Redundancy reducing processes in single neurons

Interaction mechanisms between excitatory and inhibitory impulse sequences operating on neurons play an important role for the processing of information by the nervous system. For instance, the convergence of excitatory and inhibitory influences on retinal ganglion cells to form their receptive fields has been taken as an example for the process of neuronal sharpening by lateral inhibition. In order to analyze quantitatively the functional behavior of such a system, Shannon's entropy method for multiple access channels has been applied to biological two-inputs-one-output systems using the theoretical model developed by Tsukada et al. (1979). Here we give an extension of this procedure from the point of view to reduce redundancy of information in the input signal space of single neurons and attempt to obtain a new interpretation for the information processing of the system. The concept for the redundancy reducing mechanism in single neurons is examined and discussed for the following two processes. The first process is concerned with a signal space formed by superposing two random sequences on the input of a neuron. In this process, we introduce a coding technique to encode the inhibitory sequence by using the timing of the excitatory sequence, which is closely related to an encoding technique of multiple access channels with a correlated source (Marko, 1966, 1970, 1973; Slepian and Wolf, 1973) and which is an invariant transformation in the input signal space without changing the information contents of the input. The second process is concerned with a procedure of reducing redundant signals in the signal space mentioned before. In this connection, it is an important point to see how single neurons reduce the dimensionality of the signal space via transformation with a minimum loss of effective information. For this purpose we introduce the criterion that average transmission of information from signal space to the output does not change when redundant signals are added. This assumption is based on the fact that two signals are equivalent if and only if they have identical input-output behavior. The mechanism is examined and estimated by using a computer-simulated model. As the result of such a simulation we can estimate the minimal segmentation in the signal space which is necessary and sufficient for temporal pattern sensitivity in neurons.     

A substitution matrix for structural alphabet based on structural alignment of homologous proteins and its applications

Analysis of protein structures based on backbone structural patterns known as structural alphabets have been shown to be very useful. Among them, a set of 16 pentapeptide structural motifs known as protein blocks (PBs) has been identified and upon which backbone model of most protein structures can be built. PBs allows simplification of 3D space onto 1D space in the form of sequence of PBs. Here, for the first time, substitution probabilities of PBs in a large number of aligned homologous protein structures have been studied and are expressed as a simplified 16 x 16 substitution matrix. The matrix was validated by benchmarking how well it can align sequences of PBs rather like amino acid alignment to identify structurally equivalent regions in closely or distantly related proteins using dynamic programming approach. The alignment results obtained are very comparable to well established structure comparison methods like DALI and STAMP. Other interesting applications of the matrix have been investigated. We first show that, in variable regions between two superimposed homologous proteins, one can distinguish between local conformational differences and rigid-body displacement of a conserved motif by comparing the PBs and their substitution scores. Second, we demonstrate, with the example of aspartic proteinases, that PBs can be efficiently used to detect the lobe/domain flexibility in the multidomain proteins. Lastly, using protein kinase as an example, we identify regions of conformational variations and rigid body movements in the enzyme as it is changed to the active state from an inactive state.     

Making light work of enzyme catalysis: protochlorophyllide oxidoreductase

In the chlorophyll biosynthetic pathway, the enzyme protochlorophyllide oxidoreductase (POR) catalyses a key light-driven reaction that triggers a profound transformation in plant development. Because POR is activated by light, it can provide information on the way in which light energy can be harnessed to power enzyme reactions and it presents us with a unique opportunity to study catalysis at low temperatures and on ultrafast timescales that are not accessible for most analyses of enzyme function. Recent advances in our understanding of the catalytic mechanism of POR illustrate why it is an important generic model for studying enzyme catalysis and reaction dynamics.     

Guiding conformation space search with an all-atom energy potential

The most significant impediment for protein structure prediction is the inadequacy of conformation space search. Conformation space is too large and the energy landscape too rugged for existing search methods to consistently find near-optimal minima. To alleviate this problem, we present model-based search, a novel conformation space search method. Model-based search uses highly accurate information obtained during search to build an approximate, partial model of the energy landscape. Model-based search aggregates information in the model as it progresses, and in turn uses this information to guide exploration toward regions most likely to contain a near-optimal minimum. We validate our method by predicting the structure of 32 proteins, ranging in length from 49 to 213 amino acids. Our results demonstrate that model-based search is more effective at finding low-energy conformations in high-dimensional conformation spaces than existing search methods. The reduction in energy translates into structure predictions of increased accuracy.     

