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Molecular computing revisited: a Moore's Law?

Moore's Law states that the processing power of microchips doubles every one to two years. This observation might apply to the nascent field of molecular computing, in which biomolecules carry out logical operations. Incorporation of new technologies that improve sensitivity and throughput has increased the complexity of problems that can be addressed. It is an ultimate goal for molecular computers to use the full potential of massive parallelism.

Algorithms↗

A new data-acquisition system for the measurement of the net water flux across epithelia.

We describe a computer-based data-acquisition system designed for the measurement of net water flux across epithelia. It is based on the detection of a liquid meniscus position in a capillary tube using an electro-optical device. Then the data are digitized, transferred to the computer main memory and saved in a file. The advantages of the system are: (a) to measure net water transfer with an accuracy of 50 nl; (b) to switch from absorptive to secretory conditions in real time; (c) data are directly digitized to be analytically, graphically and statistically treated; (d) the specially developed software allows change of time intervals for data acquirement and the scale in graphic events; (e) the software also allows recall to the monitor screen of graphics from previous tests or to print them on paper; (f) a simple mechanical structure, saving maintenance and time; and (g) high reliability.

Animals↗

Computer-generated time lines for visualizing and editing epidemiological and biomedical data.

Most biomedical data have a temporal dimension. Time-line displays spatialize this dimension and help the viewer comprehend large sets of complex data. If we add ways for users to selectively expand the details of data visible on a time line, even more information can be organized and accessed. Design issues for this kind of display include: how to display time scales that are often wider than the physical display space; how to display events with brief duration; how to display data for two or more events that overlap in time; how to manage the display of data details; how to allow database editing from a time line; and how to facilitate time-based analytical techniques. We describe a time-line display system that addresses each of these issues, and show how it can be used to organize data for an epidemiological study of parental radiation exposure and childhood leukemia. We also suggest further refinements of the time line technique for other biomedical applications.

Child↗

Computing with DNA by operating on plasmids.

A new method of computing using DNA plasmids is introduced and the potential advantages are listed. The new method is illustrated by reporting a laboratory computation of an instance of the NP-complete algorithmic problem of computing the cardinal number of a maximal independent subset of the vertex set of a graph. A circular DNA plasmid, specifically designed for this method of molecular computing, was constructed. This computational plasmid contains a specially inserted series of DNA sequence segments, each of which is bordered by a characteristic pair of restriction enzyme sites. For the computation reported here, the DNA sequence segments of this series were used to represent the vertices of the graph being investigated. By applying a scheme of enzymatic treatments to the computational plasmids, modified plasmids were generated from which the solution of the computational problem was selected. This new method of computing is applicable to a wide variety of algorithmic problems. Further computations in this style are in progress.

Computing Methodologies↗

An improved surface-based method for DNA computation.

DNA computing is a novel method for solving a class of intractable computational problems, in which the computing time can grow exponentially with problem size. Up to now, many accomplishments have been achieved to improve its performance and increase its reliability, among which a surface-based method is an efficient candidate. In this paper, the surface-based approach proposed by Liu, Q., Wang, L., Frutos, A.G., Condon, A.E., Corn, R.M., and Smith, L.M., 2000, DNA computing on surfaces. Nature 403, 175-179 is analyzed and an improved surface-based method for DNA computation (i.e. the hybrid DNA/optical computing method) is proposed. Compared with Liu et al.'s approach, our method has some significant advantages such as low cost, short operating time, reusable surface and simple experimental steps. Moreover, the concept of combining easily patterned DNA computing steps with equally parallel, but generally uniform and not easily patterned optical computing steps is an important new direction.

Computing Methodologies↗

Distributed algorithms over communicating membrane systems.

