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Enhanced by Neuroinformation

Computation Reviews

(88 References)

Seeman, N. C. (2003). "DNA in a material world." Nature 421(6921): 427-31.

            The specific bonding of DNA base pairs provides the chemical foundation for genetics. This powerful molecular recognition system can be used in nanotechnology to direct the assembly of highly structured materials with specific nanoscale features, as well as in DNA computation to process complex information. The exploitation of DNA for material purposes presents a new chapter in the history of the molecule.

Jager, G. and A. Postma (2003). "On the hemispheric specialization for categorical and coordinate spatial relations: a review of the current evidence." Neuropsychologia 41(4): 504-15.

            This article reviews current evidence on the hemispheric specialization hypothesis for two types of spatial relations representations; categorical versus coordinate [Psychol. Rev. 94 (1987) 148; J. Exp. Psychol.: Percept. Perform. 15 (1989) 723]. Categorical representations capture general properties of the spatial structure of a visual stimulus, without defining the exact metric properties. Coordinate representations specify precise spatial locations of objects or parts in terms of metric units. It is claimed that a hemispheric difference in contribution to the computation of both types of spatial relations representations exists, in which the left hemisphere is specialized for the computation of categorical spatial representations while the right hemisphere is specialized for the computation of coordinate ones. Several forms of research (experimental, computer simulations, patient studies and neuroimaging studies) are reviewed. In general, there is convergent evidence for a conceptual separation of coordinate and categorical processing, with strongest indications for a relative right hemisphere advantage in encoding coordinate spatial relations, and weaker support for left hemispheric categorical specialization. The pattern appears to be critically linked to receptive field properties of the two hemispheres and as such is modulated by certain elementary visual characteristics of the displayed stimuli.

Jacoby, E., J. Davies, et al. (2003). "Design of small molecule libraries for NMR screening and other applications in drug discovery." Curr Top Med Chem 3(1): 11-23.

            There are conceptual differences between high-throughput screening (HTS) and fragment-based screening by NMR. The number of compounds in libraries for NMR screening may be significantly smaller than those used for HTS. Because one relies on a small library its design is significantly important and is the object of this article. A short introduction on fragment-based NMR screening approaches will be provided. Although there are currently very few reports describing the design of libraries of small molecules for NMR screening, aspects of the question of how to compile diverse collections of small molecular fragments useful for drug design were previously addressed for the purposes of combinatorial library design and de novo drug design. As these disciplines are highly interrelated and are applied in an interconnected manner with NMR screening within the drug discovery process, a review of combinatorial library design and especially the building block or fragment selection strategies applied for combinatorial library design and de novo design is well suited to reveal fundamental strategies and potential techniques for the design of NMR screening libraries. This section will be rounded off by a report on hands-on-experience with the design of the Novartis second-site NMR screening library and practical considerations for the design of compound mixtures. Rather than providing an exact protocol general guidelines will be indicated.

Zajac, F. E., R. R. Neptune, et al. (2002). "Biomechanics and muscle coordination of human walking. Part I: introduction to concepts, power transfer, dynamics and simulations." Gait Posture 16(3): 215-32.

            Current understanding of how muscles coordinate walking in humans is derived from analyses of body motion, ground reaction force and EMG measurements. This is Part I of a two-part review that emphasizes how muscle-driven dynamics-based simulations assist in the understanding of individual muscle function in walking, especially the causal relationships between muscle force generation and walking kinematics and kinetics. Part I reviews the strengths and limitations of Newton-Euler inverse dynamics and dynamical simulations, including the ability of each to find the contributions of individual muscles to the acceleration/deceleration of the body segments. We caution against using the concept of biarticular muscles transferring power from one joint to another to infer muscle coordination principles because energy flow among segments, even the adjacent segments associated with the joints, cannot be inferred from computation of joint powers and segmental angular velocities alone. Rather, we encourage the use of dynamical simulations to perform muscle-induced segmental acceleration and power analyses. Such analyses have shown that the exchange of segmental energy caused by the forces or accelerations induced by a muscle can be fundamentally invariant to whether the muscle is shortening, lengthening, or neither. How simulation analyses lead to understanding the coordination of seated pedaling, rather than walking, is discussed in this first part because the dynamics of pedaling are much simpler, allowing important concepts to be revealed. We elucidate how energy produced by muscles is delivered to the crank through the synergistic action of other non-energy producing muscles; specifically, that a major function performed by a muscle arises from the instantaneous segmental accelerations and redistribution of segmental energy throughout the body caused by its force generation. Part II reviews how dynamical simulations provide insight into muscle coordination of walking.

Winfree, A. T. (2002). "Chemical waves and fibrillating hearts: discovery by computation." J Biosci 27(5): 465-73.

Straub, J. E., J. Guevara, et al. (2002). "Long time dynamic simulations: exploring the folding pathways of an Alzheimer's amyloid Abeta-Peptide." Acc Chem Res 35(6): 473-81.

            We describe the MaxFlux algorithm for the computation of likely pathways for global macromolecular conformational transitions. The algorithm assumes an overdamped diffusive dynamics for the biomolecule, appropriate to large scale conformational changes. As an application of the MaxFlux method, we explore conformational transitions between alpha-helical, collapsed coil, and beta-sheet conformations of an amyloid Abeta-peptide. The resulting transition pathways are analyzed in terms of the mechanism of conformational transition and the progression of the peptide energetics in both an aqueous and a membrane-mimicking nonpolar solvent.

Siegal, M. and R. Varley (2002). "Neural systems involved in "theory of mind"." Nat Rev Neurosci 3(6): 463-71.

            What is the nature of our ability to understand and reason about the beliefs of others--the possession of a "theory of mind", or ToM? Here, we review findings from imaging and lesion studies indicating that ToM reasoning is supported by a widely distributed neural system. Some functional components of this system, such as language-related regions of the left hemisphere, the frontal lobes and the right temporal parietal cortex, are not solely dedicated to the computation of mental states. However, the system also includes a core, domain-specific component that is centred on the amygdala circuitry. We provide a framework in which impairments of ToM can be viewed in terms of abnormalities of the core system, the failure of a co-opted system that is necessary for performance on a particular set of tasks, or the absence of an experiential trigger for the emergence of ToM.

Shapiro, J. A. (2002). "Genome organization and reorganization in evolution: formatting for computation and function." Ann N Y Acad Sci 981: 111-34.

            This volume deals with the role of epigenetics in life and evolution. The most dynamic forms of functional genome formatting involve DNA interacting with cellular complexes that do not alter sequence information. Such important epigenetic phenomena are the main subjects of other articles in this volume. This article focuses on the long-lived form of genome formatting that lies within the DNA sequence itself. I argue for a computational view of genome function as the long-term information storage organelle of each cell. Structural formatting consists of organizing various signals and coding sequences into computationally ready systems facilitating genome expression and genome transmission. The basic features of genome organization can be understood by examining the E. coli lac operon as a paradigmatic genomic system. Multiple systems are connected through distributed signals and repetitive DNA to form higher-order genome system architectures. Molecular discoveries about mechanisms of DNA restructuring show that cells possess the natural genetic engineering functions necessary for evolutionary change by rearranging genomic components and reorganizing system architectures. The concepts of cellular computation and decision-making, genome system architecture, and natural genetic engineering combine to provide a new way of framing evolutionary theories and understanding genome sequence information.

Rousseau, A. and P. Marquet (2002). "Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs." Fundam Clin Pharmacol 16(4): 253-62.

            Over the last 10 years, proofs of the clinical interest of therapeutic drug monitoring (TDM) of certain anticancer drugs have been established. Numerous studies have shown that TDM is an efficient tool for controlling the toxicity of therapeutic drugs, and a few trials have even demonstrated that it can improve their efficacy. This article critically reviews TDM tools based on pharmacokinetic modelling of anticancer drugs. The administered dose of anticancer drugs is sometimes adjusted individually using either a priori or a posteriori methods. The most frequent clinical application of a priori formulae concerns carboplatin and allows the computation of the first dose based on biometrical and biological data such as weight, age, gender, creatinine clearance and glomerular filtration rate. A posteriori methods use drug plasma concentrations to adjust the subsequent dose(s). Thus, nomograms allowing dose adjustment on the basis of blood concentration are routinely used for 5-fluorouracil given as long continuous infusions. Multilinear regression models have been developed, for example for etoposide, doxorubicin. carboplatin, cyclophosphamide and irinotecan, to predict a single exposure variable [such as area under concentration-time curve (AUC)] from a small number of plasma concentrations obtained at predetermined times after a standard dose. These models can only be applied by using the same dose and schedule as the original study. Bayesian estimation offers more flexibility in blood sampling times and, owing to its precision and to the amount of information provided, is the method of choice for ensuring that a given patient benefits from the desired systemic exposure. Unlike the other a posteriori methods, Bayesian estimation is based on population pharmacokinetic studies and can take into account the effects of different individual factors on the pharmacokinetics of the drug. Bayesian estimators have been used to determine maximum tolerated systemic exposure thresholds (e.g. for topotecan or teniposide) as well as for the routine monitoring of drugs characterized by a very high interindividual pharmacokinetic variability such as methotrexate or carboplatin. The development of these methods has contributed to improving cancer chemotherapy in terms of patient outcome and survival and should be pursued.

