GO功能类与基因差异表达的关联规则挖掘算法

针对基因功能分类体系Gene Ontology的层次结构特点,修改关联规则挖掘算法Apriori,开发“挖掘与基因差异表达关联的GO功能组合”软件(RuleGO).RuleGO以基因表达谱上的差异表达基因集合和不差异表达基因集合为输入,输出组合特征功能类与基因差异表达现象的关联规则,有助于解释基因差异表达现象的本质原因,如疾病发病机制、药物作用机理等.将RuleGO 和OntoExpress应用在结肠癌和腺癌表达谱数据集上,结果显示,RuleGO比OntoExpress能发现更多的与差异表达现象关联的特征功能类,更能看到在OntoExpress上不能发现的组合特征功能类.另外,结果显示,将规则的置信度和支持度要求设置较高时,一般只有组合功能类才能满足要求,这提示在基因表达谱分析中不宜采用单个角度的单个功能分类单元,考虑功能分类单元的组合可能更有意义.     

The structural proteins of scaleless-mutant chick epidermis.

Epidermis isolated from the anterior tarsometatarsus region of scaleless mutant chick legs was found to contain only α fibrous protein rather than the usual feather one. The polyacrylamide disc electrophoretic pattern of structural proteins isolated from mutant epidermis was also different from that of normal tissue. X-ray diffraction analysis of the claw of mutant chicks, however, showed the usual feather pattern. These results indicated that failure of scale induction rather than a defect in synthesis of feather protein is the abnormality in the mutant chick.     

Some goodness-of-fit methods for the Poisson plus added zeros distribution.

Methods for making inferences about the Poisson plus added zeros distribution and the truncated Poisson distribution are presented and illustrated with bacteriological data. Some of the methods are designed for testing the compatibility of the zero frequency with the Poisson distribution, whereas others are given for testing the goodness of fit for the truncated Poisson. In particular, a modified form of the Fisher index of dispersion is presented which is suitable for the truncated case. It is shown that the use of the usual expression of the index of dispersion for testing the adequacy of the truncated Poisson is not correct and leads to accepting inadequate fits more frequently than expected on the basis of test of significance. Furthermore, three test statistics are presented for testing the compatability of the zero frequency with the Poisson distribution. The results of the simulation show that two test statistics, one due to Cochran (W. G. Cochran, Biometrics 10:417-451, 1954) and the other to Rao and Chakravarti (C. R. Rao and I. M. Chakravarti, Biometrics 12:264-282, 1956), are preferable to those from the likelihood ratio test.     

Some goodness-of-fit methods for the Poisson plus added zeros distribution

Methods for making inferences about the Poisson plus added zeros distribution and the truncated Poisson distribution are presented and illustrated with bacteriological data. Some of the methods are designed for testing the compatibility of the zero frequency with the Poisson distribution, whereas others are given for testing the goodness of fit for the truncated Poisson. In particular, a modified form of the Fisher index of dispersion is presented which is suitable for the truncated case. It is shown that the use of the usual expression of the index of dispersion for testing the adequacy of the truncated Poisson is not correct and leads to accepting inadequate fits more frequently than expected on the basis of test of significance. Furthermore, three test statistics are presented for testing the compatability of the zero frequency with the Poisson distribution. The results of the simulation show that two test statistics, one due to Cochran (W. G. Cochran, Biometrics 10:417-451, 1954) and the other to Rao and Chakravarti (C. R. Rao and I. M. Chakravarti, Biometrics 12:264-282, 1956), are preferable to those from the likelihood ratio test.     

Mathematical properties of neuronal TD-rules and differential Hebbian learning: a comparison

