Inverse system perturbations as a new methodology for identifying transcriptomic signaling participants in balanced biological processes

We devise a novel, systems-biology approach for identifying genetic participants in homeostatic biological processes. The central idea is that genes which are inversely regulated in alignment with positive and negative system perturbation are strong candidates for significant regulatory involvement in a given homeostatic process. This allows us to integrate known genetic participants together with hitherto unknown ones into a signaling network. We illustrate this concept and justify the underlying rationale in the exemplary case of the formation of blood vessels (angiogenesis) in the progression of pancreatic cancer where we have introduced a gene regulatory network governing the shift from a non angiogenic phenotype to an angiogenic phenotype in pancreatic tissue (‘angiogenic switch’). The envisaged pay-off of our approach is an improved understanding of signaling networks as well as the discovery of yet unknown genetic agents for diagnostic and therapeutic purposes. Subject to mild constraints, the same algorithm for the identification of signalling components can in principle be implemented across a wide spectrum of homeostatic processes including, e.g., apoptosis and fibrogenesis.     

Tracing dynamic biological processes during phase transition

Background

Phase transition widely exists in the biological world, such as transformation of cell cycle phases, cell differentiation stages, disease development, and so on. Such a nonlinear phenomenon is considered as the conversion of a biological system from one phenotype/state to another. Studies on the molecular mechanisms of biological phase transition have attracted much attention, in particular, on different genotypes (or expression variations) in a specific phase, but with less of focus on cascade changes of genes' functions (or system state) during the phase shift or transition process. However, it is a fundamental but important mission to trace the temporal characteristics of a biological system during a specific phase transition process, which can offer clues for understanding dynamic behaviors of living organisms.

Results

By overcoming the hurdles of traditional time segmentation and temporal biclustering methods, a causal process model (CPM) in the present work is proposed to study the biological phase transition in a systematic manner, i.e. first, we make gene-specific segmentation on time-course expression data by developing a new boundary gene estimation scheme, and then infer functional cascade dynamics by constructing a temporal block network. After the computational validation on synthetic data, CPM was used to analyze the well-known Yeast cell cycle data. It was found that the dynamics of the boundary genes are periodic and consistent with the phases of the cell cycle, and the temporal block network indeed demonstrates a meaningful cascade structure of the enriched biological functions. In addition, we further studied protein modules based on the temporal block network, which reflect temporal features in different cycles.

Conclusions

All of these results demonstrate that CPM is effective and efficient comparing to traditional methods, and is able to elucidate essential regulatory mechanism of a biological system even with complicated nonlinear phase transitions.

     

Extracellular proteases of mycelial fungi as participants of pathogenic processes

The interest in proteases secreted by mycelial fungi is due to several reasons of which one of the most important is their involvement in the initiation and development of the pathogenic process. A comparison of saprophytic and phytopathogenic mycelial fungi revealed one characteristic feature, namely, the appearance of a new trypsin-like activity in phytopathogens that is absent in saprophytes. To clear up the question of whether the degree of pathogenicity of a fungus is related to the activity of secreted trypsin-like protease, several species of Fusarium of various pathogenicity were compared. In two species, F. sporotrichioides (which causes ear fusa-riosis of rye) and F. heterosporum (the causative agent of root rot in wheat), a clear correlation between the activity and pathogenicity was revealed: the more pathogenetic F. sporotrichioides exhibited a higher extracellular trypsin-like activity than the less pathogenetic species F. heterosporum. Thus, the presence of trypsin-like activity in a saprotroph-pathogen pair may be an indicator of the pathogenicity of a fungus; in some cases, the value of this activity may indicate the degree of its pathogenicity. This suggests that trypsin-like proteases specific to phytopathogens are directly involved in the pathogenetic process, probably, through interaction with the "sentry" protein or the product of the resistance gene.     

