At the Biological Modeling and Simulation Frontier

We provide a rationale for and describe examples of synthetic modeling and simulation (M&S) of biological systems. We explain how synthetic methods are distinct from familiar inductive methods. Synthetic M&S is a means to better understand the mechanisms that generate normal and disease-related phenomena observed in research, and how compounds of interest interact with them to alter phenomena. An objective is to build better, working hypotheses of plausible mechanisms. A synthetic model is an extant hypothesis: execution produces an observable mechanism and phenomena. Mobile objects representing compounds carry information enabling components to distinguish between them and react accordingly when different compounds are studied simultaneously. We argue that the familiar inductive approaches contribute to the general inefficiencies being experienced by pharmaceutical R&D, and that use of synthetic approaches accelerates and improves R&D decision-making and thus the drug development process. A reason is that synthetic models encourage and facilitate abductive scientific reasoning, a primary means of knowledge creation and creative cognition. When synthetic models are executed, we observe different aspects of knowledge in action from different perspectives. These models can be tuned to reflect differences in experimental conditions and individuals, making translational research more concrete while moving us closer to personalized medicine

An integrated approach to the biomechanics and motor control of cricket fast bowling techniques

To date, scientific investigations into the biomechanical aspects of cricket fast bowling techniques have predominantly focused on identifying the mechanical factors that may predispose fast bowlers to lower back injury with a relative paucity of research being conducted on the technical features that underpin proficient fast bowling performance. In this review paper, we critique the scientific literature examining fast bowling performance. We argue that, although many published investigations have provided some useful insights into the biomechanical factors that contribute to a high ball release speed and, to a lesser extent, bowling accuracy, this research has not made a substantive contribution to knowledge enhancement and has only had a very minor influence on coaching practice. To significantly enhance understanding of cricket fast bowling techniques and, therefore, have greater impact on practice, we recommend that future scientific research adopts an interdisciplinary focus, integrating biomechanical measurements with the analytical tools and concepts of dynamical systems motor control theory. The use of qualitative (topological) analysis techniques, in particular, promises to increase understanding of the coordinative movement patterns that define 'technique' in cricket fast bowling and potentially help distinguish between functional and dysfunctional aspects of technique for individual fast bowlers

Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans

Identification of the genes underlying complex phenotypes and the definition of the evolutionary forces that have shaped eukaryotic genomes are among the current challenges in molecular genetics1, 2, 3. Variation in gene copy number is increasingly recognized as a source of inter-individual differences in genome sequence and has been proposed as a driving force for genome evolution and phenotypic variation3, 4, 5. Here we show that copy number variation of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the newly described, rat-specific Fcgr3 paralogue, Fcgr3-related sequence (Fcgr3-rs), as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B, an orthologue of rat Fcgr3, was associated with glomerulonephritis in the autoimmune disease systemic lupus erythematosus. The finding that gene copy number polymorphism predisposes to immunologically mediated renal disease in two mammalian species provides direct evidence for the importance of genome plasticity in the evolution of genetically complex phenotypes, including susceptibility to common human disease