Drug-like analogues of the parasitic worm-derived immunomodulator ES-62 are therapeutic in the MRL/Lpr model of systemic lupus erythematosus

Introduction ES-62, a phosphorylcholine (PC)-containing immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, protects against nephritis in the MRL/Lpr mouse model of systemic lupus erythematosus (SLE). However, ES-62 is not suitable for development as a therapy and thus we have designed drug-like small molecule analogues (SMAs) based around its active PC-moiety. To provide proof of concept that ES-62-based SMAs exhibit therapeutic potential in SLE, we have investigated the capacity of two SMAs to protect against nephritis when administered to MRL/Lpr mice after onset of kidney damage. Methods SMAs 11a and 12b were evaluated for their ability to suppress antinuclear antibody (ANA) generation and consequent kidney pathology in MRL/Lpr mice when administered after the onset of proteinuria. Results SMAs 11a and 12b suppressed development of ANA and proteinuria. Protection reflected downregulation of MyD88 expression by kidney cells and this was associated with reduced production of IL-6, a cytokine that exhibits promise as a therapeutic target for this condition. Conclusions SMAs 11a and 12b provide proof of principle that synthetic compounds based on the safe immunomodulatory mechanisms of parasitic worms can exhibit therapeutic potential as a novel class of drugs for SLE, a disease for which current therapies remain inadequate

Forces involved with the extraction of casings used in rotary bored piling

Temporary casings are regularly used in the construction of rotary bored piles, to support the pile bore in potentially unstable soils and also to prevent water ingress from loose or water logged soils. The preferred method of removal of casing is by pulling with a crawler crane. However, the magnitude of force generated, particularly during the initial stage of casing extraction, is unknown. This paper describes a series of 50g centrifuge tests designed to model the casing and surrounding soil during extraction by crane. In each test different sized model casings were installed at various embedment depths into a layer of clay overlain by a well-graded sand to provide an array of data. The depth of granular overburden was varied from 60 mm to 120 mm to allow for assessment of the influence of this material on the extraction force whilst the casing sizes modelled 900 mm and 1800 mm prototypes

The unrestricted Skyrme-tensor time-dependent Hartree-Fock and its application to the nuclear response from spherical to triaxial nuclei

The nuclear time-dependent Hartree-Fock model formulated in the three-dimensional space,based on the full Skyrme energy density functional and complemented with the tensor force,is presented for the first time. Full self-consistency is achieved by the model. The application to the isovector giant dipole resonance is discussed in the linear limit, ranging from spherical nuclei (16O, 120Sn) to systems displaying axial or triaxial deformation (24Mg, 28Si, 178Os, 190W, 238U). Particular attention is paid to the spin-dependent terms from the central sector of the functional, recently included together with the tensor. They turn out to be capable of producing a qualitative change on the strength distribution in this channel. The effect on the deformation properties is also discussed. The quantitative effects on the linear response are small and, overall, the giant dipole energy remains unaffected. Calculations are compared to predictions from the (quasi)-particle random phase approximation and experimental data where available, finding good agreement

A detailed binding free energy study of 2 : 1 ligand–DNA complex formation by experiment and simulation

In 2004, we used NMR to solve the structure of the minor groove binder thiazotropsin A bound in a 2 : 1 complex to the DNA duplex, d(CGACTAGTCG)2. In this current work, we have combined theory and experiment to confirm the binding thermodynamics of this system. Molecular dynamics simulations that use polarizable or non-polarizable force fields with single and separate trajectory approaches have been used to explore complexation at the molecular level. We have shown that the binding process invokes large conformational changes in both the receptor and ligand, which is reflected by large adaptation energies. This is compensated for by the net binding free energy, which is enthalpy driven and entropically opposed. Such a conformational change upon binding directly impacts on how the process must be simulated in order to yield accurate results. Our MM-PBSA binding calculations from snapshots obtained from MD simulations of the polarizable force field using separate trajectories yield an absolute binding free energy (-15.4 kcal mol-1) very close to that determined by isothermal titration calorimetry (-10.2 kcal mol-1). Analysis of the major energy components reveals that favorable non-bonded van der Waals and electrostatic interactions contribute predominantly to the enthalpy term, whilst the unfavorable entropy appears to be driven by stabilization of the complex and the associated loss of conformational freedom. Our results have led to a deeper understanding of the nature of side-by-side minor groove ligand binding, which has significant implications for structure-based ligand development

Resonant transmission of microwaves through a finite length subwavelength metallic slit

Copyright © 2005 IOP Publishing Ltd and Deutsche Physikalische Gesellschaft. This is the published version of an article published in New Journal of Physics Vol. 7, article 250. DOI:10.1088/1367-2630/7/1/250The resonant transmission of microwaves polarized perpendicular to a single subwavelength slit of finite length is presented in detail. It is shown that the resonant frequency rises monotonically as slit length is reduced. Increasing confinement of the resonant fields within the slit is shown to cause the frequency rise. Angle dependence of the transmission is also presented. The results show clearly Fabry-Perot-like standing waves in the direction of propagation with waveguide mode behaviour in the orthogonal direction

