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The synchrony of Siberian lemming (Lemmus sibiricus L.) population dynamics was investigated during a ship-borne expedition along the Palaearctic tundra coast in the summer of 1994. On 12 sites along the coast from the Kola Peninsula to Wrangel Island, relative densities of lemmings were recorded using a standardised snap-trapping programme. The phase position of the lemming cycle in each of the studied populations was determined based on current density estimates, signs of previous density and the age profile of each population (ageing based on eye lens mass). In addition, dendrochronological methods were used to determine when the last peak in the density of microtine populations occurred at each site. The examined lemming populations were in different phases of the lemming cycle. Some populations were in the peak phase, as indicated by high current densities, an age profile in which older individuals were well represented, and signs of high previous density (abundant old lemming faeces). Other populations were in the decline phase, as reflected in a moderate current density, a predominance of older individuals and signs of high previous density. Populations in the low phase had an extremely low current density and showed signs of high previous density, while populations in the increase phase had a moderate current density, a predominance of younger individuals and showed signs of low previous density. The results of phase determinations based on dendrochronological methods support the findings based on lemming demography. Recent Russian studies carried out on some of the sites also agreed with our phase determination results. Thus, on a regional scale (across the whole Palaearctic tundra), the population dynamics of Siberian lemmings can be considered asynchronous. However, sites situated adjacent to each other were often phase synchronous, suggesting a more fine-grained pattern of dynamics with synchrony over distances as long as 1000 km or so, e.g. the Yamal and Taymyr Peninsulas.

The reproduction of female Siberian lemmings in the increase and peak phases of the lemming cycle was investigated in connection with a ship-borne expedition along the Siberian arctic tundra. The cycle phase of each studied lemming population was determined using demographic analyses, i.e. current density indices (captured lemmings per 100 traps per 24 h), information on previous density (frequency of old lemming faeces and runways), and information from dendrochronological analyses revealing the most recent winters with a high intensity of willow-stem scarring caused by lemmings. The cycle phase determination was corroborated with data on the age profiles of the populations. The reproductive behaviour of female lemmings differed markedly in relation to cycle phase. In increase-phase populations, all captured females (including young and winter born) were reproducing (had embryos or were lactating), and females started to reproduce early in life, i.e. when

Inflammatory bowel disease is characterized by a number of immunological alterations, not the least in the T-cell compartment. Numerous animal models of colitis have revealed aberrant thymocyte dynamics associated with skewed thymocyte development. The recent advancements in quantitative methods have proposed critical kinetic alterations in the thymocyte development during the progression of colitis. This review focuses on the aberrant thymocyte dynamics in G alpha i2-deficient mice as this mouse model provides most quantitative data of the thymocyte development associated with colitis. Herein, we discuss several dynamic changes during the progression of colitis and propose a hypothesis for the underlying causes for the skewed proportions of the thymocyte populations seen in the G alpha i2-deficient mice and in other mouse models of colitis.

We present a theoretical framework for simulating the synaptic accumulation of the costimulatory molecules CD28, CTLA-4, B7-1, and B7-2, based on a system of mean-field, ordinary differential equations, and rigorous biophysical and expression data. The simulations show that binding affinity, stoichiometric properties, expression levels, and, in particular, competition effects all profoundly influence complex formation at cellular interfaces. B7-2 engages 33-fold more CD28 than CTLA-4 at the synapse in contrast to B7-1, which ligates ∼7-fold more CTLA-4 than CD28. Although B7-1 completely dominates interactions with CTLA-4, forming linear arrays of 7-18 receptor-ligand pairs, CTLA-4 is fully engaged by B7-2 when B7-1 is absent. Additional simulations reveal the sensitivity of CD28 interactions to modeled transport processes. The results support the concept that B7-2 and B7-1 are the dominant ligands of CD28 and CTLA-4, respectively, and indicate that the inability of B7-2 to recruit CTLA-4 to the synapse cannot be due to the differential binding properties of B7-1 and B7-2 only. We discuss the apparent redundancy of B7-1 in the context of a potentially dynamic synaptic microenvironment, and in light of functions other than the direct enhancement of T cell inhibition by CTLA-4.

