Additive manufacturing using extra-terrestrial multi-component ceramic materials

Powder Bed Fusion (PBF) based Additive Manufacturing (AM) is a category of advanced manufacturing technologies that can fabricate three-dimensional assets directly from CAD data, on a successive layer-by-layer strategy by using thermal energy from a laser source, to irradiate and fuse particles on a powder bed. The aim of this research was to investigate the application of this advanced manufacturing technique to laser process ceramic multicomponent materials into 3D layered structures. These ceramic materials matched those found on the Lunar and/or Martian surface. These indigenous extra-terrestrial materials could potentially be used for manufacturing physical assets onsite (i.e. off World) on future planetary exploration missions and could cover a range of potential applications including infrastructure, radiation shielding, thermal storage, etc. JSC-1A Lunar and JSC-Mars-1A Martian soil simulants, mimicking the mineralogical and basic properties of these planetary indigenous materials were used for the purpose of this study and processed with commercially available laser additive manufacturing equipment. The results of the laser processing were investigated and quantified through mechanical hardness testing, optical and scanning electron microscopy (SEM) and energy dispersive x-ray spectroscopy (EDS). The research resulted in the identification of a range of parameters that resulted in the successful manufacture of three-dimensional components from Lunar and Martian ceramic multicomponent simulant materials. The feasibility of using thermal based additive manufacturing with multi-component ceramic materials has therefore been established which represents a potential solution to off-world bulk structure manufacture due to there being no requirement for additional materials and resources other than the manufacturing equipment to be shipped off-world

A concise and scalable strategy for the total synthesis of dictyodendrin B based on sequential C-H functionalization.

A sequential CH functionalization strategy for the synthesis of the marine alkaloid dictyodendrin B is reported. Our synthesis begins from commercially available 4-bromoindole and involves six direct functionalizations around the heteroarene core as part of a gram-scale strategy towards the natural product.We are grateful to AstraZeneca, Pfizer, and EPSRC (A.K.P., F.O. and R.H.S.) and the ERC and EPSRC for fellowships (M.J.G.).This is the author accepted manuscript. The final version is available from Wiley at http://onlinelibrary.wiley.com/doi/10.1002/anie.201500067/abstract

Aspects of the noncommutative torus

In this thesis a class of finite real spectral triples for the geometry on a fuzzy torus is introduced. The geometries are shown to be related via an action of a general integral matrix. Each geometry is shown to have four real spectral triples corresponding to the four unique spin structures found on the 2-torus. The spectrum of the Dirac operator on each geometry, and spin structure, is calculated and shown to be the quantum integer analogues of the spectrum of the Dirac operator on the corresponding commutative 2-torus. The spectrum of the noncommutative Dirac operator is then shown to converge to the spectrum of the commutative Dirac operator as the algebra becomes commutative. Finally, an outline for the proof of a fuzzy torus converging to a commutative torus, via the defined Dirac operator, is presented

Exploiting horizontal pleiotropy to search for causal pathways within a Mendelian randomization framework

In Mendelian randomization (MR) analysis, variants that exert horizontal pleiotropy are typically treated as a nuisance. However, they could be valuable in identifying alternative pathways to the traits under investigation. Here, we developed MR-TRYX, a framework that exploits horizontal pleiotropy to discover putative risk factors for disease. We begin by detecting outliers in a single exposure-outcome MR analysis, hypothesising they are due to horizontal pleiotropy. We search across hundreds of complete GWAS summary datasets to systematically identify other (candidate) traits that associate with the outliers. We developed a multi-trait pleiotropy model of the heterogeneity in the exposure-outcome analysis due to pathways through candidate traits. Through detailed investigation of several causal relationships, many pleiotropic pathways are uncovered with already established causal effects, validating the approach, but also alternative putative causal pathways. Adjustment for pleiotropic pathways reduces the heterogeneity across the analyses

Rivastigmine for gait stability in patients with Parkinson's disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial

