A logical model for growth and differentiation in multi-celled organisms

This paper is an attempt to provide a logical model for the process of growth and differentiation in a multi-cellular organism. More specifically it is intended to show how genetic information relating to macroscopic structure and coded in the form of a logical tree could be progressively embodied in the organism as it develops by repeated division from a single cell. The aim is to establish biological analogies rather than mathematical interest, and reproduction, adaption, and the coordinating action of hormones are discussed within the general logical framework.     

Abundant Microorganism in Soil

The presence in soil of large numbers of a catalase-negative, microaerophilic, coccoid microorganism was demonstrated. Use of media of high nutrient value, without incorporation of inhibitors, and growth in the absence of antagonistic microorganisms were utilized to isolate this organism from soil dilutions greater than those providing growth by other means. The organism described does not grow on soil extract agars and is missed by conventional counting techniques for soil organisms. On the basis of morphological and growth characteristics, this organism appears to have at least some taxonomic relationships to the families Actinomycetaceae and Mycobacteriaceae. It is proposed that this organism makes up much of the coccoid microflora of soil as observed by light and ultraviolet fluorescence microscopy.     

Helicobacter nemestrinae sp. nov., a spiral bacterium found in the stomach of a pigtailed macaque (Macaca nemestrina)

A new microaerophilic, spirally curved, rod-shaped bacterium was isolated from the gastric mucosa of a pigtailed macaque (Macaca nemestrina). The gram-negative cells of this bacterium are oxidase, catalase, and urease positive and strongly resemble Helicobacter pylori (Campylobacter pylori) cells. Like H. pylori, this organism does not metabolize glucose, does not reduce nitrate or produce indole, does not produce H2S from triple sugar iron agar, does not hydrolyze hippurate or esculin, and does not grow in the presence of 1% glycine, 1.5% salt, or 1% bile. Also like H. pylori, it is resistant to nalidixic acid and susceptible to cephalothin. However, unlike H. pylori, the colorless colonies are flat and have irregular edges. This organism has a unique cellular fatty acid composition, forming a new gas-liquid chromatography group, group K, and a distinctive DNA content (24 mol% guanine plus cytosine). It exhibits less than 10% DNA-DNA homology (as determined by the nylon filter blot method at 65 degrees C) with other members of the genus Helicobacter. Although the levels of DNA relatedness between previously described Helicobacter species and the new organism are low (less than 10%) and the difference in guanine-plus-cytosine content is large (24 versus 36 to 41 mol%), the genus Helicobacter is the only genus in which it is logical to include the organism at this time. We propose that our single strain represents a new species, Helicobacter nemestrinae, and we designate strain T81213-NTB (= ATCC 49396) as the type strain.     

人体和动物模型的体表物理信息地形图的研究

对人体头面、躯干、四肢、耳廓各局部几十个及整个人体等体表部位正、背面等210个部位进行超微弱冷光和温度测量,输入电子计算机,经特殊的自编程序处理,获得十分清晰的,由3000多数据构成的各个局部或人体整体的冷光和温度地形图。 对家兔左、右耳廓、胸腹部、背部都分别观察32个部位的冷光与体表温度,经计算机分析处理,每观察区域获得约由2000个数据构成的精确的冷光、温度地形分市图。并可见不同生理、病理状态及不同病程家兔体表冷光、温度等地形图呈有规律的改变。 此外,我们还编制了以体表左右相应对称部位差值为分析数据进行地形图分析的程序,用以人体和动物体表物理信息对称规律的研究。 本工作以图形的形式显示物理参量在体表的广泛的分布规律,以揭示机体内部的不同生理、病理状态。本方法定位准确、直观醒目,为研究体表信息及机体生命活动规律提供了与逐点直接测量方法相互补充的有益的新手段。     

Utilizing logical relationships in genomic data to decipher cellular processes

The wealth of available genomic data has spawned a corresponding interest in computational methods that can impart biological meaning and context to these experiments. Traditional computational methods have drawn relationships between pairs of proteins or genes based on notions of equality or similarity between their patterns of occurrence or behavior. For example, two genes displaying similar variation in expression, over a number of experiments, may be predicted to be functionally related. We have introduced a natural extension of these approaches, instead identifying logical relationships involving triplets of proteins. Triplets provide for various discrete kinds of logic relationships, leading to detailed inferences about biological associations. For instance, a protein C might be encoded within an organism if, and only if, two other proteins A and B are also both encoded within the organism, thus suggesting that gene C is functionally related to genes A and B. The method has been applied fruitfully to both phylogenetic and microarray expression data, and has been used to associate logical combinations of protein activity with disease state phenotypes, revealing previously unknown ternary relationships among proteins, and illustrating the inherent complexities that arise in biological data.     