Exponential model describing methane production kinetics in batch anaerobic digestion: a tool for evaluation of biochemical methane potential assays

Biochemical methane potential assays, usually run in batch mode, are performed by numerous laboratories to characterize the anaerobic degradability of biogas substrates such as energy crops, agricultural residues, and organic wastes. Unfortunately, the data obtained from these assays lacks common, universal bases for comparison, because standard protocols did not diffuse to the entire scientific community. Results are usually provided as final values of the methane yields of substrates. However, methane production curves generated in these assays also provide useful information about substrate degradation kinetics, which is rarely exploited. A basic understanding of the kinetics of the biogas process may be a first step towards a convergence of the assay methodologies on an international level. Following this assumption, a modeling toolbox containing an exponential model adjusted with a simple data-fitting method has been developed. This model should allow (a) quality control of the assays according to the goodness of fit of the model onto data series generated from the digestion of standard substrates, (b) interpretation of substrate degradation kinetics, and (c) estimate of the ultimate methane yield at infinite time. The exponential model is based on two assumptions: (a) the biogas process is a two-step reaction yielding VFA as intermediate products, and methane as the final product, and (b) the digestible substrate can be divided into a rapidly degradable and a slowly degradable fraction.     

Lessons from yeast: the spindle pole body and the centrosome

The yeast spindle pole body (SPB) is the functional equivalent of the centrosome. Most SPB components have been identified and their functions partly established. This involved a large variety of techniques which are described here, and the potential use of some of these in the centrosome field is highlighted. In particular, very useful structural information on the SPB was obtained from a reconstituted complex, the γ-tubulin complex, and also from a sub-particle, SPB cores, prepared by extraction of an enriched SPB preparation. The labelling of SPB proteins with GFP at the N or C termini, using GFP tags inserted into the genome, gave informative electron microscopy localization and fluorescence resonance energy transfer data. Examples are given of more precise functional data obtained by removing domains from one SPB protein, Spc110p, without affecting its essential function. Finally, a structural model for SPB duplication is described and the differences between SPB and centrosome duplication discussed.     

MOL3D,a modular and interactive program for molecular modeling and conformational analysis: I — basic modules

MOL3D is a generalized machine-independent computer program that lets the user interactively build 3D structures with different display options, such as wire, ball-and-stick and CPK representations. The program, which uses its own graphics package and driver, is designed to be very user friendly through the use of commands and menus. It has powerful transformation capabilities, such as software rotations, superpositions and zooming, and it is equipped with a fragment database that allows the user to build complex structures. The algorithm presented here is designed to perform computations in all the conformational space and therefore can be used to predict experimentally available quantities, such as NMR coupling constants. The program is efficient in the sense that it handles only dihedral angles in the first steps; as a result, it allows a rapid sampling of a great number of points through the entire conformational space. The user can choose between grid and Monte-Carlo searches of energy minimization, using a reasonable amount of computer time.     

An intelligent biological information management system

MOTIVATION: As biomedical researchers are amassing a plethora of information in a variety of forms resulting from the advancements in biomedical research, there is a critical need for innovative information management and knowledge discovery tools to sift through these vast volumes of heterogeneous data and analysis tools. In this paper we present a general model for an information management system that is adaptable and scalable, followed by a detailed design and implementation of one component of the model. The prototype, called BioSifter, was applied to problems in the bioinformatics area. RESULTS: BioSifter was tested using 500 documents obtained from PubMed database on two biological problems related to genetic polymorphism and extracorporal shockwave lithotripsy. The results indicate that BioSifter is a powerful tool for biological researchers to automatically retrieve relevant text documents from biological literature based on their interest profile. The results also indicate that the first stage of information management process, i.e. data to information transformation, significantly reduces the size of the information space. The filtered data obtained through BioSifter is relevant as well as much smaller in dimension compared to all the retrieved data. This would in turn significantly reduce the complexity associated with the next level transformation, i.e. information to knowledge.     