Rey, S., P. A. Carrupt, et al. (2002). "The Hydrogen-Bond: computational approaches and applications to drug design." Ann Pharm Fr 60(6): 386-96.

            This mini-review begins with a presentation of the hydrogen-bond in the context of other intermolecular recognition forces of significance in molecular biology and molecular pharmacology. This is followed by a survey of the various computational methods available to calculate the hydrogen-bonding capacity of compounds. Such methods use quantum mechanics, molecular mechanics, or algorithms based on experimental fragmental values. A recent and promising advance in the computation of H-bonding capacity is the development of specific molecular interaction fields (MIFs) known as molecular hydrogen-bonding potentials (MHBPs). Their interest in relating molecular properties to pharmacokinetic behaviour is highlighted with two examples, namely oral drug absorption and blood-brain barrier permeation.

Polk, T. A., P. Simen, et al. (2002). "A computational approach to control in complex cognition." Brain Res Cogn Brain Res 15(1): 71-83.

            Cognitive deficits associated with dorsolateral prefrontal cortex (DLPFC) damage are often most apparent in higher cognitive tasks that involve problem solving and managing multiple goals. However, computational models of prefrontal deficits on such tasks are difficult to construct. Problem solving is most naturally modeled with symbolic systems (e.g. production systems), but the effects of lesions are most naturally modeled with subsymbolic systems (neural networks). We show that when we adopt a simple and plausible model of neural computation, there is a natural and explicit mapping from symbolic, goal-driven cognition onto neural computation. We exploit this mapping to construct a neural network model that is capable of solving complex problems in the Tower of London task. The model leads to a specific hypothesis about the role of DLPFC in such tasks, namely, that DLPFC represents internally generated subgoals that modulate competition among posterior representations. When intact, the model accurately simulates the behavior of college students even on the most difficult problems. Furthermore, when the subgoal component is lesioned, it accurately simulates the behavior of prefrontal patients, including the fact that their deficits are most apparent on the most difficult tasks and that they have special difficulty with tasks that require inhibiting a prepotent response.

Niederberger, C. S. (2002). "Understanding the epidemiology of fertility treatments." Urol Clin North Am 29(4): 829-40.

            The science of statistics forms the basis of much of what urologists do and why. Understanding basic statistics is crucial to the appropriate interpretation of urologic studies. As valid as they are, the statistics taught in medical school represent only a small part of what computation can do for the urologist. Contemporary tools such as neural computation coupled with electronic technology that provides increasingly greater computational power in smaller space hold promise to integrate into the field of clinical urology as seamlessly as a ballpoint pen or cystoscope.

Menzel, S. (2002). "Genetic and molecular analyses of complex metabolic disorders: genetic linkage." Ann N Y Acad Sci 967: 249-57.

            Wide efforts have taken place with complex metabolic disorders to emulate the success that linkage analysis has had in explaining the nature of monogenic metabolic diseases such as MODY (maturity-onset diabetes of the young) and FH (familial hypercholesterolemia). New linkage methods are being specifically developed and tested for complex disorders since some of the basic assumptions of traditional linkage analysis used with Mendelian traits are not valid. The nature of complex diseases precludes the use of extended families under the hypothesis that the same disease allele acts in most affected individuals throughout a pedigree. Rather, a multitude of genes and of rare and common alleles creates an apparently chaotic pattern of heterogeneity within and between families. Therefore, very simple family structures, in many studies even isolated sibling pairs, form the basis of efforts to compare the inheritance of disease with that of the chromosomal regions under investigation. Also, assumptions about how individual loci contribute to the overall disease inheritance used for the models applied in linkage computation have to be kept to a minimum. The overall effect of this, together with the potentially weak influence of many loci, is a heavy toll on the statistical power to detect individual contributing genes. This may be the reason why very few scans so far have yielded disease loci that meet genome-wide significance criteria. The confirmation of original loci in secondary studies has proven, as predicted, to be very difficult. Nevertheless, the overall emerging picture is very encouraging: one of the genome scans in type 2 diabetes has been carried through to the positional cloning of the underlying genetic variant, namely, the calpain 10-associated polymorphism in type 2 diabetes. Several other loci have been detected repeatedly throughout studies in various human racial groups, such as the chromosome 1q and 20q diabetes loci, and have become the target of collaborative fine-mapping efforts. Modifications to present methodology are in development with the goal to increase statistical power: examples are the use of intermediate traits with potentially increased genetic homogeneity, the investigation of admixed populations, and the study of linkage disequilibrium over wide genomic regions.

Makeig, S. (2002). "Response: event-related brain dynamics -- unifying brain electrophysiology." Trends Neurosci 25(8): 390.

Maeda, N. (2002). "Evaluation of optical quality of corneas using corneal topographers." Cornea 21(7 Suppl): S75-8.

            PURPOSE: To review the evaluation of the optical quality of the cornea by corneal topography. METHODS AND RESULTS: Color-coded maps show qualitatively the characteristics and severity of irregular astigmatism at the entrance pupil. Topographic indices such as the surface regularity index and predicted corneal acuity are derived from computation of the corneal power distribution, and they are highly correlated with high-contrast visual acuity. Fourier analysis can be used to represent the irregular and regular astigmatism components simultaneously. Zernike polynomials can be used to calculate higher-order wavefront aberrations due to the corneal surface. CONCLUSION: Evaluation of the optical properties of the cornea using a corneal topographer is useful for assessing quality of vision.

Lombardi, F. (2002). "Clinical implications of present physiological understanding of HRV components." Card Electrophysiol Rev 6(3): 245-9.

            Time and frequency domain analysis of heart rate variability (HRV) is a non invasive technique capable of providing information on autonomic modulation of the sinus node and of stratifying risk after myocardial infarction and in heart failure. One of the basic assumptions used to explain the negative predictive value of reduced HRV was the concept that overall HRV was largely dependent on vagal mechanisms and that a reduction in HRV could reflect an increased sympathetic and a reduced vagal modulation of sinus node; i.e., an autonomic imbalance favouring cardiac electrical instability. This initial interpretation was challenged by several findings indicating a greater complexity of the relationship between neural input and sinus node responsiveness as well as the possible interference with non neural mechanisms.Nevertheless, the prognostic value of time and geometric parameters of HRV has been consistently confirmed. More complex is the interpretation of spectral parameters particularly when they are computed on 24-hour recordings. Under controlled conditions, instead, the computation of low and high frequency components and of their ratio seems to provide information on sympatho-vagal balance in normal subjects as well as in most patients with preserved left ventricular function, thus providing an unique tool to investigate neural control mechanisms. More recently, analysis on nonlinear dynamics of HRV has been utilized to describe the fractal-like characteristics of the variability signal and has been shown to identify patients at risk for sudden cardiac death.In conclusion, in spite of an incomplete understanding of the physiological significance of HRV parameters, this non invasive methodology is of substantial utility to evaluate autonomic control mechanisms and to identify patients with an increased cardiac mortality.

Loewenstein, Y. (2002). "A possible role of olivary gap-junctions in the generation of physiological and pathological tremors." Mol Psychiatry 7(2): 129-31.

Kirby, S. (2002). "Natural language from artificial life." Artif Life 8(2): 185-215.

            This article aims to show that linguistics, in particular the study of the lexico-syntactic aspects of language, provides fertile ground for artificial life modeling. A survey of the models that have been developed over the last decade and a half is presented to demonstrate that ALife techniques have a lot to offer an explanatory theory of language. It is argued that this is because much of the structure of language is determined by the interaction of three complex adaptive systems: learning, culture, and biological evolution. Computational simulation, informed by theoretical linguistics, is an appropriate response to the challenge of explaining real linguistic data in terms of the processes that underpin human language.

Joel, D., Y. Niv, et al. (2002). "Actor-critic models of the basal ganglia: new anatomical and computational perspectives." Neural Netw 15(4-6): 535-47.

            A large number of computational models of information processing in the basal ganglia have been developed in recent years. Prominent in these are actor-critic models of basal ganglia functioning, which build on the strong resemblance between dopamine neuron activity and the temporal difference prediction error signal in the critic, and between dopamine-dependent long-term synaptic plasticity in the striatum and learning guided by a prediction error signal in the actor. We selectively review several actor-critic models of the basal ganglia with an emphasis on two important aspects: the way in which models of the critic reproduce the temporal dynamics of dopamine firing, and the extent to which models of the actor take into account known basal ganglia anatomy and physiology. To complement the efforts to relate basal ganglia mechanisms to reinforcement learning (RL), we introduce an alternative approach to modeling a critic network, which uses Evolutionary Computation techniques to 'evolve' an optimal RL mechanism, and relate the evolved mechanism to the basic model of the critic. We conclude our discussion of models of the critic by a critical discussion of the anatomical plausibility of implementations of a critic in basal ganglia circuitry, and conclude that such implementations build on assumptions that are inconsistent with the known anatomy of the basal ganglia. We return to the actor component of the actor-critic model, which is usually modeled at the striatal level with very little detail. We describe an alternative model of the basal ganglia which takes into account several important, and previously neglected, anatomical and physiological characteristics of basal ganglia-thalamocortical connectivity and suggests that the basal ganglia performs reinforcement-biased dimensionality reduction of cortical inputs. We further suggest that since such selective encoding may bias the representation at the level of the frontal cortex towards the selection of rewarded plans and actions, the reinforcement-driven dimensionality reduction framework may serve as a basis for basal ganglia actor models. We conclude with a short discussion of the dual role of the dopamine signal in RL and in behavioral switching.