The Use of Streptococcus faecalis as an Indicator of the Hygienic Condition of Meat Preserves and the Possibility of Interference by Aerococcus viridans

Summary: Few arguments may be put forward in favour of the use of Escherichia coli as an indicator of the hygienic condition of preserved meat products. In products of this type E. coli occurs only rarely. The proposal, which is supported by logical considerations and practical experience, to replace this organism by Streptococcus faecalis as an indicator of possible faecal contamination is strongly upheld by the authors. However, it is necessary to stress that the ubiquitous micro-organism, Aerococcus viridans , occurs frequently in preserved meat products and, as it strongly resembles Strep. faecalis , may cause difficulties in the hygienic evaluation of such foods. The morphological and biological characteristics found suitable for differentiating these two organisms are described. Results supporting the view that Aerococcus, Pediococcus and Gaffkya be considered as distinct genera are also given.     

The mathematical logic of life

Protein synthesis can be likened to a particular coded information storage, transmission and execution system. Noise, error or mutations are the essential phenomena to which a living organism is subjected. Genetic coding aims at preserving the integrity of a structure under aggression from the surroundings. It can be shown that the different amino acids translated in the proteins, except the particular case of SER, obey a logical code for optimization of resistance to mutation effects. The study of the structure of this code allows a better comprehension of the logic of life.     

节律性转录因子驱动哺乳动物昼夜节律生物钟简

生物体通过内在的昼夜节律生物钟调整生理行为和代谢生化反应来适应昼夜环境周期性变化。哺乳动物的昼夜节律生物钟核心连锁环通过驱动特异性的转录因子来维持整个基因组转录的节律性。生物钟与代谢的内稳态密切相关,生物钟的紊乱会引起各种疾病,该领域的研究能够促进时间疗法的发展来维持生命的健康,甚至可以延缓衰老。     

Logical analysis of the budding yeast cell cycle

The budding yeast Saccharomyces cerevisiae is a model organism that is commonly used to investigate control of the eukaryotic cell cycle. Moreover, because of the extensive experimental data on wild type and mutant phenotypes, it is also particularly suitable for mathematical modelling and analysis. Here, I present a new Boolean model of the budding yeast cell cycle. This model is consistent with a wide range of wild type and mutant phenotypes and shows remarkable robustness against perturbations, both to reaction times and the states of component genes/proteins. Because of its simple logical nature, the model is suitable for sub-network analysis, which can be used to identify a four node core regulatory circuit underlying cell cycle regulation. Sub-network analysis can also be used to identify key sub-dynamics that are essential for viable cell cycle control, as well as identifying the sub-dynamics that are most variable between different mutants.     

Cancer research: A hurdle race

Cancer research has shifted in recent years from studying intracellular processes (identification of damaged genes and signaling pathways) to extracellular (hierarchy of tumor cells, cell transitions, clone competition) and tissue (interactions of a tumor with its environment) research. But then the next step seems to be logical: studying biochemistry of tumor-bearing organisms (namely, cancer-induced changes in cellular and tissue metabolism leading to the organism’s death). These data can help to develop new methods of cancer treatment. This article discusses some of the challenges of contemporary oncology and possible ways to overcome them.     

On the Computing Potential of Intracellular Vesicles

Collision-based computing (CBC) is a form of unconventional computing in which travelling localisations represent data and conditional routing of signals determines the output state; collisions between localisations represent logical operations. We investigated patterns of Ca²⁺-containing vesicle distribution within a live organism, slime mould Physarum polycephalum, with confocal microscopy and observed them colliding regularly. Vesicles travel down cytoskeletal ‘circuitry’ and their collisions may result in reflection, fusion or annihilation. We demonstrate through experimental observations that naturally-occurring vesicle dynamics may be characterised as a computationally-universal set of Boolean logical operations and present a ‘vesicle modification’ of the archetypal CBC ‘billiard ball model’ of computation. We proceed to discuss the viability of intracellular vesicles as an unconventional computing substrate in which we delineate practical considerations for reliable vesicle ‘programming’ in both in vivo and in vitro vesicle computing architectures and present optimised designs for both single logical gates and combinatorial logic circuits based on cytoskeletal network conformations. The results presented here demonstrate the first characterisation of intracelluar phenomena as collision-based computing and hence the viability of biological substrates for computing.     

Logical networks and probability

The logical network of a Pitts-McCulloch type is developed further with the specific addition of a motivational system which acts as a differential reinforcer to the network. A consideration is given to the various ways that probabilities enter the logical net transforming it into a probability net, and lastly some notes are added on the possibility of including the strategies of Theory of Games in the logical network.     

