Canine Insulinoma (A Case Report)

Canine Insulinoma is a disease of old dogs which results from a functional neoplasm involving the beta cells of the islets of Langherhans of the pancreas. These are the same cells that are involved in diabetes mellitus where insulin production is decreased instead of increased. The insulinoma dog is usually admitted with signs of weakness, ataxia, restlessness, ravenous appetite, and convulsions

Dealing with change and uncertainty within the regulatory frameworks for flood defense infrastructure in selected European countries

Whereas existing literature on the interactions between law, adaptive governance and resilience in the water sector often focuses on quality or supply issues, this paper addresses adaptation in national water laws in relation to increasing flood risks. In particular, this paper analyzes the extent to which legal rules governing flood defense infrastructure in a selection of European countries (Sweden, France, England and the Netherlands) allow for response and adaptation to change and uncertainty. While there is evidence that the legal rules on the development of new infrastructure require that changing conditions be considered, the adaptation of existing infrastructure is a more complicated matter. Liability rules fail to adequately address damages resulting from causes external to the action or inaction of owners and managers, in particular extreme events. A trend towards clearer, and in some cases, increased public powers to ensure the safety of flood defense infrastructure is observed. The paper concludes that legal rules should ensure not only that decisions to build flood defenses are based on holistic and future-oriented assessments, but also that this is reflected in the implementation and operation of these structures

The European Union approach to flood risk management and improving societal resilience: lessons from the implementation of the Floods Directive in six European countries

Diversity in flood risk management approaches is often considered to be a strength. However in some national settings, and especially for transboundary rivers, variability and the incompatibility of approaches can reduce the effectiveness of flood risk management. Placed in the context of increasing flood risks, as well as the potential for flooding to undermine the European Union's sustainable development goals, a desire to increase societal resilience to flooding has prompted the introduction of a common European Framework. This paper provides a legal and policy analysis of the implementation of the Floods Directive (2007/60/EC) in six countries; Belgium (Flemish Region), England, France, the Netherlands, Poland and Sweden. Evaluation criteria from existing legal and policy literature frame the study of the Directive and its impact on enhancing or constraining societal resilience by using an adaptive governance approach. These criteria are initially used to analyze the key components of the EU approach, before providing insight of the implementation of the Directive at a national level. Similarities and differences in the legal translation of European goals into existing flood risk management are analyzed alongside their relative influence on policy and practice. The research highlights that the impact of the Floods Directive on increasing societal resilience has been nationally variable, in part due to its focus on procedural obligations, rather than on more substantive requirements. Analysis shows that despite a focus on transboundary river basin management, in some cases existing traditions of flood risk management, have overridden objectives to harmonize flood risk management. This could be strengthened by requiring more stringent cooperation and providing the competent authorities in International River Basins Districts with more power. Despite some shortcomings in directly impacting flood risk outcomes, the Directive has positively stimulated discussion and flood risk management planning in countries that were perhaps lagging behind

The European Union approach to flood risk management and improving societal resilience: lessons from the implementation of the Floods Directive in six European countries

Diversity in flood risk management approaches is often considered to be a strength. However in some national settings, and especially for transboundary rivers, variability and the incompatibility of approaches can reduce the effectiveness of flood risk management. Placed in the context of increasing flood risks, as well as the potential for flooding to undermine the European Union's sustainable development goals, a desire to increase societal resilience to flooding has prompted the introduction of a common European Framework. This paper provides a legal and policy analysis of the implementation of the Floods Directive (2007/60/EC) in six countries; Belgium (Flemish Region), England, France, the Netherlands, Poland and Sweden. Evaluation criteria from existing legal and policy literature frame the study of the Directive and its impact on enhancing or constraining societal resilience by using an adaptive governance approach. These criteria are initially used to analyze the key components of the EU approach, before providing insight of the implementation of the Directive at a national level. Similarities and differences in the legal translation of European goals into existing flood risk management are analyzed alongside their relative influence on policy and practice. The research highlights that the impact of the Floods Directive on increasing societal resilience has been nationally variable, in part due to its focus on procedural obligations, rather than on more substantive requirements. Analysis shows that despite a focus on transboundary river basin management, in some cases existing traditions of flood risk management, have overridden objectives to harmonize flood risk management. This could be strengthened by requiring more stringent cooperation and providing the competent authorities in International River Basins Districts with more power. Despite some shortcomings in directly impacting flood risk outcomes, the Directive has positively stimulated discussion and flood risk management planning in countries that were perhaps lagging behind

