Capturing expert knowledge with argumentation: a case study in bioinformatics

MOTIVATION: The output of a bioinformatic tool such as BLAST must usually be interpreted by an expert before reliable conclusions can be drawn. This may be based upon the expert's experience, additional data and statistical analysis. Often the process is laborious, goes unrecorded and may be biased. Argumentation is an established technique for reasoning about situations where absolute truth or precise probability is impossible to determine. RESULTS: We demonstrate the application of argumentation to 3D-PSSM, a protein structure prediction tool. The expert's interpretation of results is represented as an argumentation framework. Given a 3D-PSSM result, an automated procedure constructs arguments for and against the conclusion that the result is a good predictor of protein structure. In addition to capturing the unique expertise of the author of 3D-PSSM for distribution to users, an improvement in recall of 5-10 percentage points is achieved. This technique can be applied to a wide range of bioinformatic tools. AVAILABILITY: Example public server and benchmarking data are available at http://www.sbg.bio.ic.ac.uk/~brj03/argumentation/paper/. Source code available on request.     

The distribution of pressure behind a soft contact lens

We determine the pressure distribution behind a soft contact lens that is necessary to keep the lens in conformity with an axisymmetric substrate. The substrate consists of two regions: a central portion, the cornea, supposed to be an ellipsoid; and a peripheral region, the sclera, taken to be a sphere. The pressure is obtained as part of a numerical solution of the axisymmetric equilibrium equations for an initially curved, linearly elastic membrane. The relaxed shape of the lens is assumed to be an axisymmetric ellipsoid with a central curvature and a shape factor different from those of the cornea. The variation in the thickness of the lens from its center to edge is approximated by a polynomial. Pressure distributions are obtained for several typical soft contact lens fittings.     

Evolution and valuing

Human evolution can shed light on ethics through an account of valuing. This basic human activity is to be explained as a judgement on our desires in the light of a self appraisal with respect to desires of higher order. These concern what we desire to be and how we desire to lead a life. It is argued that the conditions of valuing may be found at least in primitive form in the use of language, which surely has an evolutionary explanation. But values may be trivial or false; to be ethically correct they must be authentic and objective. Because belief and desire are plastic to cultural influence, we cannot expect an evolutionary account of this last appraisal.     

Accurate Alternative Measurements for Female Lifetime Reproductive Success in Drosophila melanogaster

Fitness is an individual’s ability to survive and reproduce, and is an important concept in evolutionary biology. However, accurately measuring fitness is often difficult, and appropriate fitness surrogates need to be identified. Lifetime reproductive success, the total progeny an organism can produce in their lifetime, is thought to be a suitable proxy for fitness, but the measure of an organism’s reproductive output across a lifetime can be difficult or impossible to obtain. Here we demonstrate that the short-term measure of reproductive success across five days provides a reasonable prediction of an individual''s total lifetime reproductive success in Drosophila melanogaster. However, the lifetime reproductive success of a female that has only mated once is not correlated to the lifetime reproductive success of a female that is allowed to mate multiple times, demonstrating that these measures should not serve as surrogates nor be used to make inferences about one another.     

Evolutionary stability: States and strategies

Different aspects and modifications of the definition of an evolutionarily stable (ES) strategy that have been considered in the literature can be incorporated in a unifying concept which regards the population context. This concept of evolutionary stability will generally characterize population states in both pure- and mixed-strategist models. In particular, it includes ES strategies, represented as a phenotype unique in an ES population. For an important class of mixed-strategist models, no strict ESS can exist. This will be the case whenever the success of an individual strategy is considered to follow as an average from the successes of its behavioural components. Instead, ESS results may be obtained from what will be called a “degenerate” form of the model, which is simply an ESS model on the level of elementary actions. Then, however, the correct interpretation of an ESS is not an individual phenotype but rather a population mixture of elementary actions. If an ES state exists in a mixed-strategist model it may be determined by an equilibrium condition; if there is an ES strategy, a different approach—mainly maximum considerations—is needed for finding it. An equilibrium condition does not hold for the components of an ES strategy straightforwardly; but it can be derived in terms of an auxiliary ESS model that considers first-order effects of the components. Several examples illustrate the significance of these results. Particularly, two models on “Games between Relatives” are reconsidered in order to display both their formal interrelation and the different meaning of their results in the context of mixed-strategist models.     

Quantitative measurements of force and displacement using an optical trap.

We combined a single-beam gradient optical trap with a high-resolution photodiode position detector to show that an optical trap can be used to make quantitative measurements of nanometer displacements and piconewton forces with millisecond resolution. When an external force is applied to a micron-sized bead held by an optical trap, the bead is displaced from the center of the trap by an amount proportional to the applied force. When the applied force is changed rapidly, the rise time of the displacement is on the millisecond time scale, and thus a trapped bead can be used as a force transducer. The performance can be enhanced by a feedback circuit so that the position of the trap moves by means of acousto-optic modulators to exert a force equal and opposite to the external force applied to the bead. In this case the position of the trap can be used to measure the applied force. We consider parameters of the trapped bead such as stiffness and response time as a function of bead diameter and laser beam power and compare the results with recent ray-optic calculations.     

