Activity graphs: A language for flexible consultation systems

An intelligent decision system (IDS) uses artificial intelligence principles to deliver automated, interactive decision analysis (DA) consultations. Network methods adapted from operations research underlie two key IDS components: influence diagrams and activity graphs. Influence diagrams, which are familiar to DA researchers and practitioners, represent decision problems inevent space. Activity graphs, which are introduced in this paper, represent processes inaction space. While activity graphs can represent any process, we use them as a knowledge-engineering and programming language to represent the process knowledge of skilled decision analysts in the context of a specific class of decisions. This paper defines activity graphs as an extension of directed AND-OR graphs. Anactivity tree is a directed AND-OR tree consisting of nodes, which may contain activities (small computer programs) and connectors that establish logical relationships among nodes and define logical resolution agendas. Anactivity graph is a directed, multiply connected network of activity trees. Activity graphs may involve recursion. Development of the activity graph language is motivated by our desire to enable professional decision analysts — or other experts — with limited advanced programming experience to design and build consultation systems that combine the guidance offered by protocol systems with the flexibility and generality of transaction systems. This paper defines the activity graph language in detail. A simple example illustrates key concepts. The paper also discusses our experience using a computer system that implements activity graphs for developing commercial IDSs.     

Stable isotope labeling tandem mass spectrometry (SILT) to quantify protein production and clearance rates

In all biological systems, protein amount is a function of the rate of production and clearance. The speed of a response to a disturbance in protein homeostasis is determined by turnover rate. Quantifying alterations in protein synthesis and clearance rates is vital to understanding disease pathogenesis (e.g., aging, inflammation). No methods currently exist for quantifying production and clearance rates of low-abundance (femtomole) proteins in vivo. We describe a novel, mass spectrometry-based method for quantitating low-abundance protein synthesis and clearance rates in vitro and in vivo in animals and humans. The utility of this method is demonstrated with amyloid-beta (Abeta), an important low-abundance protein involved in Alzheimer's disease pathogenesis. We used in vivo stable isotope labeling, immunoprecipitation of Abeta from cerebrospinal fluid, and quantitative liquid chromatography electrospray-ionization tandem mass spectrometry (LC-ESI-tandem MS) to quantify human Abeta protein production and clearance rates. The method is sensitive and specific for stable isotope-labeled amino acid incorporation into CNS Abeta (+/-1% accuracy). This in vivo method can be used to identify pathophysiologic changes in protein metabolism and may serve as a biomarker for monitoring disease risk, progression, or response to novel therapeutic agents. The technique is adaptable to other macromolecules, such as carbohydrates or lipids.     

The quality of media reports on discoveries related to human genetic diseases

OBJECTIVES: To examine (1) the quality of media reports (newspapers, television and public radio) of genetic discoveries with medical relevance and (2) factors related to the completeness and balance of the stories. METHODS: Analysis of the accuracy, balance, and completeness of 228 media stories reporting 24 genetic discoveries between 1996 and 2000 using a previously validated instrument. RESULTS: Although usually accurate, the stories contained only 45.5 +/- 13.8% (mean +/- SD) of relevant items. Stories appearing on television and stories reporting discoveries of genes for rare diseases were the least complete. Stories in non-US English-speaking newspapers included more content items per word than US stories. Less balanced stories exaggerated the benefits of discoveries, ignored possible risks, and did not present a range of expert opinion. Scientists were sometimes the source of exaggeration. CONCLUSIONS: To increase the quality of media reports about genetic discoveries, stories should include more relevant items and be written by journalists skilled in science writing. Scientists will have to resist the tendency to exaggerate. These conclusions may apply to media stories of other discoveries as well.     

High affinity, paralog-specific recognition of the Mena EVH1 domain by a miniature protein

Many protein domains involved in cell signaling contain or interact with proline-rich sequences, and the design of molecules that perturb signaling pathways represents a foremost goal of chemical biology. Previously we described a protein design strategy in which the well-folded alpha-helix in avian pancreatic polypeptide (aPP) presents short alpha-helical recognition epitopes. The miniature proteins designed in this way recognize even shallow protein clefts with high affinity and specificity. Here we show that the well-folded type-II polyproline helix in aPP can present the short PPII-helical recognition epitope within the ActA protein of Listeria monocytogenes. Like miniature proteins that use an alpha-helix for protein recognition, the miniature protein designed in this way displays high affinity for a natural ActA target, the EVH1 domain Mena1-112, and achieves the elusive goal of paralog specificity, discriminating well between EVH1 domains Mena1-112, VASP1-115, and Evl1-112. Most importantly, the miniature protein competed with ActA in Xenopus laevis egg cytoplasmic extracts, decreasing actin-dependent motility of L. monocytogenes and causing extreme speed variations and discontinuous tail formation. Our results suggest that miniature proteins based on aPP may represent an excellent framework for the design of ligands that differentiate the roles of EVH1 domains in vitro and in vivo.     

Sleep,circadian rhythms,and the pathogenesis of Alzheimer Disease

Disturbances in the sleep–wake cycle and circadian rhythms are common symptoms of Alzheimer Disease (AD), and they have generally been considered as late consequences of the neurodegenerative processes. Recent evidence demonstrates that sleep–wake and circadian disruption often occur early in the course of the disease and may even precede the development of cognitive symptoms. Furthermore, the sleep–wake cycle appears to regulate levels of the pathogenic amyloid-beta peptide in the brain, and manipulating sleep can influence AD-related pathology in mouse models via multiple mechanisms. Finally, the circadian clock system, which controls the sleep–wake cycle and other diurnal oscillations in mice and humans, may also have a role in the neurodegenerative process. In this review, we examine the current literature related to the mechanisms by which sleep and circadian rhythms might impact AD pathogenesis, and we discuss potential therapeutic strategies targeting these systems for the prevention of AD.     

Ethical aspects of genetic testing in the workplace

The European Group on Ethics and New Technologies, which advises the European Commission, has published an opinion paper on ethical aspects of genetic testing in the workplace. The paper goes well beyond the usual ethical issues, presenting a summary of genetic testing in the workplace in the United States and Europe and criteria for appropriate testing. Unlike many other documents on ethics, it pays close attention to the problem of false-positive and false-negative test results. Although no genetic tests are currently appropriate for screening workers or applicants for jobs in which occupational hazards exist, inappropriate testing has occurred and regulations are needed to ensure that only appropriate testing is used in the future. Workers or their representatives should be involved in deciding when and how genetic testing in the workplace is done.