This paper presents fundamental distributed algorithms over membrane systems with antiport carriers. We describe distributed algorithms for collecting and dispersing information, leader election in these systems, and the mutual exclusion problem. Finally, we consider membrane systems producing correct results despite some failures at some of the components or the communication links. We show that membrane systems with antiport carriers provide an appropriate model for distributed computing, particularly for message-passing algorithms interpreted here as membrane transport in both directions, namely when two chemicals behave as input and output messages and pass the membranes in both directions using antiport carriers.

Algorithms↗

Simulation and verification of P systems through communicating X-machines.

The aim of this paper is to prove the suitability of a parallel distributed computational model, communicating X-machines, to simulate in a natural way a well established model of molecular computation, P systems, and to present some further benefits of the approach allowing us to check for some formal properties. A set of rules to transform any P system with symbol-objects into a communicating X-machine model is presented and a variation of temporal logic for X-machines is briefly discussed, which facilitates model checking of desired properties of the system. Finally, the benefits resulting from the transformation are discussed.

Algorithms↗

Modeling the topological organization of cellular processes.

The cell as a dynamical system presents the characteristics of having a dynamical structure. That is, the exact phase space of the system cannot be fixed before the evolution and integrative cell models must state the evolution of the structure jointly with the evolution of the cell state. This kind of dynamical systems is very challenging to model and simulate. New programming concepts must be developed to ease their modeling and simulation. In this context, the goal of the MGS project is to develop an experimental programming language dedicated to the simulation of this kind of systems. MGS proposes a unified view on several computational mechanisms (CHAM, Lindenmayer systems, Paun systems, cellular automata) enabling the specification of spatially localized computations on heterogeneous entities. The evolution of a dynamical structure is handled through the concept of transformation which relies on the topological organization of the system components. An example based on the modeling of spatially distributed biochemical networks is used to illustrate how these notions can be used to model the spatial and temporal organization of intracellular processes.

Algorithms↗

Conformon-driven biopolymer shape changes in cell modeling.

Conceptual models of the atom preceded the mathematical model of the hydrogen atom in physics in the second decade of the 20th century. The computer modeling of the living cell in the 21st century may follow a similar course of development. A conceptual model of the cell called the Bhopalator was formulated in the mid-1980s, along with its twin theories known as the conformon theory of molecular machines and the cell language theory of biopolymer interactions [Ann. N.Y. Acad. Sci. 227 (1974) 211; BioSystems 44 (1997) 17; Ann. N.Y. Acad. Sci. 870 (1999a) 411; BioSystems 54 (2000) 107; Semiotica 138 (1-4) (2002a) 15; Fundamenta Informaticae 49 (2002b) 147]. The conformon theory accounts for the reversible actions of individual biopolymers coupled to irreversible chemical reactions, while the cell language theory provides a theoretical framework for understanding the complex networks of dynamic interactions among biopolymers in the cell. These two theories are reviewed and further elaborated for the benefit of both computational biologists and computer scientists who are interested in modeling the living cell and its functions. One of the critical components of the mechanisms of cell communication and cell computing has been postulated to be space- and time-organized teleonomic (i.e. goal-directed) shape changes of biopolymers that are driven by exergonic (free energy-releasing) chemical reactions. The generalized Franck-Condon principle is suggested to be essential in resolving the apparent paradox arising when one attempts to couple endergonic (free energy-requiring) biopolymer shape changes to the exergonic chemical reactions that are catalyzed by biopolymer shape changes themselves. Conformons, defined as sequence-specific mechanical strains of biopolymers first invoked three decades ago to account for energy coupling in mitochondria, have been identified as shape changers, the agents that cause shape changes in biopolymers. Given a set of space- and time-organized teleonomic shape changes of biopolymers driven by conformons, all of the functions of the cell can be accounted for in molecular terms-at least in principle. To convert a conceptual model of the cell into a computer model, it is necessary to represent the conceptual model in an algebraic language. To this end, we have begun to apply the process algebra of Milner [Communicating and Mobile Systems: The pi-calculus, Cambridge University Press, Cambridge, 1999] to develop what is here called the "shape algebra," capable of describing complex and mobile patterns of interactions among biomolecules leading to cell functions.

