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1. Histone deacetylase inhibitors containing chiral heterocyclic capping groups

Author

Matthews, C. J. and Marson, C.

Subjects
540
Abstract

Histone deacetylase (HDAC) enzymes are one of the best characterised epigenetic targets; aberrant activity of one or more of the 11 zinc-dependent HDAC isoforms has been associated with many different cancers, as well as several other diseases. Some HDAC inhibitors have been proven to be efficacious in treating cancer; three are FDA approved for treating cutaneous T-cell lymphoma or multiple myeloma. Animal models of other diseases have shown that HDAC inhibitors have potential as therapeutic agents. However the clinical use of HDAC inhibitors is currently limited by toxicity and side effects, amongst other problems, possibly arising because the inhibitors are not isoform selective. This thesis focuses on attempts to synthesise novel HDAC inhibitors with increased isoform selectivity. A series of mocetinostat analogues substituted at the 4-poisition of the terminal 2-aminophenyl ring, was synthesised and tested for inhibition of HDAC isoforms, but no improvement over mocetinostat was found. Subsequently multiple series of compounds containing a chiral heterocycle, in place of the pyrimidine ring in mocetinostat, were prepared and evaluated against a selection of HDAC isoforms. The development of highly convergent methodology enabled the rapid synthesis of these chiral mocetinostat analogues. Several compounds were discovered that are more potent and selective inhibitors than mocetinostat against HDAC3. Those compounds containing a 2-amino-linked dihydrooxazole ring were the most potent, and in all cases the amino-linked heterocycle outperformed its thioetherlinked analogue. Mocetinostat and a novel chiral analogue were shown to be slow, tightbinding inhibitors of HDAC2 and HDAC3. Attempts were made to discover a novel zinc-binding group; a selection of potential bi-dentate zinc-chelating fragments was assayed and 8-hydroxyquinoline emerged as a promising candidate for HDAC8 inhibition. Accordingly some substituted 8-hydroxyquinolines were prepared in order to conduct a brief SAR study of the novel zinc-binding group, however no improvement on the unsubstituted 8-hydroxyquinoline was found.

Published
2016

2. The Decay of Pure Quantum Turbulence in Superfluid 3He-B

Author

Bradley, D. I., Clubb, D. O., Fisher, S. N., Guénault, A. M., Haley, R. P., Matthews, C. J., Pickett, G. R., Tsepelin, V., and Zaki, K.

Subjects
Condensed Matter - Other Condensed Matter
Abstract

We describe measurements of the decay of pure superfluid turbulence in superfluid 3He-B, in the low temperature regime where the normal fluid density is negligible. We follow the decay of the turbulence generated by a vibrating grid as detected by vibrating wire resonators. Despite the absence of any classical normal fluid dissipation processes, the decay is consistent with turbulence having the classical Kolmogorov energy spectrum and is remarkably similar to that measured in superfluid 4He at relatively high temperatures. Further, our results strongly suggest that the decay is governed by the superfluid circulation quantum rather than kinematic viscosity., Comment: 4 pages, 2 figures

Published
2007

4. Abundance estimate of the Hudson Bay-Davis Strait walrus (Odobenus rosmarus rosmarus) stock from aerial surveys flown in September 2017.

Author

Mosnier, A., Matthews, C. J. D., and Hammill, M. O.

