Future directions in computer simulation

Developments in computer hardware and software are making significant improvements in the availability of simulation for biomedical researchers. This paper reviews past and present techniques for digital computer simulation and looks at improvements likely in the near future. In the area of hardware, personal computers are making computing and simulation more widely available and at the same time, supercomputers and special-purpose numerical processors are making it possible to solve larger problems. Software developments for simulation are reducing the time, effort and special skills required to produce a simulation program. A new hierarchical linker is proposed to make it easy to synthesize a global model by combining existing submodels. In the more distant future, computer models may be constructed graphically and with the assistance of intelligent programs capable of analysis and information retrieval.     

Successful Application of Evolutionary Algorithms in Engineering Design

Evolutionary or bionic strategies have proven to be powerful tools in many optimisation studies. Starting with some parent generations, producing sets of children, selecting the best children to be new parents yields impressive improvements of the objective when used with some experience and sufficient equipment. During some years of research the parameters of evolutionary optimisation have been investigated. Many successful applications showed where and how to use it. Especially in the case of objective functions with some or many local maxima, evolutionary approaches may propose solutions which gradient based optimisation would hardly find.When used with a large number of optimisation parameters, evolutionary methods seem to be superior to other strategies, as the chances to find good proposals within an acceptable number of trials and within affordable time are much higher.Nevertheless, evolutionary approaches like all optimisation methods require large numbers of studies of individual solutions. The computer power necessary to apply these strategies should not be underestimated. Even with today low cost and high availability of computers, the time to solve problems may be surprisingly long. So all ways of parallel processing, using single computers with many processors or clusters of many computers may speed up the time to do the optimisation.The basic terms of the method are outlined, some problems discussed, some examples given and some proposals made, how to use evolutionary methods in engineering optimisation. Finally some warnings are given trying to prevent potential users from non-realistic expectations. Optimisation is a difficult and consuming process. This holds for evolutionary optimisation as well.     

How to convert a traditional electron microscopy laboratory to digital imaging: follow the 'middle road'

Today, electron microscopy (EM) is increasingly confronted by the revolution in image-processing technology provoked by modern computers. Digital cameras are fast replacing film-based cameras in EM, as elsewhere, and the procedures for digital image-archiving, image-analysis, and image publication are rapidly evolving. To take advantage of these advances, we have chosen for the moment a 'middle road', in which film remains our basic recording medium in the electron microscope, but immediately thereafter, all film-based images are converted to digital files for further analysis and processing. The rationale behind this approach is that film still offers far greater sensitivity and resolution (providing an image equivalent to> 10 000 pixels per inch in a 1-s exposure), and film is still far easier to organize and archive than digital images of comparable resolution. However, digital manipulation of EM images has become mandatory. Hence, we explain here, in some detail, how we convert from film to digital.     

John Kendrew and myoglobin: Protein structure determination in the 1950s

The essay reviews John Kendrew's pioneering work on the structure of myoglobin for which he shared the Nobel Prize for Chemistry in 1962. It reconstructs the status of protein X‐ray crystallography at the time Kendrew entered the field in 1945, after distinctive service in operational research during the war. It reflects on the choice of sperm whale myoglobin as research material. In particular, it highlights Kendrew's early use of digital electronic computers for crystallographic computations and the marshaling of other tools and approaches that made it possible to solve the structure at increasing resolution. The essay further discusses the role of models in structure resolution and their broader reception. It ends by briefly reviewing Kendrew's other contributions in the formation and institutionalization of molecular biology.     

Business Impact of Pervasive Technologies: Opportunities and Risks

Despite heavy investment in integrated information systems, many business problems still prevail due to a lack of integration between the real and virtual world. Low data granularity presently limits enterprise computing. In order to solve these problems, data granularity needs to be increased and the digital management control loop must to be closed. Pervasive Computing, including automatic identification, is the technological enabler. Once closed digital management control loops are in place and generating high data granularity, incremental process changes such as an automatic quality check, enhance the overall efficiency of controlling intensive processes. Object value logging and embedded services are examples of more radical changes, which not only affect processes, but also business models. However, although the pervasive technology-based development road map of future enterprise computing systems seems to be straightforward, various risks and challenges have the potential to strongly influence the technology adoption path.     

Towards a biomolecular computer.

A new version of computing and information processing devices may result from major principles of information processing at molecular level. Non-discrete biomolecular computers based on these principles seems to be capable of solving problems of high computational complexity. One of the possible ways to implement these devices is based on biochemical non-linear dynamical systems. Means and ways to materialize biomolecular computers are discussed.     

Digital operations can be deceptive. Squid giant axon membrane.

Action potentials produced by current clamp stimuli have been used to voltage-clam axons, an analogue, and computers. The final currents reproduced the original stimulus except during the action potential, when fluctuations of greater than +/- 20% were found. But all of these operations were digitalized. When the original action potential from an analogue was recorded directly on magnetic tape and played back as the voltage clamp, the original stimulus was reproduced within experimental error. Five collaborators and I have shown that the digital transients can accumulate to surprising values.     