Phospholipids as components of the nuclear matrix: their possible biological significance

The phospholipid involvement in the regulation of the functional and structural properties of the nuclear matrix is discussed analysing the results obtained with the enzymic removal of these molecules. Namely phospholipids seem to mediate hydrophobic interactions between nucleic acids and matrix fibrils either directly or indirectly through an association with the non-histone proteins of the matrix.     

Phospholipids as a possible instrument for translocation of nascent proteins across biological membranes

The interaction of phospholipids with precursor proteins, particularly with the mitochondrial precursor protein apocytochromec is reviewed and integrated with other aspects of protein insertion and translocation, leading to a model for (apo)cytochrome c import into mitochondria, in which phospholipids play a dominant role.     

Phospholipids as ionophores.

The ionophoretic capabilities of phospholipids have been examined by direct measurement in a Pressman cell of the phospholipid-mediated translocation of cations across an organic phase separating two aqueous phases. Cardiolipin and phosphatidic acid were the most active inonophores among the phospholipids tested, with activities comparable to that of X537A in respect to the translocation of divalent cations. Cardiolipin translocates both divalent and monovalent cations at approximately equal rates. The ionophoretic activity of cardiolipin could be modulated by other phospholipids (inhibition), by butacaine (stimulation), by complexation with cytochrome c (inhibition), and by ruthenium red and lanthanum (inhibition). The rate of translocation of cations mediated by cardiolipin was independent of pH over a wide pH range (5.4 to 8.3). The same general pattern of properties observed for cardiolipin applied to phosphatidic acid except for stimulation by butacaine. Complexation of phospholipid mixtures, such as asolectin or mitochondrial lipid, with reduced cytochrome c, enhanced the ionophoretic capability of these phospholipids by 1 order of magnitude. The complex thus formed has the properties of a polyionophore. The possible physiological significance of this enormous ionophoretic potential of phospholipids is examined.     

Studying and modelling dynamic biological processes using time-series gene expression data

Biological processes are often dynamic, thus researchers must monitor their activity at multiple time points. The most abundant source of information regarding such dynamic activity is time-series gene expression data. These data are used to identify the complete set of activated genes in a biological process, to infer their rates of change, their order and their causal effects and to model dynamic systems in the cell. In this Review we discuss the basic patterns that have been observed in time-series experiments, how these patterns are combined to form expression programs, and the computational analysis, visualization and integration of these data to infer models of dynamic biological systems.     

Phospholipids as Plant Growth Regulators

In this paper the potential to use phospholipids and lysophospholipids as plant growth regulators is discussed. Recent evidence shows that phospholipids and phospholipases play an important signalling role in the normal course of plant development and in the response of plants to abiotic and biotic stress. It is apparent that phospholipase A (PLA), C (PLC) and D (PLD), lysophospholipids, and phosphatidic acid (PA) are key components of plant lipid signalling pathways. By comparison, there is very little information available on the effect of exogenously applied phospholipids on plant growth and development. This paper serves to introduce phospholipids as a novel class of plant growth regulator for use in commercial plant production. The biochemistry and physiology of phospholipids is discussed in relation to studies in which phospholipids and lysophospholipids have been applied to plants and plant parts. Implicit in the observations is that phospholipids impact the hypersensitive response and systemic acquired resistance in plants to improve crop performance and product quality. Based on published data, a scheme outlining a possible mode of action of exogenously applied phospholipids is proposed.     

From neuron to behavior: dynamic equation-based prediction of biological processes in motor control

This article presents the use of continuous dynamic models in the form of differential equations to describe and predict temporal changes in biological processes and discusses several of its important advantages over discontinuous bistable ones, exemplified on the stick insect walking system. In this system, coordinated locomotion is produced by concerted joint dynamics and interactions on different dynamical scales, which is therefore difficult to understand. Modeling using differential equations possesses, in general, the potential for the inclusion of biological detail, the suitability for simulation, and most importantly, parameter manipulation to make predictions about the system behavior. We will show in this review article how, in case of the stick insect walking system, continuous dynamical system models can help to understand coordinated locomotion.     

