Julian Tenison Woods in Japan: Two Journeys

The Linnean Society of New South Wales includes among its members Fr Julian Edmund Tenison Woods, a distinguished nineteenth century Australian scientist. From 1883 to 1886, Woods conducted scientific research and travelled in Southeast and East Asia. This included two visits to Japan. This article gives some reconstruction of his travels in Japan, outlines his scientific work, and provides some of the later output which Woods generated as author, as collector, and as artist. The article also touches on the secretive nature of his work in Japan, though without giving a definitive conclusion

The uncertain future of China's law graduates

The purpose of this seminar is twofold: First, to provide an overview of legal education system in the People’s Republic of China. Second, to look at the uncertain situation of graduates from this system today, and to consider some of the consequences of that uncertainty. An appendix provides a list of English-language references on legal education in China.Roderick O'Brie

Positivity-preserving scheme for two-dimensional advection-diffusion equations including mixed derivatives

In this work, we propose a positivity-preserving scheme for solving two-dimensional advection-diffusion equations including mixed derivative terms, in order to improve the accuracy of lower-order methods. The solution to these equations, in the absence of mixed derivatives, has been studied in detail, while positivity-preserving solutions to mixed derivative terms have received much less attention. A two-dimensional diffusion equation, for which the analytical solution is known, is solved numerically to show the applicability of the scheme. It is further applied to the Fokker-Planck collision operator in two-dimensional cylindrical coordinates under the assumption of local thermal equilibrium. For a thermal equilibration problem, it is shown that the scheme conserves particle number and energy, while the preservation of positivity is ensured and the steady-state solution is the Maxwellian distribution. Keywords: Advection-diusion, Fokker-Planck equation, low-order positivity-preserving schem

Adapting to the motion of multiple independent targets using multileaf collimator tracking for locally advanced prostate cancer: Proof of principle simulation study.

Purpose: For patients with locally advanced cancer, multiple targets are treated simultaneously with radiotherapy. Differential motion between targets can compromise the treatment accuracy, yet there are currently no methods able to adapt to independent target motion. This study developed a multileaf collimator (MLC) tracking algorithm for differential motion adaptation and evaluated it in simulated treatments of locally advanced prostate cancer. Methods: A multi-target MLC tracking algorithm was developed that consisted of three steps: (a) dividing the MLC aperture into two possibly overlapping sections assigned to the prostate and lymph nodes, (b) calculating the ideally shaped MLC aperture as a union of the individually translated sections, and (c) fitting the MLC positions to the ideal aperture shape within the physical constraints of the MLC leaves. The multi-target tracking method was evaluated and compared with two existing motion management methods: single-target tracking and no tracking. Treatment simulations of six locally advanced prostate cancer patients with three prostate motion traces were performed for all three motion adaptation methods. The geometric error for each motion adaptation method was calculated using the area of overexposure and underexposure of each field. The dosimetric error was estimated by calculating the dose delivered to the prostate, lymph nodes, bladder, rectum, and small bowel using a motion-encoded dose reconstruction method. Results: Multi-target MLC tracking showed an average improvement in geometric error of 84% compared to single-target tracking, and 83% compared to no tracking. Multi-target tracking maintained dose coverage to the prostate clinical target volume (CTV) D98% and planning target volume (PTV) D95% to within 4.8% and 3.9% of the planned values, compared to 1.4% and 0.7% with single-target tracking, and 20.4% and 31.8% with no tracking. With multi-target tracking, the node CTV D95%, PTV D90%, and gross tumor volume (GTV) D95% were within 0.3%, 0.6%, and 0.3% of the planned values, compared to 9.1%, 11.2%, and 21.1% for single-target tracking, and 0.8%, 2.0%, and 3.2% with no tracking. The small bowel V57% was maintained within 0.2% to the plan using multi-target tracking, compared to 8% and 3.5% for single-target tracking and no tracking, respectively. Meanwhile, the bladder and rectum V50% increased by up to 13.6% and 5.2%, respectively, using multi-target tracking, compared to 2.7% and 1.9% for single-target tracking, and 11.2% and 11.5% for no tracking. Conclusions: A multi-target tracking algorithm was developed and tracked the prostate and lymph nodes independently during simulated treatments. As the algorithm optimizes for target coverage, tracking both targets simultaneously may increase the dose delivered to the organs at risk

