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A component-based FPGA design framework for neuronal ion channel dynamics simulations.

Neuron-machine interfaces such as dynamic clamp and brain-implantable neuroprosthetic devices require real-time simulations of neuronal ion channel dynamics. Field-programmable gate array (FPGA) has emerged as a high-speed digital platform ideal for such application-specific computations. We propose an efficient and flexible component-based FPGA design framework for neuronal ion channel dynamics simulations, which overcomes certain limitations of the recently proposed memory-based approach. A parallel processing strategy is used to minimize computational delay, and a hardware-efficient factoring approach for calculating exponential and division functions in neuronal ion channel models is used to conserve resource consumption. Performances of the various FPGA design approaches are compared theoretically and experimentally in corresponding implementations of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) synaptic ion channel models. Our results suggest that the component-based design framework provides a more memory economic solution, as well as more efficient logic utilization for large word lengths, whereas the memory-based approach may be suitable for time-critical applications where a higher throughput rate is desired.

Action Potentials↗

From vagueness in medical thought to the foundations of fuzzy reasoning in medical diagnosis.

OBJECTIVE: This article delineates a relatively unknown path in the history of medical philosophy and medical diagnosis. It is concerned with the phenomenon of vagueness in the physician's "style of thinking" and with the use of fuzzy sets, systems, and relations with a view to create a model of such reasoning when physicians make a diagnosis. It represents specific features of medical ways of thinking that were mentioned by the Polish physician and philosopher Ludwik Fleck in 1926. The paper links Lotfi Zadeh's work on system theory before the age of fuzzy sets with system-theory concepts in medical philosophy that were introduced by the philosopher Mario Bunge, and with the fuzzy-theoretical analysis of the notions of health, illness, and disease by the Iranian-German physician and philosopher Kazem Sadegh-Zadeh. MATERIAL: Some proposals to apply fuzzy sets in medicine were based on a suggestion made by Zadeh: symptoms and diseases are fuzzy in nature and fuzzy sets are feasible to represent these entity classes of medical knowledge. Yet other attempts to use fuzzy sets in medicine were self-contained. The use of this approach contributed to medical decision-making and the development of computer-assisted diagnosis in medicine. CONCLUSION: With regard to medical philosophy, decision-making, and diagnosis; the framework of fuzzy sets, systems, and relations is very useful to deal with the absence of sharp boundaries of the sets of symptoms, diagnoses, and phenomena of diseases. The foundations of reasoning and computer assistance in medicine were the result of a rapid accumulation of data from medical research. This explosion of knowledge in medicine gave rise to the speculation that computers could be used for the medical diagnosis. Medicine became, to a certain extent, a quantitative science. In the second half of the 20th century medical knowledge started to be stored in computer systems. To assist physicians in medical decision-making and patient care, medical expert systems using the theory of fuzzy sets and relations (such as the Viennese "fuzzy version" of the Computer-Assisted Diagnostic System, CADIAG, which was developed at the end of the 1970s) were constructed. The development of fuzzy relations in medicine and their application in computer-assisted diagnosis show that this fuzzy approach is a framework to deal with the "fuzzy mode of thinking" in medicine.

Diagnosis↗

Generalized linear models with random effects; salamander mating revisited.

In recent years much effort has been devoted to extending regression methodology to non-Gaussian data, where responses are not independent. These methods for dependent responses are suitable for data from longitudinal studies or nested designs. However, use of these methods for crossed designs seems to have serious limitations due to the intensive computations involved because of the intractable nature of the joint distribution. In this paper, we cast the problem in a Bayesian framework and use a Monte Carlo method, the Gibbs sampler, to avoid current computational limitations. The flexibility of this approach is illustrated by analyzing the interesting salamander mating data reported by McCullagh and Nelder (1989, Generalized Linear Models, 2nd edition, London: Chapman and Hall).

Analysis of Variance↗

THE THREE DS OF PCR-BASED GENOMIC ANALYSIS OF PHYTOBACTERIA: Diversity, Detection, and Disease Diagnosis.