Redox processes in biological systems

General principles of organization and distinctive features of the redox processes of biological systems are discussed. We paid special attention to the most examined parts of redox biology. As one of the approaches to the generalization of accumulated knowledge about redox processes, the so-called redox hypothesis of oxidative stress was examined. Extrapolation of this hypothesis on the processes taking place in plant cells, formulated on the basis of thiol-disulfide metabolism of animal cells, may help to systematize the available knowledge about redox processes in plants.     

Eutrophication processes in Spanish reservoirs as revealed by biological records in profundal sediments

Eutrophication of reservoirs can be detected by changes in the abundance of insect and crustacean remains in the sediments. In recently constructed reservoirs, the time of impoundment can be determined through the presence of chironomid head capsules. The initial phase is characterised by highly enriched water as can be seen by the abundance of Bosmina remains. If further nutrient input into the reservoir remains low, the upper part of the sediment column is almost completely lacking in invertebrate remains.     

Fitting dynamic growth models of biological phenomena from sample observations through Gaussian diffusion processes

This paper addresses the building of stochastic models that adequately describe dynamic phenomena and, in particular, those that occur in the Biosciences. In this context, the empirical fitting of a Gaussian diffusion process from sample data of a dynamic growth phenomenon is considered. In order to do this, a methodology based on approximations to its mean and variance functions is presented. Finally, several applications based on simulated and real data have been carried out.     

Effectiveness of ladybirds as biological control agents: Patterns and processes

Aphidophagous species of ladybirds have generally proved ineffective biocontrol agents, whereas many coccidophagous species have proved very effective, especiallyRodolia cardinalis (Caltagirone & Doutt, 1989). Two hypotheses have been proposed to account for this pattern: the optimum food utilization/satiation hypothesis (Mills, 1982) and the generation time ratio hypothesis (Kindlmann & Dixon, 1996). In this paper the extensive literature on ladybirds is used to test these hypotheses.     

Furin as proprotein convertase and its role in normal and pathological biological processes

Furin belongs to intracellular serine Ca²⁺-dependent endopeptidases of the subtilisin family, also known as proprotein convertases (PC). Human furin is synthesized as a zymogen with a molecular weight of 104 kDа, which is then autocatalytically activated in two stages. This process occurs during zymogen migration from the endoplasmic reticulum to the Golgi apparatus, where a large part of furin is accumulated. The molecular weight of the active furin is 98 kDа. Furin is the enzyme with narrow substrate specificity: it hydrolyzes peptide bonds at the site of paired basic amino acids and is active in a wide range of pH (5.0–8.0). The main biological function of furin as PC consists in activation of functionally important protein precursors. This is accompanied by initiation of cascades of reactions, which lead to appearance of biologically active molecules involved in realization of specific biological functions both in normal and in some pathological processes. The list of furin substrates includes biologically important proteins such as enzymes, hormones, growth/differentiation, receptors, adhesion proteins, plasma proteins. Furin plays an important role in the development of such processes as proliferation, invasion, cell migration, survival, maintenance of homeostasis, embryogenesis, as well as the development of a number of pathologies, including cardiovascular, cancer, and neurodegenerative diseases. Furin and furin-like proprotein convertases are key factors in the realization of the regulatory functions of proteolytic enzymes; the latter is currently considered as the most important function (compared with well recognized protease function in degradation of proteins).     

Entropy flow in cyclic biological processes

Biological processes are quantized, molecular, and often cyclical. Taken altogether, they comprise a heat engine working between an upper thermal reservoir at 6000 K and a lower thermal reservoir at 300 K. For optimum efficiency, such a heat engine would give out as much entropy at 300 K as it takes in at 6000 K. Yet the individual processes comprising this heat engine are quantized and molecular. What does entropy mean for them? Can we trace the entropy flow in the separate molecular cycles that are all we have when we look carefully at the overall heat engine? I think we can, and in doing so will learn why so many biological units are 5–10 μm in size.