Subjects
*WALRUS, *AERIAL surveys, *AERIAL photogrammetry, *STRAITS
Abstract

From September 1st to 17th, 2017, three planes conducted an aerial photographic survey to estimate the abundance of walrus from the Hudson Bay-Davis Strait stock (HBDS). Most of the distribution range of this stock was covered, including the eastern, southern and southwestern coasts of Baffin Island, Hudson Strait, Southampton Island and the northwestern coast of Hudson Bay. A total of 13,375 walrus were counted within the HBDS distribution area, including 1,179 individuals along the east coast of Baffin Island and 12,196 in Hudson Strait and northern Hudson Bay. Correcting raw counts using the mean proportion of hauled out animals obtained from the literature (P = 0.3) resulted in an abundance estimate of 44,582 animals (95% CI = 19,485-102,004). This abundance estimate is considerably larger than the estimate of the last survey conducted in 2014 (i.e., 7,100 animals [95% CI = 2,500-20,400]). However, the 2014 survey coverage did not include the HBDS range along the east coast of Baffin Island and part of northwestern Hudson Bay overflown in 2017. Considering only the area in common between the two surveys still results in a large difference, with 11,554 walruses detected in 2017 and a population estimate of 38,514 (95% CI = 15,091-98,290) individuals. Walrus haulout behaviour and possible exchange from other stocks/regions (e.g., Foxe Basin) are among the hypotheses proposed to explain this difference. [ABSTRACT FROM AUTHOR]

Published
2023

5. How many walrus are there in the Hudson Bay-Davis Strait stock?

Author

Hammill, M. O., Mosnier, A., and Matthews, C. J. D.

Subjects
WALRUS, STRAITS, AERIAL surveys, LIVESTOCK, TIME series analysis
Abstract

A Bayesian surplus production model was fitted to aerial survey estimates of abundance (n = 10) and reported harvests of walruses from the Hudson Bay-Davis Strait (HBDS) stock from 1954-2017. Model fit was poor, owing to the high abundance estimate resulting from the most recent survey conducted in 2017. Modelling exercises to explore possible reasons for the high estimate in 2017 included higher than assumed proportion of animals hauled out during the survey, as well as an influx of animals moving into Hudson Bay and Hudson Strait from neighbouring regions. Model fit improved when the possibility of mixing of animals between the HBDS and Foxe Basin management stocks was considered, and when the assumed proportion of animals hauled out was increased from 0.3 to 0.8. The survey abundance estimate from 2017 likely reflected one or a combination of these factors. The model-derived abundance estimate for the northern Hudson Bay-Strait component of the stock was 8,200 (95% CI = 5,800-19,700). Adding this to the survey-estimated abundance for walruses along the east coast of Baffin Island (3,900; 95% CI = 2,200-7,200), for which a sufficient time series of abundance estimates for population modelling was unavailable, provided a total HBDS stock abundance estimate of 12,200 (95% CI = 7,000-20,800) in 2017. The estimated potential biological removal (PBR) using this estimate and a recovery factor of 1 was 360 animals. The total annual removal through hunting, after adjusting reported catches for struck-and-loss and non-reporting, is estimated at 137 animals for the HBDS stock. [ABSTRACT FROM AUTHOR]

Published
2023

14. Management Approaches, Abundance Indices and Total Allowable Harvest levels of Belugas in Hudson Bay.

Author

Hammill, M. O., Mosnier, A., Gosselin, J.-F., Matthews, C. J. D., Marcoux, M., and Ferguson, S. H.

Subjects
WHITE whale, WHITE whale hunting, TOTAL allowable catch, MAXIMUM sustainable yield (Population ecology), WHALE population estimates, FISHERY management
Abstract

Copyright of Canadian Science Advisory Secretariat Research Document is the property of Her Majesty the Queen in Right of Canada as represented by the Minister of Fisheries & Oceans and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2017

15. Vortex rings in superfluid He-3-B at low temperatures.

Author

Bradley, D. Ian, Fisher, Shaun N., Guénault, A.M., Haley, Richard P., Matthews, C. J., Pickett, George R., Roberts, John Edward, O'Sullivan, Samantha, Tsepelin, Viktor, Bradley, D. Ian, Fisher, Shaun N., Guénault, A.M., Haley, Richard P., Matthews, C. J., Pickett, George R., Roberts, John Edward, O'Sullivan, Samantha, and Tsepelin, Viktor

Abstract

Turbulence in classical fluids has far-reaching technological implications but is poorly understood. A better understanding might be gained from studying turbulence in quantum systems. In a pure superfluid (at low temperatures), there is no viscosity and vortex lines are quantised. Quantum turbulence consists of a tangle of quantised vortex lines which interact via their self-induced flow. We have recently developed techniques for detecting vortices in superfluid He-3-B in the low temperature limit. We find that the transition to turbulence from a moving grid occurs by the entanglement of emitted vortex rings. Here, we discuss the propagation of the ballistic vortex rings emitted at low grid velocities. We have measured the temperature at which the rings decay before reaching the detectors. Our results, at two different pressures, confirm that the vortex rings decay in accordance with mutual friction.