A confusingly wide variety of temporally asymmetric learning rules exists related to reinforcement learning and/or to spike-timing dependent plasticity, many of which look exceedingly similar, while displaying strongly different behavior. These rules often find their use in control tasks, for example in robotics and for this rigorous convergence and numerical stability is required. The goal of this article is to review these rules and compare them to provide a better overview over their different properties. Two main classes will be discussed: temporal difference (TD) rules and correlation based (differential hebbian) rules and some transition cases. In general we will focus on neuronal implementations with changeable synaptic weights and a time-continuous representation of activity. In a machine learning (non-neuronal) context, for TD-learning a solid mathematical theory has existed since several years. This can partly be transfered to a neuronal framework, too. On the other hand, only now a more complete theory has also emerged for differential Hebb rules. In general rules differ by their convergence conditions and their numerical stability, which can lead to very undesirable behavior, when wanting to apply them. For TD, convergence can be enforced with a certain output condition assuring that the δ-error drops on average to zero (output control). Correlation based rules, on the other hand, converge when one input drops to zero (input control). Temporally asymmetric learning rules treat situations where incoming stimuli follow each other in time. Thus, it is necessary to remember the first stimulus to be able to relate it to the later occurring second one. To this end different types of so-called eligibility traces are being used by these two different types of rules. This aspect leads again to different properties of TD and differential Hebbian learning as discussed here. Thus, this paper, while also presenting several novel mathematical results, is mainly meant to provide a road map through the different neuronally emulated temporal asymmetrical learning rules and their behavior to provide some guidance for possible applications.     

Functional–structural models optimize the placement of foliage units for multiple whole-canopy functions

I present examples of plant functional–structural models (FSMs) that are used to evaluate how foliage units affect whole-canopy functions, and I show that multi-criteria optimization is an effective tool for these models. FSMs produce plant structures through the repeated application of a set of rules for the placement of foliage units. The models are blind (rules are the same regardless of dynamic simulation conditions), sighted (rules change with interference from other foliage units) or self-regulatory (rules change depending on the conditions of the simulation, i.e., internal conditions). In the examples presented, the models are used to optimize plant morphology for one or more measures of plant performance; these measures include movement of materials and associated hydraulic functions, foliage display, light interception and net carbon, mechanical support and stability, and reproductive success. It is consistently found that no morphology is optimal for any single measure of plant performance, and the rules for plant development are not stationary in space and time. In multi-criteria optimization, alternative morphologies are compared against multiple measures of plant performance; these are optimized simultaneously using Pareto optimality, which yields the set of mutually co-dominant solutions not dominated by any other solution. Two solutions are considered to be mutually co-dominant if improvement with respect to one criterion is at the expense of another criterion. I conclude that multi-criteria optimization is an essential tool for the use of FSMs to relate processes at the foliage level to whole-canopy function and to explain the structural diversity of old-growth forests.     

Recognition and architecture of the framework structure of protein

Based on the concept that the framework structure of a protein is determined by its secondary structure sequence, a new method for recognition and prediction of the structural class is suggested. By use of parameters N(alpha), N(beta), and N(beta(alpha)beta) (the number of alpha-helices, beta-strands, and beta(alpha)beta fragments), one can recognize the structural class with an accuracy higher than 90% when applied to the complete set (standard set) published in October 1995 and the structure data newly released before July 1998 (test set). Furthermore, the framework structures of beta, alpha, and alpha/beta protein are studied. It is found that these structures can be built from some basic units and that their architecture obeys some definite rules. Based on the packing of these basic units a set of rules for the recognition of topologies of the framework structure are worked out. When applied to the 1995 standard set and the 1998 test set the rates of correct recognition are higher than 77%. The simplicity and universality of framework structures are indicated which may be related to the evolutionary conservation of these folds. Proteins 2000;39:9-25.     

An Extended ANOVA F‐Test with Applications to the Heterogeneity Problem in Meta‐Analysis

The classical F‐test in the one‐way random effects ANOVA model is extended to solve the long outstanding problem of testing the between‐group variance on values also different from zero. This is done first for homoscedastic and heteroscedastic cases in not necessarily balanced models and secondly for balanced homoscedastic models. By simulation, the tests are shown to attain acceptable significance levels and high power even in data that do not follow the usual ANOVA model. An important application of the tests is given by the heterogeneity questions concerning the treatment effects across studies in meta‐analysis.     

Light-induced mass turnover in a mono-species community of mixotrophs.

