Dynamics of Cellular Responses to Radiation

Understanding the consequences of exposure to low dose ionizing radiation is an important public health concern. While the risk of low dose radiation has been estimated by extrapolation from data at higher doses according to the linear non-threshold model, it has become clear that cellular responses can be very different at low compared to high radiation doses. Important phenomena in this respect include radioadaptive responses as well as low-dose hyper-radiosensitivity (HRS) and increased radioresistance (IRR). With radioadaptive responses, low dose exposure can protect against subsequent challenges, and two mechanisms have been suggested: an intracellular mechanism, inducing cellular changes as a result of the priming radiation, and induction of a protected state by inter-cellular communication. We use mathematical models to examine the effect of these mechanisms on cellular responses to low dose radiation. We find that the intracellular mechanism can account for the occurrence of radioadaptive responses. Interestingly, the same mechanism can also explain the existence of the HRS and IRR phenomena, and successfully describe experimentally observed dose-response relationships for a variety of cell types. This indicates that different, seemingly unrelated, low dose phenomena might be connected and driven by common core processes. With respect to the inter-cellular communication mechanism, we find that it can also account for the occurrence of radioadaptive responses, indicating redundancy in this respect. The model, however, also suggests that the communication mechanism can be vital for the long term survival of cell populations that are continuously exposed to relatively low levels of radiation, which cannot be achieved with the intracellular mechanism in our model. Experimental tests to address our model predictions are proposed.     

Lung cancer in Mayak workers: interaction of smoking and plutonium exposure

Lung cancer mortality among 5058 male workers of the Mayak Production Association has been analyzed with emphasis on the interaction of smoking and radiation exposure by using the two-step clonal expansion (TSCE) model of carcinogenesis. The cohort consists of all Mayak workers with known smoking status, who were employed in the period 1948–1972, and who either had the plutonium concentration in urine measured or who worked in the reactors, where plutonium exposure was negligible. Those who died during the first two years after the first urine sampling were excluded. The follow-up extended until the end of 1998. During this time, 2176 workers died, including 244 lung cancer cases. Mayak workers were exposed to external (gamma and neutron) radiation, and in the radiochemical and plutonium plants to plutonium. In the preferred TSCE model, internal radiation and smoking act on the clonal expansion of pre-carcinogenic clones. Assuming a plutonium radiation weighting factor of 20, the excess relative risk per lung dose was estimated to be 0.11 (95% CI: 0.08; 0.17) Sv⁻¹. Most of the lung cancer deaths are found to be due to smoking. The second main factor is the interaction of smoking and internal radiation. The model is sub-multiplicative in relative risks due to smoking and radiation. In a multiplicative version of the TSCE model, internal radiation acts on initiation and transformation rates. This model version agrees with conventional epidemiological risk models, because it also suggests a higher risk estimate than the preferred TSCE model. However, it fits the data less well than the preferred model. An erratum to this article can be found at     

Extracting three-way gene interactions from microarray data

MOTIVATION: It is an important and difficult task to extract gene network information from high-throughput genomic data. A common approach is to cluster genes using pairwise correlation as a distance metric. However, pairwise correlation is clearly too simplistic to describe the complex relationships among real genes since co-expression relationships are often restricted to a specific set of biological conditions/processes. In this study, we described a three-way gene interaction model that captures the dynamic nature of co-expression relationship between a gene pair through the introduction of a controller gene. RESULTS: We surveyed 0.4 billion possible three-way interactions among 1000 genes in a microarray dataset containing 678 human cancer samples. To test the reproducibility and statistical significance of our results, we randomly split the samples into a training set and a testing set. We found that the gene triplets with the strongest interactions (i.e. with the smallest P-values from appropriate statistical tests) in the training set also had the strongest interactions in the testing set. A distinctive pattern of three-way interaction emerged from these gene triplets: depending on the third gene being expressed or not, the remaining two genes can be either co-expressed or mutually exclusive (i.e. expression of either one of them would repress the other). Such three-way interactions can exist without apparent pairwise correlations. The identified three-way interactions may constitute candidates for further experimentation using techniques such as RNA interference, so that novel gene network or pathways could be identified.     

