Social learning and the replication process: an experimental investigation

Human cultural traits typically result from a gradual process that has been described as analogous to biological evolution. This observation has led pioneering scholars to draw inspiration from population genetics to develop a rigorous and successful theoretical framework of cultural evolution. Social learning, the mechanism allowing information to be transmitted between individuals, has thus been described as a simple replication mechanism. Although useful, the extent to which this idealization appropriately describes the actual social learning events has not been carefully assessed. Here, we used a specifically developed computer task to evaluate (i) the extent to which social learning leads to the replication of an observed behaviour and (ii) the consequences it has for fitness landscape exploration. Our results show that social learning does not lead to a dichotomous choice between disregarding and replicating social information. Rather, it appeared that individuals combine and transform information coming from multiple sources to produce new solutions. As a consequence, landscape exploration was promoted by the use of social information. These results invite us to rethink the way social learning is commonly modelled and could question the validity of predictions coming from models considering this process as replicative.     

Persistence Length of Chromatin Determines Origin Spacing in Xenopus Early-Embryo DNA Replication: Quantitative Comparisons between Theory and Experiment

In Xenopus early embryos, replication origins neither require specific DNA sequences nor is there an efficient S/M checkpoint, even though the whole genome (3 billion bases) is completely duplicated within 10-20 minutes. This leads to the “random-completion problem” of DNA replication in embryos, where one needs to find a mechanism that ensures complete, faithful, timely reproduction of the genome without any sequence dependence of replication origins. We analyze recent DNA replication data in Xenopus laevis egg extracts and find discrepancies with models where replication origins are distributed independently of chromatin structure. Motivated by these discrepancies, we have investigated the role that chromatin looping may play in DNA replication. We find that the loop-size distribution predicted from a wormlike-chain model of chromatin can account for the spatial distribution of replication origins in this system quantitatively. Together with earlier findings of increasing frequency of origin firings, our results can explain the random-completion problem. The agreement between experimental data (molecular combing) and theoretical predictions suggests that the intrinsic stiffness of chromatin loops plays a fundamental biological role in DNA replication in early-embryo Xenopus in regulating the origin spacing.     

Persistence length of chromatin determines origin spacing in Xenopus early-embryo DNA replication: quantitative comparisons between theory and experiment

In Xenopus early embryos, replication origins neither require specific DNA sequences nor is there an efficient S/M checkpoint, even though the whole genome (3 billion bases) is completely duplicated within 10-20 minutes. This leads to the "random-completion problem" of DNA replication in embryos, where one needs to find a mechanism that ensures complete, faithful, timely reproduction of the genome without any sequence dependence of replication origins. We analyze recent DNA replication data in Xenopus laevis egg extracts and find discrepancies with models where replication origins are distributed independently of chromatin structure. Motivated by these discrepancies, we have investigated the role that chromatin looping may play in DNA replication. We find that the loop-size distribution predicted from a wormlike-chain model of chromatin can account for the spatial distribution of replication origins in this system quantitatively. Together with earlier findings of increasing frequency of origin firings, our results can explain the random-completion problem. The agreement between experimental data (molecular combing) and theoretical predictions suggests that the intrinsic stiffness of chromatin loops plays a fundamental biological role in DNA replication in early-embryo Xenopus in regulating the origin spacing.     

人类疾病动物模型制备效果评价软件应用评测

目的建立人类疾病动物模型制备效果评价软件,并将其应用于科研模型制备效果评价工作,推动模型制备效果评价数量化、精确化和标准化。方法以研制模型制备效果评估软件为基本内容,采用面向对象程序设计方法 ,通过对GUI图形界面的操作完成模型制备效果评价工作。结果通过上海市内业界人员的实际应用,该软件显示了稳定性、快捷性和科学性。结论应用人类疾病动物模型制备效果评价软件可以提高模型制备效果评估的效率,推动了实验动物模型制备效果评价的精确量化和标准化进程。     

One Giant Leap for Categorizers: One Small Step for Categorization Theory

We explore humans’ rule-based category learning using analytic approaches that highlight their psychological transitions during learning. These approaches confirm that humans show qualitatively sudden psychological transitions during rule learning. These transitions contribute to the theoretical literature contrasting single vs. multiple category-learning systems, because they seem to reveal a distinctive learning process of explicit rule discovery. A complete psychology of categorization must describe this learning process, too. Yet extensive formal-modeling analyses confirm that a wide range of current (gradient-descent) models cannot reproduce these transitions, including influential rule-based models (e.g., COVIS) and exemplar models (e.g., ALCOVE). It is an important theoretical conclusion that existing models cannot explain humans’ rule-based category learning. The problem these models have is the incremental algorithm by which learning is simulated. Humans descend no gradient in rule-based tasks. Very different formal-modeling systems will be required to explain humans’ psychology in these tasks. An important next step will be to build a new generation of models that can do so.     