Somatic cell nuclear transfer efficiency: How can it be improved through nuclear remodeling and reprogramming?

Fertile offspring from somatic cell nuclear transfer (SCNT) is the goal of most cloning laboratories. For this process to be successful, a number of events must occur correctly. First the donor nucleus must be in a state that is amenable to remodeling and subsequent genomic reprogramming. The nucleus must be introduced into an oocyte cytoplasm that is capable of facilitating the nuclear remodeling. The oocyte must then be adequately stimulated to initiate development. Finally the resulting embryo must be cultured in an environment that is compatible with the development of that particular embryo. Much has been learned about the incredible changes that occur to a nucleus after it is placed in the cytoplasm of an oocyte. While we think that we are gaining an understanding of the reorganization that occurs to proteins in the donor nucleus, the process of cloning is still very inefficient. Below we will introduce the procedures for SCNT, discuss nuclear remodeling and reprogramming, and review techniques that may improve reprogramming. Finally we will briefly touch on other aspects of SCNT that may improve the development of cloned embryos.     

Public health strategies for distribution of influenza vaccine during an influenza pandemic

In order to consider the ethical issues around vaccine distribution during an influenza pandemic, it is critical to have an understanding of the role of influenza vaccine in a pandemic, the rate at which vaccine is likely to be come available, who will likely produce and "own" the vaccine, how vaccine distribution and administration might be accomplished, and which are the groups that might be deemed highest priority to be vaccinated against influenza. The United States and Connecticut have been considering the more challenging of these issues and have learned from Canada, which previously discussed and made decisions on the challenges related to vaccine distribution. Although there is still some critical advance thinking that needs to be done, planning for the response to an influenza pandemic is now at an advanced stage. The keys to preparedness at this stage are to be aware of the vaccine distribution options, to know the benefits and limitations of each option, and to be flexible but nimble in dealing with a real pandemic.     

The importance of the prediction model in the validation of alternative tests

An overview is presented of the validation process adopted by the European Centre for the Validation of Alternative Methods, with particular emphasis on the central role of the prediction model (PM). The development of an adequate PM is considered to be just as important as the development of an adequate test system, since the validity of an alternative test can only be established when both components (the test system and the PM) have successfully undergone validation. It is argued, however, that alternative tests and their associated PMs do not necessarily need to undergo validation at the same time, and that retrospective validation may be appropriate when a test system is found to be reliable, but the case for its relevance remains to be demonstrated. For an alternative test to be considered "scientifically valid", it is necessary for three conditions to be fulfilled, referred to here as the criteria for scientific relevance, predictive relevance, and reliability. A minimal set of criteria for the acceptance of any PM is defined, but it should be noted that required levels of predictive ability need to be established on a case-by-case basis, taking into account the inherent variability of the alternative and in vivo test data. Finally, in view of the growing shift in emphasis from the use of stand-alone alternative tests to alternative testing strategies, the importance of making the PM an integral part of the testing strategy is discussed.     

Computer-aided stereographic representation of an object reconstructed from micrographs of serial thin sections

A method is described which allows a three-dimensional object to be reconstructed from micrographs of serial thin sections using computer graphic techniques. The reconstructed object, which can be rotated three- dimensionally, is displayed on a colour visual display unit and the surface of the object is shaded in order that it can be observed to provide an illusion of a three-dimensional structure. Moreover, the technique makes it possible to represent an inner structure when seen through an outer one, also to observe other sectioned face views. The method as described here allows rapid visual evaluation of the results of three-dimensional reconstruction from serial thin sections when recorded with the aid of a light or an electron microscope.     

An analysis of extended and exponentially-fed-batch cultures.

Under certain conditions it is shown that an extended culture is equivalent to an exponentially-fed-batch culture, that an exponentially-fed-batch culture (and an extended culture) can be maintained at a steady state and that an exponentially-fed-batch culture may be mimicked by a continuous-flow culture with a constant dilution rate. Operational conditions required to maintain steady states are specified.     

Energetics of permeation of thin lipid membranes by ions

The energy of an ion in a thin hydrocarbon membrane relative to its energy in a bulk aqueous phase is considered in terms of the electrostatic and surface components that may be expected to be involved. Except when diffusion activation energies are large compared to partition free energies, the latter will control permeation rate and the state of an ion having the lowest partition energy will be critical for its permeability. This minimum is found when an ion is surrounded with a thin layer of water. All ions of the same charge will tend to be at their lowest state in a sphere of water of the same size. It is concluded, therefore, that all ions of a given charge will have about the same permeability in lipid membranes.     