We formulate a simple model for growth of a facultative photoautotroph with chemoheterotrophic capabilities. The organism is described by zero, one or three reserve components, and one structural component, all taken to be generalized compounds. The rules of synthesizing units are used for interactions among the uptake processes of the various nutrients and light (parallel processing), and for the merging of autotrophic and heterotrophic activities (sequential processing). For simplicity, we focus on the assimilation of inorganic carbon, inorganic nitrogen and light, and of two organic compounds (dead reserves and dead structure) that originate from aging. The process of resource recycling in a closed environment, as driven by light, and its links with community's structure (amount of biomass) is analysed in this simplest of all communities. Explicit analytical expressions for the steady states show how structure and function depend on the system parameters light, total carbon and total nitrogen. The behaviour resembles the Monod model for the Canonical Community, a three-species ecosystem consisting of producers, consumers and decomposers. If trophic preferences of a mixotroph are allowed to follow a random walk across generations, a trophic structure evolves where mixotrophs coexist with auto- and heterotrophs. Depth profiles are presented for the implied steady-state concentrations of dissolved inorganic carbon and nitrogen.     

THE EFFECT OF CALCIUM WITHDRAWAL ON THE STRUCTURE AND FUNCTION OF THE TOAD BLADDER

Previous reports have indicated that calcium is necessary to support active sodium transport by the toad bladder, and may be required as well in the action of vasopressin on both toad bladder and frog skin. The structure and function of the toad bladder has been studied in the absence of calcium, and a reinterpretation of the previous findings now appears possible. When calcium is withdrawn from the bathing medium, epithelial cells detach from one another and eventually from their supporting tissue. The short-circuit current (the conventional means of determining active sodium transport) falls to zero, and vasopressin fails to exert its usual effect on short-circuit current and water permeability. However, employing an indirect method for the estimation of sodium transport (oxygen consumption), it is possible to show that vasopressin exerts its usual effect on Q_oo2 when sodium is present in the bathing medium. Hence, it appears that the epithelial cells maintain active sodium transport when calcium is rigorously excluded from the bathing medium, and continue to respond to vasopressin. The failure of conventional techniques to show this can be attributed to the structural alterations in the epithelial layer in the absence of calcium. These findings may provide a model for the physiologic action of calcium in epithelia such as the renal tubule.     

The Formation of Multi-synaptic Connections by the Interaction of Synaptic and Structural Plasticity and Their Functional Consequences

Cortical connectivity emerges from the permanent interaction between neuronal activity and synaptic as well as structural plasticity. An important experimentally observed feature of this connectivity is the distribution of the number of synapses from one neuron to another, which has been measured in several cortical layers. All of these distributions are bimodal with one peak at zero and a second one at a small number (3–8) of synapses.In this study, using a probabilistic model of structural plasticity, which depends on the synaptic weights, we explore how these distributions can emerge and which functional consequences they have.We find that bimodal distributions arise generically from the interaction of structural plasticity with synaptic plasticity rules that fulfill the following biological realistic constraints: First, the synaptic weights have to grow with the postsynaptic activity. Second, this growth curve and/or the input-output relation of the postsynaptic neuron have to change sub-linearly (negative curvature). As most neurons show such input-output-relations, these constraints can be fulfilled by many biological reasonable systems.Given such a system, we show that the different activities, which can explain the layer-specific distributions, correspond to experimentally observed activities.Considering these activities as working point of the system and varying the pre- or postsynaptic stimulation reveals a hysteresis in the number of synapses. As a consequence of this, the connectivity between two neurons can be controlled by activity but is also safeguarded against overly fast changes.These results indicate that the complex dynamics between activity and plasticity will, already between a pair of neurons, induce a variety of possible stable synaptic distributions, which could support memory mechanisms.     

Proton affinity changes driving unidirectional proton transport in the bacteriorhodopsin photocycle

Bacteriorhodopsin is the smallest autonomous light-driven proton pump. Proposals as to how it achieves the directionality of its trans-membrane proton transport fall into two categories: accessibility-switch models in which proton transfer pathways in different parts of the molecule are opened and closed during the photocycle, and affinity-switch models, which focus on changes in proton affinity of groups along the transport chain during the photocycle. Using newly available structural data, and adapting current methods of protein protonation-state prediction to the non-equilibrium case, we have calculated the relative free energies of protonation microstates of groups on the transport chain during key conformational states of the photocycle. Proton flow is modeled using accessibility limitations that do not change during the photocycle. The results show that changes in affinity (microstate energy) calculable from the structural models are sufficient to drive unidirectional proton transport without invoking an accessibility switch. Modeling studies for the N state relative to late M suggest that small structural re-arrangements in the cytoplasmic side may be enough to produce the crucial affinity change of Asp96 during N that allows it to participate in the reprotonation of the Schiff base from the cytoplasmic side. Methodologically, the work represents a conceptual advance compared to the usual calculations of pK(a) using macroscopic electrostatic models. We operate with collective states of protonation involving all key groups, rather than the individual-group pK(a) values traditionally used. When combined with state-to-state transition rules based on accessibility considerations, a model for non-equilibrium proton flow is obtained. Such methods should also be applicable to other active proton-transport systems.     