Stiffness Tomography by Atomic Force Microscopy

The atomic force microscope is a convenient tool to probe living samples at the nanometric scale. Among its numerous capabilities, the instrument can be operated as a nano-indenter to gather information about the mechanical properties of the sample. In this operating mode, the deformation of the cantilever is displayed as a function of the indentation depth of the tip into the sample. Fitting this curve with different theoretical models permits us to estimate the Young's modulus of the sample at the indentation spot. We describe what to our knowledge is a new technique to process these curves to distinguish structures of different stiffness buried into the bulk of the sample. The working principle of this new imaging technique has been verified by finite element models and successfully applied to living cells.     

RecQ helicases and cellular responses to DNA damage

The faithful replication of the genome is essential for the survival of all organisms. It is not surprising therefore that numerous mechanisms have evolved to ensure that duplication of the genome occurs with only minimal risk of mutation induction. One mechanism of genome destabilization is replication fork demise, which can occur when a translocating fork meets a lesion or adduct in the template. Indeed, the collapse of replication forks has been suggested to occur in every replicative cell cycle making this a potentially significant problem for all proliferating cells. The RecQ helicases, which are essential for the maintenance of genome stability, are thought to function during DNA replication. In particular, RecQ helicase mutants display replication defects and have phenotypes consistent with an inability to efficiently reinitiate replication following replication fork demise. Here, we review some current models for how replication fork repair might be effected, and discuss potential roles for RecQ helicases in this process.     

蛋白质起始的DNA病毒复制机制

DNA聚合酶在DNA合成过程中需要的引物包括RNA引物、DNA自我引物和蛋白质引物3种类型。新DNA链(如冈崎片段)的复制多是在DNA模板上合成一段RNA引物,细小病毒利用其基因组末端的反向末端重复序列(ITRs)自我折叠成DNA引物,而一些DNA、RNA病毒及真菌质粒起始复制反应的引物则是蛋白质。以感染原核生物的噬菌体Phi29和真核DNA病毒腺病毒为例,从复制过程所涉及的蛋白质、对复制原点的识别、复制起始反应、新链的延伸、复制终止过程等方面详细阐述DNA病毒由蛋白质引发的复制机制,并对已商品化的Phi29 DNA聚合酶产品多重置换扩增及单细胞测序等的应用以及基于噬菌体Phi29蛋白质起始的最小复制系统体外扩增异源DNA等最新的应用研究作相关总结介绍。     

Bridging scales in the evolution of infectious disease life histories: theory

A significant goal of recent theoretical research on pathogen evolution has been to develop theory that bridges within- and between-host dynamics. The main approach used to date is one that nests within-host models of pathogen replication in models for the between-host spread of infectious diseases. Although this provides an elegant approach, it nevertheless suffers from some practical difficulties. In particular, the information required to satisfactorily model the mechanistic details of the within-host dynamics is not often available. Here, we present a theoretical approach that circumvents these difficulties by quantifying the relevant within-host factors in an empirically tractable way. The approach is closely related to quantitative genetic models for function-valued traits, and it also allows for the prediction of general characteristics of disease life history, including the timing of virulence, transmission, and host recovery. In a companion paper, we illustrate the approach by applying it to data from a model system of malaria.     

New evidence of an old problem: The coupling of genome replication to cell growth in bacteria

The problem of coordinating genome replication with cell growth in bacteria was posed over four decades ago. Unlike for eukaryotes, this problem has not been completely solved even for Escherichia coli, which has been comprehensively studied by molecular biologists, to say nothing of other bacteria. Current models of the bacterial life cycle solve the coupling problem by introducing a phenomenological hypothesis that considers the dynamic coordination of growth and replication but does not unveil the underlying molecular mechanisms. Here we review the mechanisms regulating genome replication initiation with regards to their coupling to growth processes in the three best investigated bacterial species: E. coli, Bacillus subtilis, and Caulobacter crescentus. A putative correlation between the type of cell growth laws and the actual mechanisms regulating the replication of DNA formed during the process of evolution in various classes of bacteria, is discussed, including those intracellular parasites in which degenerative evolution has discarded most of their genomes. We contemplate the concept of a universal growth law for bacterial cells and some features in the formation of a primitive negative replication regulating mechanism in the context of the coupling problem.     

