data Set of Experimental and Hypothetical Polymorphs for Testing Computational Modeling Methods

Organic crystal structure prediction (CSP) studies have led to the rapid development of methods for predicting the relative energies of known and computer-generated crystal structures. There is a compromise between the level of theoretical treatment, its reliability across different types of organic systems, how its accuracy depends on the size and shape of the unit cell, and the size and the number of structures that can be modeled at an affordable computational cost. We have used our database of crystal structure prediction studies, often performed as a complement to experimental screening, to produce sets comprising 6 to 15 crystal structures, covering known polymorphs, observed packings of closely related molecules, and CSP-generated energetically competitive but distinct structures, for 20 organic molecules. These have been chosen to illustrate some of the issues that need consideration in any lattice energy method, seeking to be generally applicable to moderate-sized organic molecules, including small drug molecules. We included the methods of crystallization reported for the experimental polymorphs. In all of the examples, the original CSP used electronic structure calculations on the molecule to give the conformational energy and an anisotropic atom-atom model for the electrostatic intermolecular energy, combined with an empirical “exp-6” repulsion dispersion model to give the intermolecular lattice energy. The lattice energies and structures are compared with those obtained by reoptimizing with periodic, plane-wave, dispersion-corrected density functional theory, specifically PBE with the TS dispersion correction, and with single point energies where the many body dispersion (MBD) dispersion correction is applied, as an example of a widely used “workhorse” method. The use of this data set for a preliminary test of modeling methods is illustrated for two Machine Learned Foundation Models, MACE-MP-0 and MACE-OFF23. The challenges in modeling the putative and observed polymorphs for a range of molecules, their energies, and the possible level of agreement with experimental data are illustrated. Very similar molecules can differ significantly in the polymorphs observed, only partially reflecting the range of polymorph screening experiments used and the energetically competitive structures produced by CSP approaches based on a purely thermodynamic paradigm

Quasi-Normal Modes of Stars and Black Holes

Perturbations of stars and black holes have been one of the main topics of relativistic astrophysics for the last few decades. They are of particular importance today, because of their relevance to gravitational wave astronomy. In this review we present the theory of quasi-normal modes of compact objects from both the mathematical and astrophysical points of view. The discussion includes perturbations of black holes (Schwarzschild, Reissner-Nordstr\"om, Kerr and Kerr-Newman) and relativistic stars (non-rotating and slowly-rotating). The properties of the various families of quasi-normal modes are described, and numerical techniques for calculating quasi-normal modes reviewed. The successes, as well as the limits, of perturbation theory are presented, and its role in the emerging era of numerical relativity and supercomputers is discussed.Comment: 74 pages, 7 figures, Review article for "Living Reviews in Relativity

Systematic Finite-Temperature Reduction of Crystal Energy Landscapes

Crystal structure prediction methods are prone to overestimate the number of potential polymorphs of organic molecules. In this work, we aim to reduce the overprediction by systematically applying molecular dynamics simulations and biased sampling methods to cluster subsets of structures that can easily interconvert at finite temperature and pressure. Following this approach, we rationally reduce the number of predicted putative polymorphs in crystal structure prediction (CSP)-generated crystal energy landscapes. This uses an unsupervised clustering approach to analyze independent finite-temperature molecular dynamics trajectories and hence identify a representative structure of each cluster of distinct lattice energy minima that are effectively equivalent at finite temperature and pressure. Biased simulations are used to reduce the impact of limited sampling time and to estimate the work associated with polymorphic transformations. We demonstrate the proposed systematic approach by studying the polymorphs of urea and succinic acid, reducing an initial set of over 100 energetically plausible CSP structures to 12 and 27 respectively, including the experimentally known polymorphs. The simulations also indicate the types of disorder and stacking errors that may occur in real structures

Reducing crystal structure overprediction of ibuprofen with large scale molecular dynamics simulations

The control of the crystal form is a central issue in the pharmaceutical industry. The identification of putative polymorphs through Crystal Structure Prediction (CSP) methods is based on lattice energy calculations, which are known to significantly over-predict the number of plausible crystal structures. A valuable tool to reduce overprediction is to employ physics-based, dynamic simulations to coalesce lattice energy minima separated by small barriers into a smaller number of more stable geometries once thermal effects are introduced. Molecular dynamics simulations and enhanced sampling methods can be employed in this context to simulate crystal structures at finite temperature and pressure. Here we demonstrate the applicability of approaches based on molecular dynamics to systematically process realistic CSP datasets containing several hundreds of crystal structures. The system investigated is ibuprofen, a conformationally flexible active pharmaceutical ingredient that crystallises both in enantiopure forms and as a racemic mixture. By introducing a hierarchical approach in the analysis of finite-temperature supercell configurations, we can post-process a dataset of 555 crystal structures, identifying 65% of the initial structures as labile, while maintaining all the experimentally known crystal structures in the final, reduced set. Moreover, the extensive nature of the initial dataset allows one to gain quantitative insight into the persistence and the propensity to transform of crystal structures containing common hydrogen-bonded intermolecular interaction motifs