A comparative approach for the investigation of biological information processing: An examination of the structure and function of computer hard drives and DNA

Background  

The robust storage, updating and utilization of information are necessary for the maintenance and perpetuation of dynamic systems. These systems can exist as constructs of metal-oxide semiconductors and silicon, as in a digital computer, or in the "wetware" of organic compounds, proteins and nucleic acids that make up biological organisms. We propose that there are essential functional properties of centralized information-processing systems; for digital computers these properties reside in the computer's hard drive, and for eukaryotic cells they are manifest in the DNA and associated structures.     

Information processing in molecular systems

Information processing, or selective dissipation, is mediated by switching elements in classical systems and by enzyme catalysis in biochemical systems. There are important differences in the character of this dissipation (from the standpoint of energy and control) in self-reproducing systems based on molecular interactions and those based on conventional computers. Conventional computers process information in a single level mode, i.e., the state of each unit of the system is accessed independently. This includes the manipulable memory units which store the computer program. In contrast, molecular self-reproducing systems process information in a hierarchical mode, based on the fact of hierarchy in molecular structure. In particular, the enzyme is described genetically at the primary level of structure (amino acid sequence) but functions at the higher, tertiary level on the basis of the interactions of many manipulable units. As a consequence it is not possible to program a biochemical system in any conventional sense. However, this is compensated by an increased capacity for accumulating appropriate information through evolution by variation and natural selection. This is possible because systems operating in the hierarchical mode are amenable to gradual modification of function. The degree of gradualness is itself an evolved property of biological molecules.     

Elastic energy storage in tendons: mechanical differences related to function and age

We investigated the possibility that tendons that normally experience relatively high stresses and function as springs during locomotion, such as digital flexors, might develop different mechanical properties from those that experience only relatively low stresses, such as digital extensors. At birth the digital flexor and extensor tendons of pigs have identical mechanical properties, exhibiting higher extensibility and mechanical hysteresis and lower elastic modulus, tensile strength, and elastic energy storage capability than adult tendons. With growth and aging these tendons become much stronger, stiffer, less extensible, and more resilient than at birth. Furthermore, these alterations in elastic properties occur to a significantly greater degree in the high-load-bearing flexors than in the low-stress extensors. At maturity the pig digital flexor tendons have twice the tensile strength and elastic modulus but only half the strain energy dissipation of the corresponding extensor tendons. A morphometric analysis of the digital muscles provides an estimate of maximal in vivo tendon stresses and suggests that the muscle-tendon unit of the digital flexor is designed to function as an elastic energy storage element whereas that of the digital extensor is not. Thus the differences in material properties between mature flexor and extensor tendons are correlated with their physiological functions, i.e., the flexor is much better suited to act as an effective biological spring than is the extensor.     

Entomological biometeorology

Summary I would appear to have given a rather pessimistic picture of the problems in entomological biometeorology as a result of emphasizing the areas of research that are most vitally concerned with a full understanding of the insect's relation to its environment. An important part of continuing scientific study is capacity to define problems for future investigation from past experience. In spite of the fact that many research results in border fields between meteorology and biology have accumulated without any serious organization toward unifying concepts, it is encouraging that we have achieved enough insight to define some of the basic problems. Future research is in a position in many ways to contribute to the organized approach that is required to make biometeorology a science.It should also be observed that the major limiting problem of handling large volumes of data in complicated ecological studies has been solved in principle to a large extent by the digital and the analogue electronic computers. Digital computer programming has already been incorporated in some population studies for insects. Eventual extension of analogue computer methods to behaviour problems may well facilitate an understanding of more complicated systems,especially those basic to the dispersal and migration of insects.     

Pattern recognition in the computer analysis of nucleotide sequences

We have used an algorithm from the pattern recognition theory "generalized portrait" to find a distinguishing vector for Escherichia coli promoters. We have made an attempt to solve closely linked problems for choosing significant signs of that signal, multiple alignment and for calculation of the recognition vector (matrix). The promoters with known strength have been ranged with this vector. The analysis of the occurrence of predicted promoters has been carried out. The promoters search program for IBM-compatible computers is available from the authors.     

Combining Computational and Social Effort for Collaborative Problem Solving

Rather than replacing human labor, there is growing evidence that networked computers create opportunities for collaborations of people and algorithms to solve problems beyond either of them. In this study, we demonstrate the conditions under which such synergy can arise. We show that, for a design task, three elements are sufficient: humans apply intuitions to the problem, algorithms automatically determine and report back on the quality of designs, and humans observe and innovate on others’ designs to focus creative and computational effort on good designs. This study suggests how such collaborations should be composed for other domains, as well as how social and computational dynamics mutually influence one another during collaborative problem solving.     

