Conformational Analysis of Cyclic Tetra-Peptides by Global Energy Minimisation Calculations

An algorithm, based on Molecular Mechanics calculations, was developed to locate the Global Minimum Energy Conformation (GMEC) of cyclic molecules. This was used to find the GMEC of cyclotetraglycyl and also those conformations within 20 kcal/mole of this conformation. The resulting conformation is composed of four trans amino acids and has S4 symmetry. The calculated GMEC corresponds to an observed crystal structure of dihydrochlamydocin and to a proposed conformation of cyclotetraglycyI itself. The ring conformations of all observed cyclic tetra -peptides and -depsipeptides were found to correspond, more or less exactly, to some conformation in the calculated low energy set of cyclotetraglycyl. Only one exception was found and this seems to be an intermediate between two calculated conformations. The algorithm has now been further streamlined into a single computer program and is currently being used to locate the GMEC of cycloalkanes (e. g. cycloundecane) in this department and elsewhere. Calculations were also performed on various derivatives of cyclotetraglycyl. Protonation and N-Methylation were found to profoundly alter the relative energies of the various conformations in the low energy set. It was observed that for these derivatives the cis, trans, cis, trans sequence of amino acids is more stable than the all trans sequence. In addition to peptides the conformations of other 12-membered rings were found to correspond to members of the calculated set of conformations. These included 12-crown-4 ethers and cyclododecanes. In order to facilitate all of these operations a Chemical Graphics System (CGS) was developed. This is an extensive suite of computer programs which utilises a PDP11/40 minicomputer with a VR17 graphics terminal. The CCS allows interactive building and manipulation of molecular models and includes various advanced features. Foremost of these is the dynamic rotation facility which allows the user to observe a structure as it rotates about the X, Y or Z axis. Measurement of distances. angles and torsion angles is easy and the constructed structure can be directly used as input to a Molecular Mechanics calculation

Rats that sign-track are resistant to Pavlovian but not instrumental extinction

Individuals vary in the extent to which they attribute incentive salience to a discrete cue (conditioned stimulus; CS) that predicts reward delivery (unconditioned stimulus; US), which results in some individuals approaching and interacting with the CS (sign-trackers; STs) more than others (goal-trackers; GTs). Here we asked how periods of non-reinforcement influence conditioned responding in STs vs. GTs, in both Pavlovian and instrumental tasks. After classifying rats as STs or GTs by pairing a retractable lever (the CS) with the delivery of a food pellet (US), we introduced periods of non-reinforcement, first by simply withholding the US (i.e., extinction training; experiment 1), then by signaling alternating periods of reward (R) and non-reward (NR) within the same session (experiments 2 and 3). We also examined how alternating R and NR periods influenced instrumental responding for food (experiment 4). STs and GTs did not differ in their ability to discriminate between R and NR periods in the instrumental task. However, in Pavlovian settings STs and GTs responded to periods of non-reward very differently. Relative to STs, GTs very rapidly modified their behavior in response to periods of non-reward, showing much faster extinction and better and faster discrimination between R and NR conditions. These results highlight differences between Pavlovian and instrumental extinction learning, and suggest that if a Pavlovian CS is strongly attributed with incentive salience, as in STs, it may continue to bias attention toward it, and to facilitate persistent and relatively inflexible responding, even when it is no longer followed by reward

Exploration of Protein-Protein Interactions Involving Deinococcus radiodurans PriA, DnaB and SSB

Deinococcus radiodurans is a species of bacteria that has sparked a lot of interest since its discovery due to its incredible resistance to ionizing radiation. When exposed to ionizing radiation the genome of D. radiodurans will sustain over one hundred double stranded breaks. D. radiodurans demonstrates the ability to repair its genome and restart replication after sustaining, typically lethal, DNA damage. This project examined the mechanism of replication restart in D. radiodurans by investigating primosome protein PriA interacting with replicative helicase DnaB and single stranded binding protein. Many different types of gel electrophoresis were employed to investigate potential protein complex formations between D. radiodurans PriA and DnaB. Native agarose gel electrophoresis successfully revealed an interaction between D. radiodurans PriA and DnaB. Results in this work indicate that D. radiodurans PriA can interact with DnaB

A systematic review of methods to immobilise breast tissue during adjuvant breast irradiation

Greater use of 3D conformal, Intensity Modulated Radiotherapy (IMRT) and external beam partial breast irradiation following local excision (LE) for breast cancer has necessitated a review of the effectiveness of immobilisation methods to stabilise breast tissue. To identify the suitability of currently available breast (rather than thorax) immobilisation techniques an appraisal of the literature was undertaken. The aim was to identify and evaluate the benefit of additional or novel immobilisation approaches (beyond the standard supine, single arm abducted and angled breast board technique adopted in most radiotherapy departments). A database search was supplemented with an individual search of key radiotherapy peer-reviewed journals, author searching, and searching of the grey literature. A total of 27 articles met the inclusion criteria. The review identified good reproducibility of the thorax using the standard supine arm-pole technique. Reproducibility with the prone technique appears inferior to supine methods (based on data from existing randomised controlled trials). Assessing the effectiveness of additional breast support devices (such as rings or thermoplastic material) is hampered by small sample sizes and a lack of randomised data for comparison. Attention to breast immobilisation is recommended, as well as agreement on how breast stability should be measured using volumetric imaging. Keywords: Breast, immobilisation, positioning, reproducibility, review.</p