Understanding the component stoichiometry of the T cell antigen receptor (TCR) triggering apparatus is essential for building realistic models of signal initiation. Recent studies suggesting that the TCR and other signaling-associated proteins are preclustered on resting T cells relied on measurements of the behavior of membrane proteins at interfaces with functionalized glass surfaces. Using fluorescence recovery after photobleaching, we show that, compared with the apical surface, the mobility of TCRs is significantly reduced at Jurkat T cell/glass interfaces, in a signaling-sensitive manner. Using two biophysical approaches that mitigate these effects, bioluminescence resonance energy transfer and two-color coincidence detection microscopy, we show that, within the uncertainty of the methods, the membrane components of the TCR triggering apparatus, i.e. the TCR complex, MHC molecules, CD4/Lck and CD45, are exclusively monovalent or monomeric in human T cell lines, implying that TCR triggering depends only on the kinetics of TCR/pMHC interactions. These analyses also showed that constraining proteins to two dimensions at the cell surface greatly enhances random interactions versus those between the membrane and the cytoplasm. Simulations of TCR-pMHC complex formation based on these findings suggest how unclustered TCR triggering-associated proteins might nevertheless be capable of generating complex signaling outputs via the differential recruitment of cytosolic effectors to the cell membrane.

In the present work a general systems biology approach has been used to study the complex regulatory network controlling the transcription of the spa gene, encoding protein A, a major surface protein and an important virulence factor of Staphylococcus aureus. A valid mathematical model could be formulated using parameter values, which were fitted to quantitative Northern blot data from various S. aureus regulatory mutants using a gradient search method. The model could correctly predict spa expression levels in 4 different regulatory mutants not included in the parameter value search, and in 2 other S. aureus strains, SH1000 and UAMS-1. The mathematical model revealed that sarA and sarS seem to balance each other in a way that when the activating impact of sarS is small, e.g. in the wild-type, the repressive impact of sarA is small, while in an agr-deficient background, when the impact of sarS is maximal, the repressive impact of sarA is close to its maximum. Furthermore, the model revealed that Rot and SarS act synergistically to stimulate spa expression, something that was not obvious from experimental data. We believe that this mathematical model can be used to evaluate the significance of other putative interactions in the regulatory network governing spa transcription.

In the present study, we have investigated 37 invasive Staphylococcus aureus strains (collected between 1997 and 2005) from 33 human episodes of septicaemia causing either endocarditis or vertebral osteomyelitis. All S. aureus strains were typed using pulsed field gel electrophoresis (PFGE), and most strains belonged to any of 4 different PFGE clusters. There was no correlation between any of the PFGE clusters with site of infection. All strains showed highly different expression patterns of extracellular proteins, i.e. we found a vast variation in the number of proteins and amount of individual proteins expressed by the different strains. There was no correlation between any cluster of exoprotein patterns with endocarditis or with vertebral osteomyelitis. We did not find any correlation between agr group and endocarditis, as previously reported. On the other hand, a correlation between some of the PFGE clusters with a certain agr group was found. Known risk factors for S. aureus infections were observed in a majority of the patients.

Human embryonic stem cells (hESCs) can differentiate into a variety of specialized cell types. Thus, they provide a model system for embryonic development to investigate the molecular processes of cell differentiation and lineage commitment. The development of the cardiac lineage is easily detected in mixed cultures by the appearance of spontaneously contracting areas of cells. We performed gene expression profiling of undifferentiated and differentiating hESCs and monitored 468 genes expressed during cardiac development and/or in cardiac tissue. Their transcription during early differentiation of hESCs through embryoid bodies (EBs) was investigated and compared with spontaneously differentiating hESCs maintained on feeders in culture without passaging (high-density (HD) protocol). We observed a larger variation in the gene expression between cells from a single cell line that were differentiated using two different protocols than in cells from different cell lines that were cultured according to the same protocol. Notably, the EB protocol resulted in more reproducible transcription profiles than the HD protocol. The results presented here provide new information about gene regulation during early differentiation of hESCs with emphasis on the cardiomyogenic program. In addition, we also identified regulatory elements that could prove critical for the development of the cardiomyocyte lineage.