线粒体DNA复制及其调控

从线粒体DNA复制的模型与机制、复制的调控、复制忠实性及其损伤修复3个方面对近年来的研究文献进行了总结.在复制的模型与机制方面,对传统的D环复制的细节有了更深入的了解,新的实验方法的结果显示,在哺乳动物中还存在着链结合单向复制和链结合双向复制2种模型.在线粒体DNA复制的调控方面,近年来研究较多的调控因子主要包括mtDNA聚合酶γ、线粒体单链结合蛋白(mtSSB)、引物酶、解旋酶、连接酶、拓扑异构酶、转录因子mtTFA等,介绍了这些因子的最新研究进展及调控机制;对mtDNA复制时期和拷贝数量调控机制的研究也有突破,确定了Abf2p是mtDNA复制时期与拷贝数目的调控因子.在mtDNA复制的忠实性及其损伤修复研究方面,主要涉及到DNA Polγ的校正功能、错配修复、重组修复、DNA切除修复等,在mtDNA损伤修复中仅存在碱基切除修复机制,缺少核苷酸切除修复机制.     

核骨架——细胞核内生命活动的重要结构体系

综合分析了国际国内近年来有关核骨架研究的新进展,从几个方面的研究事实,包括核骨架对染色质ＤＮＡ的有序组织,核骨架参与ＤＮＡ复制和基因的表达与调控以及核骨架的起源进化等,阐明核骨架是细胞核内染色质结构的有序组织者和功能活动的参与者,核内纷繁复杂的生命活动能有条不紊地进行,核骨架在其中扮演了重要角色。     

Penalized likelihood and multiple testing

The classical multiple testing model remains an important practical area of statistics with new approaches still being developed. In this paper we develop a new multiple testing procedure inspired by a method sometimes used in a problem with a different focus. Namely, the inference after model selection problem. We note that solutions to that problem are often accomplished by making use of a penalized likelihood function. A classic example is the Bayesian information criterion (BIC) method. In this paper we construct a generalized BIC method and evaluate its properties as a multiple testing procedure. The procedure is applicable to a wide variety of statistical models including regression, contrasts, treatment versus control, change point, and others. Numerical work indicates that, in particular, for sparse models the new generalized BIC would be preferred over existing multiple testing procedures.     

Modeling composting kinetics: A review of approaches

Composting kinetics modeling is necessary to design and operate composting facilities that comply with strict market demands and tight environmental legislation. Current composting kinetics modeling can be characterized as inductive, i.e. the data are the starting point of the modeling process and determine the type of model used. It is argued that the inductive empirical approach has been developed to its limit of practicality. Further progress is not expected because of limits in measurement techniques and the resources needed to perform all experiments needed.Contrary to the inductive, the deductive modeling approach uses the existing theory as its starting point for model development. Deductive models of realistic situations contain many basic parameters representing the theoretical basis. These basic parameters however tend to be non-identifiable, limiting practical application.To overcome this problem, it is proposed that the basic parameters in the deductive model must be combined to a smaller number of so-called combined parameter that are identifiable. In this way a model is developed that can incorporate both the theoretical knowledge introduced via the basic parameter and the information of data as represented by the identifiable combined parameters.As an example of how information of both theory and data can be used, the case of the temperature effect on the composting rate is analyzed. The temperature effect is quantified as the activation energy E, a parameter derived from the well-known Arrhenius equation. The theoretical analysis shows that the E-value changes strongly during the process, which is very remarkable, as the E value of basic parameter remains constant. These results are in accordance with literature findings. The results suggest that the multiplicative approach used in first-order modeling should be reconsidered, as both the literature findings as well as the theoretical analysis of the model predict a shift in E-value. Missing a shift in the E-value could lead for instance to instability in temperature control algorithms.     

Analysis of lung parenchyma as a parametric porous medium.