Published
2007

16. Decay of quantum turbulence generated by a vibrating grid at low temperatures in superfluid He-3-B.

Author

Bradley, D. Ian, Fisher, Shaun N., Guénault, A.M., Haley, Richard P., Matthews, C. J., Pickett, George R., Tsepelin, Viktor, Zaki, K., Bradley, D. Ian, Fisher, Shaun N., Guénault, A.M., Haley, Richard P., Matthews, C. J., Pickett, George R., Tsepelin, Viktor, and Zaki, K.

Abstract

We describe measurements of the decay of quantum turbulence produced by a vibrating grid in superfluid He-3-B at low temperatures. Two nearby NbTi vibrating wire resonators at different distances from the grid are used to detect the turbulence via a reduction in the quasiparticle damping owing to Andreev reflection by the flow around the vortex lines. The decay time constant of this turbulence, after stopping the grid motion, is longer at the wire furthest from the grid. This suggests that either the tangle evolves and moves away from the grid once the grid motion has been stopped, or that there is a faster decay mechanism in operation close to the grid.

Published
2006

17. Decay of pure quantum turbulence in superfluid He-3-B.

Author

Bradley, D. Ian, Clubb, D. O., Fisher, Shaun N., Guénault, A.M., Haley, Richard P., Matthews, C. J., Pickett, George R., Tsepelin, Viktor, Zaki, K., Bradley, D. Ian, Clubb, D. O., Fisher, Shaun N., Guénault, A.M., Haley, Richard P., Matthews, C. J., Pickett, George R., Tsepelin, Viktor, and Zaki, K.

Abstract

We describe measurements of the decay of pure superfluid turbulence in superfluid He-3-B, in the low temperature regime where the normal fluid density is negligible. We follow the decay of the turbulence generated by a vibrating grid as detected by vibrating wire resonators. Despite the absence of any classical normal fluid dissipation processes, the decay is consistent with turbulence having the classical Kolmogorov energy spectrum and is remarkably similar to that measured in superfluid He-4 at relatively high temperatures. Further, our results strongly suggest that the decay is governed by the superfluid circulation quantum rather than kinematic viscosity.

Published
2006

18. The generation of quantum turbulence in He-3-B by a vibrating grid at low temperatures.

Author

Bradley, D. Ian, Fisher, Shaun N., Guénault, A.M., Haley, Richard P., Matthews, C. J., Pickett, George R., Tsepelin, Viktor, Zaki, K., Bradley, D. Ian, Fisher, Shaun N., Guénault, A.M., Haley, Richard P., Matthews, C. J., Pickett, George R., Tsepelin, Viktor, and Zaki, K.

Abstract

We have measured the onset of quantum turbulence generated by a vibrating grid resonator in He-3-B. Our measurements were carried out in the low temperature regime where the normal fluid component is very dilute and can be described as a gas of ballistic quasiparticles. Consequently, the normal fluid component can not participate in turbulence generation. We have measured the onset of turbulence from the grid motion using two nearby vibrating wire resonators. The vibrating wires show a reduction in thermal quasiparticle damping due to Andreev reflection in the surrounding turbulent velocity field. Our measurements reveal a transition in the transient behavior of the onset of the vorticity signal at the vibrating wire resonators as a function of the grid velocity.

Published
2006

19. Coherent spin precession in superfluid He-3-B excited in a field minimum at low temperatures.

Author

Fisher, Shaun N., Guénault, A.M., Matthews, C. J., Skyba, P., Pickett, George R., Zaki, K. L., Fisher, Shaun N., Guénault, A.M., Matthews, C. J., Skyba, P., Pickett, George R., and Zaki, K. L.