Issues in protection from galactic cosmic rays

Radiation risks to astronauts depend on the microscopic fluctuations of energy absorption events in specific tissues. These fluctuations depend not only on the space environment but also on the modifications of that environment by the shielding provided by structures surrounding the astronauts and the attenuation characteristics of the astronaut's body. The effects of attenuation within the shield and body depends on the tissue biological response to these microscopic fluctuations. In the absence of an accepted method for estimating astronaut risk, we examined the attenuation characteristics using conventional linear energy transfer (LET)-dependent quality factors (as one means of representing relative biological effectiveness, RBE) and a track-structure repair model to fit cell transformation (and inactivation) data in the C3H10 T1/2 mouse cell system obtained for various ion beams. Although the usual aluminum spacecraft shield is effective in reducing dose equivalent with increasing shield thickness, cell transformation rates are increased for thin aluminum shields. Clearly, the exact nature of the biological response to LET and track width is critical to evaluation of biological protection factors provided by a shield design. A significant fraction of biological injury results from the LET region above 100 keV/µm. Uncertainty in nuclear cross-sections results in a factor of 2–3 in the transmitted LET spectrum beyond depths of 15 g/cm², but even greater uncertainty is due to the combined effects of uncertainty in biological response and nuclear parameters. Clearly, these uncertainties must be reduced before the shield design can be finalised.Submitted paper presented at the International Symposium on Heavy Ion Research: Space, Radiation Protection and Therapy, Sophia-Antipolis, France, 21–24 March 1994     

Weighted-ensemble Brownian dynamics simulations for protein association reactions.

A new method, weighted-ensemble Brownian dynamics, is proposed for the simulation of protein-association reactions and other events whose frequencies of outcomes are constricted by free energy barriers. The method features a weighted ensemble of trajectories in configuration space with energy levels dictating the proper correspondence between "particles" and probability. Instead of waiting a very long time for an unlikely event to occur, the probability packets are split, and small packets of probability are allowed to diffuse almost immediately into regions of configuration space that are less likely to be sampled. The method has been applied to the Northrup and Erickson (1992) model of docking-type diffusion-limited reactions and yields reaction rate constants in agreement with those obtained by direct Brownian simulation, but at a fraction of the CPU time (10(-4) to 10(-3), depending on the model). Because the method is essentially a variant of standard Brownian dynamics algorithms, it is anticipated that weighted-ensemble Brownian dynamics, in conjunction with biophysical force models, can be applied to a large class of association reactions of interest to the biophysics community.     

A random-walk model of human mortality and aging

Consideration is made of the roles of certain types of state space and time scales for a random-walk model of individual physiological status change and death. Because the actual measurement of physiological variables omits many variables relevant to survival, we are forced to view this model as operating in a stochastic state space for a population of individuals where only the frequency distributions are deterministic. In this stochastic state space, under the assumption that the “history” of prior movement contains no additional information, the forward partial differential equation is obtained for the distribution of a population whose movement in the selected space is determined by the randomwalk equations. If the initial distribution of the population in the state space is normal, then certain assumptions about movement and mortality will operate to preserve normality thereafter. Under the assumption of normality, simultaneous ordinary differential equations can be derived from the forward partial differential equation defining the distribution function. Examination of the ordinary simultaneous differential equations shows how parameters for certain models of aging and mortality can be obtained.     

Inverse analysis of empirical matrices of idiotypic network interactions

The concept of shape space proposed by Perelson and Oster (1979,J. Theor. Biol. 81, 645–670) has been a useful tool for theoretical immunologists, who have invoked it to model idiotypic binding, which plays a significant role in mathematical models of immune networks. The actual construction of such a space from its definition requires specialized experimental information, which is not completely available. In this article, we discuss, with illustrative examples, how graphical representations similar to the idea of shape space can be derived by analyzing real affinity matrices, and the relative merits of such representations to approximations that might be obtained by the approach of Perelson and Oster. We also give directions for future research with a view toward applications.     

Tests for Hazard Transformation

The semiparametric Cox proportional hazards model is routinely adopted to model time-to-event data. Proportionality is a strong assumption, especially when follow-up time, or study duration, is long. Zeng and Lin (J. R. Stat. Soc., Ser. B, 69:1–30, 2007) proposed a useful generalisation through a family of transformation models which allow hazard ratios to vary over time. In this paper we explore a variety of tests for the need for transformation, arguing that the Cox model is so ubiquitous that it should be considered as the default model, to be discarded only if there is good evidence against the model assumptions. Since fitting an alternative transformation model is more complicated than fitting the Cox model, especially as procedures are not yet incorporated in standard software, we focus mainly on tests which require a Cox fit only. A score test is derived, and we also consider performance of omnibus goodness-of-fit tests based on Schoenfeld residuals. These tests can be extended to compare different transformation models. In addition we explore the consequences of fitting a misspecified Cox model to data generated under a true transformation model. Data on survival of 1043 leukaemia patients are used for illustration.     