Ishida, K. and T. Asao (2002). "Self-association and unique DNA binding properties of the anti-cancer agent TAS-103, a dual inhibitor of topoisomerases I and II." Biochim Biophys Acta 1587(2-3): 155-63.

            The objective of our study was to investigate the self-association and DNA-binding properties of the DNA topoisomerases I (Topo I) and II (Topo II) dual inhibitor: 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinoline-7-on e dihydrochloride (TAS-103), by means of 1H-NMR and 31P-NMR spectroscopy, structure computation techniques, thermal melting study, and UV-Visible spectroscopy. In aqueous solution, all chemical shifts of TAS-103 underwent upfield shifts depending with an increase in concentration. The two-dimensional (2D)-NMR spectra and structure computations indicated that TAS-103 self-associated through pi-pi stacking and hydrophobic interactions of the aromatic chromophores. Thermal melting indicated that the binding of TAS-103 to DNA with a potency equal to that of ethidium bromide (EtBr). The UV-Visible spectra of TAS-103 titrated by several DNA exhibited hypochromic and hypsochromic effects. The 31P-NMR spectrum of the 6:1 TAS-103/d(CGCGAATTCGCG)(2) complex showed two broadening signals. 2D-NMR spectra of the 1:1 TAS-103/d(CGCGAATTCGCG)(2) complex indicated that the chemical shift differences of the DNA are very small. However, those of the terminal region are relatively large. The chemical shift differences of TAS-103 showed that the proton resonances except H2 underwent downfield shifts. From these observations, we conclude that TAS-103 binds to DNA by two modes. The major binding mode is on the surface (outside binding) and the minor binding mode by intercalation.

Hochstein, S. and M. Ahissar (2002). "View from the top: hierarchies and reverse hierarchies in the visual system." Neuron 36(5): 791-804.

            We propose that explicit vision advances in reverse hierarchical direction, as shown for perceptual learning. Processing along the feedforward hierarchy of areas, leading to increasingly complex representations, is automatic and implicit, while conscious perception begins at the hierarchy's top, gradually returning downward as needed. Thus, our initial conscious percept--vision at a glance--matches a high-level, generalized, categorical scene interpretation, identifying "forest before trees." For later vision with scrutiny, reverse hierarchy routines focus attention to specific, active, low-level units, incorporating into conscious perception detailed information available there. Reverse Hierarchy Theory dissociates between early explicit perception and implicit low-level vision, explaining a variety of phenomena. Feature search "pop-out" is attributed to high areas, where large receptive fields underlie spread attention detecting categorical differences. Search for conjunctions or fine discriminations depends on reentry to low-level specific receptive fields using serial focused attention, consistent with recently reported primary visual cortex effects.

Grigera, J. R. (2002). "Molecular dynamics simulation for ligand-receptor studies. Carbohydrates interactions in aqueous solutions." Curr Pharm Des 8(17): 1579-604.

            The review deals with the problem of the study of ligand-receptor interactions and the use of Molecular Dynamics (MD) simulation to approach such a problem. After a short review of the fundamentals of MD we describe the medium in which all biology takes place, water. Emphasis is put on the water models appropriate for simulation of macromolecular systems explicitly including the water molecules. We consider the quality of the water model both in terms of simplicity and performance to describe the liquid water properties. Heavy water, although not a biologically viable medium, is considered since many experiments make use of it as a solvent. Sweetness of carbohydrates is considered as an example of the procedure suitable to characterize active sites on the ligands. Consideration is given to the computation of the binding constants through molecular dynamics. The computation of the Free Energy is described and illustrated. The potentiality of MD for studies of ligand-receptor interactions is limited by the computer resources, for even with large computing facilities the need of relatively long simulation times severely restricts the study of large systems. A method is described in which several shells are treated at different levels of approximation, form mechanical response and mean electrical field to quantum mechanics, through stochastic dynamics and atomic classical MD. The review closes with a brief account of the perspectives of the method.

Egan, W. J. and G. Lauri (2002). "Prediction of intestinal permeability." Adv Drug Deliv Rev 54(3): 273-89.

            This review focuses on computational methods for the prediction of passive intestinal permeability. Existing computational models are surveyed and assessed in terms of descriptors, model type/complexity, speed of computation, predictive performance, and interpretability. Challenges to the successful computational prediction of intestinal permeability, i.e. data quantity, measurement imprecision, confounding factors such as solubility, metabolism, or active efflux, and the need for robust statistical methods, are also discussed.

Biswas, A. and K. Das (2002). "A Bayesian analysis of bivariate ordinal data: Wisconsin epidemiologic study of diabetic retinopathy revisited." Stat Med 21(4): 549-59.

            In many biomedical experiments one may often encounter bivariate data which are component-wise ordinal. The data set of the ophthalmologic experiment of the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) is an example of such data. Several authors considered the analysis of such data from different viewpoints. The present work reviews the existing literature based on the WESDR data and on the basis of some latent variables provide the technique for analysing such data more easily in a Bayesian framework. Computation supports the methodology to a great extent. A comparison between our approach and the likelihood based approach considered by Kim has also been made.

Batzer, M. A. and P. L. Deininger (2002). "Alu repeats and human genomic diversity." Nat Rev Genet 3(5): 370-9.

            During the past 65 million years, Alu elements have propagated to more than one million copies in primate genomes, which has resulted in the generation of a series of Alu subfamilies of different ages. Alu elements affect the genome in several ways, causing insertion mutations, recombination between elements, gene conversion and alterations in gene expression. Alu-insertion polymorphisms are a boon for the study of human population genetics and primate comparative genomics because they are neutral genetic markers of identical descent with known ancestral states.

Avidan, G. and M. Behrmann (2002). "Correlations between the fMRI BOLD signal and visual perception." Neuron 34(4): 495-7.

            Using fMRI and a psychophysical task involving letter identification, Kleinschmidt et al. (2002) (this issue of Neuron) delineate two patterns of neural activation, which manifest in different cortical regions: a transient activation, correlated with the change of a percept, and a longer-term hysteresis, correlated with the maintenance of the percept. These findings are provocative and suggest that neural hysteresis is mediated by visual structures that interact with higher-order regions to support longer-term maintenance of a percept.

Andrus, M. R. and M. T. Roth (2002). "Health literacy: a review." Pharmacotherapy 22(3): 282-302.

            Illiteracy has become an increasingly important problem, especially as it relates to health care. A national survey found that almost half of the adult population has deficiencies in reading or computation skills. Literacy is defined as the basic ability to read and speak English, whereas functional health literacy is the ability to read, understand, and act on health information. Up to 48% of English-speaking patients do not have adequate functional health literacy. The consequences of inadequate health literacy include poorer health status, lack of knowledge about medical care and medical conditions, decreased comprehension of medical information, lack of understanding and use of preventive services, poorer self-reported health, poorer compliance rates, increased hospitalizations, and increased health care costs. The medical community must acknowledge this issue and develop strategies to ensure that patients receive assistance in overcoming the barriers that limit their ability to function adequately in the health care environment.

Amiel-Tison, C. (2002). "Update of the Amiel-Tison neurologic assessment for the term neonate or at 40 weeks corrected age." Pediatr Neurol 27(3): 196-212.

            Amiel-Tison neurologic assessment at term has recently been updated for clinical application. Experience in this field, in addition to a better understanding of pathophysiologic characteristics of the immature brain, has taught us that an increased precision in assessing central nervous system function in the neonate is compatible with a simplification of the clinical instrument. The complete procedure takes approximately 5 minutes. A simple 0, 1, and 2 scoring system is proposed. Because this coding system is not quantitative, any computation of quotient or total score is inappropriate. Rather, a final synthesis based on clusters of signs and symptoms is advisable. A distinct final synthesis is proposed for term newborn infants in the first week of life and for preterm neonates at approximately 40 weeks of age corrected. Clinical profiles emerging from repeated assessments in the term newborn and early clinical findings indicating a brain damage of prenatal origin are described. Interrater reliability has been proved to be more than satisfactory. Such an assessment is useful for any newborn infant in maternity wards or for any preterm infant approximately 40 weeks of age, with or without abnormal imaging findings.

Zadeh, L. A. (2001). "From computing with numbers to computing with words. From manipulation of measurements to manipulation of perceptions." Ann N Y Acad Sci 929: 221-52.

