Modeling expert forecasting knowledge for incorporation into expert systems

The use of continuous multivariate models to represent experts' knowledge of relations among a set of variables is reviewed. Such knowledge models can be incorporated into expert systems, complementing contingent rules, especially when representing experts' knowledge of functional relations among entities in noisy domains. Past work has most commonly involved linear averaging models in static domains, although nonlinear models and dynamic domains are also possible. Detecting errors in continuous multivariate models requires a different approach from detecting errors in collections of if-then rules. Methods for eliciting expert knowledge include modeling judgments made in real or hypothetical situations and using expert's self-insight directly to assist in construction of the model. Procedures for managing each of these methods have been computerized and could be included as elicitation tools in expert system building environments.     

Architecture and material properties of diatom shells provide effective mechanical protection

Diatoms are the major contributors to phytoplankton blooms in lakes and in the sea and hence are central in aquatic ecosystems and the global carbon cycle. All free-living diatoms differ from other phytoplankton groups in having silicified cell walls in the form of two 'shells' (the frustule) of manifold shape and intricate architecture whose function and role, if any, in contributing to the evolutionary success of diatoms is under debate. We explored the defence potential of the frustules as armour against predators by measuring their strength. Real and virtual loading tests (using calibrated glass microneedles and finite element analysis) were performed on centric and pennate diatom cells. Here we show that the frustules are remarkably strong by virtue of their architecture and the material properties of the diatom silica. We conclude that diatom frustules have evolved as mechanical protection for the cells because exceptional force is required to break them. The evolutionary arms race between diatoms and their specialized predators will have had considerable influence in structuring pelagic food webs and biogeochemical cycles.     

Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis

PHD2 serves as an oxygen sensor that rescues blood supply by regulating vessel formation and shape in case of oxygen shortage. However, it is unknown whether PHD2 can influence arteriogenesis. Here we studied the role of PHD2 in collateral artery growth by using hindlimb ischaemia as a model, a process that compensates for the lack of blood flow in case of major arterial occlusion. We show that Phd2 (also known as Egln1) haplodeficient (Phd2(+/-)) mice displayed preformed collateral arteries that preserved limb perfusion and prevented tissue necrosis in ischaemia. Improved arteriogenesis in Phd2(+/-) mice was due to an expansion of tissue-resident, M2-like macrophages and their increased release of arteriogenic factors, leading to enhanced smooth muscle cell (SMC) recruitment and growth. Both chronic and acute deletion of one Phd2 allele in macrophages was sufficient to skew their polarization towards a pro-arteriogenic phenotype. Mechanistically, collateral vessel preconditioning relied on the activation of canonical NF-κB pathway in Phd2(+/-) macrophages. These results unravel how PHD2 regulates arteriogenesis and artery homeostasis by controlling a specific differentiation state in macrophages and suggest new treatment options for ischaemic disorders.     

Watching hydrogen-bond dynamics in a beta-turn by transient two-dimensional infrared spectroscopy

X-ray crystallography and nuclear magnetic resonance measurements provide us with atomically resolved structures of an ever-growing number of biomolecules. These static structural snapshots are important to our understanding of biomolecular function, but real biomolecules are dynamic entities that often exploit conformational changes and transient molecular interactions to perform their tasks. Nuclear magnetic resonance methods can follow such structural changes, but only on millisecond timescales under non-equilibrium conditions. Time-resolved X-ray crystallography has recently been used to monitor the photodissociation of CO from myoglobin on a subnanosecond timescale, yet remains challenging to apply more widely. In contrast, two-dimensional infrared spectroscopy, which maps vibrational coupling between molecular groups and hence their relative positions and orientations, is now routinely used to study equilibrium processes on picosecond timescales. Here we show that the extension of this method into the non-equilibrium regime allows us to observe in real time in a short peptide the weakening of an intramolecular hydrogen bond and concomitant opening of a beta-turn. We find that the rate of this process is two orders of magnitude faster than the 'folding speed limit' established for contact formation between protein side chains.