Extra-ocular muscle MRI in genetically-defined mitochondrial disease

Conventional and quantitative MRI was performed in patients with chronic progressive external ophthalmoplegia (CPEO), a common manifestation of mitochondrial disease, to characterise MRI findings in the extra-ocular muscles (EOMs) and investigate whether quantitative MRI provides clinically relevant measures of disease

Gas compression systematically delays the onset of viscous fingering

Using gas to drive liquid from a Hele-Shaw cell leads to classical viscous fingering. Strategies for suppressing fingering have received substantial attention. For steady injection of an incompressible gas, the intensity of fingering is controlled by the capillary number Ca. Here, we show that gas compression leads to an unsteady injection rate controlled primarily by a dimensionless compressibility number C. Increasing C systematically delays the onset of fingering at high Ca, highlighting compressibility as an overlooked but fundamental aspect of gas-driven fingering

Compression-driven viscous fingering in a radial Hele-Shaw cell

The displacement of a viscous liquid by a gas within a Hele-Shaw cell is a classical problem. The gas-liquid interface is hydrodynamically unstable, forming striking finger-like patterns that have attracted research interest for decades. Generally, both the gas and liquid phases are taken to be incompressible, with the capillary number being the key parameter that determines the severity of the instability. Here, we consider a radially outward displacement driven by the steady compression of a gas reservoir. The associated gas-injection rate is then unsteady due to the compressibility of the gas. We identify a second nondimensional parameter, the compressibility number, that plays a strong role in the development of the fingering pattern. We use an axisymmetric model to study the impact of compressibility number on the unsteady evolution of injection rate and gas pressure. We use linear stability analysis to show that increasing the compressibility number delays the onset of finger development relative to the corresponding incompressible case. Finally, we present and compare a series of experiments and fully nonlinear simulations over a broad range of capillary and compressibility numbers. These results show that increasing the compressibility number systematically decreases the severity of the fingering pattern at high capillary number. Our results provide an unprecedented comparison of experiments with simulations for viscous fingering, a comprehensive understanding of the role of compressibility in unstable gas-liquid displacement flows, and insight into a new mechanism for controlling the development of fingering patterns

Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen

Speaking England: nationalism(s) in early modern literature and culture

This dissertation explores conceptions of nationalism in early modern English literature and culture. Specifically, it examines multiple definitions of nation in dramatic works by William Shakespeare (Cymbeline), John Fletcher (Bonduca), Thomas Dekker (The Shoemaker's Holiday), and Robert Daborne (A Christian Turned Turk) as well as in antiquarian studies of England by William Camden (Britannia and Remains Concerning Britain) and Richard Verstegan (Restitution of Decayed Intelligence). This dissertation argues that early modern English nationalism is a dynamic phenomenon that extends beyond literary and historical genres typically associated with questions of national identity, such as history plays, legal tracts, and chronicle histories. Nationalism, this dissertation demonstrates, appears in Roman-Britain romances and tragedies, city comedies, and both dramatic and prose accounts of piracy. Nation appears in myriad voices - from ancient British queens to shoemakers and pirates. And the nationalisms they articulate are as varied as the genres in which they appear as nation is negotiated both across and within these works. Furthermore, this dissertation illustrates that not only are concepts of nation and national identity being explored, the very terms on which to construct nation are being defined and re-defined. Nation is variously filtered through a myriad of issues including the influence of the monarch (particularly James I), origin, language, gender, class, ethnicity, religion and national rivals. This dissertation also discusses works which move us beyond our pre-conceived notions about nation by advocating more corporate cosmopolitan models. The models are based on such qualities as membership, occupation, productivity and the pursuit of wealth rather than birth order or location. These corporate and piratical nationalisms extend beyond the confining geopolitical borders of most concepts of nation. Early modern English nationalism is not singularly defined by the monarch, the church, the legal system, or even antiquarian studies of Britain and England. It is not singularly defined by any one voice or text

Fluid-fluid phase separation in a soft porous medium

Various biological and chemical processes lead to the nucleation and growth of non-wetting fluid bubbles within the pore space of a granular medium, such as the formation of gas bubbles in liquid-saturated lake-bed sediments. In sufficiently soft porous materials, the non-wetting nature of these bubbles can result in the formation of open cavities within the granular solid skeleton. Here, we consider this process through the lens of phase separation, where thermomechanics govern the separation of the non-wetting phase from a fluid-fluid-solid mixture. We construct a phase-field model informed by large-deformation poromechanics, in which two immiscible fluids interact with a poroelastic solid skeleton. Our model captures the competing effects of elasticity and fluid-fluid-solid interactions. We use a phase-field damage model to capture the mechanics of the granular solid. As a model problem, we consider an initial distribution of non-wetting fluid in the pore space that separates into multiple cavities. We use simulations and linear-stability analysis to identify the key parameters that control phase separation, the conditions that favour the formation of cavities, and the characteristic size of the resulting cavities