A New Approach to Homeostatic Regulation: Towards a Unified View of Physiological and Ecological Concepts

Stoichiometric homeostasis is the ability of an organism to keep its body chemical composition constant, despite varying inputs. Stoichiometric homeostasis therefore constrains the metabolic needs of consumers which in turn often feed on resources not matching these requirements. In a broader context, homeostasis also relates to the capacity of an organism to maintain other biological parameters (e.g. body temperature) at a constant level over ambient environmental variations. Unfortunately, there are discrepancies in the literature and ecological and physiological definitions of homeostasis are disparate and partly contradictory. Here, we address this matter by reviewing the existing knowledge considering two distinct groups, regulators and conformers and, based on examples of thermo- and osmoregulation, we propose a new approach to stoichiometric homeostasis, unifying ecological and physiological concepts. We suggest a simple and precise graphical way to identify regulators and conformers: for any given biological parameter (e.g. nutrient stoichiometry, temperature), a sigmoidal relation between internal and external conditions can be observed for conformers while an inverse sigmoidal response is characteristic of regulators. This new definition and method, based on well-studied physiological mechanisms, unifies ecological and physiological approaches and is a useful tool for understanding how organisms are affected by and affect their environment.     

Process attributes in bio-ontologies

ABSTRACT: BACKGROUND: Biomedical processes can provide essential information about the (mal-) functioning of an organism and are thus frequently represented in biomedical terminologies and ontologies, including the GO Biological Process branch. These processes often need to be described and categorised in terms of their attributes, such as rates or regularities. The adequate representation of such process attributes has been a contentious issue in bio-ontologies recently; and domain ontologies have correspondingly developed ad hoc workarounds that compromise interoperability and logical consistency. RESULTS: We present a design pattern for the representation of process attributes that is compatible with upper ontology frameworks such as BFO and BioTop. Our solution rests on two key tenets: firstly, that many of the sorts of process attributes which are biomedically interesting can be characterised by the ways that repeated parts of such processes constitute, in combination, an overall process; secondly, that entities for which a full logical definition can be assigned do not need to be treated as primitive within a formal ontology framework. We apply this approach to the challenge of modelling and automatically classifying examples of normal and abnormal rates and patterns of heart beating processes, and discuss the expressivity required in the underlying ontology representation language. We provide full definitions for process attributes at increasing levels of domain complexity. CONCLUSIONS: We show that a logical definition of process attributes is feasible, though limited by the expressivity of DL languages so that the creation of primitives is still necessary. This finding may endorse current formal upper-ontology frameworks as a way of ensuring consistency, interoperability and clarity.     

The Applicability of Habitat Evaluation Methodologies in Ecological Risk Assessment

Traditionally, ecological risk assessments (ERAs) have emphasized risks to individual organisms or populations of species. Although habitats may be a potential target for chemical stressors, and are considered in the framework for ERAs, the actual use of habitat evaluation methods in this process is limited. Habitats obviously represent an important entity to protect since damaged aquatic and wildlife habitats may be totally irretrievable over a human life span compared to deleterious biochemical and physiological changes which may be reversible within the life cycle of an organism, if exposure is terminated. Habitat methods have been largely used as management tools to evaluate impacts of planned water and land development projects. Habitat evaluation methods represent a structured, systematic and logical approach to determine changes to habitats because they consider important life requisites and environmental variables limiting to species. Their use in the ERA process will provide a means to differentiate habitat changes resulting from physical, chemical and/or biological factors or a combination of such factors. In addition, minimal and optimum habitat suitability can be determined for different habitat variables under different chemical exposure scenarios. The objectives of this paper are to review several available habitat evaluation methods and discuss their use in risk assessment. Particular emphasis is given to USFWS's Habitat Evaluation Procedures (HEPs) and the Instream Flow Incremental Method (IFIM).     

Implications of Liebig's law of the minimum for the use of ecological indicators based on abundance

Many ecological responses to environmental variables or anthropogenic agents are difficult and expensive to measure. Therefore it is attractive to describe such responses in terms of indicators that are easier to measure. In ecosystem management, indicators can be used to monitor spatial and temporal changes in an environmental feature. The aim of this paper is to show that it is important to take Liebig's law of the minimum into consideration to understand when it is appropriate or inappropriate to use ecological indicators based on abundance. When developing indicators that relate the abundance of an organism to an environmental factor, it is likely that this relationship will be polygonal rather than a simple linear relationship. The upper boundary of the distribution describes how abundance is limited by this factor, while the variation below the upper boundary is explained by situations when factors other than the factor of interest limit abundance. The variation below the upper boundary of the distribution means that the use of indicators to examine spatial patterns in the response of abundance to an environmental factor can be problematic. Thus, while abundance-based indicators can identify sites that are in a good condition, they are less useful to detect those affected by environmental degradation. In contrast, abundance-based ecological indicators may enable temporal monitoring of the impact of environmental factors, as it is expected that limiting factors are less variable in time than in space. In conclusion, when multiple factors are limiting, a significant correlation between an indicator and a variable is not enough to validate the status of a factor as an indicator.     