Negotiations between animals and bacteria: the 'diplomacy' of the squid-vibrio symbiosis

A shared characteristic among animals is their propensity to form stable, beneficial relationships with prokaryotes. Usually these associations occur in the form of consortia, i.e. a diverse assemblage of bacteria interacting with a single animal host. These complex communities, while common, have been difficult to characterize. The two-partner symbiosis between the squid Euprymna scolopes and the marine luminous bacterium Vibrio fischeri offers the opportunity to study the interaction between animal and bacterial cells, because both partners can be cultured in the laboratory and the symbiosis can be manipulated experimentally. This system is being used to characterize the mechanisms by which animals establish, develop and maintain stable alliances with bacteria. This review summarizes the progress to date on the development of this model.     

The survival response of a biological system to mixed radiations

The concept of additive radiation action is applied to the process of merging of the intermediate lesions at a common stage in the radiation inactivation pathways for lesions produced by different radiations. This gives rise to a natural nonindependent effect for combined irradiation. Even though the exact nature of this common intermediate lesion is unknown, the effect of this lesion additivity can still be formulated into a mathematical model using the assumptions: (1) there exists a stage in the chain of radiation inactivation events where different types of lesion precursors, produced by different types of radiations in a mixture, inflict lesions which become functionally indistinguishable and hence additive thereafter, to produce the same end point observed; (2) all precursors of all types are simultaneously competing for the opportunity to inflict lesions at the stage indicated in assumption 1, and each precursor has equal opportunity regardless of its origin; (3) if the radiations are delivered sequentially within a sufficiently short time, the lesion precursors of both radiations arrive at the above stage at about the same time and hence inflict lesions which are additive as described in assumptions 1 and 2. The model is quantitative but contains no free-fitting parameters. It is shown to be capable of explaining a large variety of apparently unrelated published experimental results observed for mixtures of high- and low-LET radiations.     

Protein interaction networks in medicine and disease

The physical interaction of proteins is subject to intense investigation that has revealed that proteins are assembled into large densely connected networks. In this review, we will examine how signaling pathways can be combined to form higher order protein interaction networks. By using network graph theory, these interaction networks can be further analyzed for global organization, which has revealed unique aspects of the relationships between protein networks and complex biological phenotypes. Moreover, several studies have shown that the structure and dynamics of protein networks are disturbed in complex diseases such as cancer progression. These relationships suggest a novel paradigm for treatment of complex multigenic disease where the protein interaction network is the target of therapy more so than individual molecules within the network.     

Phylogenetic evidence for an ancient rapid radiation of Caribbean sponge-dwelling snapping shrimps (Synalpheus)

A common challenge in reconstructing phylogenies involves a high frequency of short internal branches, which makes basal relationships difficult to resolve. Often it is not clear whether this pattern results from insufficient or inappropriate data, versus from a rapid evolutionary radiation. The snapping shrimp genus Synalpheus, which contains in excess of 100 species and is a prominent component of coral-reef faunas worldwide, provides an example. Its taxonomy has long been problematic due to the subtlety of diagnostic characters and apparently widespread variability within species. Here we use partial mt COI and 16S rRNA sequences and morphological characters to reconstruct relationships among 31 species in the morphologically well-defined gambarelloides species group, a putative clade of obligate sponge associates that is mostly endemic to the Caribbean and contains the only known eusocial marine animals. Analysis of the combined data produced a single tree with good support for many terminal clades and for relationships with outgroups, but poor support for branches near the base of the gambarelloides group. Most basal branches are extremely short and terminal branches are long, suggesting a relatively ancient, but rapid radiation of the gambarelloides group. This hypothesis is supported by significant departure from a null model of temporally random cladogenesis. Calibration of divergence times among gambarelloides-group species using data from three geminate pairs of Synalpheus species separated by the isthmus of Panamá suggests a major radiation between approximately 5 and 7 Mya, a few My before final closure of the Panamanian seaway during a period of spreading carbonate environments in the Caribbean; a second, smaller radiation occurred approximately 4 Mya. This molecular evidence for a rapid radiation among Caribbean marine organisms in the late Miocene/early Pliocene is strikingly similar to patterns documented from fossil data for several other Caribbean reef-associated invertebrate taxa. The similar patterns and timing of cladogenesis evidenced by molecular and fossil data for different Caribbean and East Pacific taxa suggests that the radiation involved a wide range of organisms, and strengthens the case that poor basal resolution in the gambarelloides group of Synalpheus reflects a real evolutionary phenomenon. The rapid radiation also helps explain the historical difficulty of diagnosing species in Synalpheus.     