Development of a high-throughput ex-vivo burn wound model using porcine skin, and its application to evaluate new approaches to control wound infection

Biofilm formation in wounds is considered a major barrier to successful treatment, and has been associated with the transition of wounds to a chronic non-healing state. Here, we present a novel laboratory model of wound biofilm formation using ex-vivo porcine skin and a custom burn wound array device. The model supports high-throughput studies of biofilm formation and is compatible with a range of established methods for monitoring bacterial growth, biofilm formation, and gene expression. We demonstrate the use of this model by evaluating the potential for bacteriophage to control biofilm formation by Staphylococcus aureus, and for population density dependant expression of S. aureus virulence factors (regulated by the Accessory Gene Regulator, agr) to signal clinically relevant wound infection. Enumeration of colony forming units and metabolic activity using the XTT assay, confirmed growth of bacteria in wounds and showed a significant reduction in viable cells after phage treatment. Confocal laser scanning microscopy confirmed the growth of biofilms in wounds, and showed phage treatment could significantly reduce the formation of these communities. Evaluation of agr activity by qRT-PCR showed an increase in activity during growth in wound models for most strains. Activation of a prototype infection-responsive dressing designed to provide a visual signal of wound infection, was related to increased agr activity. In all assays, excellent reproducibility was observed between replicates using this mode

Molecular crowding defines a common origin for the Warburg effect in proliferating cells and the lactate threshold in muscle physiology

Aerobic glycolysis is a seemingly wasteful mode of ATP production that is seen both in rapidly proliferating mammalian cells and highly active contracting muscles, but whether there is a common origin for its presence in these widely different systems is unknown. To study this issue, here we develop a model of human central metabolism that incorporates a solvent capacity constraint of metabolic enzymes and mitochondria, accounting for their occupied volume densities, while assuming glucose and/or fatty acid utilization. The model demonstrates that activation of aerobic glycolysis is favored above a threshold metabolic rate in both rapidly proliferating cells and heavily contracting muscles, because it provides higher ATP yield per volume density than mitochondrial oxidative phosphorylation. In the case of muscle physiology, the model also predicts that before the lactate switch, fatty acid oxidation increases, reaches a maximum, and then decreases to zero with concomitant increase in glucose utilization, in agreement with the empirical evidence. These results are further corroborated by a larger scale model, including biosynthesis of major cell biomass components. The larger scale model also predicts that in proliferating cells the lactate switch is accompanied by activation of glutaminolysis, another distinctive feature of the Warburg effect. In conclusion, intracellular molecular crowding is a fundamental constraint for cell metabolism in both rapidly proliferating- and non-proliferating cells with high metabolic demand. Addition of this constraint to metabolic flux balance models can explain several observations of mammalian cell metabolism under steady state conditions

Evaluation of rate law approximations in bottom-up kinetic models of metabolism.