Engaging stakeholders in research to address water-energy-food (WEF) nexus challenges

The water–energy–food (WEF) nexus has become a popular, and potentially powerful, frame through which to analyse interactions and interdependencies between these three systems. Though the case for transdisciplinary research in this space has been made, the extent of stakeholder engagement in research remains limited with stakeholders most commonly incorporated in research as end-users. Yet, stakeholders interact with nexus issues in a variety of ways, consequently there is much that collaboration might offer to develop nexus research and enhance its application. This paper outlines four aspects of nexus research and considers the value and potential challenges for transdisciplinary research in each. We focus on assessing and visualising nexus systems; understanding governance and capacity building; the importance of scale; and the implications of future change. The paper then proceeds to describe a novel mixed-method study that deeply integrates stakeholder knowledge with insights from multiple disciplines. We argue that mixed-method research designs—in this case orientated around a number of cases studies—are best suited to understanding and addressing real-world nexus challenges, with their inevitable complex, non-linear system characteristics. Moreover, integrating multiple forms of knowledge in the manner described in this paper enables research to assess the potential for, and processes of, scaling-up innovations in the nexus space, to contribute insights to policy and decision making

Behavioural interventions for primary and secondary dysmenorrhoea

Background: Dysmenorrhoea refers to the occurrence of painful menstrual cramps of uterine origin and is a common gynaecological condition with considerable morbidity. The behavioural approach assumes that psychological and environmental factors interact with, and influence, physiological processes. Behavioural interventions for dysmenorrhoea may include both physical and cognitive procedures and focus on both physical and psychological coping strategies for dysmenorrhoeic symptoms rather than modification of any underlying organic pathology. Objectives: To determine the effectiveness of any behavioural interventions for the treatment of primary or secondary dysmenorrhoea when compared to each other, placebo, no treatment, or conventional medical treatments for example non-steroidal anti-inflammatory drugs (NSAIDs). Search strategy: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched April 2005), Cochrane Central Register of Controlled Trials (CENTRAL on The Cochrane Library, Issue 2, 2005), MEDLINE (1966 to April 2005), EMBASE (1980 to April 2005), Social Sciences Index (1980 to April 2005), PsycINFO (1972 to April 2005) and CINAHL (1982 to April 2005) and reference lists of articles. Selection criteria: Randomised controlled trials comparing behavioural interventions with placebo or other interventions in women with dysmenorrhoea. Data collection and analysis: Two authors independently assessed trial quality and extracted data. Main results: Five trials involving 213 women were included. Behavioural intervention vs control: One trial of pain management training reported reduction in pain and symptoms compared to a control. Three trials of relaxation compared to control reported varied results, two trials showed no difference in symptom severity scores however one trial reported relaxation was effective for reducing symptoms in menstrual sufferers with spasmodic symptoms. Two trials reported less restriction in daily activities following treatment with either relaxation of pain management training compared to a control. One trial also reported less time absent from school following treatment wit pain management training compared to a control. Behavioural intervention vs other behavioural interventions: Three trials showed no difference between behavioural interventions for the outcome of improvement in symptoms. One trial showed that relaxation resulted in a decrease in the need for resting time compared to the relaxation and imagery. Authors' conclusions: There is some evidence from five RCTs that behavioural interventions may be effective for dysmenorrhoea however results should be viewed with caution as they varied greatly between trials due to inconsistency in the reporting of data, small trial size, poormethodological quality and age of the trials

Unintended consequences: Unknowable and unavoidable, or knowable and unforgivable?

This is the final version. Available on open access from Frontiers Media via the DOI in this recordRecognizing that there are multiple environmental limits within which humanity can safely operate, it is essential that potential negative outcomes of seemingly positive actions are accounted for. This alertness to unintended consequences underscores the importance of so called ‘nexus’ research, which recognizes the integrated and interactive nature of water, energy and food systems, and aims to understand the broader implications of developments in any one of these systems. This article presents a novel framework for categorizing such detrimental unintended consequences, based upon how much is known about the system in question and the scope for avoiding any such unintended consequences. The framework comprises four categories (Knowable and Avoidable; Knowable and Unavoidable; Unknowable and Avoidable, and Unknowable and Unavoidable). The categories are explored with reference to examples in both the water-energy-food nexus and planetary boundary frameworks. The examples highlight the potential for the unexpected to happen and explore dynamic nature of the situations that give rise to the unexpected. The article concludes with guidance on how the framework can be used to increase confidence that best efforts have been made to navigate our way towards secure and sustainable water, energy and food systems, avoiding and/or managing unintended consequences along the way.Engineering and Physical Sciences Research Council (EPSRC