In search of a thermodynamic description of biomass yields for the chemotrophic growth of microorganisms

Correlations for the prediction of biomass yields are valuable, and many proposals based on a number of parameters (Y(ATP), Y(Ave), eta(o), Y(c), Gibbs energy efficiencies, and enthalpy efficiencies) have been published. This article critically examines the properties of the proposed parameters with respect to the general applicability to chemotrophic growth systems, a clear relation to the Second Law of Thermodynamics, the absence of intrinsic problems, and a requirement of only black box information. It appears that none of the proposed parameters satisfies all these requirements. Particularly, the various energetic efficiency parameters suffer from major intrinsic problems. However, this article will show that the Gibbs energy dissipation per amount of produced biomass (kJ/C-mod) is a parameter which satisfies the requirements without having intrinsic problems. A simple correlation is found which provides the Gibbs energy dissipation/C-mol biomass as a function of the nature of the C-source (expressed as the carbon chain length and the degree of reduction). This dissipation appears to be nearly independent of the nature of the electron acceptor (e.g., O(2), No(3) (-), fermentation). Hence, a single correlation can describe a very wide range of microbial growth systems. In this respect, Gibbs energy dissipation is much more useful than heat production/C-mol biomass, which is strongly dependent on the electron acceptor used. Evidence is presented that even a net heat-uptake can occur in certain growth systems.The correlation of Gibbs energy dissipation thus obtained shows that dissipation/C-mol biomass increases for C-sources with smaller chain length (C(6) --> C(1)), and increases for both higher and lower degrees of reduction than 4. It appears that the dissipation/C-mol biomass can be regarded as a simple thermodynamic measure of the amount of biochemical "work" required to convert the carbon source into biomass by the proper irreversible carbon-carbon coupling and oxidation/reduction reactions. This is supported by the good correlation between the theoretical ATP requirement for biomass formation on different C-sources and the dissipation values (kJ/C-mol biomass) found. The established correlation for the Gibbs energy dissipation allows the prediction of the chemotrophic biomass yield on substrate with an error of 13% in the yield range 0.01 to 0.80 C-mol biomass/(C)-mol substrate for aerobic/anaerobic/denitrifying growth systems.     

AUDIO COMPUTERS—THEORY OF OPERATION AND GUIDELINES FOR SELECTION OF SYSTEMS AND COMPONENTS

ABSTRACT

Computers are available that can store, synthesize and replay sounds using digital technology. I describe the major components of audio computers, the principles of digital sound acquisition and playback, and information and caveats for scientists interested in acquiring an audio computer system for their own use. A tutorial on analog filter application is also included as well as a diagnostic procedure and a buyer's check list.     

Imaging techniques in microbiology

Recent advances in optical imaging have dramatically expanded the capabilities of the light microscope and its usefulness in microbiology research. Some of these advances include improved fluorescent probes, better cameras, new techniques such as confocal and deconvolution microscopy, and the use of computers in imaging and image analysis. These new technologies have now been applied to microbiological problems with resounding success.     

Exploring the dark genome: implications for precision medicine

Mammalian Genome - The increase in the number of both patients and healthcare practitioners who grew up using the Internet and computers (so-called “digital natives”) is likely to...     

Digital genetics: unravelling the genetic basis of evolution

Digital genetics, or the genetics of digital organisms, is a new field of research that has become possible as a result of the remarkable power of evolution experiments that use computers. Self-replicating strands of computer code that inhabit specially prepared computers can mutate, evolve and adapt to their environment. Digital organisms make it easy to conduct repeatable, controlled experiments, which have a perfect genetic 'fossil record'. This allows researchers to address fundamental questions about the genetic basis of the evolution of complexity, genome organization, robustness and evolvability, and to test the consequences of mutations, including their interaction and recombination, on the fate of populations and lineages.     

The mutation buffering concept of biomolecular structure

Redundant elements in proteins and nucleic acids serve to buffer the effect of point mutations on features of conformation critical for function. Mutation buffering associated with mechanistically redundant amino acids facilitates the evolution of proteins. Such redundant amino acids accumulate by hitch-hiking along with the evolutionary advances which they facilitate. Redundancies in DNA (such as introns and repetitive DNA) prevent extraneous sequence dependent conformational effects from interfering with readout. They also facilitate regulatory evolution. According to the mutation buffering concept biological organizations are selected to facilitate evolution. As a consequence biological information processing is very different from information processing in man-made computers. The link between molecular conformation, evolutionary processes, and information processing is formulated in terms of a tradeoff principle. By utilizing mutation buffering biological systems sacrifice programmability; by achieving programmability digital computers make mutation buffering computationally expensive and hence sacrifice evolutionary adaptability.     

The use of different statistical methods in epidemiological analysis to assess the seasonality and territorial spread of infectious diseases

To solve the problems connected with the evaluation of the seasonal and territorial distribution of infectious diseases, indications and limitations for the use of the following statistical methods have been worked out: the calculation of the monthly morbidity level, the proportion of cases of infectious diseases falling on the months of seasonal morbidity rises, the proportion of such cases appearing due to the influence of seasonal factors, the total and partial indices, the average monthly rate of increase in seasonal morbidity, the complex evaluation of seasonal morbidity, the evaluation of the nonparallelism of two curves, the determination of the mean quadratic deviations and Shannon's entropy. The algorithms based on these methods lie in the foundation of 11 computer programs, forming the software complex "Epidanalysis" and provided with the service menu permitting an epidemiologist to proceed from the task via indications and limitations to the corresponding program. The programs are intended for different types of computers (IBM PC XT, EC-1640, Robotron 1715).