The advent of molecular biology in general and the polymerase chain reaction in particular have greatly facilitated genomic analyses of microorganisms, provide enhanced capability to characterize and classify strains, and facilitate research to assess the genetic diversity of populations. The diversity of large populations can be assessed in a relatively efficient manner using rep-PCR-, AFLP-, and AP-PCR/RAPD-based genomic fingerprinting methods, especially when combined with computer-assisted pattern analysis. Genetic diversity maps provide a framework to understand the taxonomy, population structure, and dynamics of phytobacteria and provide a high-resolution framework to devise sensitive, specific, and rapid methods for pathogen detection, plant disease diagnosis, as well as management of disease risk. A variety of PCR-based fingerprinting protocols such as rDNA-based PCR, ITS-PCR, ARDRA, T-RFLPs, and tRNA-PCR have been devised, and numerous innovative approaches using specific primers have been adopted to enhance both the detection and identification of phytobacteria. PCR-based protocols, combined with computer-based analysis, have provided novel fundamental knowledge of the ecology and population dynamics of bacterial pathogens, and present exciting new opportunities for basic and applied studies in plant pathology.

Journal Article↗

The SAPPHIRE toolkit: an interactive system for the evaluation of primary healthcare computing.

Since April 1992, the SAPPHIRE Project (Systems Accreditation Project in Primary Healthcare Informatics Requirements and Evaluations) has been funded by the Department of Health in the United Kingdom with the goal of providing a framework for the fair and objective evaluation of General Medical Practice (GMP) computer systems [1]. SAPPHIRE is comprised of three 'facets': A comprehensive specification list for GMP information systems. An Assessment methodology to apply the SAPPHIRE specifications. The Integrated Toolkit. The SAPPHIRE Integrated Toolkit has been developed as an interactive computer-based guide for use in the processes of GMP system procurement and education. By integrating the two other 'facets' of SAPPHIRE, it provides a means of matching a set of user-defined specifications against the systems under consideration. This is achieved by enabling the Toolkit user to interactively weight the presented SAPPHIRE specifications to their individual requirements and then match this weighted specification against a database of benchtest results for available systems. The output from this matching process then gives the range of systems which most clearly meet that particular user's needs as well as highlighting the areas where systems fail to meet their defined requirements. Since the SAPPHIRE specification list is a lengthy document comprised of technical language, the Toolkit uses a range of browsing models to display the specifications in accessible ways to the end-user. These browsing models present the specifications in contexts that are familiar to the everyday experience of healthcare employees and hence are easy to access and understand. In addition, the Toolkit offers a 'Quick Route Questionnaire' which accesses a shortcut to the matching process described above. his presentation will demonstrate the main functions of the Toolkit and outline specific scenarios of use. Another area of discussion will be the approach of the SAPPHIRE Project to the problems and issues of computer system evaluation, with reference to the Toolkit in a communications context, assisting in the transfer of understanding between the technical language of system designers and suppliers and the healthcare professional, who may lack computer expertise [2]. The SAPPHIRE Toolkit has a wide range of applications for facilitating the procurement of, and the education processes entailed in, primary healthcare computing. We view the Toolkit as a potential benefit to many aspects of the healthcare profession, including General Practice, Surgery, Healthcare IT Administration, and Information System Supply and Management.

Ambulatory Care Information Systems↗

Photodissociation of HBr. 1. Electronic structure, photodissociation dynamics, and vector correlation coefficients.

Ab initio potential energy curves, transition dipole moments, and spin-orbit coupling matrix elements are computed for HBr. These are then used, within the framework of time-dependent quantum-mechanical wave-packet calculations, to study the photodissociation dynamics of the molecule. Total and partial integral cross sections, the branching fraction for the formation of excited-state bromine atoms Br(2P(1/2)), and the lowest order anisotropy parameters, beta, for both ground and excited-state bromine are calculated as a function of photolysis energy and compared to experimental and theoretical data determined previously. Higher order anisotropy parameters are computed for the first time for HBr and compared to recent experimental measurements. A new expression for the Re[a1(3) (parallel, perpendicular)] parameter describing coherent parallel and perpendicular production of ground-state bromine in terms of the dynamical functions is given. Although good agreement is obtained between the theoretical predictions and the experimental measurements, the discrepancies are analyzed to establish how improvements might be achieved. Insight is obtained into the nonadiabatic dynamics by comparing the results of diabatic and fully adiabatic calculations.

