Crystal structures of four indole derivatives as possible cannabinoid allosteric antagonists

Acknowledgements We thank the EPSRC National Crystallography Service (University of Southampton) for the data collections and the EPSRC National Mass Spectrometry Service (University of Swansea) for the HRMS data. We thank John Low for carrying out the Cambridge Database survey.Peer reviewedPublisher PD

The Biological Role of Water in Extreme Conditions

Despite exposure to extreme conditions, extremophilic organisms have developed a range of mechanisms to survive these detrimental perturbations to their solvent environment. In this thesis we study how extremes of pressure and salinity affect the aqueous environment with which extremophiles interact. To do this we employ a combination of neutron scattering with computational modelling to examine the perturbations to water structure, and nuclear magnetic resonance to examine the perturbations to water dynamics. We first examine perturbations to water structure and dynamics by simple monovalent model potassium halide salts and find that we can extract atom scale information which we can link to bulk measurable thermodynamic properties. We then use neutron diffraction to study the organic osmolyte TMAO in solution, which is used by high pressure adapted organisms to protect their biochemistry and find that it can preserve the structure of water against pressure induced perturbations. We then study aqueous magnesium perchlorate, a salt which is found in high concentrations in the Martian regolith, and likely in the surface lakes, and show that it induces a pressure-like effect on water structure. We then show that TMAO can also resist this pressure-like structural perturbation in the same way it can resist pressure induced structural perturbations. Finally, we investigate how magnesium perchlorate hinders biomolecular self-assembly by studying the amino acid glycine and the stability of the model protein I27. These fundamental insights help us to understand how observed adaptations in extremophilic organisms help them survive, with implications in medical and industrial settings

The fast transient sky with Gaia

The ESA Gaia satellite scans the whole sky with a temporal sampling ranging from seconds and hours to months. Each time a source passes within the Gaia field of view, it moves over 10 CCDs in 45 s and a lightcurve with 4.5 s sampling (the crossing time per CCD) is registered. Given that the 4.5 s sampling represents a virtually unexplored parameter space in optical time domain astronomy, this data set potentially provides a unique opportunity to open up the fast transient sky. We present a method to start mining the wealth of information in the per CCD Gaia data. We perform extensive data filtering to eliminate known on-board and data processing artefacts, and present a statistical method to identify sources that show transient brightness variations on ~2 hours timescales. We illustrate that by using the Gaia photometric CCD measurements, we can detect transient brightness variations down to an amplitude of 0.3 mag on timescales ranging from 15 seconds to several hours. We search an area of ~23.5 square degrees on the sky, and find four strong candidate fast transients. Two candidates are tentatively classified as flares on M-dwarf stars, while one is probably a flare on a giant star and one potentially a flare on a solar type star. These classifications are based on archival data and the timescales involved. We argue that the method presented here can be added to the existing Gaia Science Alerts infrastructure for the near real-time public dissemination of fast transient events.Comment: 10 pages, 5 figures and 5 tables; MNRAS in pres

Experimentally verified parameter sets for modelling heterogeneous neocortical pyramidal-cell populations

Models of neocortical networks are increasingly including the diversity of excitatory and inhibitory neuronal classes. Significant variability in cellular properties are also seen within a nominal neuronal class and this heterogeneity can be expected to influence the population response and information processing in networks. Recent studies have examined the population and network effects of variability in a particular neuronal parameter with some plausibly chosen distribution. However, the empirical variability and covariance seen across multiple parameters are rarely included, partly due to the lack of data on parameter correlations in forms convenient for model construction. To addess this we quantify the heterogeneity within and between the neocortical pyramidal-cell classes in layers 2/3, 4, and the slender-tufted and thick-tufted pyramidal cells of layer 5 using a combination of intracellular recordings, single-neuron modelling and statistical analyses. From the response to both square-pulse and naturalistic fluctuating stimuli, we examined the class-dependent variance and covariance of electrophysiological parameters and identify the role of the h current in generating parameter correlations. A byproduct of the dynamic I-V method we employed is the straightforward extraction of reduced neuron models from experiment. Empirically these models took the refractory exponential integrate-and-fire form and provide an accurate fit to the perisomatic voltage responses of the diverse pyramidal-cell populations when the class-dependent statistics of the model parameters were respected. By quantifying the parameter statistics we obtained an algorithm which generates populations of model neurons, for each of the four pyramidal-cell classes, that adhere to experimentally observed marginal distributions and parameter correlations. As well as providing this tool, which we hope will be of use for exploring the effects of heterogeneity in neocortical networks, we also provide the code for the dynamic I-V method and make the full electrophysiological data set available

Trimethylamine N-oxide (TMAO) Resists The Compression of Water Structure by Magnesium Perchlorate : Terrestrial Kosmotrope vs Martian Chaotrope - dataset

The presence of magnesium perchlorate (Mg(ClO4)2) as the dominating ionic compound in the Martian regolith and the recent discovery of a subsurface lake on Mars suggests that beneath the Martian surface may lie an aqueous environment suitable for life, rich in chaotropic ions. Closer to Earth, terrestrial organisms use osmolytes, such as trimethylamine N-oxide (TMAO), to overcome the biologically damaging effects of pressure. While previous studies have revealed that Mg(ClO4)2 acts to modify water structure as if it has been pressurized, little is known about the competing effects of chaotropes and kosmotropes. Therefore the question here is whether TMAO can help to preserve the hydrogen bond network of water against the pressurising effect of Mg(ClO4)2? We address this question using neutron scattering, computational modelling using Empirical Potential Structure Refinement (EPSR) analysis, and a new approach to quantifying hydrogen bond conformations and energies. We find that the addition of 1.0 M TMAO to 0.2 M Mg(ClO4)2 or 2.7 M Mg(ClO4)2 is capable of partially restoring the hydrogen bond network of water, and the fraction of water molecules in conformations associated with hydrogen bond switching. This suggests that terrestrial protecting osmolytes could provide a protective mechanism to the extremes found in Martian environments for biological systems

Crystal structures of four indole derivatives with a phenyl substituent at the 2-position and a carbonyl group at the 3-position : the C(6) N-H⋯O chain remains the same, but the weak reinforcing inter-actions are different

Acknowledgements We thank the EPSRC National Crystallography Service (University of Southampton) for the data collections and the EPSRC National Mass Spectrometry Service (University of Swansea) for the HRMS data.Peer reviewedPublisher PD

Weak interactions in the crystal structures of two indole derivatives

Acknowledgements We thank the EPSRC National Crystallography Service (University of Southampton) for the data collections and the EPSRC National Mass Spectrometry Service (University of Swansea) for the HRMS data.Peer reviewedPublisher PD

Different N—H···π interactions in two indole derivatives

Acknowledgements We thank the EPSRC National Crystallography Service (University of Southampton) for the data collections and the EPSRC National Mass Spectrometry Service (University of Swansea) for the HRMS dataPeer reviewedPublisher PD