            Interest in issues relating to consciousness has grown markedly during the last several years. And yet, nobody can claim that consciousness is a well-understood concept that lends itself to precise analysis. It may be argued that, as a concept, consciousness is much too complex to fit into the conceptual structure of existing theories based on Aristotelian logic and probability theory. An approach suggested in this paper links consciousness to perceptions and perceptions to their descriptors in a natural language. In this way, those aspects of consciousness which relate to reasoning and concept formation are linked to what is referred to as the methodology of computing with words (CW). Computing, in its usual sense, is centered on manipulation of numbers and symbols. In contrast, computing with words, or CW for short, is a methodology in which the objects of computation are words and propositions drawn from a natural language (e.g., small, large, far, heavy, not very likely, the price of gas is low and declining, Berkeley is near San Francisco, it is very unlikely that there will be a significant increase in the price of oil in the near future, etc.). Computing with words is inspired by the remarkable human capability to perform a wide variety of physical and mental tasks without any measurements and any computations. Familiar examples of such tasks are parking a car, driving in heavy traffic, playing golf, riding a bicycle, understanding speech, and summarizing a story. Underlying this remarkable capability is the brain's crucial ability to manipulate perceptions--perceptions of distance, size, weight, color, speed, time, direction, force, number, truth, likelihood, and other characteristics of physical and mental objects. Manipulation of perceptions plays a key role in human recognition, decision and execution processes. As a methodology, computing with words provides a foundation for a computational theory of perceptions: a theory which may have an important bearing on how humans make--and machines might make--perception-based rational decisions in an environment of imprecision, uncertainty, and partial truth. A basic difference between perceptions and measurements is that, in general, measurements are crisp, whereas perceptions are fuzzy. One of the fundamental aims of science has been and continues to be that of progressing from perceptions to measurements. Pursuit of this aim has led to brilliant successes. We have sent men to the moon; we can build computers that are capable of performing billions of computations per second; we have constructed telescopes that can explore the far reaches of the universe; and we can date the age of rocks that are millions of years old. But alongside the brilliant successes stand conspicuous underachievements and outright failures. We cannot build robots that can move with the agility of animals or humans; we cannot automate driving in heavy traffic; we cannot translate from one language to another at the level of a human interpreter; we cannot create programs that can summarize non-trivial stories; our ability to model the behavior of economic systems leaves much to be desired; and we cannot build machines that can compete with children in the performance of a wide variety of physical and cognitive tasks. It may be argued that underlying the underachievements and failures is the unavailability of a methodology for reasoning and computing with perceptions rather than measurements. An outline of such a methodology--referred to as a computational theory of perceptions--is presented in this paper. The computational theory of perceptions (CTP) is based on the methodology of CW. In CTP, words play the role of labels of perceptions, and, more generally, perceptions are expressed as propositions in a natural language. CW-based techniques are employed to translate propositions expressed in a natural language into what is called the Generalized Constraint Language (GCL). In this language, the meaning of a proposition is expressed as a generalized constraint, X isr R, where X is the constrained variable, R is the constraining relation, and isr is a variable copula in which r is an indexing variable whose value defines the way in which R constrains X. Among the basic types of constraints are possibilistic, veristic, probabilistic, random set, Pawlak set, fuzzy graph, and usuality. The wide variety of constraints in GCL makes GCL a much more expressive language than the language of predicate logic. In CW, the initial and terminal data sets, IDS and TDS, are assumed to consist of propositions expressed in a natural language. These propositions are translated, respectively, into antecedent and consequent constraints. Consequent constraints are derived from antecedent constraints through the use of rules of constraint propagation. The principal constraint propagation rule is the generalized extension principle. (ABSTRACT TRUNCATED)

Xiao, W. and P. J. Oefner (2001). "Denaturing high-performance liquid chromatography: A review." Hum Mutat 17(6): 439-74.

            Denaturing high-performance liquid chromatography (DHPLC) compares two or more chromosomes as a mixture of denatured and reannealed PCR amplicons, revealing the presence of a mutation by the differential retention of homo- and heteroduplex DNA on reversed-phase chromatography supports under partial denaturation. Temperature determines sensitivity, and its optimum can be predicted by computation. Single-nucleotide substitutions, deletions, and insertions have been detected successfully by on-line UV or fluorescence monitoring within 2-3 minutes in unpurified amplicons as large as 1.5 Kb. Sensitivity and specificity of DHPLC consistently exceed 96%. These features and its low cost make DHPLC one of the most powerful tools for the re-sequencing of the human and other genomes. Aside from its application to the mutational analysis of candidate genes, DHPLC has proven instrumental in elucidating human evolution and in the mapping of genes. Employing completely denaturing conditions, the utility of DHPLC has been extended to the genotyping of known polymorphisms by utilizing the ability of poly(styrene-divinylbenzene) to resolve single-stranded DNA molecules of identical size that differ in a single base. Under completely denaturing conditions, it is thus possible to resolve all possible base substitutions with the single exception of C-->G transversions. Improvements in throughput became feasible with the recent introduction of monolithic poly(styrene-divinylbenzene) capillaries that lend themselves to the fabrication of arrays connected to a multi-color laser induced fluorescence scanner or a mass spectrometer.

Wassle, H. (2001). "Knock out of direction selectivity in the retina." Neuron 30(3): 644-6.

            Retinal ganglion cells show direction selectivity in their responses to moving stimuli. The circuitry necessary to generate directional selectivity in these cells has been long debated. Yoshida et al. (2001) use immunotoxin-mediated cell ablation to demonstrate that the starburst amacrine cell is at the core of this computation.

Vandenberghe, S., Y. D'Asseler, et al. (2001). "Iterative reconstruction algorithms in nuclear medicine." Comput Med Imaging Graph 25(2): 105-11.

            Iterative reconstruction algorithms produce accurate images without streak artifacts as in filtered backprojection. They allow improved incorporation of important corrections for image degrading effects, such as attenuation, scatter and depth-dependent resolution. Only some corrections, which are important for accurate reconstruction in positron emission tomography and single photon emission computed tomography, can be applied to the data before filtered backprojection. The main limitation for introducing iterative algorithms in nuclear medicine has been computation time, which is much longer for iterative techniques than for filtered backprojection. Modern algorithms make use of acceleration techniques to speed up the reconstruction. These acceleration techniques and the development in computer processors have introduced iterative reconstruction in daily nuclear medicine routine. We give an overview of the most important iterative techniques and discuss the different corrections that can be incorporated to improve the image quality.

van Schaik, A. (2001). "Building blocks for electronic spiking neural networks." Neural Netw 14(6-7): 617-28.

            We present an electronic circuit modelling the spike generation process in the biological neuron. This simple circuit is capable of simulating the spiking behaviour of several different types of biological neurons. At the same time, the circuit is small so that many neurons can be implemented on a single silicon chip. This is important, as neural computation obtains its power not from a single neuron, but from the interaction between a large number of neurons. Circuits that model these interactions are also presented in this paper. They include the circuits for excitatory, inhibitory and shunting inhibitory synapses, a circuit which models the regeneration of spikes on the axon, and a circuit which models the reduction of input strength with the distance of the synapse to the cell body on the dendrite of the cell. Together these building blocks allow the implementation of electronic spiking neural networks.

Ullman, M. T. (2001). "The declarative/procedural model of lexicon and grammar." J Psycholinguist Res 30(1): 37-69.

            Our use of language depends upon two capacities: a mental lexicon of memorized words and a mental grammar of rules that underlie the sequential and hierarchical composition of lexical forms into predictably structured larger words, phrases, and sentences. The declarative/procedural model posits that the lexicon/grammar distinction in language is tied to the distinction between two well-studied brain memory systems. On this view, the memorization and use of at least simple words (those with noncompositional, that is, arbitrary form-meaning pairings) depends upon an associative memory of distributed representations that is subserved by temporal-lobe circuits previously implicated in the learning and use of fact and event knowledge. This "declarative memory" system appears to be specialized for learning arbitrarily related information (i.e., for associative binding). In contrast, the acquisition and use of grammatical rules that underlie symbol manipulation is subserved by frontal/basal-ganglia circuits previously implicated in the implicit (nonconscious) learning and expression of motor and cognitive "skills" and "habits" (e.g., from simple motor acts to skilled game playing). This "procedural" system may be specialized for computing sequences. This novel view of lexicon and grammar offers an alternative to the two main competing theoretical frameworks. It shares the perspective of traditional dual-mechanism theories in positing that the mental lexicon and a symbol-manipulating mental grammar are subserved by distinct computational components that may be linked to distinct brain structures. However, it diverges from these theories where they assume components dedicated to each of the two language capacities (that is, domain-specific) and in their common assumption that lexical memory is a rote list of items. Conversely, while it shares with single-mechanism theories the perspective that the two capacities are subserved by domain-independent computational mechanisms, it diverges from them where they link both capacities to a single associative memory system with broad anatomic distribution. The declarative/procedural model, but neither traditional dual- nor single-mechanism models, predicts double dissociations between lexicon and grammar, with associations among associative memory properties, memorized words and facts, and temporal-lobe structures, and among symbol-manipulation properties, grammatical rule products, motor skills, and frontal/basal-ganglia structures. In order to contrast lexicon and grammar while holding other factors constant, we have focused our investigations of the declarative/procedural model on morphologically complex word forms. Morphological transformations that are (largely) unproductive (e.g., in go-went, solemn-solemnity) are hypothesized to depend upon declarative memory. These have been contrasted with morphological transformations that are fully productive (e.g., in walk-walked, happy-happiness), whose computation is posited to be solely dependent upon grammatical rules subserved by the procedural system. Here evidence is presented from studies that use a range of psycholinguistic and neurolinguistic approaches with children and adults. It is argued that converging evidence from these studies supports the declarative/procedural model of lexicon and grammar.

Tanaka, S. (2001). "Computational approaches to the architecture and operations of the prefrontal cortical circuit for working memory." Prog Neuropsychopharmacol Biol Psychiatry 25(1): 259-81.