Abstract

The persistent precessing domain (PPD) is an isolated region of coherent spin precession which is observed in the B phase of superfluid He-3 at the lowest achievable temperatures. It has many unusual properties and its free decay can exceed 1000 s at the lowest temperatures. Previous observations of the PPD were highly irreproducible but we now find the PPD to be very reproducible when there is a field minimum along the cell axis. Here we discuss measurements of the PPD as we control the magnetic field profile, allowing the depth of the minimum to be adjusted.

Published
2005

20. The thermal damping of an aerogel resonator in superfluid He-3-B at ultra low temperatures.

Author

Bradley, D. Ian, Fisher, Shaun N., Guénault, A.M., Matthews, C. J., Skyba, P., Pickett, George R., Zaki, K. L., Bradley, D. Ian, Fisher, Shaun N., Guénault, A.M., Matthews, C. J., Skyba, P., Pickett, George R., and Zaki, K. L.

Abstract

We present measurements of the thermal damping of a cylindrical aerogel sample oscillating in superfluid He-3-B in the low temperature regime. The measurements are made at low pressures where the He-3 confined in the aerogel is normal. As in the case of conventional vibrating Wire resonators, the thermal damping arises from quasiparticle collisions at the wire surface and is enhanced by many orders of magnitude by Andreev scattering from the superfluid backflow around the resonator. However, in the case of aerogel, incoming quasiparticles must be absorbed and thermalised within the aerogel before being re-emitted.

Published
2005

21. Turbulence generated by vibrating wire resonators in superfluid He-4 at low temperatures.

Author

Bradley, D. Ian, Clubb, D. O., Fisher, Shaun N., Guénault, A.M., Haley, Richard P., Matthews, C. J., Pickett, George R., Zaki, K. L., Bradley, D. Ian, Clubb, D. O., Fisher, Shaun N., Guénault, A.M., Haley, Richard P., Matthews, C. J., Pickett, George R., and Zaki, K. L.

Abstract

We have measured responses of vibrating wire resonators in superfluid He-4 at millikelvin temperatures. We find evidence for turbulence generation above a critical velocity on the order of a few cm/s. At the critical velocity for the onset of turbulence, the resonator velocity abruptly decreases and shows hysteretic behavior. Surprisingly we find that the resonant frequencies of the resonators increase in the turbulent regime. We also find that the critical velocity may be reduced by the presence of turbulence generated by a neighboring vibrating wire resonator, allowing the detection of existing turbulence in the low temperature regime.

Published
2005

22. Emission of discrete vortex rings by a vibrating grid in superfluid He-3-B : a precursor to quantum turbulence.

Author

Bradley, D. Ian, Clubb, D. O., Fisher, Shaun N., Guénault, A.M., Haley, Richard P., Matthews, C. J., Pickett, George R., Tsepelin, Viktor, Zaki, K., Bradley, D. Ian, Clubb, D. O., Fisher, Shaun N., Guénault, A.M., Haley, Richard P., Matthews, C. J., Pickett, George R., Tsepelin, Viktor, and Zaki, K.

Abstract

We report a transition in the vorticity generated by a grid moving in the B phase of superfluid He-3 at T < T-c. The evolution of the vorticity after arresting the grid shows a dramatic change in the decay rate at a critical grid velocity. We believe this to reflect a sharp transition from ballistic vortex-ring production at low grid velocities to quantum turbulence at higher velocities and that independent isolated vortex rings provide the precursors to the developed turbulence. Furthermore we believe that this may be a feature of all quantum turbulence arising from repetitive mechanical agitation.

Published
2005

23. Spatial manipulation of the persistent precessing spin domain in superfluid He-3-B.

Author

Bradley, D. Ian, Clubb, D. O., Fisher, Shaun N., Guénault, A.M., Matthews, C. J., Pickett, George R., Skyba, P., Bradley, D. Ian, Clubb, D. O., Fisher, Shaun N., Guénault, A.M., Matthews, C. J., Pickett, George R., and Skyba, P.

