Studies towards a fast and efficient total synthesis of LL-Z1640-2

LL-Z1640-2 (5Z-7-Oxo-zeaenol) was first isolated in 1978 from a culture broth. Although LL-Z1640-2 was initially classified as an anti-protazoan agent, it was not until 1999 that it’s cytokine release inhibiting activity was discovered. More recently LL-Z1640-2 has been reported to selectively inhibit the kinase activity of TAK1. TAK1 (transforming growth factor β-activated protein kinase 1) is a major member of the mitogen activated protein kinase kinase kinase (MAPKKK) family. TAK1 is responsible for the activation and control of at least three signalling pathways that play crucial roles in the inflammatory response. Hence, TAK1 has emerged as a prime target for the treatment and regulation of chronic inflammatory diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel disease. LL-Z1640-2 is structurally related to other 14 membered resorcylic lactones such as 7-oxo-zeaenol, zeaenol and radicicol. Although there has been a significant amount of work dedicated to the synthesis of radicicol, the efforts towards LLZ1640-2 have been rather limited. At the outset of the research contained within this thesis, only two total syntheses of LL-Z1640-2 had been published. They were both lengthy (>20 steps) making them impractical for lead development. The work described in this thesis illustrates the attempted flexible and convergent synthesis of LL-Z1640-2 from the simple, commercially available, starting materials 2-deoxy-D-ribose and methyl 2,4,6-trihydroxybenzoate

Measurement of throughput variation across a large format volume-phase holographic grating

In this paper, we report measurements of diffraction efficiency and angular dispersion for a large format (~ 25 cm diameter) Volume-Phase Holographic (VPH) grating optimized for near-infrared wavelengths (0.9 ~ 1.8 μm). The aim of this experiment is to see whether optical characteristics vary significantly across the grating. We sampled three positions in the grating aperture with a separation of 5 cm between each. A 2 cm diameter beam is used to illuminate the grating. At each position, throughput and diffraction angle were measured at several wavelengths. It is found that whilst the relationship between diffraction angle and wavelength is nearly he same at the three positions, the throughputs vary by up to ~ 10% from position to position. We explore the origin of the throughput variation by comparing the data with predictions from coupled-wave analysis. We find that it can be explained by a combination of small variations over the grating aperture in gelatin depth and/or refractive index modulation amplitude, and amount of energy loss by internal absorption and/or surface reflection

Syndromic surveillance to assess the potential public health impact of the Icelandic volcanic ash plume across the United Kingdom, April 2010

The Eyjafjallajökull volcano in Iceland erupted on 14 April 2010 emitting a volcanic ash plume that spread across the United Kingdom and mainland Europe. The Health Protection Agency and Health Protection Scotland used existing syndromic surveillance systems to monitor community health during the incident: there were no particularly unusual increases in any of the monitored conditions. This incident has again demonstrated the use of syndromic surveillance systems for monitoring community health in real time

Open source drug discovery - A limited tutorial

Open science is a new concept for the practice of experimental laboratory-based research, such as drug discovery. The authors have recently gained experience in how to run such projects and here describe some straightforward steps others may wish to take towards more openness in their own research programmes. Existing and inexpensive online tools can solve many challenges, while some psychological barriers to the free sharing of all data and ideas are more substantia

Nonlinear Stability in the Generalised Photogravitational Restricted Three Body Problem with Poynting-Robertson Drag

The Nonlinear stability of triangular equilibrium points has been discussed in the generalised photogravitational restricted three body problem with Poynting-Robertson drag. The problem is generalised in the sense that smaller primary is supposed to be an oblate spheroid. The bigger primary is considered as radiating. We have performed first and second order normalization of the Hamiltonian of the problem. We have applied KAM theorem to examine the condition of non-linear stability. We have found three critical mass ratios. Finally we conclude that triangular points are stable in the nonlinear sense except three critical mass ratios at which KAM theorem fails.Comment: Including Poynting-Robertson Drag the triangular equilibrium points are stable in the nonlinear sense except three critical mass ratios at which KAM theorem fail

Silica suspension and coating developments for Advanced LIGO

The proposed upgrade to the LIGO detectors to form the Advanced LIGO detector system is intended to incorporate a low thermal noise monolithic fused silica final stage test mass suspension based on developments of the GEO 600 suspension design. This will include fused silica suspension elements jointed to fused silica test mass substrates, to which dielectric mirror coatings are applied. The silica fibres used for GEO 600 were pulled using a Hydrogen-Oxygen flame system. This successful system has some limitations, however, that needed to be overcome for the more demanding suspensions required for Advanced LIGO. To this end a fibre pulling machine based on a CO2 laser as the heating element is being developed in Glasgow with funding from EGO and PPARC. At the moment a significant limitation for proposed detectors like Advanced LIGO is expected to come from the thermal noise of the mirror coatings. An investigation on mechanical losses of silica/tantala coatings was carried out by several labs involved with Advanced LIGO R&D. Doping the tantala coating layer with titania was found to reduce the coating mechanical dissipation. A review of the results is given here