Compulsory moral bioenhancement should be covert

Some theorists argue that moral bioenhancement ought to be compulsory. I take this argument one step further, arguing that if moral bioenhancement ought to be compulsory, then its administration ought to be covert rather than overt. This is to say that it is morally preferable for compulsory moral bioenhancement to be administered without the recipients knowing that they are receiving the enhancement. My argument for this is that if moral bioenhancement ought to be compulsory, then its administration is a matter of public health, and for this reason should be governed by public health ethics. I argue that the covert administration of a compulsory moral bioenhancement program better conforms to public health ethics than does an overt compulsory program. In particular, a covert compulsory program promotes values such as liberty, utility, equality, and autonomy better than an overt program does. Thus, a covert compulsory moral bioenhancement program is morally preferable to an overt moral bioenhancement program.     

CHEAP LISTENING? – REFLECTIONS ON THE CONCEPT OF WRONGFUL DISABILITY1

This paper investigates the concept of wrongful disability. That concept suggests that parents are morally obligated to prevent the genetic transmission of certain conditions and so, if they do not, any resulting disability is 'wrongful'. In their book From Chance to Choice, Buchanan, Brock, Daniels and Wikler defend the concept of wrongful disability using the principle of avoidability via substitution. That principle is scrutinised here. It is argued that the idea of avoidability via substitution is both conceptually problematic and rather insensitive. Instead, it is suggested that the question of whether or not bringing a particular disability about is wrongful does not simply hinge on whether or not substitution takes place. Rather, it involves an evaluation of parental aspirations and responsibilities. It is argued that the desire need not be responsible for creating challenges for others that lie outside what is perceived to be an acceptable range provides a justification for termination of pregnancy on the grounds of projected disability that neither commits one to wrongful life claim, nor requires that one substitute a non-disabled child instead. The ramifications of such an approach are explored. The paper concludes by suggesting that the question of what is considered to be an acceptable range of human capability is an increasingly important one. It is argued that, when addressing that question, we should be acutely aware of the social context that may go some way to define what we consider to be an acceptable range.     

Reducing model complexity of the general Markov model of evolution

The selection of an optimal model for data analysis is an important component of model-based molecular phylogenetic studies. Owing to the large number of Markov models that can be used for data analysis, model selection is a combinatorial problem that cannot be solved by performing an exhaustive search of all possible models. Currently, model selection is based on a small subset of the available Markov models, namely those that assume the evolutionary process to be globally stationary, reversible, and homogeneous. This forces the optimal model to be time reversible even though the actual data may not satisfy these assumptions. This problem can be alleviated by including more complex models during the model selection. We present a novel heuristic that evaluates a small fraction of these complex models and identifies the optimal model.     

Anæsthesia in Chest Surgery,with Special Reference to Controlled Respiration and Cyclopropane: (Section of Anæsthetics)