Abstract

Using pulsed NMR we have been studying the properties of the persistent precessing domain (PPD) in superfluid He-3-B at ultralow temperatures. These precessing spin domains are very long-lived, persisting for periods of over half an hour under favourable conditions. In the current experiment, by using two NMR coils, we are able to monitor the spatial location of the domain. The PPD is trapped in a field minimum along the axis of the cell, the position of which we can manipulate by variation of the field gradient. We find that the signal lifetime becomes much shorter and independent of temperature when the region of precession is brought into close proximity to the closed end of the experimental cell, suggesting that an extra temperature-independent dissipation mechanism comes into play in the vicinity of the cell walls.

Published
2004

24. Vortex generation in superfluid He-3 by a vibrating grid.

Author

Bradley, D. Ian, Clubb, D. O., Fisher, Shaun N., Guénault, A.M., Matthews, C. J., Pickett, George R., Bradley, D. Ian, Clubb, D. O., Fisher, Shaun N., Guénault, A.M., Matthews, C. J., and Pickett, George R.

Abstract

Recently we have found that a vibrating wire resonator produces turbulence in superfluid He-3-B at low temperatures when driven above its pair-breaking critical velocity. The vorticity is produced along with a beam of excitations from pair breaking. Here, we discuss preliminary measurements of turbulence generated from an oscillating grid at low temperatures. The grid oscillator is made from a goal-post shaped vibrating wire resonator supporting a fine copper mesh. While the dissipation by a conventional wire resonator is dominated by pair-breaking at the velocities required for turbulence generation, the dissipation of the grid oscillator appears to be dominated by turbulence. This allows us to generate turbulence without the unwanted effects of a quasiparticle beam. Preliminary measurements suggest that the grid turbulence has a rather different behaviour from that generated by conventional wire resonators.

Published
2004

29. Decay of Pure Quantum Turbulence in SuperfluidHe3−B

Author

Bradley, D. I., primary, Clubb, D. O., additional, Fisher, S. N., additional, Guénault, A. M., additional, Haley, R. P., additional, Matthews, C. J., additional, Pickett, G. R., additional, Tsepelin, V., additional, and Zaki, K., additional

Published
2006
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40. Oestrogen and progesterone do not regulate the expression of retinoic acid receptors and retinoid 'X' receptors in human endometrial stromal cells in vitro.

Author

Kumarendran, M.Kumar, Matthews, C.Jane, Levasseur, Mark D., Prentice, Andrew, Thomas, Eric J., Redfern, Christopher P.F., Kumarendran, M K, Matthews, C J, Levasseur, M D, Prentice, A, Thomas, E J, and Redfern, C P

Abstract

Elucidation of the gene structure for retinoic acid receptor-β (RAR-β) has suggested a potential role for oestrogen in regulating the expression of RAR-β. We have previously shown that all three RAR types are expressed in human endometrial stromal cells in vitro and that RAR-β expression is induced in response to retinoic acid. The aim of this study was to ask whether oestradiol and progesterone could play a part in regulating the expression of RARs in human endometrial stromal cells and to establish the patterns of expression of a related group of nuclear retinoid receptors, retinoid ‘X’ receptors (RXRs) and their potential for regulation by steroid hormones. The RAR expression patterns of endometrial stromal cells, grown in steroid-free medium, did not change in response to the presence of steroid hormones. Furthermore, the retinoic acid-mediated induction of RAR-β was not affected by oestradiol or progesterone, and was dependent on the continued presence of retinoic acid. Of the three RXR types, only RXR-α was detectably expressed in stromal cells in vitro and the expression of RXR-α did not change in response to steroid hormones or retinoic acid. These data indicate that oestradiol and progesterone are not important in the regulation of RAR and RXR expression in human endometrial stromal cells. [ABSTRACT FROM PUBLISHER]