            1. This article reviews recent progress in the computational studies towards the architecture and operations of the prefrontal cortical circuit, which are keys to understand the mechanisms of working memory processing. 2. The recurrent excitatory connections form closed-loop circuits, which contribute to the sustainment of delay-period activity. These connections subserve the cortical amplification of the activity. 3. Recent experimental studies (Wilson et al. 1994; Rao et al. 1999, 2000) suggested that at least two architectonically distinct types of intracortical inhibition, isodirectional and cross-directional inhibition, play significant roles in the formation of memory fields. 4. Computer simulations of a prefrontal cortical circuit model (Tanaka 1999, 2000a) showed that the isodirectional inhibition in the model regulated the amplitude of memory fields (i.e., the maximum firing rate) while the cross-directional inhibition contributed to the sharpening of the memory fields or the tuning curves. 5. The above characteristics enable the prefrontal cortical circuit to control memory fields, which would be necessary to general working memory processing. It would also be interesting to know whether different subtypes of the interneurons have distinct roles. 6. Another important issue is how neuromodulators contribute to working memory processing. Recent computer simulations by Durstewitz et al. (1999, 2000) showed that stronger dopamine action required stronger intervening input to destroy working memory, suggesting that dopamine contributes to the stabilization of working memory representation. 7. Further elucidation of these issues based on more detailed anatomical data of the cortical circuitry would make the architecture and operations of the prefrontal cortical circuit be more clearly described.

Shin, J. (2001). "Adaptation in spiking neurons based on the noise shaping neural coding hypothesis." Neural Netw 14(6-7): 907-19.

            Shin, Koch and Douglas [Shin, J., Koch, C., & Douglas, R. (1999). Adaptive neural coding dependent on the time-varying statistics of the somatic input current. Neural Computation, 11, 1983-2003] proposed an adaptive neural coding model that makes spiking neurons adapt its input/output relation to the stimulus statistics. In a surprisingly precise manner, the adaptive neural coding model has been supported by recent experiments. However, the previous report has two problems: (a) although the adaptive neural coding model was developed based on the noise shaping neural coding hypothesis, their connection was not explained clearly in the previous report; and (b) the previous model did not suggest a biologically plausible method to estimate the stimulus mean and variance from spike-evoked intracellular calcium concentration. In this paper, I present how the noise shaping neural coding hypothesis produced such a precise model without any available experimental data at that time. Moreover, I propose a computational model for a biologically plausible signal statistics extraction from spike-evoked intracellular calcium concentration. An asymmetry in contrast adaptation time between increasing and decreasing variance, observed in biological experiments, is explained using the signal statistics extraction method. In addition, a new perspective on the relationship between the spike train of spiking neurons and EEG (or local field potential (LFP)) is suggested based on the noise shaping neural coding hypothesis.

Shimojo, S. and L. Shams (2001). "Sensory modalities are not separate modalities: plasticity and interactions." Curr Opin Neurobiol 11(4): 505-9.

            Historically, perception has been viewed as a modular function, with the different sensory modalities operating independently of each other. Recent behavioral and brain imaging studies challenge this view, by suggesting that cross-modal interactions are the rule and not the exception in perception, and that the cortical pathways previously thought to be sensory-specific are modulated by signals from other modalities.

Salinas, E. and T. J. Sejnowski (2001). "Gain modulation in the central nervous system: where behavior, neurophysiology, and computation meet." Neuroscientist 7(5): 430-40.

            Gain modulation is a nonlinear way in which neurons combine information from two (or more) sources, which may be of sensory, motor, or cognitive origin. Gain modulation is revealed when one input, the modulatory one, affects the gain or the sensitivity of the neuron to the other input, without modifying its selectivity or receptive field properties. This type of modulatory interaction is important for two reasons. First, it is an extremely widespread integration mechanism; it is found in a plethora of cortical areas and in some subcortical structures as well, and as a consequence it seems to play an important role in a striking variety of functions, including eye and limb movements, navigation, spatial perception, attentional processing, and object recognition. Second, there is a theoretical foundation indicating that gain-modulated neurons may serve as a basis for a general class of computations, namely, coordinate transformations and the generation of invariant responses, which indeed may underlie all the brain functions just mentioned. This article describes the relationships between computational models, the physiological properties of a variety of gain-modulated neurons, and some of the behavioral consequences of damage to gain-modulated neural representations.

Rannala, B. and G. Bertorelle (2001). "Using linked markers to infer the age of a mutation." Hum Mutat 18(2): 87-100.

            Advances in sequencing and genotyping technologies over the last decade have enabled geneticists to easily characterize genetic variation at the nucleotide level. Hundreds of genes harboring mutations associated with genetic disease have now been identified by positional cloning. Using variation at closely linked genetic markers, it is possible to predict the times in the past at which particular mutations arose. Such studies suggest that many of the rare mutations underlying human genetic disorders are relatively young. Studies of variation at genetic markers linked to particular mutations can provide insights into human geographic history, and historical patterns of natural selection and disease, that are not available from other sources. We review two approaches for estimating allele age using variation at linked genetic markers. A phylogenetic approach aims to reconstruct the gene tree underlying a sample of chromosomes carrying a particular mutation, obtaining a "direct" estimate of allele age from the age of the root of this tree. A population genetic approach relies on models of demography, mutation, and/or recombination to estimate allele age without explicitly reconstructing the gene tree. Phylogenetic methods are best suited for studies of ancient mutations, while population genetic methods are better suited for studies of recent mutations. Methods that rely on recombination to infer the ages of alleles can be fine-tuned by choosing linked markers at optimal map distances to maximize the information available about allele age. A limitation of methods that rely on recombination is the frequent lack of a fine-scale linkage map. Maximum likelihood and Bayesian methods for estimating allele age that rely on intensive numerical computation are described, as well as "composite" likelihood and moment-based methods that lead to simple estimators. The former provide more accurate estimates (particularly for large samples of chromosomes) and should be employed if computationally practical.

Poughon, L., C. G. Dussap, et al. (2001). "Energy model and metabolic flux analysis for autotrophic nitrifiers." Biotechnol Bioeng 72(4): 416-33.

            The behavior of pure cultures of nitrifying microorganisms under autotrophic growth operating conditions was investigated and the relations between their energy metabolism and their anabolism analyzed by means of metabolic network computation. The description of the metabolism of the nitrifiers is extended to their energy metabolism by introducing compartmentalization (cytoplasmic and periplasmic sides) and studying coupling between the electron transport chain and the proton gradient generation. The energy model of Nitrosomonas and Nitrobacter was developed based on the oxidoreduction reactions known to be involved. The electron transport chains and the associated proton translocation for these models are described. Several possible hypotheses are analyzed and discussed concerning the thermodynamic consistency of all the oxidoreduction reactions. For Nitrosomonas, the most delicate point is the second step of hydroxylamine oxidation. For Nitrobacter a new energy model is proposed in which NO plays an important role as node in the distribution of electrons from NO(2)(-) oxidation to the membrane electron transport chain. The compartmentalization enables us to consider a proton gradient dissipation flux as the expression of the overall energy loss in metabolic analysis (the so-called maintenance phenomena). The energy model (electron transport chain, proton gradient) is associated with an overall description of the metabolism of Nitrosomonas and Nitrobacter in terms of metabolic flux calculation. This representation demonstrates that a maintenance in nitrifiers expressed as a proton leak is no higher than for other aerobes. The yields calculated from the energy models integrated with the metabolic models of nitrifiers are consistent with the experimental yields in the literature.

Pallas, S. L. (2001). "Intrinsic and extrinsic factors that shape neocortical specification." Trends Neurosci 24(7): 417-23.

            Increasing evidence points to the importance of intrinsic molecular cues in specifying the regional identity of mammalian neocortex. Few such cues, however, have been found to be restricted to individual functionally defined cortical areas before the arrival of afferent information. In contrast, thalamocortical axons are specifically targeted to individual cortical areas, raising the possibility that they can instruct some aspects of cortical areal identity. Cortical structure and function can be altered by modifying the source or pattern of activity in thalamocortical afferents. In particular, studies of cross-modal plasticity have shown that in many respects, one sensory cortical area can substitute for another after a switch of input modality during development. Afferent inputs might therefore direct the formation of their own processing circuitry, a possibility that has important implications for brain development, plasticity and evolution.

Murray, A. (2001). "Analogue VLSI for probabilistic networks and spike-time computation." Int J Neural Syst 11(1): 23-32.

            The history and some of the methods of analogue neural VLSI are described. The strengths of analogue techniques are described, along with residual problems to be solved. The nature of hardware-friendly and hardware-appropriate algorithms is reviewed and suggestions are offered as to where analogue neural VLSI's future lies.

Manwani, A. and C. Koch (2001). "Detecting and estimating signals over noisy and unreliable synapses: information-theoretic analysis." Neural Comput 13(1): 1-33.

            The temporal precision with which neurons respond to synaptic inputs has a direct bearing on the nature of the neural code. A characterization of the neuronal noise sources associated with different sub-cellular components (synapse, dendrite, soma, axon, and so on) is needed to understand the relationship between noise and information transfer. Here we study the effect of the unreliable, probabilistic nature of synaptic transmission on information transfer in the absence of interaction among presynaptic inputs. We derive theoretical lower bounds on the capacity of a simple model of a cortical synapse under two different paradigms. In signal estimation, the signal is assumed to be encoded in the mean firing rate of the presynaptic neuron, and the objective is to estimate the continuous input signal from the postsynaptic voltage. In signal detection, the input is binary, and the presence or absence of a presynaptic action potential is to be detected from the postsynaptic voltage. The efficacy of information transfer in synaptic transmission is characterized by deriving optimal strategies under these two paradigms. On the basis of parameter values derived from neocortex, we find that single cortical synapses cannot transmit information reliably, but redundancy obtained using a small number of multiple synapses leads to a significant improvement in the information capacity of synaptic transmission.