"I am your mother and your father!": In vitro derived gametes and the ethics of solo reproduction

In this paper, we will discuss the prospect of human reproduction achieved with gametes originating from only one person. According to statements by a minority of scientists working on the generation of gametes in vitro, it may become possible to create eggs from men’s non-reproductive cells and sperm from women’s. This would enable, at least in principle, the creation of an embryo from cells obtained from only one individual: ‘solo reproduction’. We will consider what might motivate people to reproduce in this way, and the implications that solo reproduction might have for ethics and policy. We suggest that such an innovation is unlikely to revolutionise reproduction and parenting. Indeed, in some respects it is less revolutionary than in vitro fertilisation as a whole. Furthermore, we show that solo reproduction with in vitro created gametes is not necessarily any more ethically problematic than gamete donation—and probably less so. Where appropriate, we draw parallels with the debate surrounding reproductive cloning. We note that solo reproduction may serve to perpetuate reductive geneticised accounts of reproduction, and that this may indeed be ethically questionable. However, in this it is not unique among other technologies of assisted reproduction, many of which focus on genetic transmission. It is for this reason that a ban on solo reproduction might be inconsistent with continuing to permit other kinds of reproduction that also bear the potential to strengthen attachment to a geneticised account of reproduction. Our claim is that there are at least as good reasons to pursue research towards enabling solo reproduction, and eventually to introduce solo reproduction as an option for fertility treatment, as there are to do so for other infertility related purposes

In vitro metabolic profile and in vivo antischistosomal activity studies of (η(6)-Praziquantel)Cr(CO)3 derivatives

In vitro metabolic behavior was investigated for two chromium tricarbonyl derivatives of the antischistosomal drug praziquantel (PZQ) with the formula (η(6)-PZQ)Cr(CO)3 (1 and 2), by use of human liver microsomes. The metabolic profiles of the derivatives differ significantly. The optically pure (η(6)-PZQ)Cr(CO)3 derivatives (S, Sp)-1, (R, Rp)-1, (S, Rp)-2, and (R, Sp)-2 were also prepared to assess the eudysmic ratios of 1 and 2 against Schistosoma mansoni in vitro. A strong enantioselective antischistosomal activity was observed. The R-enantiomers are highly active against adult schistosomes in vitro (IC50 0.08-0.13 μM), whereas both S-enantiomers lack activity. The in vivo activity of 1 and 2 was then studied in mice harboring a chronic S. mansoni infection. A single dose of 1 and 2 (400 mg/kg) resulted in low worm burden reductions of 24% and 29% (p > 0.05)

A unified ML framework for solubility prediction across organic solvents

We report a single machine learning (ML)-based model to predict the solubility of drug/drug-like compounds across 49 organic solvents, extensible to more. By adopting a cross-solvent data structure, we enable the exploitation of valuable relational information between systems. The effect is major, with even a single experimental measurement of a solute in a different solvent being enough to significantly improve predictions on it, and successive ones improving them further. Working with a sparse dataset of only 714 experimental data points spanning 75 solutes and 49 solvents (81% sparsity), a ML-based model with a prediction RMSE of 0.75 log S (g/100 g) for unseen solutes was produced. This compares favourably with conductor-like screening model for real solvents (COSMO-RS), an industry-standard model based on thermodynamic laws, which yielded a prediction RMSE of 0.97 for the same dataset. The error for our method reduced to a mean RMSE of 0.65 when one instance of the solute (in a different solvent) was included in the training data; this iteratively reduced further to 0.60, 0.57 and 0.56 when two, three and four instances were available, respectively. This standard of performance not only meets or exceeds those of alternative ML-based solubility models insofar as they can be compared but reaches the perceived ceiling for solubility prediction models of this type. In parallel, we assess the performance of the model with and without the addition of COSMO-RS output as an additional descriptor. We find that a significant benefit is gained from its addition, indicating that mechanistic methods can bring insight that simple molecular descriptors cannot and should be incorporated into a data-driven prediction of molecular properties where possible

Children of Prisoners: Their Situation and Role in Long-Term Crime Prevention

Studies suggest that maintaining family ties can help reduce the likelihood of reoffending, and that while parental imprisonment can increase a child’s likelihood to offend, positive responses to the situation can aid the children’s well-being, attitude and attainment. Drawing on findings from the recently completed EU-funded COPING Project on the mental health of children of prisoners, this chapter explores the factors that aid a child’s ability to cope with parental imprisonment and the actions that different stakeholders can take to support them. It identifies some of the mental health impacts at different stages of parental imprisonment, the roles played by non-imprisoned parents/carers and by schools, and suggests options for further clarifying the factors that help and hinder children of prisoners in the short and long term