Background Falls are a frequent and serious complication of Parkinson's disease and are related partly to an underlying cholinergic deficit that contributes to gait and cognitive dysfunction in these patients. Gait dysfunction can lead to an increased variability of gait from one step to another, raising the likelihood of falls. In the ReSPonD trial we aimed to assess whether ameliorating this cholinergic deficit with the acetylcholinesterase inhibitor rivastigmine would reduce gait variability. Methods We did this randomised, double-blind, placebo-controlled, phase 2 trial at the North Bristol NHS Trust Hospital, Bristol, UK, in patients with Parkinson's disease recruited from community and hospital settings in the UK. We included patients who had fallen at least once in the year before enrolment, were able to walk 18 m without an aid, had no previous exposure to an acetylcholinesterase inhibitor, and did not have dementia. Our clinical trials unit randomly assigned (1:1) patients to oral rivastigmine or placebo capsules (both taken twice a day) using a computer-generated randomisation sequence and web-based allocation. Rivastigmine was uptitrated from 3 mg per day to the target dose of 12 mg per day over 12 weeks. Both the trial team and patients were masked to treatment allocation. Masking was achieved with matched placebo capsules and a dummy uptitration schedule. The primary endpoint was difference in step time variability between the two groups at 32 weeks, adjusted for baseline age, cognition, step time variability, and number of falls in the previous year. We measured step time variability with a triaxial accelerometer during an 18 m walking task in three conditions: normal walking, simple dual task with phonemic verbal fluency (walking while naming words beginning with a single letter), and complex dual task switching with phonemic verbal fluency (walking while naming words, alternating between two letters of the alphabet). Analysis was by modified intention to treat; we excluded from the primary analysis patients who withdrew, died, or did not attend the 32 week assessment. This trial is registered with ISRCTN, number 19880883. Findings Between Oct 4, 2012 and March 28, 2013, we enrolled 130 patients and randomly assigned 65 to the rivastigmine group and 65 to the placebo group. At week 32, compared with patients assigned to placebo (59 assessed), those assigned to rivastigmine (55 assessed) had improved step time variability for normal walking (ratio of geometric means 0·72, 95% CI 0·58–0·88; p=0·002) and the simple dual task (0·79; 0·62–0·99; p=0·045). Improvements in step time variability for the complex dual task did not differ between groups (0·81, 0·60–1·09; p=0·17). Gastrointestinal side-effects were more common in the rivastigmine group than in the placebo group (p<0·0001); 20 (31%) patients in the rivastigmine group versus three (5%) in the placebo group had nausea and 15 (17%) versus three (5%) had vomiting

Triangulating evidence from observational and Mendelian randomization studies of ketone bodies for cognitive performance

BACKGROUND: Ketone bodies (KBs) are an alternative energy supply for brain functions when glucose is limited. The most abundant ketone metabolite, 3-β-hydroxybutyrate (BOHBUT), has been suggested to prevent or delay cognitive impairment, but the evidence remains unclear. We triangulated observational and Mendelian randomization (MR) studies to investigate the association and causation between KBs and cognitive function. METHODS: In observational analyses of 5506 participants aged ≥ 45 years from the Whitehall II study, we used multiple linear regression to investigate the associations between categorized KBs and cognitive function scores. Two-sample MR was carried out using summary statistics from an in-house KBs meta-analysis between the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium and Kettunen et al. (N = 45,031), and publicly available summary statistics of cognitive performance and Alzheimer's disease (AD) from the Social Science Genetic Association Consortium (N = 257,841), and the International Genomics of Alzheimer's Project (N = 54,162), respectively. Both strong (P < 5 × 10-8) and suggestive (P < 1 × 10-5) sets of instrumental variables for BOHBUT were applied. Finally, we performed cis-MR on OXCT1, a well-known gene for KB catabolism. RESULTS: BOHBUT was positively associated with general cognitive function (β = 0.26, P = 9.74 × 10-3). In MR analyses, we observed a protective effect of BOHBUT on cognitive performance (inverse variance weighted: βIVW = 7.89 × 10-2, PIVW = 1.03 × 10-2; weighted median: βW-Median = 8.65 × 10-2, PW-Median = 9.60 × 10-3) and a protective effect on AD (βIVW =  - 0.31, odds ratio: OR = 0.74, PIVW = 3.06 × 10-2). Cis-MR showed little evidence of therapeutic modulation of OXCT1 on cognitive impairment. CONCLUSIONS: Triangulation of evidence suggests that BOHBUT has a beneficial effect on cognitive performance. Our findings raise the hypothesis that increased BOHBUT may improve general cognitive functions, delaying cognitive impairment and reducing the risk of AD