Laurent, G., M. Stopfer, et al. (2001). "Odor encoding as an active, dynamical process: experiments, computation, and theory." Annu Rev Neurosci 24: 263-97.

            We examine early olfactory processing in the vertebrate and insect olfactory systems, using a computational perspective. What transformations occur between the first and second olfactory processing stages? What are the causes and consequences of these transformations? To answer these questions, we focus on the functions of olfactory circuit structure and on the role of time in odor-evoked integrative processes. We argue that early olfactory relays are active and dynamical networks, whose actions change the format of odor-related information in very specific ways, so as to refine stimulus identification. Finally, we introduce a new theoretical framework ("winnerless competition") for the interpretation of these data.

Israel, O., Z. Keidar, et al. (2001). "The fusion of anatomic and physiologic imaging in the management of patients with cancer." Semin Nucl Med 31(3): 191-205.

            Imaging is of major clinical importance in the noninvasive evaluation and management of patients with cancer. Computed tomography (CT) and other anatomic imaging modalities, such as magnetic resonance imaging (MRI) or ultrasound, have a high diagnostic ability by visualizing lesion morphology and by providing the exact localization of malignant sites. Nuclear medicine provides information on the function and metabolism of cancer. Over the last decade, there have been numerous attempts to combine data obtained from different imaging techniques. Fused images of nuclear medicine and CT (or to a lesser extent, MRI) overcome the inherent limitations of both modalities. Valuable physiologic information benefits from a precise topographic localization. Coregistered data have been shown to be useful in the evaluation of patients with cancer at diagnosis and staging, in monitoring the response to treatment, and during follow up, for early detection of recurrence. Time-consuming and difficult realignment and computation for fusion of independent studies have, until now, limited the use of registration techniques to pilot studies performed in a small number of patients. The development of the new technology of single photon emission computed tomography/CT and positron emission tomography/CT that allows for combined functional and anatomic data acquisition has the potential to make fusion an everyday clinical tool.

Ichihara, K. (2001). "[Standardization of statistical procedures and evaluation scheme in external quality-control survey]." Rinsho Byori 49(9): 879-84.

            Numerous external quality assessment surveys are being conducted by variety of organizations throughout Japan, but the statistical processing and evaluation scheme are not compatible. Standardization of the procedures is essential to make comparison of results among surveys possible. A coding system is available only for names of analytes and analytical equipments. Systematic coding for analytical principles, manufacturers and standard materials is necessary. Regarding computation of peer-group statistics, the mean and SD are often biased when there are many, or wildly, outlying values. Therefore it is recommended to use an iterative method. The methodology removes a relatively large proportion of the population in the tails of the distribution and re-inflates the SD to compensate for the trimming, thus reaching an unbiased mean and SD by iteration. It is also useful to compute between-method CV and within method-CV by one-way analysis of variance. They represent overall levels of standardization and reproducibility of the analyte, respectively. The evaluation of results is usually based on the peer-group mean and SD. The scheme is unfair for those belonging to a peer-group with a narrow SD. It is recommended to use so-called "common CV evaluation scheme", which is based on a within-method CV computed from overall test results after excluding those peer-groups with large CVs. The common CV is applied to the unbiased peer-group mean to get the evaluation SD. For standardized data processing and statistical analysis, it is crucial to develop a unified, generalized soft ware. We developed its prototype named SurveyMaster I & II and herein introduce their potentials.

Horiuchi, T. and K. Hynna (2001). "Spike-based VLSI modeling of the ILD system in the echolocating bat." Neural Netw 14(6-7): 755-62.

            The azimuthal localization of objects by echolocating bats is based on the difference of echo intensity received at the two ears, known as the interaural level difference (ILD). Mimicking the neural circuitry in the bat associated with the computation of ILD, we have constructed a spike-based VLSI model that can produce responses similar to those seen in the lateral superior olive (LSO) and some parts of the inferior colliculus (IC). We further explore some of the interesting computational consequences of the dynamics of both synapses and cellular mechanisms.

Harvey, M. A. and E. Versi (2001). "Predictive value of clinical evaluation of stress urinary incontinence: a summary of the published literature." Int Urogynecol J Pelvic Floor Dysfunct 12(1): 31-7.

            Our objective was to evaluate the symptom and sign of stress incontinence in predicting the presence of urodynamically diagnosed genuine stress incontinence (GSI). The study was a computation of the sensitivity and predictive values from the published literature (1975-1998), evaluating the history and/or physical examination for the diagnosis of GSI, with calculation of efficacy variables. Results show that the isolated symptom of stress incontinence has a positive predictive value (PPV) of 56% for the diagnosis of pure GSI and 79% for GSI with additional abnormalities. The PPV of stress incontinence in association with other symptoms is 77% in detecting GSI (with or without additional abnormalities). A positive cough stress test has a PPV of 55% for detecting pure GSI and 91% for the mixed condition (GSI plus additional diagnosis). When isolated, the symptom or the sign of stress incontinence is a poor predictor of GSI. In combination, the prediction may be more promising.

Goddard, N. H., M. Hucka, et al. (2001). "Towards NeuroML: model description methods for collaborative modelling in neuroscience." Philos Trans R Soc Lond B Biol Sci 356(1412): 1209-28.

            Biological nervous systems and the mechanisms underlying their operation exhibit astonishing complexity. Computational models of these systems have been correspondingly complex. As these models become ever more sophisticated, they become increasingly difficult to define, comprehend, manage and communicate. Consequently, for scientific understanding of biological nervous systems to progress, it is crucial for modellers to have software tools that support discussion, development and exchange of computational models. We describe methodologies that focus on these tasks, improving the ability of neuroscientists to engage in the modelling process. We report our findings on the requirements for these tools and discuss the use of declarative forms of model description--equivalent to object-oriented classes and database schema--which we call templates. We introduce NeuroML, a mark-up language for the neurosciences which is defined syntactically using templates, and its specific component intended as a common format for communication between modelling-related tools. Finally, we propose a template hierarchy for this modelling component of NeuroML, sufficient for describing models ranging in structural levels from neuron cell membranes to neural networks. These templates support both a framework for user-level interaction with models, and a high-performance framework for efficient simulation of the models.

Gelperin, A. (2001). "Smelling well with a code in the nodes." Neuron 30(2): 307-9.

Foster, J. A. (2001). "Evolutionary computation." Nat Rev Genet 2(6): 428-36.

            Evolution does not require DNA, or even living organisms. In computer science, the field known as 'evolutionary computation' uses evolution as an algorithmic tool, implementing random variation, reproduction and selection by altering and moving data within a computer. This harnesses the power of evolution as an alternative to the more traditional ways to design software or hardware. Research into evolutionary computation should be of interest to geneticists, as evolved programs often reveal properties - such as robustness and non-expressed DNA - that are analogous to many biological phenomena.

Fernandez, C., C. Hilty, et al. (2001). "Solution NMR studies of the integral membrane proteins OmpX and OmpA from Escherichia coli." FEBS Lett 504(3): 173-8.

            Membrane proteins are usually solubilized in polar solvents by incorporation into micelles. Even for small membrane proteins these mixed micelles have rather large molecular masses, typically beyond 50000 Da. The NMR technique TROSY (transverse relaxation-optimized spectroscopy) has been developed for studies of structures of this size in solution. In this paper, strategies for the use of TROSY-based NMR experiments with membrane proteins are discussed and illustrated with results obtained with the Escherichia coli integral membrane proteins OmpX and OmpA in mixed micelles with the detergent dihexanoylphosphatidylcholine (DHPC). For OmpX, complete sequence-specific NMR assignments have been obtained for the polypeptide backbone. The 13C chemical shifts and nuclear Overhauser effect data then resulted in the identification of the regular secondary structure elements of OmpX/DHPC in solution, and in the collection of an input of conformational constraints for the computation of the global fold of the protein. For OmpA, the NMR assignments are so far limited to about 80% of the polypeptide chain, indicating different dynamic properties of the reconstituted OmpA beta-barrel from those of OmpX. Overall, the present data demonstrate that relaxation-optimized NMR techniques open novel avenues for studies of structure, function and dynamics of integral membrane proteins.

Feng, J. (2001). "Is the integrate-and-fire model good enough?--a review." Neural Netw 14(6-7): 955-75.

            We review some recent results on the behaviour of the integrate-and-fire (IF) model, the FitzHugh-Nagumo (FHN) model, a simplified version of the FHN (IF-FHN) model and the Hodgkin-Huxley (HH) model with correlated inputs. The effect of inhibitory inputs on the model behaviour is also taken into account. Here, inputs exclusively take the form of diffusion approximation and correlated inputs mean correlated synaptic inputs (Sections 2 and 3). It is found that the IF and HH models respond to correlated inputs in totally opposite ways, but the IF-FHN model shows similar behaviour to the HH model. Increasing inhibitory input to single neuronal models, such as the FHN model and the HH model can sometimes increase their firing rates, which we termed inhibition-boosted firing (IBF). Using the IF model and the IF-FHN model, we theoretically explore how and when IBF can happen. The computational complexity of the IF-FHN model is very similar to the conventional IF model, but the former captures some interesting and essential features of biophysical models and could serve as a better model for spiking neuron computation.