Is non-genic inheritance involved in carcinogenesis? A cytotactic model of transformation

There is convincing evidence that the patterns formed by microtubules and by other fibres and organelles in ciliates are partly determined by non-genic inherited information, the so-called cytotactic information. There is also some evidence that this exists in metazoan cells and is perhaps involved in neoplastic transformation. On this background a cytotactic model of transformation which allows new interpretation of several characteristics of cancer cells has been developed. It proposes (a) that most cells contain cytotactic information, (b) that mechanisms to repair modifications of this information exist, and (c) that transformation may result when the cytotactic information is modified beyond repair. The model further proposes that (d) the modified cytotactic information is unevenly distributed between daughter cells at the following divisions so that cells with abnormal patterns, increasing pleomorphy and malignancy, and possibly altered gene functions are formed. The cytotactic transformation is proposed to take place in one or in two steps and to be inducible not only by many usual carcinogens but also by for example aborted cell divisions. A cytotactic interpretation of cancers induced by asbestos and of certain other observations is attempted.     

Visually guided orientation in flies: case studies in computational neuroethology

To understand the functioning of nervous systems and, in particular, how they control behaviour we must bridge many levels of complexity from molecules, cells and synapses to perception behaviour. Although experimental analysis is a precondition for understanding by nervous systems, it is in no way sufficient. The understanding is aided at all levels of complexity by modelling. Modelling proved to be an inevitable tool to test the experimentally established hypotheses. In this review it will by exemplified by three case studies that the appropriate level of modelling needs to be adjusted to the particular computational problems that are to be solved. (1) Specific features of the highly virtuosic pursuit behaviour of male flies can be understood on the basis of a phenomenological model that relates the visual input to the motor output. (2) The processing of retinal image motion as is experienced by freely moving animals can be understood on the basis of a model consisting of algorithmic components and components which represent a simple equivalent circuit of nerve cells. (3) Behaviourally relevant features of the reliability of encoding of visual motion information can be understood by modelling the transformation of postsynaptic potentials into sequences of spike trains.     

Functional equivalence of industrial metal cleaning processes comparison of metal cleaning processes within LCA

In an LCA case study, the three most frequent industrial metal cleaning technologies were assessed: Cleaning based on aqueous cleaning agents, non-halogenated hydrocarbon solvents and halogenated hydrocarbon solvents. Beside optimisation analysis, the comparison of the cleaning processes was a main goal of the study. The function of metal cleaning processes can be described with a set of parameters called functional parameters. In order to compare different cleaning processes within LCA, it is a precondition that all relevant functional parameters be equivalent. However, metal cleaning processes from different companies normally differ in most of the functional parameters and, thus, are not functionally equivalent. Therefore, it is necessary to calculate the material and energy flows of the processes corresponding to a reference function as a basis for comparison. This can be achieved by simulating the processes according to the functional parameters with the help of a process model. For a general comparison of the technologies, it is also necessary to consider the assessed machines having the same level of optimisation and the same scale.     

水稻无脊椎动物多样性的K-L变换编目分析

K-L变换可消除样品各特征间的相关性,去除信息量较少或信息虚假的坐标轴,降低特征空间的维数,用较少量的特征描述样品,是目前最为有效的数据信息压缩抽取方法。利用K-L变换,样品之间变化较小的分类单元（目或功能群等）,不会作为重要特征保留下来。因此,数量上占优势、或害虫防治中有重要地位的分类单元并不一定是识别样品的重要特征。可以藉K-L变换明确构成样品变异的主要分类单元,从而对不同地区、不同季节的取样实践有一定的指导意义、用通常的多样性指数分析及多样性差异显著性分析无法解决这个问题。用K-L变换可大大压缩数据存储空间。对数据量很大的生物多样性分析有较大的应用价值。反映样品所携信息量的热带水稻田无脊椎动物目主要是半翅目,中腹足目,以及表腹亚目。其中,在旱季半翅目占主要地位,而在雨季中腹足目占主要地位。就无脊椎动物目的组成而言,它们是构成样品变异的主要类群,是取样中需要得到特别注意的目。反映样品信息的无脊椎动物功能群主要是外部植食类,植食多食性类,半水生水面爬行类,粗粒残物取食类,以及陆生爬行、跳跃或猎者类,是取样中要重点考虑的一些类群。