Extent of stacking disorder in diamond

Hexagonal diamond has been predicted computationally to display extraordinary physical properties including a hardness that exceeds cubic diamond. However, a recent electron microscopy study has shown that so-called hexagonal diamond samples are in fact not discrete materials but faulted and twinned cubic diamond. We now provide a quantitative analysis of cubic and hexagonal stacking in diamond samples by analysing X-ray diffraction data with the DIFFaX software package. The highest fractions of hexagonal stacking we find in materials which were previously referred to as hexagonal diamond are below 60%. The remainder of the stacking sequences are cubic. We show that the cubic and hexagonal sequences are interlaced in a complex way and that naturally occurring Lonsdaleite is not a simple phase mixture of cubic and hexagonal diamond. Instead, it is structurally best described as stacking disordered diamond. The future experimental challenge will be to prepare diamond samples beyond 60% hexagonality and towards the so far elusive 'perfect' hexagonal diamond

Conformational control of anticancer activity: the application of arene-linked dinuclear ruthenium(II) organometallics

Dinuclear metal complexes have emerged as a promising class of biologically active compounds which possess unique anticancer activity. Here, we describe a novel series of arene-linked dinuclear organometallic Ru(II) complexes, where the relative conformation of the ruthenium centres is controlled by the stereochemical configuration of 1,2-diphenylethylenediamine linker moieties, as confirmed by X-ray crystallography. The reactivity and cytotoxicity of these compounds is compared to flexible dinuclear and mononuclear analogues, demonstrating in all cases the complexes can undergo aquation, coordinate to typical biological donor ligands and importantly, in the case of dinuclear analogues, crosslink oligonucleotide and peptide sequences. Differences in the conformation of the isomeric dinuclear compounds lead to significantly different levels of cytotoxicity against A2780, A2780cisR and HEK-293 cell lines; isomers with a closed conformation are significantly more cytotoxic than isomers with a more open conformation and they are also significantly less susceptible to acquired resistance mechanisms operating in the A2780cisR cell line. These rigid dinuclear compounds possess markedly increased cytotoxicity relative to the non-cytotoxic mononuclear analogues that does not appear to be related to differences in complex lipophilicity or cellular uptake, which, in general, remain similar in magnitude across the series. Thus, the molecular conformation of such dinuclear species may be crucial in determining the nature of the adducts formed on coordination to biological targets in a cellular environment, and opens up a novel route toward the development of more active metal-based anticancer agents

Viral Vector-based Improvement of Optic Nerve Regeneration: Characterization of Individual Axons\u27 Growth Patterns and Synaptogenesis in a Visual Target

Lack of axon growth ability in the central nervous system poses a major barrier to achieving functional connectivity after injury. Thus, a non-transgenic regenerative approach to reinnervating targets has important implications in clinical and research settings. Previous studies using knockout (KO) mice have demonstrated long distance axon regeneration. Using an optic nerve injury model, here we evaluate the efficacy of viral, RNAi and pharmacological approaches that target the PTEN and STAT3 pathways to improve long distance axon regeneration in wild type (WT) mice. Our data show that adeno-associated virus (AAV) expressing short hairpin RNA (shRNA) against PTEN (shPTEN) enhances retinal ganglion cell axon regeneration after crush injury. However, compared to the previous data in PTEN KO mice, AAV-shRNA results in a lesser degree of regeneration, likely due to incomplete gene silencing inherent to RNAi. In comparison, an extensive enhancement in regeneration is seen when AAV-shPTEN is coupled to AAV encoding ciliary neurotrophic factor (CNTF) and to a cyclic adenosine monophosphate (cAMP) analogue, allowing axons to travel long distances and reach their target. We apply whole tissue imaging that facilitates three-dimensional visualization of single regenerating axons and document heterogeneous terminal patterns in the targets. This shows that some axonal populations generate extensive arbors and make synapses with the target neurons. Collectively, we show a combinatorial viral RNAi and pharmacological strategy that improves long distance regeneration in WT animals and provide single fiber projection data that indicates a degree of preservation of target recognition

Potential of cycloaddition reactions to generate cytotoxic metal drugs in vitro

Severe general toxicity issues blight many chemotherapeutics utilized in the treatment of cancers, resulting in the need for more selective drugs able to exert their biological activity at only the required location(s). Toward this aim, we report the development of an organometallic ruthenium compound, functionalized through a η6-bound arene ligand with a bicyclononyne derivative, able to participate in strain-promoted cycloaddition reactions with tetrazines. We show that combination of the ruthenium compound with a ditetrazine in biological media results in the in situ formation of a dinuclear molecule that is more cytotoxic toward cancer cells than the starting mononuclear ruthenium compound and tetrazine components. Such an approach may be extended to in vivo applications to construct a cytotoxic metallodrug at a tumor site, providing a novel approach toward the turn-on cytotoxicity of metallodrugs in the treatment of cancer

Recent progress in the development of organometallics for the treatment of cancer

From their early successes in medicine, organometallic compounds continue to attract interest as potential chemotherapeutics to treat a range of diseases. Here, we show from recent literature selected largely from the last two years that organometallics offer unique opportunities in medicine and, increasingly, a mechanistic-based approach is applied to their development, which has not always been the case