Bayesian Dynamical Systems Modelling in the Social Sciences

Data arising from social systems is often highly complex, involving non-linear relationships between the macro-level variables that characterize these systems. We present a method for analyzing this type of longitudinal or panel data using differential equations. We identify the best non-linear functions that capture interactions between variables, employing Bayes factor to decide how many interaction terms should be included in the model. This method punishes overly complicated models and identifies models with the most explanatory power. We illustrate our approach on the classic example of relating democracy and economic growth, identifying non-linear relationships between these two variables. We show how multiple variables and variable lags can be accounted for and provide a toolbox in R to implement our approach.     

Paediatric bed fall computer simulation model development and validation

Falls from beds and other household furniture are common scenarios stated to conceal child abuse. Knowledge of the biomechanics associated with short-distance falls may aid clinicians in distinguishing between abusive and accidental injuries. Computer simulation is a useful tool to investigate injury-producing events and to study the effect of altering event parameters on injury risk. In this study, a paediatric bed fall computer simulation model was developed and validated. The simulation was created using Mathematical Dynamic Modeling^® software with a child restraint air bag interaction (CRABI) 12-month-old anthropomorphic test device (ATD) representing the fall victim. The model was validated using data from physical fall experiments of the same scenario with an instrumented CRABI ATD. Validation was conducted using both observational and statistical comparisons. Future parametric sensitivity studies using this model will lead to an improved understanding of relationships between child (fall victim) parameters, fall environment parameters and injury potential.     

Phylogenetic systematics of Southeast Asian flying lizards (Iguania: Agamidae: Draco) as inferred from mitochondrial DNA sequence data

Phylogenetic analysis of mitochondrial DNA sequence data using maximum parsimony, minimum evolution (of log-determinant distances), and maximum-likelihood optimality criteria provided a robust estimate of Draco phylogenetic relationships. Although the analyses based on alternative optimality criteria were not entirely congruent, non-parametric bootstrap analyses identified many well-supported clades that were common to the analyses under the three altrenative criteria. Relationships within the major clades are generally well resolved and strongly supported, although this is not the case for the Philippine volans subclade. The hypothesis that a clade composed primarily of Philippine species represents a rapid radiation could not be rejected. A revised taxonomy for Draco is provided.     

Trophic interaction modifications: an empirical and theoretical framework

Consumer–resource interactions are often influenced by other species in the community. At present these ‘trophic interaction modifications’ are rarely included in ecological models despite demonstrations that they can drive system dynamics. Here, we advocate and extend an approach that has the potential to unite and represent this key group of non‐trophic interactions by emphasising the change to trophic interactions induced by modifying species. We highlight the opportunities this approach brings in comparison to frameworks that coerce trophic interaction modifications into pairwise relationships. To establish common frames of reference and explore the value of the approach, we set out a range of metrics for the ‘strength’ of an interaction modification which incorporate increasing levels of contextual information about the system. Through demonstrations in three‐species model systems, we establish that these metrics capture complimentary aspects of interaction modifications. We show how the approach can be used in a range of empirical contexts; we identify as specific gaps in current understanding experiments with multiple levels of modifier species and the distributions of modifications in networks. The trophic interaction modification approach we propose can motivate and unite empirical and theoretical studies of system dynamics, providing a route to confront ecological complexity.     

Relationships between lipid membrane area, hydrophobic thickness, and acyl-chain orientational order. The effects of cholesterol.

A microscopic interaction model for a fully hydrated lipid bilayer membrane containing cholesterol is used to calculate, as a function of temperature and composition, the membrane area, the membrane hydrophobic thickness, and the average acyl-chain orientational order parameter, S. The order parameter, S, is related to the first moment, M1, of the quadrupolar magnetic resonance spectrum which can be measured for lipids with perdeuterated chains. On the basis of these model calculations as well as recent experimental measurements of M1 using magnetic resonance and of membrane area using micromechanical measurements, a discussion of the possible relationships between membrane area, hydrophobic thickness, and moments of nuclear magnetic resonance spectra is presented. It is pointed out that S under certain circumstances may be useful for estimating the hydrophobic membrane thickness. This is particularly advantageous for multicomponent membranes where structural data are difficult to obtain by using diffraction techniques. The usefulness of the suggested relationships is demonstrated for cholesterol-containing bilayers.     