Exploration of piperidine 3D fragment chemical space : synthesis and 3D shape analysis of fragments derived from 20 regio- and diastereoisomers of methyl substituted pipecolinates

Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we report the synthesis of piperidine-based 3D fragment building blocks - 20 regio- and diastereoisomers of methyl substituted pipecolinates using simple and general synthetic methods. cis-Piperidines, accessed through a pyridine hydrogenation were transformed into their trans-diastereoisomers using conformational control and unified reaction conditions. Additionally, diastereoselective lithiation/trapping was utilised to access trans-piperidines. Analysis of a virtual library of fragments derived from the 20 cis- and trans-disubstituted piperidines showed that it consisted of 3D molecules with suitable molecular properties to be used in fragment-based drug discovery programs

Multiplexed experimental strategies for fragment library screening against challenging drug targets using SPR biosensors

Surface plasmon resonance (SPR) biosensor methods are ideally suited for fragment-based lead discovery. However, generally applicable experimental procedures and detailed protocols are lacking, especially for structurally or physico-chemically challenging targets or when tool compounds are not available. Success depends on accounting for the features of both the target and the chemical library, purposely designing screening experiments for identification and validation of hits with desired specificity and mode-of-action, and availability of orthogonal methods capable of confirming fragment hits. The range of targets and libraries amenable to an SPR biosensor-based approach for identifying hits is considerably expanded by adopting multiplexed strategies, using multiple complementary surfaces or experimental conditions. Here we illustrate principles and multiplexed approaches for using flow-based SPR biosensor systems for screening fragment libraries of different sizes (90 and 1056 compounds) against a selection of challenging targets. It shows strategies for the identification of fragments interacting with 1) large and structurally dynamic targets, represented by acetyl choline binding protein (AChBP), a Cys-loop receptor ligand gated ion channel homologue, 2) targets in multi protein complexes, represented by lysine demethylase 1 and a corepressor (LSD1/CoREST), 3) structurally variable or unstable targets, represented by farnesyl pyrophosphate synthase (FPPS), 4) targets containing intrinsically disordered regions, represented by protein tyrosine phosphatase 1B (PTP1B), and 5) aggregation-prone proteins, represented by an engineered form of human tau (tau K18M). Practical considerations and procedures accounting for the characteristics of the proteins and libraries, and that increase robustness, sensitivity, throughput and versatility are highlighted. The study shows that the challenges for addressing these types of targets is not identification of potentially useful fragments per se, but establishing methods for their validation and evolution into leads

Design and Synthesis of 56 Shape Diverse 3-D Fragments

Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2-D molecules. Herein, we describe a workflow for the design and synthesis of 56 3-D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1.5 kcal mol -1 above the energy of the global minimum energy conformer) is carried out prior to synthesis and is also used to select targets for synthesis. The 3-D fragments were designed to contain suitable synthetic handles for future fragment elaboration. Finally, by comparing our 3-D fragments with six commercial libraries, it is clear that our collection has high three-dimensionality and shape diversity

