Inhibition of cathepsin L-like proteases by cathepsin V propeptide

The N-terminal propeptide domains of several cathepsin L-like cysteine proteases have been shown to possess potent inhibitory activity. Here we report the first kinetic characterisation of the inhibition properties of the cathepsin V propeptide (CatV PP). Using a facile recombinant approach we demonstrate expression, purification and evaluation of the CatV PP. This propeptide was found to behave as a tight-binding inhibitor against CatV (K (i) 10.2 nm). It also functions as an inhibitor against other members of the CatL-like subclass (CatL, 9.8 nm; CatS, 10.7 nm; and CatK, 149 nm) and had no discernible effects upon the more distantly related CatB.

Development of a risk model for adverse drug events in the elderly

The aim of this study was to develop a predictive model for adverse drug events (ADEs) in elderly patients. Socio-demographic and medical data were collected from chart reviews, computerised information and a patient interview, for a population of 929 elderly patients (aged greater than or equal to 65 years) whose admission to the Waveney/B raid Valley Hospital in Northern Ireland was not scheduled. A further 204 patients formed a validation group. An ADE score was assigned to each patient using a modified Naranjo algorithm scoring system. The ADE scores ranged from 0 to 8. For the purposes of developing a risk model, scores of 4 or more were considered to constitute a high risk of an ADE.

Azimuthal asymmetry in collective electron dynamics in relativistically transparent laser-foil interactions

Asymmetry in the collective dynamics of ponderomotively-driven electrons in the interaction of an ultraintense laser pulse with a relativistically transparent target is demonstrated experimentally. The 2D profile of the beam of accelerated electrons is shown to change from an ellipse aligned along the laser polarization direction in the case of limited transparency, to a double-lobe structure aligned perpendicular to it when a significant fraction of the laser pulse co-propagates with the electrons. The temporally-resolved dynamics of the interaction are investigated via particle-in-cell simulations. The results provide new insight into the collective response of charged particles to intense laser fields over an extended interaction volume, which is important for a wide range of applications, and in particular for the development of promising new ultraintense laser-driven ion acceleration mechanisms involving ultrathin target foils.

Laser-engineered dissolving microneedle arrays for protein delivery: potential for enhanced intradermal vaccination

OBJECTIVES: We aimed to highlight the utility of novel dissolving microneedle (MN)-based delivery systems for enhanced transdermal protein delivery. Vaccination remains the most accepted and effective approach in offering protection from infectious diseases. In recent years, much interest has focused on the possibility of using minimally invasive MN technologies to replace conventional hypodermic vaccine injections.

METHODS: The focus of this study was exploitation of dissolving MN array devices fabricated from 20% w/w poly(methyl vinyl ether/maleic acid) using a micromoulding technique, for the facilitated delivery of a model antigen, ovalbumin (OVA).

KEY FINDINGS: A series of in-vitro and in-vivo experiments were designed to demonstrate that MN arrays loaded with OVA penetrated the stratum corneum and delivered their payload systemically. The latter was evidenced by the activation of both humoral and cellular inflammatory responses in mice, indicated by the production of immunoglobulins (IgG, IgG1, IgG2a) and inflammatory cytokines, specifically interferon-gamma and interleukin-4. Importantly, the structural integrity of the OVA following incorporation into the MN arrays was maintained.

CONCLUSION: While enhanced manufacturing strategies are required to improve delivery efficiency and reduce waste, dissolving MN are a promising candidate for 'reduced-risk' vaccination and protein delivery strategies.

Pro-neural transcription factors as cancer markers

BACKGROUND: The aberrant transcription in cancer of genes normally associated with embryonic tissue differentiation at various organ sites may be a hallmark of tumour progression. For example, neuroendocrine differentiation is found more commonly in cancers destined to progress, including prostate and lung. We sought to identify proteins which are involved in neuroendocrine differentiation and differentially expressed in aggressive/metastatic tumours.

