Transglutaminase inhibition ameliorates experimental diabetic nephropathy

Diabetic nephropathy is characterized by excessive extracellular matrix accumulation resulting in renal scarring and end-stage renal disease. Previous studies have suggested that transglutaminase type 2, by formation of its protein crosslink product epsilon-(gamma-glutamyl)lysine, alters extracellular matrix homeostasis, causing basement membrane thickening and expansion of the mesangium and interstitium. To determine whether transglutaminase inhibition can slow the progression of chronic experimental diabetic nephropathy over an extended treatment period, the inhibitor NTU281 was given to uninephrectomized streptozotocin-induced diabetic rats for up to 8 months. Effective transglutaminase inhibition significantly reversed the increased serum creatinine and albuminuria in the diabetic rats. These improvements were accompanied by a fivefold decrease in glomerulosclerosis and a sixfold reduction in tubulointerstitial scarring. This was associated with reductions in collagen IV accumulation by 4 months, along with reductions in collagens I and III by 8 months. This inhibition also decreased the number of myofibroblasts, suggesting that tissue transglutaminase may play a role in myofibroblast transformation. Our study suggests that transglutaminase inhibition ameliorates the progression of experimental diabetic nephropathy and can be considered for clinical application.

Transglutaminase inhibition reduces fibrosis and preserves function in experimental chronic kidney disease

Progressive tissue fibrosis is involved in debilitating diseases that affect organs including the lungs, liver, heart, skin, and kidneys. Recent evidence suggests that tissue transglutaminase, an enzyme that crosslinks proteins, may be involved in tissue fibrosis by crosslinking and stabilizing the extracellular matrix or by recruiting and activating the large latent transforming growth factor (TGF)-β1 complex. We treated rats that had undergone 5/6-nephrectomy with two different irreversible inhibitors of transglutaminase and found that both prevented a decline in kidney function and reduced the development of glomerulosclerosis and tubulointerstitial fibrosis by up to 77% and 92%, respectively. Treatment reduced the accumulation of collagen I and collagen III, with the primary mechanism of action being direct interference with the crosslinking of extracellular matrix rather than altered regulation of TGFβ1. We conclude that inhibition of transglutaminase offers a potential therapeutic option for chronic kidney disease and other conditions that result from tissue fibrosis. Copyright © 2007 by the American Society of Nephrology.

Managing uncertainty in integrated environmental modelling:the UncertWeb framework

Web-based distributed modelling architectures are gaining increasing recognition as potentially useful tools to build holistic environmental models, combining individual components in complex workflows. However, existing web-based modelling frameworks currently offer no support for managing uncertainty. On the other hand, the rich array of modelling frameworks and simulation tools which support uncertainty propagation in complex and chained models typically lack the benefits of web based solutions such as ready publication, discoverability and easy access. In this article we describe the developments within the UncertWeb project which are designed to provide uncertainty support in the context of the proposed ‘Model Web’. We give an overview of uncertainty in modelling, review uncertainty management in existing modelling frameworks and consider the semantic and interoperability issues raised by integrated modelling. We describe the scope and architecture required to support uncertainty management as developed in UncertWeb. This includes tools which support elicitation, aggregation/disaggregation, visualisation and uncertainty/sensitivity analysis. We conclude by highlighting areas that require further research and development in UncertWeb, such as model calibration and inference within complex environmental models.

UncertWeb processing service:making models easer to access on the web

Models are central tools for modern scientists and decision makers, and there are many existing frameworks to support their creation, execution and composition. Many frameworks are based on proprietary interfaces, and do not lend themselves to the integration of models from diverse disciplines. Web based systems, or systems based on web services, such as Taverna and Kepler, allow composition of models based on standard web service technologies. At the same time the Open Geospatial Consortium has been developing their own service stack, which includes the Web Processing Service, designed to facilitate the executing of geospatial processing - including complex environmental models. The current Open Geospatial Consortium service stack employs Extensible Markup Language as a default data exchange standard, and widely-used encodings such as JavaScript Object Notation can often only be used when incorporated with Extensible Markup Language. Similarly, no successful engagement of the Web Processing Service standard with the well-supported technologies of Simple Object Access Protocol and Web Services Description Language has been seen. In this paper we propose a pure Simple Object Access Protocol/Web Services Description Language processing service which addresses some of the issues with the Web Processing Service specication and brings us closer to achieving a degree of interoperability between geospatial models, and thus realising the vision of a useful 'model web'.