Reduction in saturated fat intake for cardiovascular disease

BACKGROUND: Reducing saturated fat reduces serum cholesterol, but effects on other intermediate outcomes may be less clear. Additionally, it is unclear whether the energy from saturated fats eliminated from the diet are more helpfully replaced by polyunsaturated fats, monounsaturated fats, carbohydrate or protein. OBJECTIVES: To assess the effect of reducing saturated fat intake and replacing it with carbohydrate (CHO), polyunsaturated (PUFA), monounsaturated fat (MUFA) and/or protein on mortality and cardiovascular morbidity, using all available randomised clinical trials. SEARCH METHODS: We updated our searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid) and Embase (Ovid) on 15 October 2019, and searched Clinicaltrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) on 17 October 2019. SELECTION CRITERIA: Included trials fulfilled the following criteria: 1) randomised; 2) intention to reduce saturated fat intake OR intention to alter dietary fats and achieving a reduction in saturated fat; 3) compared with higher saturated fat intake or usual diet; 4) not multifactorial; 5) in adult humans with or without cardiovascular disease (but not acutely ill, pregnant or breastfeeding); 6) intervention duration at least 24 months; 7) mortality or cardiovascular morbidity data available. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed inclusion, extracted study data and assessed risk of bias. We performed random-effects meta-analyses, meta-regression, subgrouping, sensitivity analyses, funnel plots and GRADE assessment. MAIN RESULTS: We included 15 randomised controlled trials (RCTs) (16 comparisons, ~59,000 participants), that used a variety of interventions from providing all food to advice on reducing saturated fat. The included long-term trials suggested that reducing dietary saturated fat reduced the risk of combined cardiovascular events by 21% (risk ratio (RR) 0.79; 95% confidence interval (CI) 0.66 to 0.93, 11 trials, 53,300 participants of whom 8% had a cardiovascular event, I² = 65%, GRADE moderate-quality evidence). Meta-regression suggested that greater reductions in saturated fat (reflected in greater reductions in serum cholesterol) resulted in greater reductions in risk of CVD events, explaining most heterogeneity between trials. The number needed to treat for an additional beneficial outcome (NNTB) was 56 in primary prevention trials, so 56 people need to reduce their saturated fat intake for ~four years for one person to avoid experiencing a CVD event. In secondary prevention trials, the NNTB was 32. Subgrouping did not suggest significant differences between replacement of saturated fat calories with polyunsaturated fat or carbohydrate, and data on replacement with monounsaturated fat and protein was very limited. We found little or no effect of reducing saturated fat on all-cause mortality (RR 0.96; 95% CI 0.90 to 1.03; 11 trials, 55,858 participants) or cardiovascular mortality (RR 0.95; 95% CI 0.80 to 1.12, 10 trials, 53,421 participants), both with GRADE moderate-quality evidence. There was little or no effect of reducing saturated fats on non-fatal myocardial infarction (RR 0.97, 95% CI 0.87 to 1.07) or CHD mortality (RR 0.97, 95% CI 0.82 to 1.16, both low-quality evidence), but effects on total (fatal or non-fatal) myocardial infarction, stroke and CHD events (fatal or non-fatal) were all unclear as the evidence was of very low quality. There was little or no effect on cancer mortality, cancer diagnoses, diabetes diagnosis, HDL cholesterol, serum triglycerides or blood pressure, and small reductions in weight, serum total cholesterol, LDL cholesterol and BMI. There was no evidence of harmful effects of reducing saturated fat intakes. AUTHORS' CONCLUSIONS: The findings of this updated review suggest that reducing saturated fat intake for at least two years causes a potentially important reduction in combined cardiovascular events. Replacing the energy from saturated fat with polyunsaturated fat or carbohydrate appear to be useful strategies, while effects of replacement with monounsaturated fat are unclear. The reduction in combined cardiovascular events resulting from reducing saturated fat did not alter by study duration, sex or baseline level of cardiovascular risk, but greater reduction in saturated fat caused greater reductions in cardiovascular events

China – China’s developing legal system and the recent lawyers’ qualification examination

Roderick O’Brien (an Australian lawyer teaching in China) reviews changes in the legal system in China looking at ongoing development of a legal profession and in particular the lawyers’ examination. Published in the Letter from … section of Amicus Curiae - Journal of the Institute of Advanced Legal Studies and its Society for Advanced Legal Studies. The Journal is produced by the Society for Advanced Legal Studies at the Institute of Advanced Legal Studies, University of London

China – Step by step: China’s new Contract Law

An assessment of the aims and provisions of the Contract Law introduced in China on 1st October 1999, commenting on its role in China’s moves from a command economy to a market economy.  Published in the Letter from … section of Amicus Curiae - Journal of the Institute of Advanced Legal Studies and its Society for Advanced Legal Studies. The Journal is produced by the Society for Advanced Legal Studies at the Institute of Advanced Legal Studies, University of London