Problems in chest surgery: Cases with prolonged tox?mia or amyloid disease require an an?sthetic agent of low toxicity. When sputum or blood are present in the tracheobronchial tree the an?sthesia should abolish reflex distrubances and excessive sputum be removed by suction. The technique should permit the use of a high oxygen atmosphere; controlled respiration with cyclopropane or ether fulfil these requirements. Open pneumothorax is present when a wound of the chest wall allows air to pass in and out of the pleural cavity. The lung on the affected side collapses and the mediastinum moves over and partly compresses the other lung.The dangers of an open pneumothorax: (1) Paradoxical respiration-the lung on the affected side partially inflates on expiration and collapses on inspiration. Part of the air entering the good lung has been shuttled back from the lung on the affected side and is therefore vitiated. Full expansion of the sound lung is handicapped by the initial displacement of the mediastinum which increases on inspiration. The circulation becomes embarrassed.(2) Vicious circle coughing. During a paroxysm of coughing dyspn?a will occur. This accentuates paradoxical respiration and starts a vicious circle. Death from asphyxia may result.Special duties of the an?sthetist: (1) To carry out or supervise continuous circulatory resuscitation. During a thoracotomy a drip blood transfusion maintains normal blood-pressure and pulse-rate.(2) To maintain effcient respiration.Positive pressure an?sthesia: Risk of impacting secretions in smaller bronchi with subsequent atelectasis; eventual risk of CO(2) poisoning without premonitory signs.Controlled respiration: (1) How it is produced. (2) Its uses in chest surgery.Controlled respiration means that the an?sthetist, having abolished the active respiratory efforts of the patient, maintains an efficient tidal exchange by rhythmic squeezing of the breathing bag. This may be done mechanically by Crafoord's modification of Frenkner's spiropulsator or by hand.Active respiration will cease (i) if the patient's CO(2) is lowered sufficiently by hyperventilation, (ii) if the patient's respiratory centre is depressed sufficiently by sedative and an?sthetic drugs, and (iii) by a combination of (i) and (ii) of less degree.The author uses the second method, depressing the respiratory centre with omnoponscopolamine, pentothal sodium, and then cyclopr?pane. The CO(2) absorption method is essential for this technique, and this and controlled respiration should be mastered by the an?sthetist with a familiar agent and used at first only in uncomplicated cases.The significance of cardiac arrhythmias occuring with cyclopropane is discussed.The place of the other available an?sthetic agents is discussed particularly on the advisability of using local an?sthesia for the drainage of empyema or lung abscess.Pharyngeal airway or endotracheal tube? An?sthesia may be maintained with a pharyngeal airway in many cases but intubation must be used when tracheobronchial suction may be necessary and when there may be difficulty in maintaining an unobstructed airway.A one-lung an?sthesia is ideal for pneumonectomy. This may be obtained by endotracheal an?sthesia after bronchial tamponage of the affected side (Crafoord, v. fig. 6b) or by an endobronchial intubation of the sound side (v. figs. 9b and 9c). Endobronchial placing of the breathing tube may be performed "blind". Before deciding on blind bronchial intubation, the an?sthetist must examine X-ray films for any abnormality deviating the trachea or bronchi. Though the right bronchus may be easily intubated blindly as a rule, there is the risk of occluding the orifice of the upper lobe bronchus (fig. 9d) when the patient will become cyanosed. If the tube bevel is facing its orifice the risk of occlusion will be decreased (fig. 9c).Greater accuracy in placing the tube can be effected by inserting it under direct vision. Instruments for performing this man?uvre are described.In lobectomy for bronchiectasis the an?sthetist must try to prevent the spread of infection to other parts. Ideally, the bronchus of the affected lobe should be plugged with ribbon gauze (Crafoord, v. fig. 6c) or a suction catheter with a baby balloon on it placed in the affected bronchus. In the presence of a large bronchopleural fistula controlled respiration cannot be established during operation. As the surgeon is rarely able to plug the fistula, if pneumonectomy is to be performed intubation for a one-lung an?sthesia is the best method. During other procedures it is essential to maintain quiet respiration.In war casualties it is almost always possible, with the technique described, to leave the lung on the affected side fully expanded and thus frequently to restore normal respiratory physiology. Co-operation between surgeon and an?sthetist is essential.     

The kinetics of diffusion between a spherical cell and a surrounding medium with different diffusion properties

The diffusion equation according to Fick’s law is solved for a spherical cell, surrounded by an infinite medium with different diffusion properties. The method of Laplace transform is used to obtain the formal solution, however, no inversion can be found for all times and an expansion suitable for small times is performed. The final expression found is expanded further to be more suited for the determination of the diffusion coefficient from an experimental curve. Application to a biological problem is dissussed.     

Stability in an evolutionary game

A behavior or strategy which is evolutionarily stable must be both optimal and stable. The strategy must be optimal in that it maximizes the expected fitness of all the individuals using it. In addition, the strategy must be resistant to invasion by a mutant. The difference between the Nash solution of game theory and the ESS used in ecology is that the Nash solution only satisfies an optimality criterion and not an evolutionary stability criterion. We extend the ESS definition of Maynard Smith and Price so that it can be applied directly to two-strategy evolutionary games. The concept of a balanced game is introduced, and necessary conditions are derived which are similar to the Nash necessary conditions. The balanced game necessary conditions may be used for direct calculation of ESS candidates. These results are used to examine the optimal flowering time of an annual plant experiencing competition from neighboring plants. The plant competition model is general, and the results may be applied to a wide range of interference competition problems.     

Use of flavin photochemistry to probe intraprotein and interprotein electron transfer mechanisms

Photoexcitation of flavin analogs generates the lowest triplet state (via intersystem crossing from the first excited singlet state) in the nanosecond time domain and with high quantum efficiency. The triplet, being a strong oxidant, can abstract a hydrogen atom (or an electron) from a reduced donor in a diffusion-controlled reaction. If the donor is a redox protein, the oxidation process can be used to initiate an electron transfer sequence involving either intramolecular or intermolecular reactions. If the donor is an organic compound such as EDTA, the neutral flavin semiquinone will be produced by H atom abstraction; this is a strong reductant and can subsequently transfer a hydrogen atom (or an electron) to an oxidized redox protein, thereby again initiating a sequence of intramolecular or intermolecular processes. If flavin photoexcitation is accomplished using a pulsed laser light source, the initiation of these protein electron transfer reactions can be made to occur in the nanosecond to microsecond time domain, and the sequence of events can be followed by time-resolved spectrophotometry to obtain rate constants and thus mechanistic information. The present paper describes this technology, and selected examples of its use in the investigation of redox protein mechanisms are given.