Unintended effects in genetically modified crops: revealed by metabolomics?

In Europe the commercialization of food derived from genetically modified plants has been slow because of the complex regulatory process and the concerns of consumers. Risk assessment is focused on potential adverse effects on humans and the environment, which could result from unintended effects of genetic modifications: unintended effects are connected to changes in metabolite levels in the plants. One of the major challenges is how to analyze the overall metabolite composition of GM plants in comparison to conventional cultivars, and one possible solution is offered by metabolomics. The ultimate aim of metabolomics is the identification and quantification of all small molecules in an organism; however, a single method enabling complete metabolome analysis does not exist. Given a comprehensive extraction method, a hierarchical strategy--starting with global fingerprinting and followed by complementary profiling attempts--is the most logical and economic approach to detect unintended effects in GM crops.     

Experimental evolution and the Krogh principle: generating biological novelty for functional and genetic analyses

August Krogh counseled the careful selection of the best subject organism on which to undertake mechanistic physiological research. But what if an organism with the desired properties does not exist? It is now within our power to engineer organisms genetically to achieve novel combinations of traits. I propose that it is a logical extension of the Krogh principle that we use biological methodologies to create novel organisms ideally suited for particular physiological studies. Transgenics may first come to mind as the method for such transformations, but here I suggest that an alternative and complementary technique for generating biological novelty is experimental evolution. The latter has several advantages, including modification of multiple characters in one experiment, the production of advantageous traits, the testing of evolutionary hypotheses, and the identification of previously unsuspected factors involved in adaptation. Three experiments are reviewed, each of which examined the evolution of different physiological characters in different environments and organisms: locomotor performance in mice, desiccation tolerance in fruit flies, and high temperature adaptation in bacteria. While diverse in experimental type and subject, all resulted in the successful production of new variants with enhanced function in their new environments. Each experiment successfully tested hypotheses concerning physiological evolution, and in each case, unanticipated results emerged, which suggests previously unsuspected adaptive pathways and mechanisms. In addition, replicate populations in each experiment adjusted to their common environments by several different means, which indicates that physiological evolution may follow diverse stochastic pathways during adaptation. Experimental evolution can be a valuable method to produce and investigate new physiological variants and traits. The choice of experimental subjects, according to the Krogh principle, is no longer limited to currently existing organisms but is open to our imaginations and our ingenuity.     

Logical identification of all steady states: The concept of feedback loop characteristic states

Biological regulatory systems can be described in terms of non-linear differential equations or in logical terms (using an “infinitely non-linear” approximation). Until recently, only part of the steady states of a system could be identified on logical grounds. The reason was that steady states frequently have one or more variable located on a threshold (see below); those steady states were not detected because so far no logical status was assigned to threshold values. This is why we introduced logical scales with values 0,¹θ, 1²θ, 2, ..., in which¹θ,²θ, ... are the logical values assigned to the successive thresholds of the scale. We thus have, in addition to the regular logical states,singular states in which one or more variables is located on a threshold. This permits identifyingall the steady states on logical grounds. It was noticed that each feedback loop (or reunion of disjointed loops) can be characterized by a logical state located at the thresholds at which the variables of the loop operate. This led to the concept ofloop-characteristic state, which, as we will see, enormously simplifies the analysis.The core of this paper is a formal demonstration that among the singular states of a system, only loop-characteristic states can be steady. Reciprocally, given a loop-characteristic state, there are parameter values for which this state is steady; in this case, the loop is effective (i.e. it generates multistationarity if it is a positive loop, homeostasis if it is a negative loop). This not only results in the above-mentioned radical simplification of the identification of the steady states, but in an entirely new view of the relation between feedback loops and steady states.     

The role of hydrodynamic interaction in the locomotion of microorganisms.

A general Boundary Element Method is presented and benchmarked with existing Slender Body Theory results and reflection solutions for the motion of spheres and slender bodies near plane boundaries. This method is used to model the swimming of a microorganism with a spherical cell body, propelled by a single rotating flagellum. The swimming of such an organism near a plane boundary, midway between two plane boundaries or in the vicinity of another similar organism, is investigated. It is found that only a small increase (less than 10%) results in the mean swimming speed of an organism swimming near and parallel to another identical organism. Similarly, only a minor propulsive advantage (again, less than 10% increase in mean swimming speed) is predicted when an organism swims very close and parallel to plane boundaries (such as a microscopic plate and (or) a coverslip, for example). This is explained in terms of the flagellar propulsive advantage derived from an increase in the ratio of the normal to tangential resistance coefficients of a slender body being offset by the apparently equally significant increase in the cell body drag. For an organism swimming normal to and toward a plane boundary, however, it is predicted that (assuming it is rotating its flagellum, relative to its cell body, with a constant angular frequency) the resulting swimming speed decreases asymptotically as the organism approaches the boundary.