Published
1994

41. Ion transport by human endometrial epithelia in vitro.

Author

Matthews, C J, Thomas, E J, Redfern, C P, and Hirst, B H

Abstract

Human glandular endometrial epithelial cells were cultured on porous tissue culture inserts to form tight, confluent layers. These layers generated time-dependent modifications in the ionic composition of both apical and basolateral solutions. Increases in sodium and chloride concentrations in the basolateral fluid were accompanied by reciprocal decreases in the concentrations of these ions in the apical fluid. The potassium concentration was increased in the apical, while decreased in the basolateral, solution. The total calcium concentration was slightly elevated in the apical, as compared with the basolateral fluid, while there were no alterations in pH. The endometrial layers demonstrated a significant transepithelial potential difference, and when this value was substituted in the Nernst equation a prediction of the passive distribution of ions across the cells was possible, indicating that none of the ions were in equilibrium. Addition of the sodium channel blocker amiloride to the medium bathing the cell layers reduced the modifications in ionic composition of apical and basolateral solutions. The data are consistent with other data indicating an amiloride-sensitive sodium-absorptive function for the endometrial epithelium. The ability of these primary cultures of endometrial epithelial cells to reduce the sodium while increasing the potassium concentration of the apical fluid is qualitatively in agreement with the low sodium and high potassium concentrations reported for human uterine fluid. The data suggest a role for the endometrial epithelium in generating and maintaining the distinctive ionic composition of the intra-uterine environment. [ABSTRACT FROM AUTHOR]

Published
1993

42. The expression of retinoic acid receptors in cultured human endometrial stromal cells and effects of retinoic acid.

Author

Prentice, A, Matthews, C J, Thomas, E J, and Redfern, C P

Abstract

Patterns of expression of retinoic acid receptors (RAR) in cultures of human endometrial stromal cells are described. Transcripts for all three classes of RAR were expressed in these cells but RAR-beta was expressed at a low level by comparison with RAR-alpha and RAR-gamma. The abundance of RAR-beta transcripts was elevated by treating the cells with retinoic acid, but there was no effect on the level of expression of RAR-alpha and RAR-gamma. The induction of RAR-beta by retinoic acid was detectable within 4 h and at low concentrations of retinoic acid (10(-10) M). Adenosine 3':5'-cyclic monophosphate (cAMP) analogues and forskolin, an adenylate cyclase activator, had no effect on the retinoic acid-mediated induction of RAR-beta, contrary to recent observations on embryonal carcinoma cells. However, the phosphodiesterase inhibitor, 3-isobutyl-1-methyl-xanthine (IBMX), forskolin and 8-bromo-cAMP depressed basal levels of RAR-beta expression. These data suggest that endometrial stromal cells may be a target tissue of retinoic acid in vivo, and imply a role for retinoic acid in the cyclical differentiation of human endometrium. [ABSTRACT FROM AUTHOR]

Published
1992

43. Handling the water content discontinuity at the interface between layered soils within a numerical scheme

Author

Matthews, C. J., Cook, F. J., Knight, J. H., and Braddock, R. D.

Abstract

In general, the water content (?) form of Richards' equation is not used when modeling water flow through layered soil since ? is discontinuous across soil layers. Within the literature, there have been some examples of models developed for layered soils using the ?-form of Richards' equation. However, these models usually rely on an approximation of the discontinuity at the soil layer interface. For the first time, we will develop an iterative scheme based on Newton's method, to explicitly solve for ? at the interface between 2 soils within a numerical scheme. The numerical scheme used here is the Method of Lines (MoL); however, the principles of the iterative solution could be used in other numerical techniques. It will be shown that the iterative scheme is highly effective, converging within 1 to 2 iterations. To ensure the convergence behaviour holds, the numerical scheme will be tested on a fine-over-coarse and a coarse-over-fine soil with highly contrasting soil properties. For each case, the contrast between the soil types will be controlled artificially to extend and decrease the extent of the ? discontinuity. In addition, the numerical solution will be compared against a steady-state analytical solution and a numerical solution from the literature.

Published
2005
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