Ellis, M. J. and H. Hebert (2001). "Structure analysis of soluble proteins using electron crystallography." Micron 32(5): 541-50.

            Electron crystallography as a structural determination technique has grown dramatically in use over recent years. Improvements in microscopes, equipment, practical techniques, computation facilities and image processing methods are reflected in the increasing number of near-atomic resolution structures that have been published.In this review we shall summarize the techniques involved in structure determination of soluble proteins using electron crystallography. Many soluble protein structures have been investigated in this manner over the past two decades. Here we present several examples where a variety of approaches have been used to gradually increase the information obtained.

Drai, D. and I. Golani (2001). "SEE: a tool for the visualization and analysis of rodent exploratory behavior." Neurosci Biobehav Rev 25(5): 409-26.

            The complexity of exploratory behavior creates a need for a visualization and analysis tool that will highlight regularities and help generating new hypotheses about the structure of this behavior. The hypotheses can then be formulated as algorithms that capture the patterns and quantify them. SEE is a Mathematica based software developed by us for the exploration of exploratory behavior. The raw data for SEE are a time series of the animal 's coordinates in space sampled at a rate that allows a meaningful computation of speeds. SEE permits: (i) a visualization of the path of the animal and a computation of the dynamics of activity; (ii) a decomposition of the path into several modes of motion (1st gear, 2nd gear, etc.) and a computation of the typical maximal speeds, the spatial spread, and the proportion of each of these modes; and(iii) a visualization of the location in the environment of stopping episodes, along with their dwell time. These visualizations highlight the presence of preferred places, including the animal's so-called home base, and permits a computation of the spatio-temporal diversity in the location of stopping episodes. The software also: (i) decomposes the animal's path into round trips from the home base, called 'excursions', and computes the number of stops per excursion; (ii) generates a visualization of the phase space (path+speed, traced in a three-dimensional graph) of any progression segment or list of such segments; and (iii) produces a visualization of the way places in the animal's operational world are connected to each other. SEE also permits the definition and computation of behavioral endpoints across any section of any database of raw data. The range of applicability of SEE to various experimental set ups, tracking procedures, species, and preparations is addressed in the discussion.

Doyon, F. and C. Hill (2001). "[Evaluation of diagnostic methods]." J Radiol 82(2): 117-25.

            AIM: Describe the statistical tools for the evaluation of a diagnostic test. MATERIAL AND METHODS: Description of the methods and practical examples based on published data. RESULTS: The following methods are described: 1) reproducibility of a measurement, both for a qualitative and a quantitative result, 2) comparison of a new diagnostic test to a reference test, 3) comparison of two diagnostic tests, 4) sample size computation. CONCLUSION: The tools required to evaluate diagnostic tests rigorously are available and simple. They should be used more often.

Clerget-Darpoux, F. (2001). "Extension of the lod score: the mod score." Adv Genet 42: 115-24.

            In 1955 Morton proposed the lod score method both for testing linkage between loci and for estimating the recombination fraction between them. If a disease is controlled by a gene at one of these loci, the lod score computation requires the prior specification of an underlying model that assigns the probabilities of genotypes from the observed phenotypes. To address the case of linkage studies for diseases with unknown mode of inheritance, we suggested (Clerget-Darpoux et al., 1986) extending the lod score function to a so-called mod score function. In this function, the variables are both the recombination fraction and the disease model parameters. Maximizing the mod score function over all these parameters amounts to maximizing the probability of marker data conditional on the disease status. Under the absence of linkage, the mod score conforms to a chi-square distribution, with extra degrees of freedom in comparison to the lod score function (MacLean et al., 1993). The mod score is asymptotically maximum for the true disease model (Clerget-Darpoux and Bonaiti-Pellie, 1992; Hodge and Elston, 1994). Consequently, the power to detect linkage through mod score will be highest when the space of models where the maximization is performed includes the true model. On the other hand, one must avoid overparametrization of the model space. For example, when the approach is applied to affected sibpairs, only two constrained disease model parameters should be used (Knapp et al., 1994) for the mod score maximization. It is also important to emphasize the existence of a strong correlation between the disease gene location and the disease model. Consequently, there is poor resolution of the location of the susceptibility locus when the disease model at this locus is unknown. Of course, this is true regardless of the statistics used. The mod score may also be applied in a candidate gene strategy to model the potential effect of this gene in the disease. Since, however, it ignores the information provided both by disease segregation and by linkage disequilibrium between the marker alleles and the functional disease alleles, its power of discrimination between genetic models is weak. The MASC method (Clerget-Darpoux et al., 1988) has been designed to address more efficiently the objectives of a candidate gene approach.

Chen, A. C. (2001). "New perspectives in EEG/MEG brain mapping and PET/fMRI neuroimaging of human pain." Int J Psychophysiol 42(2): 147-59.

            With the maturation of EEG/MEG brain mapping and PET/fMRI neuroimaging in the 1990s, greater understanding of pain processing in the brain now elucidates and may even challenge the classical theory of pain mechanisms. This review scans across the cultural diversity of pain expression and modulation in man. It outlines the difficulties in defining and studying human pain. It then focuses on methods of studying the brain in experimental and clinical pain, the cohesive results of brain mapping and neuroimaging of noxious perception, the implication of pain research in understanding human consciousness and the relevance to clinical care as well as to the basic science of human psychophysiology. Non-invasive brain studies in man start to unveil the age-old puzzles of pain-illusion, hypnosis and placebo in pain modulation. The neurophysiological and neurohemodynamic brain measures of experimental pain can now largely satisfy the psychophysiologist's dream, unimaginable only a few years ago, of modelling the body-brain, brain-mind, mind-matter duality in an inter-linking 3-P triad: physics (stimulus energy); physiology (brain activities); and psyche (perception). For neuropsychophysiology greater challenges lie ahead: (a) how to integrate a cohesive theory of human pain in the brain; (b) what levels of analyses are necessary and sufficient; (c) what constitutes the structural organisation of the pain matrix; (d) what are the modes of processing among and across the sites of these structures; and (e) how can neural computation of these processes in the brain be carried out? We may envision that modular identification and delineation of the arousal-attention, emotion-motivation and perception-cognition neural networks of pain processing in the brain will also lead to deeper understanding of the human mind. Two foreseeable impacts on clinical sciences and basic theories from brain mapping/neuroimaging are the plausible central origin in persistent pain and integration of sensory-motor function in pain perception.

Cariani, P. (2001). "Symbols and dynamics in the brain." Biosystems 60(1-3): 59-83.

            The work of physicist and theoretical biologist Howard Pattee has focused on the roles that symbols and dynamics play in biological systems. Symbols, as discrete functional switching-states, are seen at the heart of all biological systems in the form of genetic codes, and at the core of all neural systems in the form of informational mechanisms that switch behavior. They also appear in one form or another in all epistemic systems, from informational processes embedded in primitive organisms to individual human beings to public scientific models. Over its course, Pattee's work has explored (1) the physical basis of informational functions (dynamical vs. rule-based descriptions, switching mechanisms, memory, symbols), (2) the functional organization of the observer (measurement, computation), (3) the means by which information can be embedded in biological organisms for purposes of self-construction and representation (as codes, modeling relations, memory, symbols), and (4) the processes by which new structures and functions can emerge over time. We discuss how these concepts can be applied to a high-level understanding of the brain. Biological organisms constantly reproduce themselves as well as their relations with their environs. The brain similarly can be seen as a self-producing, self-regenerating neural signaling system and as an adaptive informational system that interacts with its surrounds in order to steer behavior.

Butler, F. M., S. P. Miller, et al. (2001). "Teaching mathematics to students with mild-to-moderate mental retardation: a review of the literature." Ment Retard 39(1): 20-31.

            A systematic search of the literature from 1989 through 1998 was conducted to identify and analyze mathematics interventions for students with mild-to-moderate mental retardation. We found that the focus of instruction has shifted from basic skills instruction to computation and problem-solving instruction. Techniques such as constant-time delay, peer tutoring, time trials, and direct instruction proved beneficial in improving mathematics skills. Further, students with mental retardation learned to employ cognitive strategies successfully when these techniques were included. Although this information is promising, we recommend that further studies be conducted in secondary schools and in inclusive settings.

Bullier, J. (2001). "Integrated model of visual processing." Brain Res Brain Res Rev 36(2-3): 96-107.

            Cortical processing of visual information requires that information be exchanged between neurons coding for distant regions in the visual field. It is argued that feedback connections are the best candidates for such rapid long-distance interconnections. In the integrated model, information arriving in the cortex from the magnocellular layers of the lateral geniculate nucleus is first sent and processed in the parietal cortex that is very rapidly activated by a visual stimulus. Results from this first-pass computation are then sent back by feedback connections to areas V1 and V2 that act as 'active black-boards' for the rest of the visual cortical areas: information retroinjected from the parietal cortex is used to guide further processing of parvocellular and koniocellular information in the inferotemporal cortex.