Uncertainty analysis in the Model Web

This thesis provides a set of tools for managing uncertainty in Web-based models and workflows.To support the use of these tools, this thesis firstly provides a framework for exposing models through Web services. An introduction to uncertainty management, Web service interfaces,and workflow standards and technologies is given, with a particular focus on the geospatial domain.An existing specification for exposing geospatial models and processes, theWeb Processing Service (WPS), is critically reviewed. A processing service framework is presented as a solutionto usability issues with the WPS standard. The framework implements support for Simple ObjectAccess Protocol (SOAP), Web Service Description Language (WSDL) and JavaScript Object Notation (JSON), allowing models to be consumed by a variety of tools and software. Strategies for communicating with models from Web service interfaces are discussed, demonstrating the difficultly of exposing existing models on the Web. This thesis then reviews existing mechanisms for uncertainty management, with an emphasis on emulator methods for building efficient statistical surrogate models. A tool is developed to solve accessibility issues with such methods, by providing a Web-based user interface and backend to ease the process of building and integrating emulators. These tools, plus the processing service framework, are applied to a real case study as part of the UncertWeb project. The usability of the framework is proved with the implementation of aWeb-based workflow for predicting future crop yields in the UK, also demonstrating the abilities of the tools for emulator building and integration. Future directions for the development of the tools are discussed.

Reciprocating power generation in a chemically driven synthetic muscle

A scalable synthetic muscle has been constructed that transducts nanoscale molecular shape changes into macroscopic motion. The working material, which deforms affinely in response to a pH stimulus, is a self-assembled block copolymer comprising nanoscopic hydrophobic domains in a weak polyacid matrix. A device has been assembled where the muscle does work on a cantilever and the force generated has been measured. When coupled to a chemical oscillator this provides a free running chemical motor that generates a peak power of 20 mW kg 1 by the serial addition of 10 nm shape changes that scales over 5 orders of magnitude. It is the nanostructured nature of the gel that gives rise to the affine deformation and results in a robust working material for the construction of scalable muscle devices.

Bifurcation study for a vertical channel with constant flux and large aspect ratio

Using suitable coupled Navier-Stokes Equations for an incompressible Newtonian fluid we investigate the linear and non-linear steady state solutions for both a homogeneously and a laterally heated fluid with finite Prandtl Number (Pr=7) in the vertical orientation of the channel. Both models are studied within the Large Aspect Ratio narrow-gap and under constant flux conditions with the channel closed. We use direct numerics to identify the linear stability criterion in parametric terms as a function of Grashof Number (Gr) and streamwise infinitesimal perturbation wavenumber (making use of the generalised Squire’s Theorem). We find higher harmonic solutions at lower wavenumbers with a resonance of 1:3exist, for both of the heating models considered. We proceed to identify 2D secondary steady state solutions, which bifurcate from the laminar state. Our studies show that 2D solutions are found not to exist in certain regions of the pure manifold, where we find that 1:3 resonant mode 2D solutions exist, for low wavenumber perturbations. For the homogeneously heated fluid, we notice a jump phenomenon existing between the pure and resonant mode secondary solutions for very specific wavenumbers .We attempt to verify whether mixed mode solutions are present for this model by considering the laterally heated model with the same geometry. We find mixed mode solutions for the laterally heated model showing that a bridge exists between the pure and 1:3 resonant mode 2D solutions, of which some are stationary and some travelling. Further, we show that for the homogeneously heated fluid that the 2D solutions bifurcate in hopf bifurcations and there exists a manifold where the 2D solutions are stable to Eckhaus criterion, within this manifold we proceed to identify 3D tertiary solutions and find that the stability for said 3D bifurcations is not phase locked to the 2D state. For the homogeneously heated model we identify a closed loop within the neutral stability curve for higher perturbation wavenumubers and analyse the nature of the multiple 2D bifurcations around this loop for identical wavenumber and find that a temperature inversion occurs within this loop. We conclude that for a homogeneously heated fluid it is possible to have abrup ttransitions between the pure and resonant 2D solutions, and that for the laterally heated model there exist a transient bifurcation via mixed mode solutions.