Anisotropy↗

Bodily systems and the spatial-functional structure of the human body.

The human body is a system made of systems. The body is divided into bodily systems proper, such as the endocrine and circulatory systems, which are subdivided into many sub-systems at a variety of levels, whereby all systems and subsystems engage in massive causal interaction with each other and with their surrounding environments. Here we offer an explicit definition of bodily system and provide a framework for understanding their causal interactions. Medical sciences provide at best informal accounts of basic notions such as system, process, and function, and while such informality is acceptable in documentation created for human beings, it falls short of what is needed for computer representations. In our analysis we will accordingly provide the framework for a formal definition of bodily system and of associated notions.

Anatomy↗

Mental representations of perspective and spatial relations from diagrams and models.

In previous research (D. J. Bryant, B. Tversky, & N. Franklin, 1992; N. Franklin & B. Tversky, 1990), the authors showed that spatial knowledge conveyed by descriptions and direct experience induces participants to take the perspective of a character surrounded by objects. In this study, the authors used models and diagrams to convey the same information. With models, as with descriptions and experience, participants adopted the character's perspective (the spatial framework analysis). With diagrams, participants took an outside perspective (the intrinsic computation analysis). Even when informationally equivalent, different depictions made salient different aspects of the world. When instructed, however, participants were able to take either the inside or the outside perspective in memory for both diagrams and models. Depth cues in depictions also govern participants' perspective. When diagrams contained rich pictorial depth cues, participants used the spatial framework analysis, and when models were viewed without access to depth cues, participants relied on the intrinsic computation analysis.

Adult↗

Humanization of a chicken anti-IL-12 monoclonal antibody.

Chicken anti-IL-12 monoclonal antibodies were isolated by phage display using spleen cells from a chicken immunized with human and mouse IL-12 as a source for library construction. One of the chicken monoclonal antibodies, DD2, exhibited binding to both human and mouse IL-12 in the single-chain Fv form and also after conversion to chicken-human chimeric IgG1/lambda antibody. The chicken DD2 variable regions were humanized by transferring their CDRs and several framework amino acids onto human acceptor variable regions. In the Vlambda, six chicken framework amino acids were identified to be important for the conformation of the CDR structure by computer modeling and therefore were retained in the humanized form; likewise, five chicken amino acids in the VH framework regions were retained in the humanized VH. The affinities of humanized DD2 IgG1/lambda to human and mouse IL-12 measured by competitive binding were nearly identical to those of chicken-human chimeric DD2 IgG1/lambda. This work demonstrates that humanization of chicken monoclonal antibodies assisted by computer modeling is possible, leading to a new way to generate therapeutic humanized antibodies against antigens to which the rodent immune system may fail to efficiently raise high affinity antibodies.

Amino Acid Sequence↗

Automatic image orientation detection via confidence-based integration of low-level and semantic cues.

Automatic image orientation detection for natural images is a useful, yet challenging research topic. Humans use scene context and semantic object recognition to identify the correct image orientation. However, it is difficult for a computer to perform the task in the same way because current object recognition algorithms are extremely limited in their scope and robustness. As a result, existing orientation detection methods were built upon low-level vision features such as spatial distributions of color and texture. Discrepant detection rates have been reported for these methods in the literature. We have developed a probabilistic approach to image orientation detection via confidence-based integration of low-level and semantic cues within a Bayesian framework. Our current accuracy is 90 percent for unconstrained consumer photos, impressive given the findings of a psychophysical study conducted recently. The proposed framework is an attempt to bridge the gap between computer and human vision systems and is applicable to other problems involving semantic scene content understanding.

Algorithms↗

Prospective clinical study of zirconia posterior fixed partial dentures: 3-year follow-up.