The incidence and risk factors for new onset atrial fibrillation in the PROSPER study

Aims Atrial fibrillation/flutter (AF) is the most common arrhythmia in older people. It associates with reduced exercise capacity, increased risk of stroke, and mortality. We aimed to determine retrospectively whether pravastatin reduces the incidence of AF and whether any electrocardiographic measures or clinical conditions might be risk factors for its development. Methods and results The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) was a randomized, double-blind controlled trial that recruited 5804 individuals aged 70-82 years with a history of, or risk factors for, vascular disease. A total of 2891 were allocated to pravastatin and 2913 to placebo; mean follow-up was 3.2 years. Electrocardiograms (ECGs), which were recorded at baseline, annually thereafter, and at run-out, were processed by computer and reviewed manually. In all, 264 of 2912 (9.1%) of the placebo group and 283 of 2888 (9.8%) of the pravastatin-treated group developed AF [hazard ratio 1.08 (0.92,1.28), P = 0.35)]. Multivariate analysis showed that PR and QTc intervals, age, left ventricular hypertrophy, and ST-T abnormalities were related to development of AF after adjustment for many variables including alcohol consumption, which itself was univariately predictive of developing AF. Previous myocardial infarction on the ECG was not a risk factor. A history of vascular disease was strongly linked with developing AF but not diabetes and hypertension. Conclusion Pravastatin does not reduce the incidence of AF in older people at risk of vascular disease, at least in the short-medium term. Risk factors for AF include older age, prolongation of PR or QTc intervals, left ventricular hypertrophy, and ST-T abnormalities on the EC

A modified Oster-Murray-Harris mechanical model of morphogenesis

There are two main modeling paradigms for biological pattern formation in developmental biology: chemical prepattern models and cell aggregation models. This paper focuses on an example of a cell aggregation model, the mechanical model developed by Oster, Murray, and Harris [Development, 78 (1983), pp. 83--125]. We revisit the Oster--Murray--Harris model and find that, due to the infinitesimal displacement assumption made in the original version of this model, there is a restriction on the types of boundary conditions that can be prescribed. We derive a modified form of the model which relaxes the infinitesimal displacement assumption. We analyze the dynamics of this model using linear and multiscale nonlinear analysis and show that it has the same linear behavior as the original Oster--Murray--Harris model. Nonlinear analysis, however, predicts that the modified model will allow for a wider range of parameters where the solution evolves to a bounded steady state. The results from both analyses are verified through numerical simulations of the full nonlinear model in one and two dimensions. The increased range of boundary conditions that are well-posed, as well as a wider range of parameters that yield bounded steady states, renders the modified model more applicable to, and more robust for, comparisons with experiments

Long term cognitive outcomes of early term (37-38 weeks) and late preterm (34-36 weeks) births: a systematic review

Background: There is a paucity of evidence regarding long-term outcomes of late preterm (34-36 weeks) and early term (37-38 weeks) delivery.  The objective of this systematic review was to assess long-term cognitive outcomes of children born at these gestations. Methods: Four electronic databases (Medline, Embase, clinicaltrials.gov and PsycINFO) were searched.  Last search was 5 th August 2016.  Studies were included if they reported gestational age, IQ measure and the ages assessed.  The protocol was registered with the International prospective register of systematic reviews (PROSPERO Record CRD42015015472).  Two independent reviewers assessed the studies.  Data were abstracted and critical appraisal performed of eligible papers. Results: Of 11,905 potential articles, seven studies reporting on 41,344 children were included.  For early term births, four studies (n = 35,711) consistently showed an increase in cognitive scores for infants born at full term (39-41 weeks) compared to those born at early term (37-38 weeks) with increases for each week of term (difference between 37 and 40 weeks of around 3 IQ points), despite differences in age of testing and method of IQ/cognitive testing.  Four studies (n = 5644) reporting childhood cognitive outcomes of late preterm births (34 - 36 weeks) also differed in study design (cohort and case control); age of testing; and method of IQ testing, and found no differences in outcomes between late preterm and term births, although risk of bias was high in included studies. Conclusion:  Children born at 39-41 weeks have higher cognitive outcome scores compared to those born at early term (37-38 weeks).  This should be considered when discussing timing of delivery.  For children born late preterm, the data is scarce and when compared to full term (37-42 weeks) did not show any difference in IQ scores

Chandra and Hubble Study of a New Transient X-ray Source in M31

We present X-ray and optical observations of a new transient X-ray source in M31 first detected 23-May-2004 at R.A.=00:43:09.940 +/- 0.65'', Dec.=41:23:32.49 +/- 0.66''. The X-ray lightcurve shows two peaks separated by several months, reminiscent of many Galactic X-ray novae. The location and X-ray spectrum of the source suggest it is a low mass X-ray binary (LMXB). Follow-up HST ACS observations of the location both during and after the outburst provide a high-confidence detection of variability for one star within the X-ray position error ellipse. This star has $\Delta$B ~ 1 mag, and there is only a ~1% chance of finding such a variable in the error ellipse. We consider this star a good candidate for the optical counterpart of the X-ray source. The luminosity of this candidate provides a prediction for the orbital period of the system of 2.3$^{+3.7}_{-1.2}$ days.Comment: 17 pages, 3 figures, 4 tables, accepted for publication in Ap