Antagonistic triblock polymer gels powered by pH oscillations

A study was conducted to create a pH-responsive layer, in which a small change in the individual polyacid or polybase gel length was transferred into a larger motion that curls up the gel. It was observed that the transfer of motion from a linear displacement into a curved displacement through the geometric design effectively increases the displacement rate. A robust, reversible, and chemically driven mechanical actuator was was produced that demonstrated its response over many pH oscillations. The affine nature of the triblock copolymers, demonstrated for for the polyacid and polybase indicated that the effect will also function at some smaller length scales, which is appropriate for a working biomimetic and soft nanotechnology device. The study also demonstrated the potential applicability of these polymeric gels and suggested the fabrication of related molecular machines and devices based on the principles of soft nanotechnology.

Integrating OpenMI and Uncertweb:managing uncertainty in OpenMI models

OpenMI is a widely used standard allowing exchange of data between integrated models, which has mostly been applied to dynamic, deterministic models. Within the FP7 UncertWeb project we are developing mechanisms and tools to support the management of uncertainty in environmental models. In this paper we explore the integration of the UncertWeb framework with OpenMI, to assess the issues that arise when propagating uncertainty in OpenMI model compositions, and the degree of integration possible with UncertWeb tools. In particular we develop an uncertainty-enabled model for a simple Lotka-Volterra system with an interface conforming to the OpenMI standard, exploring uncertainty in the initial predator and prey levels, and the parameters of the model equations. We use the Elicitator tool developed within UncertWeb to identify the initial condition uncertainties, and show how these can be integrated, using UncertML, with simple Monte Carlo propagation mechanisms. The mediators we develop for OpenMI models are generic and produce standard Web services that expose the OpenMI models to a Web based framework. We discuss what further work is needed to allow a more complete system to be developed and show how this might be used practically.

Return Migration in the Ecuadorian and Bolivian population: motivations, strategies and discourses

This article analyses the motivations for return migration among the Ecuadorians and Bolivians who, after living in Spain, returned to their countries of origin during the economic crisis that started in 2008. From the analysis of 22 interviews in-depth which took place in Ecuador and 38 in Bolivia to women, men and young people from migrant families, this decision-making process is shown to be embedded into a gendered dynamics of relationships. Particular detail is given to affective and economic elements that had an influence on the decision to return, as well as to the strategies deployed to project their readjustment back in origin. Males and females occupy differential positions within the family, work and social circle, their expectations being built in a gendered manner. Despite the fact migration has brought women greater economic power within the family group, their reintegration upon return redefines their role as main managers in the household and the dynamics that allow their social reproduction. Men, for their part, aspire to refresh their role as providers in spite of their frail labour position upon return. Social mobility for females is passed on through generations by a strong investment on education for their daughters and sons, while for males this mobility revolves around setting up family businesses and around their demonstrative abilities.

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Clopton Charter

Translation of Clopton Charter Let those who are present and those in future know that I Robert de Clopton gave and granted to my son, William, one yardland which is part of the Clopton estate / manorial demesne with all its appurtenances in exchange for his homage and service , and that I have confirmed it with this charter . The yardland in question is that which he once held as heriot / heritable property . [I have given and granted it to him] to be held and kept by him and his heirs freely and undisputedly as a holding granted in return for services and as hereditable property from me and my heirs. For this he has to pay an annual rent of twelve silver pennies, in two installments per year: six on the Feast Day of St. Michael and six on the Feast Day of St. Mary in March , on the income that belongs to me and to my heirs, without neglecting income from elsewhere; together with all goods and privileges attached to the aformentioned land in the form of fields and pastures and everything which belongs to said yardland. And I, Robert, and all my heirs shall warrant all this aforementioned yardland together with all its appurtenances to said William and his heirs against all other claims in perpetuity . However, in order that this gift and grant of mine may remain firm and immovable, I have validated this charter with my seal in the presence of [the following] witnesses: the knights Sir William of Ludinton [and] Sir Robert of Valle. William of Edricheston, William of Waleford, Robert of Sidesam, Richard of Ludinton, Nicholas the scribe , and others.