Algorithms↗

Evaluating polynomials on the molecular level--a novel approach to molecular computers.

In the past few years two fascinating and new scientific fields, the science of DNA-structure and topology and the theory of molecular computers have been growing independently. The main goal of this paper is to establish an interesting connection between them and to propose a novel paradigm for the future construction of DNA-computing devices based on supercoil energetics. The basic principle of the proposed model can also be applied to describe the communication between topologically closed segments in real genomes, which is believed to take part in the complex process of gene regulation. An implementation of the recent model is proposed by which polynomials of one real variable can be evaluated in a simple in vitro recombination assay.

Computers↗

Identification and cDNA cloning of a novel human mosaic protein, LGN, based on interaction with G alpha i2.

We have used the yeast two-hybrid system to identify proteins that interact with the alpha-subunit of the heterotrimeric GTP-binding protein, Gi2. We screened a human B cell cDNA library with full-length G alpha i2 and isolated four positive colonies, one of which expressed the 44-kDa COOH terminus of a previously unrecognized 677-amino acid (aa) protein. A full-length clone was isolated from a HeLa cell cDNA library. The deduced protein contains 10 Leu-Gly-Asn repeats, and thus we named it LGN. Computer analysis indicates that LGN is a mosaic protein with seven repeated sequences of about 40 aa in length at its N-terminal end, and four repeated sequences of about 34 aa at its C-terminal end. Each of the two repeat regions shows substantial similarity to proteins found in other organisms. RT-PCR analysis of human tissues showed that the mRNA of LGN was ubiquitously expressed. The specificity of interaction between G alpha i2 and LGN was confirmed by an in vitro binding assay using recombinant proteins. These data indicate that the yeast two-hybrid system can identify novel proteins, such as LGN, that interact with G alpha proteins. As a mosaic protein, LGN shows similarity with portions of proteins from many species and thus may define a new protein family.

Amino Acid Sequence↗

Creating a home page on the World Wide Web: an inexpensive means to promote medical education and physician recruitment.

The World Wide Web (WWW) is generally used as an information resource. It can also be used as a national and international promotional (advertising) resource, at minimal cost, to assist in physician recruitment, such as for residency training programs. Currently, only a few residency training programs have home page sites describing their programs on the WWW. Creating a WWW site that can be viewed nationally and internationally requires an internet service provider and hypertext markup language (HTML) document that designs the WWW home page site. This article provides a step-by-step method for creating a simple WWW site (including an HTML template) to promote a residency program and assist in resident recruitment. As more young physicians graduate with more extensive computer skills and familiarity, use of the WWW for physician recruitment will become a more important source of information for physician applicants.

Computer Communication Networks↗

An exhaustive DNA micro-satellite map of the human genome using high performance computing.

The current pace of the generation of sequence data requires the development of software tools that can rapidly provide full annotation of the data. We have developed a new method for rapid sequence comparison using the exact match algorithm without repeat masking. As a demonstration, we have identified all perfect simple tandem repeats (STR) within the draft sequence of the human genome. The STR elements (chromosome, position, length and repeat subunit) have been placed into a relational database. Repeat flanking sequence is also publicly accessible at http://grid.abcc.ncifcrf.gov. To illustrate the utility of this complete set of STR elements, we documented the increased density of potentially polymorphic markers throughout the genome. The new STR markers may be useful in disease association studies because so many STR elements manifest multiallelic polymorphism. Also, because triplet repeat expansions are important for human disease etiology, we identified trinucleotide repeats that exist within exons of known genes. This resulted in a list that includes all 14 genes known to undergo polynucleotide expansion, and 48 additional candidates. Several of these are non-polyglutamine triplet repeats. Other examinations of the STR database demonstrated repeats spanning splice junctions and identified SNPs within repeat elements.