BackgroundThe mechanistic description of enzyme kinetics in a dynamic model of metabolism requires specifying the numerical values of a large number of kinetic parameters. The parameterization challenge is often addressed through the use of simplifying approximations to form reaction rate laws with reduced numbers of parameters. Whether such simplified models can reproduce dynamic characteristics of the full system is an important question.ResultsIn this work, we compared the local transient response properties of dynamic models constructed using rate laws with varying levels of approximation. These approximate rate laws were: 1) a Michaelis-Menten rate law with measured enzyme parameters, 2) a Michaelis-Menten rate law with approximated parameters, using the convenience kinetics convention, 3) a thermodynamic rate law resulting from a metabolite saturation assumption, and 4) a pure chemical reaction mass action rate law that removes the role of the enzyme from the reaction kinetics. We utilized in vivo data for the human red blood cell to compare the effect of rate law choices against the backdrop of physiological flux and concentration differences. We found that the Michaelis-Menten rate law with measured enzyme parameters yields an excellent approximation of the full system dynamics, while other assumptions cause greater discrepancies in system dynamic behavior. However, iteratively replacing mechanistic rate laws with approximations resulted in a model that retains a high correlation with the true model behavior. Investigating this consistency, we determined that the order of magnitude differences among fluxes and concentrations in the network were greatly influential on the network dynamics. We further identified reaction features such as thermodynamic reversibility, high substrate concentration, and lack of allosteric regulation, which make certain reactions more suitable for rate law approximations.ConclusionsOverall, our work generally supports the use of approximate rate laws when building large scale kinetic models, due to the key role that physiologically meaningful flux and concentration ranges play in determining network dynamics. However, we also showed that detailed mechanistic models show a clear benefit in prediction accuracy when data is available. The work here should help to provide guidance to future kinetic modeling efforts on the choice of rate law and parameterization approaches

A scalable algorithm to explore the Gibbs energy landscape of genome-scale metabolic networks

The integration of various types of genomic data into predictive models of biological networks is one of the main challenges currently faced by computational biology. Constraint-based models in particular play a key role in the attempt to obtain a quantitative understanding of cellular metabolism at genome scale. In essence, their goal is to frame the metabolic capabilities of an organism based on minimal assumptions that describe the steady states of the underlying reaction network via suitable stoichiometric constraints, specifically mass balance and energy balance (i.e. thermodynamic feasibility). The implementation of these requirements to generate viable configurations of reaction fluxes and/or to test given flux profiles for thermodynamic feasibility can however prove to be computationally intensive. We propose here a fast and scalable stoichiometry-based method to explore the Gibbs energy landscape of a biochemical network at steady state. The method is applied to the problem of reconstructing the Gibbs energy landscape underlying metabolic activity in the human red blood cell, and to that of identifying and removing thermodynamically infeasible reaction cycles in the Escherichia coli metabolic network (iAF1260). In the former case, we produce consistent predictions for chemical potentials (or log-concentrations) of intracellular metabolites; in the latter, we identify a restricted set of loops (23 in total) in the periplasmic and cytoplasmic core as the origin of thermodynamic infeasibility in a large sample ($10^6$) of flux configurations generated randomly and compatibly with the prior information available on reaction reversibility.Comment: 11 pages, 6 figures, 1 table; for associated supporting material see http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.100256

Abell 746: A highly disturbed cluster undergoing multiple mergers

We present deep \textit{XMM-Newton}, Karl Jansky Very Large Array, and upgraded Giant Metrewave Radio Telescope observations of Abell 746, a cluster that hosts a plethora of diffuse emission sources that provide evidence for the acceleration of relativistic particles. Our new \textit{XMM-Newton} images reveal a complex morphology of the thermal gas with several substructures. We observe an asymmetric temperature distribution across the cluster: the southern regions exhibit higher temperatures, reaching $\sim$9\,keV, while the northern regions have lower temperatures ($\rm \leq4\,keV$), likely due to a complex merger. We find evidence of four surface brightness edges, of which three are merger-driven shock fronts. Combining our new data with the published LOw-Frequency ARray observations has unveiled the nature of diffuse sources in this system. The bright northwest relic shows thin filaments and high degree of polarization with aligned magnetic field vectors. We detect a density jump, aligned with the fainter relic to the north. To the south, we detect high-temperature regions, consistent with shock-heated regions and density jump coincident with the northern tip of the southern radio structure. Its integrated spectrum shows a high-frequency steepening. Lastly, we find that the cluster hosts large-scale radio halo emission. The comparison of the thermal and nonthermal emission reveals an anticorrelation between the bright radio and X-ray features at the center. Our findings suggest that Abell 746 is a complex system that involves multiple mergers.Comment: 21 pages, 13 figures, submitted to Ap