An analysis of the class of gene regulatory functions implied by a biochemical model

Understanding the integrated behavior of genetic regulatory networks, in which genes regulate one another's activities via RNA and protein products, is emerging as a dominant problem in systems biology. One widely studied class of models of such networks includes genes whose expression values assume Boolean values (i.e., on or off). Design decisions in the development of Boolean network models of gene regulatory systems include the topology of the network (including the distribution of input- and output-connectivity) and the class of Boolean functions used by each gene (e.g., canalizing functions, post functions, etc.). For example, evidence from simulations suggests that biologically realistic dynamics can be produced by scale-free network topologies with canalizing Boolean functions. This work seeks further insights into the design of Boolean network models through the construction and analysis of a class of models that include more concrete biochemical mechanisms than the usual abstract model, including genes and gene products, dimerization, cis-binding sites, promoters and repressors. In this model, it is assumed that the system consists of N genes, with each gene producing one protein product. Proteins may form complexes such as dimers, trimers, etc. The model also includes cis-binding sites to which proteins may bind to form activators or repressors. Binding affinities are based on structural complementarity between proteins and binding sites, with molecular binding sites modeled by bit-strings. Biochemically plausible gene expression rules are used to derive a Boolean regulatory function for each gene in the system. The result is a network model in which both topological features and Boolean functions arise as emergent properties of the interactions of components at the biochemical level. A highly biased set of Boolean functions is observed in simulations of networks of various sizes, suggesting a new characterization of the subset of Boolean functions that are likely to appear in gene regulatory networks.     

"Brother" and "Uncle": An Analysis of Rules, Structural Contradictions, and Meaning in Vietnamese Kinship

This paper analyzes the meanings of Vietnamese kinship terms on the basis of the rules that regulate their referential and nonreferential uses. These rules are not completely consistent with one another. They constitute contradictory models of and for sociocultural reality at a certain level. The structural contradictions among these models render "fuzzy" even the definitions of the prototypical uses of Vietnamese kin terms. The coexistence of alternative models makes the use of a linguistic form both a goal-directed action and the representation of an order.     

Structural trees for protein superfamilies

Structural trees for large protein superfamilies, such as β proteins with the aligned β sheet packing, β proteins with the orthogonal packing of α helices, two-layer and three-layer α/β proteins, have been constructed. The structural motifs having unique overall folds and a unique handedness are taken as root structures of the trees. The larger protein structures of each superfamily are obtained by a stepwise addition of α helices and/or β strands to the corresponding root motif, taking into account a restricted set of rules inferred from known principles of the protein structure. Among these rules, prohibition of crossing connections, attention to handedness and compactness, and a requirement for α helices to be packed in α-helical layers and β strands in β layers are the most important. Proteins and domains whose structures can be obtained by stepwise addition of α helices and/or β strands to the same root motif can be grouped into one structural class or a superfamily. Proteins and domains found within branches of a structural tree can be grouped into subclasses or subfamilies. Levels of structural similarity between different proteins can easily be observed by visual inspection. Within one branch, protein structures having a higher position in the tree include the structures located lower. Proteins and domains of different branches have the structure located in the branching point as the common fold. Proteins 28:241–260, 1997. © 1997 Wiley-Liss Inc.     

Learning to recognize objects

Several aspects of systems for learning pattern or object recognition rules are discussed. First, how are recognition rules developed and to what extent is structural pattern information embedded into these recognition rules. Second, how are these rules applied to the recognition of complex patterns such as objects embedded in scenes and how is evidence from different rules combined into a single evidence vector. Third, how can learned rules be improved through performance evaluation and feedback to rule generation stages.     