Alleles↗

Quantum optimization for training support vector machines.

Refined concepts, such as Rademacher estimates of model complexity and nonlinear criteria for weighting empirical classification errors, represent recent and promising approaches to characterize the generalization ability of Support Vector Machines (SVMs). The advantages of those techniques lie in both improving the SVM representation ability and yielding tighter generalization bounds. On the other hand, they often make Quadratic-Programming algorithms no longer applicable, and SVM training cannot benefit from efficient, specialized optimization techniques. The paper considers the application of Quantum Computing to solve the problem of effective SVM training, especially in the case of digital implementations. The presented research compares the behavioral aspects of conventional and enhanced SVMs; experiments in both a synthetic and real-world problems support the theoretical analysis. At the same time, the related differences between Quadratic-Programming and Quantum-based optimization techniques are considered.

Computing Methodologies↗

Methodological problems in the retrospective computation of responsiveness to change: the lesson of Cronbach.

OBJECTIVE: To examine the relation between responsiveness coefficients derived directly from a calculation of average change resulting from a treatment intervention (Responsiveness-Treatment or RT) and those derived from retrospective analysis of changed and unchanged groups (Responsiveness Retrospective or RR) based on a global measure of change. METHOD: Two approaches were used. First, we used simulation methods to examine the analytical relationship between the RT and RR coefficients. We then located eight studies where it was possible to compute both RT and RR coefficients. As anticipated from theoretical arguments, the RR coefficients were larger than the RT coefficients (1.50 versus 0.41, p < .0001). Within study there was no predictable relationship between the two indices. Across studies, the magnitude of the RR coefficient was strongly related to the correlation with the retrospective global scale, and unrelated to the magnitude of the RT coefficient. The simulated curves fit well with the observed data, and substantiated the observation that the relation between RT and RR coefficients is complex and only weakly related to the size of the treatment effect. CONCLUSION: Retrospective methods of computing responsiveness yield little information about the ability of an instrument to detect treatment effects, and should not be used as a basis for choice of an instrument for applications to clinical trials.

Computer Simulation↗

DNA computing.

DNA computation is a novel and exciting recent development at the interface of computer science and molecular biology. We describe the current activity in this field following the seminal work of Adleman, who recently showed how techniques of molecular biology may be applied to the solution of a computationally intractable problem.

Algorithms↗

Spreadsheet calculations of absorbed dose to water for photons and electrons according to established dosimetry protocols.

The calculation of absorbed dose to water according to a Code of Practice demands a strict adherence to the rules and data of the protocol. To ease the calculations and to avoid computational and methodological errors, we have developed a number of spreadsheets to perform the calculations in accordance with an established dosimetry protocol-in our case those of the International Atomic Energy Agency (IAEA) and the Institution of Physics and Engineering in Medicine and Biology (IPEMB). The spreadsheets are implemented as Microsoft Excel V5.0 worksheets. Only a limited selection of dosimetry equipment is used for calibration, which is performed according to only one of the methods allowed by the protocol. This voluntary limitation of equipment and methods is reflected in a spreadsheet that is beam-specific, compact, focused, and very practical. There are four main spreadsheets: high-energy photons (IAEA), high-energy electrons (IAEA), medium energy X rays (IPEMB), and low-energy X rays (IPEMB). The sheets allow the input of setup and measured data, but tabulated data and formulas are protected. Parameter values are copied from the protocols, and the relevant value is found by linear interpolation. Once the spreadsheets are drawn up correctly and thoroughly checked, protocol calculations are performed easily and accurately. The spreadsheets presented are tailored to suit our specific needs but can easily be modified to conform to the practices of any other institution. They are not intended as "cookbooks" but need to be filled in by a radiation physicist with the input data checked by a second professional. The same method is also used for calculating the Reference Air Kerma Rate of brachytherapy sources.

Calibration↗