OBJECTIVES: The purpose of this prospective clinical cohort study was to determine the success rate of 3- to 5-unit posterior fixed partial dentures (FPDs) with zirconia frameworks after 3 years of function. METHOD AND MATERIALS: Forty-five patients in need of at least 1 FPD to replace 1 to 3 posterior teeth were included. The frameworks were produced by means of a prototype computer-assisted manufacture system. They were milled with a precisely calculated increase in size out of presintered zirconia blanks and subsequently shrunk to the required size. Fifty-seven FPDs were cemented using either Variolink or Panavia TC cement. Clinical and radiographic examinations were performed at baseline, 12, 24, and 36 months after cementation. Statistical analysis was performed by descriptive statistics and the Kaplan-Meier survival analysis. Comparisons of probing depth, Plaque Index, and bleeding on probing between test (abutment) and control (contralateral) teeth were done with the McNemar test. RESULTS: Thirty-six patients with 46 FPDs were available for examination after 36 months. No fractures occurred, rendering a 100% success rate of the zirconia frameworks. Seven FPDs had to be replaced because of biologic and technical problems. The survival rate, therefore, was 84.8%. Secondary caries was found in 10.9% of the FPDs, and chipping of the veneering ceramic was found in 13.0%. There were no significant differences regarding the probing depth in test and control teeth. CONCLUSION: Zirconia frameworks demonstrated sufficient stability for replacement of posterior teeth. However, the high rates of technical problems should be reduced by further developments of the prototype processing technology.

Cementation↗

Prediction of blood-brain partitioning using Monte Carlo simulations of molecules in water.

The brain-blood partition coefficient (log BB) is a determining factor for the efficacy of central nervous system acting drugs. Since large-scale experimental determination of log BB is unfeasible, alternative evaluation methods based on theoretical models are desirable. Toward this direction, we propose a model that correlates log BB with physically significant descriptors for 76 structurally diverse molecules. We employ Monte Carlo simulations of the compounds in water to calculate such properties as the solvent-accessible surface area (SASA), the number of hydrogen bond donors and acceptors, the solute dipole, and the hydrophilic, hydrophobic and amphiphilic components of SASA. The physically significant descriptors are identified and a quantitative structure-prediction relationship is constructed that predicts log BB. This work demonstrates that computer simulations can be employed in a semi-empirical framework to build predictive QSPRs that shed light on the physical mechanism of biomolecular phenomena.

Animals↗

Neural network models of cortical functions based on the computational properties of the cerebral cortex.

We describe a biologically plausible modelling framework based on the architectural and processing characteristics of the cerebral cortex. Its key feature is a multicellular processing unit (cortical column) reflecting the modular nature of cortical organization and function. In this framework, we describe a neural network model organization and function. In this framework, we describe a neural network model of the neuronal circuits of the cerebral cortex that learn different functions associated with different parts of the cortex: 1) visual integration for invariant pattern recognition, performed by a cooperation between temporal and parietal areas; 2) visual-to-motor transformation for 3D arm reaching movements, performed by parietal and motor areas; and 3) temporal integration and storage of sensorimotor programs, performed by networks linking the prefrontal cortex to associative sensory and motor areas. The architecture of the network is inspired from the features of the architecture of cortical pathways involved in these functions. We propose two rules which describe neural processing and plasticity in the network. The first rule (adaptive tuning if gating) is an analog of operant conditioning and permits to learn to anticipate an action. The second rule (adaptive timing) is based on a bistable state of activity and permits to learn temporally separate events forming a behavioral sequence.

Cerebral Cortex↗

Why British GPs use computers and hospital doctors do not.

Almost all general medical practitioners (GPs) in the UK use computers, compared with less than one in ten of hospital doctors. This paper explains how this unexpected situation came about over a thirty-year period, identifying some of the successes and failures of British medical computing along the way. Twelve separate factors are considered. The major determinants have not been technical, but rather a strong tide of political backing for general practice and leadership from the profession at the highest level, which have combined to build an appropriate regulatory framework and financial incentives that have encouraged GPs to embrace computers. Hospital computing has some difficulties not met by GPs, but the main factor preventing progress has been the lack of any real incentive positive (carrot) or negative (stick), for hospital doctors to use computers.

Attitude to Computers↗

Glycosylation of immunoglobulin light chains associated with amyloidosis.