Why the concept of hormesis has not been incorporated into mainstream radiation health theory: Radiation perspective

Although adaptive and reparative responses to radiation were recognized in the early decades of this century, mutations and chromosome aberrations were subsequently observed to increase as linear‐nondireshold functions of the dose at low‐to‐intermediate levels of exposure. For certain cancers, likewise, although the dose‐response relationships in humans and laboratory animals have been observed to vary, depending on the type of neoplasm, the dose, dose rate, and LET of the radiation, the age, sex, and genetic background of the exposed population, and other variables, the existing data have been interpreted to suggest that the risks may not depart significantly from linearity at low doses and low dose rates. Hence, although the available data do not exclude alternative dose‐response relationships, the linear‐nonthreshold model has generally come to be used as a basis for assessing the risks of low‐level irradiation for purposes of radiation protection. While the use of this model has generally been considered to be prudent on the basis of the precautionary principle, the possibility that the model may grossly overestimate the risks of low‐level irradiation remains to be excluded. Therefore, especially in the light of the growing evidence that adaptive responses may protect against the effects of small doses of radiation, further research to clarify the relevant dose‐response relationships is strongly indicated.     

Phylogeny and spatio-temporal distribution of European Pectinidae (Mollusca: Bivalvia)

Phylogenetic relationships within Pectinidae (Bivalvia, Pteriomorphia) have been investigated primarily for Pacific and Western Atlantic or commercially valuable taxa. Most molecular phylogenetic studies have revealed monophyly of pectinid bivalves but interrelationships of the different clades are still inconsistent. However, non-commercial European Pectinidae has mostly been neglected in earlier investigations and therefore the evolution and radiation of the European Pectinidae is poorly understood. Since the fossil record of this group is well investigated, the evolutionary age of phylogenetic diversification and radiation events within this group can be dated. Thus, the connection of geological and climatic changes to radiation events within this group can be assessed. We investigated the phylogenetic relationships within European Pectinidae using mitochondrial (12S and 16S) and nuclear (18S, 28S and H3) gene markers and performed relaxed molecular clock approaches to gain information on the evolutionary age and the connection between Cenozoic climatic changes and diversification within this group. The results show concordance of radiation events with the Middle Miocene cooling event and the following climatic period with slowly decreasing temperatures. However, geological changes such as the uplift of the Gomphotherium Landbridge or the closure and re-opening of the Strait of Gibraltar also had great impact on diversification and distribution patterns within European Pectinidae.     

Analysis of interaction for mixtures of agents using the linear isobole

The linear isobole that is commonly used as a reference for the study of interaction is derived from the interaction of an agent with itself. It is shown that the general use of the linear isobole in the study of the combined effects of mixtures of agents implies interaction between the agents whether the dose-effect curves of the agents are the same or not. It is difficult to generalize the interaction between two doses of the same agent to the interaction between two doses of different agents with different action mechanisms without the use of a mechanistic model. Predictions using non-interaction defined as independent action are generally different from those using linear isobole. A simple mechanistic framework based on the concept of common intermediate lesions is introduced in this paper to relate these two methods used for the analysis of synergism and antagonism. In this framework of lesion development, two agents that have no common intermediate lesion in their action will be non-interactive (referred to as independent action). When the two agents share a common intermediate, it is shown that the combined effect will follow the linear isobole (referred to as common action). This simple framework of analysis is applicable to the general study of interaction between two agents with different types of dose-effect curves.     

