Refining animal models in fracture research: Seeking consensus in optimising both animal welfare and scientific validity for appropriate biomedical use

Background In an attempt to establish some consensus on the proper use and design of experimental animal models in musculoskeletal research, AOVET (the veterinary specialty group of the AO Foundation) in concert with the AO Research Institute (ARI), and the European Academy for the Study of Scientific and Technological Advance, convened a group of musculoskeletal researchers, veterinarians, legal experts, and ethicists to discuss, in a frank and open forum, the use of animals in musculoskeletal research. Methods The group narrowed the field to fracture research. The consensus opinion resulting from this workshop can be summarized as follows: Results & Conclusion Anaesthesia and pain management protocols for research animals should follow standard protocols applied in clinical work for the species involved. This will improve morbidity and mortality outcomes. A database should be established to facilitate selection of anaesthesia and pain management protocols for specific experimental surgical procedures and adopted as an International Standard (IS) according to animal species selected. A list of 10 golden rules and requirements for conduction of animal experiments in musculoskeletal research was drawn up comprising 1) Intelligent study designs to receive appropriate answers; 2) Minimal complication rates (5 to max. 10%); 3) Defined end-points for both welfare and scientific outputs analogous to quality assessment (QA) audit of protocols in GLP studies; 4) Sufficient details for materials and methods applied; 5) Potentially confounding variables (genetic background, seasonal, hormonal, size, histological, and biomechanical differences); 6) Post-operative management with emphasis on analgesia and follow-up examinations; 7) Study protocols to satisfy criteria established for a "justified animal study"; 8) Surgical expertise to conduct surgery on animals; 9) Pilot studies as a critical part of model validation and powering of the definitive study design; 10) Criteria for funding agencies to include requirements related to animal experiments as part of the overall scientific proposal review protocols. Such agencies are also encouraged to seriously consider and adopt the recommendations described here when awarding funds for specific projects. Specific new requirements and mandates related both to improving the welfare and scientific rigour of animal-based research models are urgently needed as part of international harmonization of standards.

Resource allocation and scheduling of multiple composite web services in cloud computing using cooperative coevolution genetic algorithm

In cloud computing, resource allocation and scheduling of multiple composite web services is an important and challenging problem. This is especially so in a hybrid cloud where there may be some low-cost resources available from private clouds and some high-cost resources from public clouds. Meeting this challenge involves two classical computational problems: one is assigning resources to each of the tasks in the composite web services; the other is scheduling the allocated resources when each resource may be used by multiple tasks at different points of time. In addition, Quality-of-Service (QoS) issues, such as execution time and running costs, must be considered in the resource allocation and scheduling problem. Here we present a Cooperative Coevolutionary Genetic Algorithm (CCGA) to solve the deadline-constrained resource allocation and scheduling problem for multiple composite web services. Experimental results show that our CCGA is both efficient and scalable.

Computational approaches for modelling intrinsic noise and delays in genetic regulatory networks

This chapter focuses on the interactions and roles between delays and intrinsic noise effects within cellular pathways and regulatory networks. We address these aspects by focusing on genetic regulatory networks that share a common network motif, namely the negative feedback loop, leading to oscillatory gene expression and protein levels. In this context, we discuss computational simulation algorithms for addressing the interplay of delays and noise within the signaling pathways based on biological data. We address implementational issues associated with efficiency and robustness. In a molecular biology setting we present two case studies of temporal models for the Hes1 gene (Monk, 2003; Hirata et al., 2002), known to act as a molecular clock, and the Her1/Her7 regulatory system controlling the periodic somite segmentation in vertebrate embryos (Giudicelli and Lewis, 2004; Horikawa et al., 2006).

Evolving noisy oscillatory dynamics in genetic regulatory networks

We introduce a genetic programming (GP) approach for evolving genetic networks that demonstrate desired dynamics when simulated as a discrete stochastic process. Our representation of genetic networks is based on a biochemical reaction model including key elements such as transcription, translation and post-translational modifications. The stochastic, reaction-based GP system is similar but not identical with algorithmic chemistries. We evolved genetic networks with noisy oscillatory dynamics. The results show the practicality of evolving particular dynamics in gene regulatory networks when modelled with intrinsic noise.

A mathematical model for genetic regulation of the lactose operon

In this paper we construct a mathematical model for the genetic regulatory network of the lactose operon. This mathematical model contains transcription and translation of the lactose permease (LacY) and a reporter gene GFP. The probability of transcription of LacY is determined by 14 binding states out of all 50 possible binding states of the lactose operon based on the quasi-steady-state assumption for the binding reactions, while we calculate the probability of transcription for the reporter gene GFP based on 5 binding states out of 19 possible binding states because the binding site O2 is missing for this reporter gene. We have tested different mechanisms for the transport of thio-methylgalactoside (TMG) and the effect of different Hill coefficients on the simulated LacY expression levels. Using this mathematical model we have realized one of the experimental results with different LacY concentrations, which are induced by different concentrations of TMG.