AL amyloidosis is a fatal disease caused by deposition of immunoglobulin light chains in a fibrillarforin (AL) in various organs. By searching the Kabat database of immunoglobulin sequences using the KabatMan software, we have shown that there is a preponderance of the consensus glycosylation sequon (AsnXxxSer/Thr) in the framework regions of amyloid light chains. We have characterised by computer graphics simulations, NMR spectroscopy and carbohydrate biochemistry the structure and conformation of the oligosaccharide from amyloid protein AL MS (lamba1) and from the amyloid associated Bence Jones protein of patient MH (kappa1). These proteins have glycosylation in the hypervariable complementarity-determining region versus framework region, respectively. Both contained a 2-6 sialylated core fucosylated biantennary chain mostly with bisecting GIcNAc. Together our results suggest that light chain glycosylation may be one of several modifications which may render the protein more prone to amyloid formation.

Amino Acid Sequence↗

"Proton holes" in long-range proton transfer reactions in solution and enzymes: A theoretical analysis.

Proton transfers are fundamental to chemical processes in solution and biological systems. Often, the well-known Grotthuss mechanism is assumed where a series of sequential "proton hops" initiates from the donor and combines to produce the net transfer of a positive charge over a long distance. Although direct experimental evidence for the sequential proton hopping has been obtained recently, alternative mechanisms may be possible in complex molecular systems. To understand these events, all accessible protonation states of the mediating groups should be considered. This is exemplified by transfers through water where the individual water molecules can exist in three protonation states (water, hydronium, and hydroxide); as a result, an alternative to the Grotthuss mechanism for a proton transfer through water is to generate a hydroxide by first protonating the acceptor and then transfer the hydroxide toward the donor through water. The latter mechanism can be most generally described as the transfer of a "proton hole" from the acceptor to the donor where the "hole" characterizes the deprotonated state of any mediating molecule. This pathway is distinct and is rarely considered in the discussion of proton-transfer processes. Using a calibrated quantum mechanical/molecular mechanical (QM/MM) model and an effective sampling technique, we study proton transfers in two solution systems and in Carbonic Anhydrase II. Although the relative weight of the "proton hole" and Grotthuss mechanisms in a specific system is difficult to determine precisely using any computational approach, the current study establishes an energetics motivated framework that hinges on the donor/acceptor pKa values and electrostatics due to the environment to argue that the "proton hole" transfer is likely as important as the classical Grotthuss mechanism for proton transport in many complex molecular systems.

Acetic Acid↗

A linear feature extraction for multiclass classification problems based on class mean and covariance discriminant information.

A parametric linear feature extraction method is proposed for multiclass classification. The skeleton of the proposed method consists of two types of schemes that are complementary to each other with regard to the discriminant information used. The approximate pairwise accuracy criterion (aPAC) and the common-mean feature extraction (CMFE) are chosen to exploit the discriminant information about class mean and about class covariance, respectively. Choosing aPAC rather than the linear discriminant analysis (LDA) can also resolve the problem of overemphasized large distances introduced by LDA, while maintaining other decent properties of LDA. To alleviate the suboptimum problem caused by a direct cascading of the two different types of schemes, there should be a mechanism for sorting and merging features based on their effectiveness. Usage of a sample-based classification error estimation for evaluation of effectiveness of features usually costs a lot of computational time. Therefore, we develop a fast spanning-tree-based parametric classification accuracy estimator as an intermediary for the aPAC and CMFE combination. The entire framework is parametric-based. This avoids paying a costly price in computation, which normally happens to the sample-based approach. Our experiments have shown that the proposed method can achieve a satisfactory performance on real data as well as simulated data.

Algorithms↗

Space-time segmentation using level set active contours applied to myocardial gated SPECT.

This paper presents a new variational method for the segmentation of a moving object against a still background, over a sequence of [two-dimensional or three-dimensional (3-D)] image frames. The method is illustrated in application to myocardial gated single photon emission computed tomography (SPECT) data, and incorporates a level set framework to handle topological changes while providing closed boundaries. The key innovation is the introduction of a geometrical constraint into the derivation of the Euler-Lagrange equations, such that the segmentation of each individual frame can be interpreted as a closed boundary of an object (an isolevel of a set of hyper-surfaces) while integrating information over the entire sequence. This results in the definition of an evolution velocity normal to the object boundary. Applying this method to 3-D myocardial gated SPECT sequences, the left ventricle endocardial and epicardial limits can be computed in each frame. This space-time segmentation method was tested on simulated and clinical 3-D myocardial gated SPECT sequences and the corresponding ejection fractions were computed.

Algorithms↗