The dynamic behavior of the lung in health and disease depends on its viscoelastic properties. To better understand these properties, several mathematical models have been utilized by many investigators. In the present work, we present a new approach that characterizes the dynamics of gas flow into a viscoelastic porous medium that models the lung structure. This problem is considered in terms of the lung input impedance on a macro level and parenchymal tissue impedance on the level of an alveolar wall. We start from a basic theoretical analysis in which macroscopic tissue deformations are represented in accordance with the linearized Navier-Stokes equations. This approach has strong theoretical underpinnings in other situations but has not been applied to analyze the impedance of the inflated lung. Our analysis provides a theoretical basis for analyzing the interaction between flow into the lungs as a biophysical diffusion process and parenchymal viscoelasticity described phenomenologically, within the frameworks of standard viscoelasticity and structural damping. This lung impedance incorporates parameters of porosity, permeability, and viscoelasticity on micro and macro levels of parenchymal tissue. The analysis shows the theoretical basis of the transformation from the impedance of alveolar walls or isolated tissue strips to that of the intact parenchyma. We also show how the loading impedance at the lung boundary may have a significant impact on the dynamic behavior of whole lung viscoelasticity. Our analysis may be useful in directing specific tests of different models and for analyzing experimental measurements of viscoelastic parameters of lung material under normal and pathological conditions.     

Replication, lies and lesser-known truths regarding experimental design in environmental microbiology

A recent analysis revealed that most environmental microbiologists neglect replication in their science (Prosser, 2010). Of all peer-reviewed papers published during 2009 in the field's leading journals, slightly more than 70% lacked replication when it came to analyzing microbial community data. The paucity of replication is viewed as an 'endemic' and 'embarrassing' problem that amounts to 'bad science', or worse yet, as the title suggests, lying (Prosser, 2010). Although replication is an important component of experimental design, it is possible to do good science without replication. There are various quantitative techniques - some old, some new - that, when used properly, will allow environmental microbiologists to make strong statistical conclusions from experimental and comparative data. Here, I provide examples where unreplicated data can be used to test hypotheses and yield novel information in a statistically robust manner.     

Analysis of the kinetic hairpin transfer model for parvoviral DNA replication

All linear DNA molecules face special problems in replicating their 5' ends, as DNA polymerases add nucleotides only to pre-existing strands with free 3'-OH groups. Parvoviruses, a group of small animal viruses with a linear single-stranded DNA genome, cope with this problem by having palindromic terminal sequences that can fold back on themselves to form hairpin structures essential in priming DNA replication. The 3' terminal sequence that initiates replication becomes reversed in orientation during the process, and if the palindrome is imperfect, two different, reverse-complementary terminal sequences are generated. The relative abundances of the terminal sequence orientations at each end of the DNA molecules can be measured and give information about the replication process. From such clues, we developed a "kinetic hairpin transfer model" based on differential rates of hairpin formation and inversion processes depending on the conformations of the 3' termini. Numerical studies showed that this simple idea can account for the diverse pattern of DNA distributions observed in the family Parvoviridae. In this paper, we simplify the model to a set of coupled linear first-order ordinary differential equations in order to delineate its essential properties by Perron-Frobenius theory. Secondly, we examine our assumption of linear kinetics by modeling enzyme catalysis of the component steps of the hairpin transfer process. We show that the rate-determining step of the process is the binding of initiation complex to the self-priming hairpin structures. Furthermore, we find that if the replication machinery is saturated by DNA substrate late in an infection, the differential equations become non-linear but the steady-state DNA distribution is still given by the solution of our original linear equations.     

Taming the complexity of protein folding

Protein folding is an important problem in structural biology with significant medical implications, particularly for misfolding disorders like Alzheimer's disease. Solving the folding problem will ultimately require a combination of theory and experiment, with theoretical models providing a comprehensive view of folding and experiments grounding these models in reality. Here we review progress towards this goal over the past decade, with an emphasis on recent theoretical advances that are empowering chemically detailed models of folding and the new results these technologies are providing. In particular, we discuss new insights made possible by Markov state models (MSMs), including the role of non-native contacts and the hub-like character of protein folded states.     

The contribution of dormant origins to genome stability: From cell biology to human genetics

The ability of a eukaryotic cell to precisely and accurately replicate its DNA is crucial to maintain genome stability. Here we describe our current understanding of the process by which origins are licensed for DNA replication and review recent work suggesting that fork stalling has exerted a strong selective pressure on the positioning of licensed origins. In light of this, we discuss the complex and disparate phenotypes observed in mouse models and humans patients that arise due to defects in replication licensing proteins.