Inference of population splits and mixtures from genome-wide allele frequency data

Many aspects of the historical relationships between populations in a species are reflected in genetic data. Inferring these relationships from genetic data, however, remains a challenging task. In this paper, we present a statistical model for inferring the patterns of population splits and mixtures in multiple populations. In this model, the sampled populations in a species are related to their common ancestor through a graph of ancestral populations. Using genome-wide allele frequency data and a Gaussian approximation to genetic drift, we infer the structure of this graph. We applied this method to a set of 55 human populations and a set of 82 dog breeds and wild canids. In both species, we show that a simple bifurcating tree does not fully describe the data; in contrast, we infer many migration events. While some of the migration events that we find have been detected previously, many have not. For example, in the human data we infer that Cambodians trace approximately 16% of their ancestry to a population ancestral to other extant East Asian populations. In the dog data, we infer that both the boxer and basenji trace a considerable fraction of their ancestry (9% and 25%, respectively) to wolves subsequent to domestication, and that East Asian toy breeds (the Shih Tzu and the Pekingese) result from admixture between modern toy breeds and "ancient" Asian breeds. Software implementing the model described here, called TreeMix, is available at http://treemix.googlecode.comComment: 28 pages, 6 figures in main text. Attached supplement is 22 pages, 15 figures. This is an updated version of the preprint available at http://precedings.nature.com/documents/6956/version/

The Crystal Structure of 5-Aminouracil and the Ambiguity of Alternative Polymorphs

The nucleobase derivative 5-aminouracil (AUr, C4H5N3O2) is of interest for its biological activity, yet the solid state structure of this compound has remained elusive owing to its propensity to crystallize as aggregates of microcrystalline particles. Here we report the first single-crystal structure of AUr determined from synchrotron x-ray diffraction data. An early crystal structure prediction effort, which assumed that AUr was rigid in the isolated molecule optimized conformation, provided several poor matches to the simulated PXRD pattern. Revisiting these crystal structures, by periodic electronic level modelling (PBE-TS optimization) gave more realistic relative lattice energies, but a good match to the experimental powder pattern required using the experimental cell parameters. PXRD and Raman spectroscopy suggest that phase impurities may be present in the bulk crystallization product, though the identity of alternative polymorphs could not be confirmed on the basis of the data available

Molecular Mechanism of Action of Antimalarial Benzoisothiazolones: Species-Selective Inhibitors of the Plasmodium spp. MEP Pathway enzyme, IspD

The methylerythritol phosphate (MEP) pathway is an essential metabolic pathway found in malaria parasites, but absent in mammals, making it a highly attractive target for the discovery of novel and selective antimalarial therapies. Using high-throughput screening, we have identified 2-phenyl benzo[d]isothiazol-3(2H)-ones as species-selective inhibitors of Plasmodium spp. 2-C-methyl-D-erythritol-4-phosphate cytidyltransferase (IspD), the third catalytic enzyme of the MEP pathway. 2-Phenyl benzo[d]isothiazol-3(2H)-ones display nanomolar inhibitory activity against P. falciparum and P. vivax IspD and prevent the growth of P. falciparum in culture, with EC50 values below 400 nM. In silico modeling, along with enzymatic, genetic and crystallographic studies, have established a mechanism-of-action involving initial non-covalent recognition of inhibitors at the IspD binding site, followed by disulfide bond formation through attack of an active site cysteine residue on the benzo[d]isothiazol-3(2H)-one core. The species-selective inhibitory activity of these small molecules against Plasmodium spp. IspD and cultured parasites suggests they have potential as lead compounds in the pursuit of novel drugs to treat malaria

Has education lost sight of children?

The reflections presented in this chapter are informed by clinical and personal experiences of school education in the UK. There are many challenges for children and young people in the modern education system and for the professionals who support them. In the UK, there are significant gaps between the highly selective education provided to those who pay privately for it and to the majority of those educated in the state-funded system. Though literacy rates have improved around the world, many children, particularly boys, do not finish their education for reasons such as boredom, behavioural difficulties or because education does not ‘pay’. Violence, bullying, and sexual harassment are issues faced by many children in schools and there are disturbing trends of excluding children who present with behavioural problems at school whose origins are not explored. Excluded children are then educated with other children who may also have multiple problems which often just make the situation worse. The experience of clinicians suggests that school-related mental health problems are increasing in severity. Are mental health services dealing with the consequences of an education system that is not meeting children’s needs? An education system that is testing- and performance-based may not be serving many children well if it is driving important decisions about them at increasingly younger ages. Labelling of children and setting them on educational career paths can occur well before they reach secondary schools, limiting potential very early on in their developmental trajectory. Furthermore, the emphasis at school on testing may come at the expense of creativity and other forms of intelligence, which are also valuable and important. Meanwhile the employment marketplace requires people with widely different skills, with an emphasis on innovation, creativity, and problem solving. Is education losing sight of the children it is educating