Analysis and exploration of the use of rule-based algorithms and consensus methods for the inferral of haplotypes

The difficulty of experimental determination of haplotypes from phase-unknown genotypes has stimulated the development of nonexperimental inferral methods. One well-known approach for a group of unrelated individuals involves using the trivially deducible haplotypes (those found in individuals with zero or one heterozygous sites) and a set of rules to infer the haplotypes underlying ambiguous genotypes (those with two or more heterozygous sites). Neither the manner in which this "rule-based" approach should be implemented nor the accuracy of this approach has been adequately assessed. We implemented eight variations of this approach that differed in how a reference list of haplotypes was derived and in the rules for the analysis of ambiguous genotypes. We assessed the accuracy of these variations by comparing predicted and experimentally determined haplotypes involving nine polymorphic sites in the human apolipoprotein E (APOE) locus. The eight variations resulted in substantial differences in the average number of correctly inferred haplotype pairs. More than one set of inferred haplotype pairs was found for each of the variations we analyzed, implying that the rule-based approach is not sufficient by itself for haplotype inferral, despite its appealing simplicity. Accordingly, we explored consensus methods in which multiple inferrals for a given ambiguous genotype are combined to generate a single inferral; we show that the set of these "consensus" inferrals for all ambiguous genotypes is more accurate than the typical single set of inferrals chosen at random. We also use a consensus prediction to divide ambiguous genotypes into those whose algorithmic inferral is certain or almost certain and those whose less certain inferral makes molecular inferral preferable.     

Do extended incubation recesses carry fitness costs in two cavity‐nesting birds?

Because extended incubation recesses, where incubating songbirds are away from nests for periods much longer than usual, occur infrequently, they have been treated as outliers in most previous studies and thus overlooked. However, egg temperatures can potentially fall below the physiological zero temperature during extended recesses, potentially affecting developing embryos. As such, evaluating extended recesses in an ecological context and identifying their possible fitness effects are important. With this aim, we used iButton data loggers to monitor the incubation behavior of female Blue Tits (Cyanistes caeruleus) and Great Tits (Parus major) during two breeding seasons in central Spain. We classified incubation recesses as extended if they were more than four times the mean recess duration for each species. Extended incubation recesses occurred more frequently in 2012 when females exhibited poorer body condition. Female Blue Tits had more extended incubation recesses than female Great Tits and, for both species, more extended recesses occurred at the beginning of the breeding season. Both nest attentiveness and average minimum nest temperature decreased when at least one extended recess occurred. Incubation periods averaged 4 d longer for nests where females had at least one extended recess, potentially increasing predation risk and resulting in lower‐quality nestlings. Overall, our results suggest that extended recesses may be more common among songbirds than previously thought and that, due to their effects on egg temperatures and attentiveness, they could impose fitness costs.     

Structural trees for proteins containing φ-motifs

In the present study, a novel structural motif of proteins referred to as the phi-motif is considered, and two novel structural trees in which the phi-motif is taken as the root structure have been constructed. The simplest phi-motif is formed by three adjacent beta-strands connected by loops and packed in one beta-sheet so that its overall fold resembles the Greek letter phi. Construction of the structural trees and modeling of folding pathways have shown that all structures of the protein superfamilies can be obtained by stepwise addition of alpha-helices and/or beta-strands to the root phi-motif taking into account a restricted set of rules inferred from known principles of protein structure. The structural trees are a good tool for structure comparison, structural classification of proteins, as well as for searching for all possible protein folds and folding pathways.     

On Being Careful What We Wish for: Some Difficulties with Operationalizing the Precautionary Principle

An important part of the Precautionary Principle is that taking action is justified for protecting public health even when there is some scientific uncertainty. We examine here the two components of this central feature of the precautionary principle, scientific uncertainty and decision making. In order to operationalize the principle we should examine the consequences of its decision rules and how they perform under various conditions. The performance of decision rules in disease screening is measured by the sensitivity and specificity of the rule, but the consequences for the patient are given by the positive and negative predictive values, determined not only by the performance of the rule by the prevalence of the disease in the population. We look at positive and negative predictive value of the Precautionary Principle from the standopoint of the costs to one or other parts of society, show that the usual rule which tends to maximize sensitivity in favor of specificity may have unexpected consequences, and demonstrate that it is sometimes possible to trade sensitivity and specificity off against each other in a way the improves both positive and negative predictive value, or worse, degrades both.We conclude by asking if certain strategies are better for one or the other kinds of uncertainty.