Bar-Gad, I. and H. Bergman (2001). "Stepping out of the box: information processing in the neural networks of the basal ganglia." Curr Opin Neurobiol 11(6): 689-95.

            The Albin-DeLong 'box and arrow' model has long been the accepted standard model for the basal ganglia network. However, advances in physiological and anatomical research have enabled a more detailed neural network approach. Recent computational models hold that the basal ganglia use reinforcement signals and local competitive learning rules to reduce the dimensionality of sparse cortical information. These models predict a steady-state situation with diminished efficacy of lateral inhibition and low synchronization. In this framework, Parkinson's disease can be characterized as a persistent state of negative reinforcement, inefficient dimensionality reduction, and abnormally synchronized basal ganglia activity.

Amundson, S. A. and A. J. Fornace, Jr. (2001). "Gene expression profiles for monitoring radiation exposure." Radiat Prot Dosimetry 97(1): 11-6.

            Previous demonstrations that the dose, dose rate, radiation quality, and elapsed time since ionising radiation exposure result in variations in the response of stress genes suggest that gene expression signatures may be informative markers of radiation exposure. Defining sets of genes that ate specific for different outcomes of interest will be key to such an approach. A generalised post-exposure prolile may identify exposed individuals within a population, while more specific fingerprints may reveal details of a radiation exposure. Changes in gene expression in human cell lines occur after as little as 0.02 Gy rays, and in peripheral blood lymphocytes alter as little as 0.2 Gy. Diverse genes are also elevated in vivo in mice 24 h after 0.2 Gy irradiation. Ongoing microarray analyses meanwhile continue to identify large numbers of potential biomarkers from varied irradiation protocols. Development of computation-intensive informatics analysis methods will be needed for management of the complex gene expression profiles resulting from such experiments. Although the preliminary data are encouraging, significant work remains before meaningful correlations with risk or practical assessment of exposure can be made by gene expression profiling.

Ahissar, M. (2001). "Perceptual training: a tool for both modifying the brain and exploring it." Proc Natl Acad Sci U S A 98(21): 11842-3.

Suter, P. M. and W. Vetter (2000). "[Obesity clinic]." Ther Umsch 57(8): 498-503.

            The cornerstone of the evaluation of an obese patient is the medical examination in combination with a few selected obesity specific measurements. Key elements in the obesity specific history are the patient's weight history, the diet history, evaluation of the present and past physical activity pattern and the evaluation of the patient's target weight. Central elements in the examination are the computation of the body mass index (BMI) as well the measurement of the waist circumference. The waist circumference shows a higher degree of correlation with different morbidities than the BMI. A waist circumference of > 80 cm in women and > 94 cm in men is associated with an increased overall morbidity risk. In general a minimal biochemical work-up--including fasting glucose, total cholesterol, HDL and triacylglycerol, urate, electrolytes and TSH--is enough. Special tests (screening examination for e.g. M. Cushing) are only indicated in the case of clinical suspicion; the determination of leptin is presently of no diagnostic nor therapeutic relevance. The indication for weight reduction should be formulated individually. In the long term weight stability has to be regarded as a success for most patients. Presently the prevention of weight gain and obesity is still the safest and most efficient "therapeutic" approach.

Sokolov, E. N. (2000). "Perception and the conditioning reflex: vector encoding." Int J Psychophysiol 35(2-3): 197-217.

            Color perception is dependent on the generation of an excitation vector which, acting on a pool of color detectors (color detector map), produces a corresponding sensation. The generation of the color excitation vector starts at the retinal level, proceeds in the lateral geniculate body, and reaches color detectors at the cortical level. Following processing at the level of declarative memory and semantic maps, results in a verbal categorization of colors. Parallel to the excitation vector pathway, a network computing color differences is operating. The computation of color differences at the retinal level possibly takes place in phasic bipolar cells and progresses in the lateral geniculate body and at the cortical level. Detectors of color differences are assumed to be a basis of respective numerical estimations in humans. Data from frogs, fish, monkeys and humans are compared.

Sibata, C. H., V. C. Colussi, et al. (2000). "Photodynamic therapy: a new concept in medical treatment." Braz J Med Biol Res 33(8): 869-80.

            A new concept in the therapy of both neoplastic and non-neoplastic diseases is discussed in this article. Photodynamic therapy (PDT) involves light activation, in the presence of molecular oxygen, of certain dyes that are taken up by the target tissue. These dyes are termed photosensitizers. The mechanism of interaction of the photosensitizers and light is discussed, along with the effects produced in the target tissue. The present status of clinical PDT is discussed along with the newer photosensitizers being used and their clinical roles. Despite the promising results from earlier clinical trials of PDT, considerable additional work is needed to bring this new modality of treatment into modern clinical practice. Improvements in the area of light source delivery, light dosimetry and the computation of models of treatment are necessary to standardize treatments and ensure proper treatment delivery. Finally, quality assurance issues in the treatment process should be introduced.

Segev, I. and M. London (2000). "Untangling dendrites with quantitative models." Science 290(5492): 744-50.

            Our understanding of the function of dendrites has been greatly enriched by an inspiring dialogue between theory and experiments. Rather than functionally ignoring dendrites, representing neurons as single summing points, we have realized that dendrites are electrically and chemically distributed nonlinear units and that this has important consequences for interpreting experimental data and for the role of neurons in information processing. Here, we examine the route to unraveling some of the enigmas of dendrites and highlight the main insights that have been gained. Future directions are discussed that will enable theory and models to keep shedding light on dendrites, where the most fundamental input-output adaptive processes take place.

Pouget, A. and L. H. Snyder (2000). "Computational approaches to sensorimotor transformations." Nat Neurosci 3 Suppl: 1192-8.

            Behaviors such as sensing an object and then moving your eyes or your hand toward it require that sensory information be used to help generate a motor command, a process known as a sensorimotor transformation. Here we review models of sensorimotor transformations that use a flexible intermediate representation that relies on basis functions. The use of basis functions as an intermediate is borrowed from the theory of nonlinear function approximation. We show that this approach provides a unifying insight into the neural basis of three crucial aspects of sensorimotor transformations, namely, computation, learning and short-term memory. This mathematical formalism is consistent with the responses of cortical neurons and provides a fresh perspective on the issue of frames of reference in spatial representations.

Pena-Reyes, C. A. and M. Sipper (2000). "Evolutionary computation in medicine: an overview." Artif Intell Med 19(1): 1-23.

            The term evolutionary computation encompasses a host of methodologies inspired by natural evolution that are used to solve hard problems. This paper provides an overview of evolutionary computation as applied to problems in the medical domains. We begin by outlining the basic workings of six types of evolutionary algorithms: genetic algorithms, genetic programming, evolution strategies, evolutionary programming, classifier systems, and hybrid systems. We then describe how evolutionary algorithms are applied to solve medical problems, including diagnosis, prognosis, imaging, signal processing, planning, and scheduling. Finally, we provide an extensive bibliography, classified both according to the medical task addressed and according to the evolutionary technique used.

Parasuraman, R., A. J. Masalonis, et al. (2000). "Fuzzy signal detection theory: basic postulates and formulas for analyzing human and machine performance." Hum Factors 42(4): 636-59.

            Signal detection theory (SDT) assumes a division of objective truths or "states of the world" into the nonoverlapping categories of signal and noise. The definition of a signal in many real settings, however, varies with context and over time. In the terminology of fuzzy logic, a real-world signal has a value that falls in a range between unequivocal presence and unequivocal absence. The definition of a response can also be nonbinary. Accordingly the methods of fuzzy logic can be combined with SDT, yielding fuzzy SDT. We describe the basic postulates of fuzzy SDT and provide formulas for fuzzy analysis of detection performance, based on four steps: (a) selection of mapping functions for signal and response; (b) use of mixed-implication functions to assign degrees of membership in hits, false alarms, misses, and correct rejections; (c) computation of fuzzy hit, false alarm, miss, and correct rejection rates; and (d) computation of fuzzy sensitivity and bias measures. Fuzzy SDT can considerably extend the range and utility of SDT by handling the contextual and temporal variability of most real-world signals. Actual or potential applications of fuzzy SDT include evaluation of the performance of human, machine, and human-machine detectors in real systems.

O'Hagan, A., J. W. Stevens, et al. (2000). "Inference for the cost-effectiveness acceptability curve and cost-effectiveness ratio." Pharmacoeconomics 17(4): 339-49.

            The aim of this article is to consider Bayesian and frequentist inference methods for measures of incremental cost effectiveness in data obtained via a clinical trial. The most useful measure is the cost-effectiveness (C/E) acceptability curve. Recent publications on Bayesian estimation have assumed a normal posterior distribution, which ignores uncertainty in estimated variances, and suggest unnecessarily complicated methods of computation. We present a simple Bayesian computation for the C/E acceptability curve and a simple frequentist analogue. Our approach takes account of errors in estimated variances, resulting in calculations that are based on distributions rather than normal distributions. If inference is required about the C/E ratio, we argue that the standard frequentist procedures give unreliable or misleading inferences, and present instead a Bayesian interval.

Medina, J. F. and M. D. Mauk (2000). "Computer simulation of cerebellar information processing." Nat Neurosci 3 Suppl: 1205-11.

            Although many functions have been ascribed to the cerebellum, the uniformity of its synaptic organization suggests that a single, characteristic computation may be common to all.