RESULTS: Expression arrays were used to identify up-regulated transcripts in a neuroendocrine (NE) transgenic mouse model of prostate cancer. Amongst these were several genes normally expressed in neural tissues, including the pro-neural transcription factors Ascl1 and Hes6. Using quantitative RT-PCR and immuno-histochemistry we showed that these same genes were highly expressed in castrate resistant, metastatic LNCaP cell-lines. Finally we performed a meta-analysis on expression array datasets from human clinical material. The expression of these pro-neural transcripts effectively segregates metastatic from localised prostate cancer and benign tissue as well as sub-clustering a variety of other human cancers.

CONCLUSION: By focussing on transcription factors known to drive normal tissue development and comparing expression signatures for normal and malignant mouse tissues we have identified two transcription factors, Ascl1 and Hes6, which appear effective markers for an aggressive phenotype in all prostate models and tissues examined. We suggest that the aberrant initiation of differentiation programs may confer a selective advantage on cells in all contexts and this approach to identify biomarkers therefore has the potential to uncover proteins equally applicable to pre-clinical and clinical cancer biology.

An address delivered before the South-Carolina institute, at its first annual fair

This document contains an address by James H. Hammond , delivered before the South Carolina Institute, held at Military Hall It mentions the resolutions that were proposed and adopted including an acknowledgements for the very able and eloquent address, appointment of five committee members for communication and to request a copy of the address for publication with James H. Hammond.

De aliado a enemigo : análisis del cambio de posición de la federación rusa y china y sus relaciones con Irán y su programa nuclear, en el seno del consejo de seguridad de la Organización de Naciones Unidas (ONU) en el periodo 2005 – 2010

El programa Nuclear de Irán ha causado polémica en el Sistema Internacional, donde muchos Estados han sido protagonistas. Dentro de estos se encuentran La Federación Rusa y China, los cuales han cambiado de posición a lo largo de los años y teniendo en cuenta sus intereses, con respecto a Irán, en el Consejo de Seguridad de la ONU entre 2005 y 2010

Uses of airborne scanning laser altimetry for river flood modelling and coastal geomorphology

Two ongoing projects at ESSC that involve the development of new techniques for extracting information from airborne LiDAR data and combining this information with environmental models will be discussed. The first project in conjunction with Bristol University is aiming to improve 2-D river flood flow models by using remote sensing to provide distributed data for model calibration and validation. Airborne LiDAR can provide such models with a dense and accurate floodplain topography together with vegetation heights for parameterisation of model friction. The vegetation height data can be used to specify a friction factor at each node of a model’s finite element mesh. A LiDAR range image segmenter has been developed which converts a LiDAR image into separate raster maps of surface topography and vegetation height for use in the model. Satellite and airborne SAR data have been used to measure flood extent remotely in order to validate the modelled flood extent. Methods have also been developed for improving the models by decomposing the model’s finite element mesh to reflect floodplain features such as hedges and trees having different frictional properties to their surroundings. Originally developed for rural floodplains, the segmenter is currently being extended to provide DEMs and friction parameter maps for urban floods, by fusing the LiDAR data with digital map data. The second project is concerned with the extraction of tidal channel networks from LiDAR. These networks are important features of the inter-tidal zone, and play a key role in tidal propagation and in the evolution of salt-marshes and tidal flats. The study of their morphology is currently an active area of research, and a number of theories related to networks have been developed which require validation using dense and extensive observations of network forms and cross-sections. The conventional method of measuring networks is cumbersome and subjective, involving manual digitisation of aerial photographs in conjunction with field measurement of channel depths and widths for selected parts of the network. A semi-automatic technique has been developed to extract networks from LiDAR data of the inter-tidal zone. A multi-level knowledge-based approach has been implemented, whereby low level algorithms first extract channel fragments based mainly on image properties then a high level processing stage improves the network using domain knowledge. The approach adopted at low level uses multi-scale edge detection to detect channel edges, then associates adjacent anti-parallel edges together to form channels. The higher level processing includes a channel repair mechanism.