Taxic and morphological diversification during the early radiation of Clupeomorpha (Actinopterygii,Teleostei)

Evolutionary radiation is a problematic concept whose definition and classification have recently changed. Radiations can be defined as the pattern of abrupt increase in diversity of a lineage. It is relevant to evaluate the presence and interaction of different types of radiation in extant and fossil organisms to adequately delimitate the radiation types and to know the diversity in the context of Earth's history. Here, we employed the superorder Clupeomorpha at the Early–Late Cretaceous boundary as a study case to investigate radiation types and their interactions, using both taxic and morphological approaches. Clupeomorpha is an extensively studied, diverse and ancient teleostean superorder with wide geographical and ecological distributions. We propose a model for calculating rates of origination in order to analyse the taxic diversification and employ geometric morphometrics to analyse the morphological diversification that occurred at the temporal boundary. The results suggest the absence of taxic radiation due to a constant increase in taxon origination. However, the expansion of the phylomorphospace occupation and the disparity increase suggest the presence of a ‘climatic–geographical’ or ‘broad diversification-like’ disparity, according to current classifications. This illustrates the incompatibility of current radiation classifications with this case study.     

Grooming interactions over infants in four species of primate

Interaction analysis is a commonly used tool in the study of human relationships by psychologists, but can be extended to an anthropological focus on comparative culture patterns. This paper utilizes video of primates and humans interacting over infants to assess the nature of the interaction and its probable success in attaining the interactants' goals. The four categories of reactive, mutual, asymmetric, and conflict asymmetric interactions are analyzed and compared between two species of macaques, orangutans, and humans, in an effort to show the complexity of relationships and goals that can ensue from a common type of interaction, and the similarities of pattern across a wide range of levels of social complexity.     

Patterns of speciation in the Yucca moths: parallel species radiations within the Tegeticula yuccasella species complex

The interaction between yuccas and yucca moths has been central to understanding the origin and loss of obligate mutualism and mutualism reversal. Previous systematic research using mtDNA sequence data and characters associated with genitalic morphology revealed that a widespread pollinator species in the genus Tegeticula was in fact a complex of pollinator species that differed in host use and the placement of eggs into yucca flowers. Within this mutualistic clade two nonpollinating "cheater" species evolved. Cheaters feed on yucca seeds but lack the tentacular mouthparts necessary for yucca pollination. Previous work suggested that the species complex formed via a rapid radiation within the last several million years. In this study, we use an expanded mtDNA sequence data set and AFLP markers to examine the phylogenetic relationships among this rapidly diverging clade of moths and compare these relationships to patterns in genitalic morphology. Topologies obtained from analyses of the mtDNA and AFLP data differed significantly. Both data sets, however, corroborated the hypothesis of a rapid species radiation and suggested that there were likely two independent species radiations. Morphological analyses based on oviposition habit produced species groupings more similar to the AFLP topology than the mtDNA topology and suggested the two radiations coincided with differences in oviposition habit. The evolution of cheating was reaffirmed to have evolved twice and the closest pollinating relative for one cheater species was identified by both mtDNA and AFLP markers. For the other cheater species, however, the closest pollinating relative remains ambiguous, and mtDNA, AFLP, and morphological data suggest this cheater species may be diverged based on host use. Much of the divergence in the species complex can be explained by geographic isolation associated with the evolution of two oviposition habits.     

Some notes on complexity in vegetation

Abstract. Vegetation is considered as a complex system with many subsystems. The system functions by using solar radiation as energy source and producing biomass and biodiversity. The different subsystems are connected by feedback loops and interact in a process of self-organisation. It appears impossible to characterize this system with mathematical expressions, because most of the basic processes are non-linear. Instead, vegetation can be described with dynamical models. Selection, competition as well as positive interactions can occur. The model accounts for the general dynamics, particularly fluctuations (when the system is in a steady state) and the climax situation. Many problems remain open: e.g. arbitrary limits of the system and its subsystems, macrostate/microstate relationships, thresholds and attractors. Single aspects of the subsystems can be linearized, but not the system as a whole and consequently its behaviour remains unpredictable.     

VANLO - Interactive visual exploration of aligned biological networks

Background  

Protein-protein interaction (PPI) is fundamental to many biological processes. In the course of evolution, biological networks such as protein-protein interaction networks have developed. Biological networks of different species can be aligned by finding instances (e.g. proteins) with the same common ancestor in the evolutionary process, so-called orthologs. For a better understanding of the evolution of biological networks, such aligned networks have to be explored. Visualization can play a key role in making the various relationships transparent.