Housekeeping genes (HKGs) are involved in basic functions needed for the sustenance of the cell and are assumed to be constitutively expressed at a constant level. Based on these features, HKGs are frequently used for normalization of gene expression data. In the present study, we used the CodeLink Gene Expression Bioarray system to interrogate changes in gene expression occurring during differentiation of human ESCs (hESCs). Notably, in the three hESC lines used for the study, we observed that the RNA levels of 56 frequently used HKGs varied to a degree that rendered them inappropriate as reference genes. Therefore, we defined a novel set of HKGs specifically for hESCs. Here we present a comprehensive list of 292 genes that are stably expressed (coefficient of variation

Th-cell differentiation is highly influenced by the local cytokine environment. Although cytokines such as IL-12 and IL-4 are known to polarize the Th-cell response towards Th1 or Th2, respectively, it is not known whether these cytokines instruct the developmental fate of uncommitted Th cells or select cells that have already been committed through a stochastic process. We present an individual based model that accommodates both stochastic and deterministic processes to simulate the dynamic behaviour of selective versus instructive Th-cell development. The predictions made by each model show distinct behaviours, which are compared with experimental observations. The simulations show that the instructive model generates an exclusive Th1 or Th2 response in the absence of an external cytokine source, whereas the selective model favours coexistence of the phenotypes. A hybrid model, including both instructive and selective development, shows behaviour similar to either the selective or the instructive model dependent on the strength of activation. The hybrid model shows the closest qualitative agreement with a number of well-established experimental observations. The predictions by each model suggest that neither pure selective nor instructive Th development is likely to be functional as exclusive mechanisms in Th1/Th2 development.

ThePseudomonas aeruginosaquorum-sensing moleculeN-3-(oxododecanoyl)-l-homoserine lactone (OdDHL) has been reported to have immunomodulatory activity in several systems, although the mechanism of that activity remains to be fully characterized. We demonstrate here, using a defined in vitro model of antigen responses by T-cell receptor (TCR)-transgenic mouse splenic CD4 T cells, that the effect of OdDHL on activation and cytokine production is complete within 4 h of antigen or mitogen stimulation and does not depend on the insertion of OdDHL in the cell membrane, despite a previous report that immunosuppression by homoserine lactones required a minimum acyl chain length of 11 carbons (S. R. Chhabra, C. Harty, D. S. W. Hooi, M. Daykin, B. W. Bycroft, P. Williams, and D. Pritchard, J. Med. Chem.46:97-104, 2003). We also demonstrate that while OdDHL can have toxic effects on nonlymphoid leukocytes, it does not induce significant cell death in T cells at the concentrations (≤10 μM) used in these experiments. In addition, we show that primary and secondary antigen-specific cytokine responses are equally susceptible to inhibition by OdDHL and that the compound inhibits the differentiation of both Th1 and Th2 cells. However, the precise balance of cytokine production by CD4 T cells stimulated in the presence of OdDHL varies with both the antigen concentration and its affinity for the transgenic TCR. Thus, conflicting reports of the nature of the immunosuppression by OdDHL may be due in part to the differences in antigen affinity and concentration in different models.

Background. The bacterium Helicobacter pylori is associated with a number of gastrointestinal diseases, such as gastric ulcer, duodenal ulcer and gastric cancer. Several histological changes may be observed during the course of infection; some may influence the progression towards cancer. The aim of this study was to build a statistical model to discover direct interactions between H. pylori and different precancerous changes of the gastric mucosa, and in what order and to what degree those may influence the development of the intestinal type of gastric cancer. Methods. To find direct and indirect interactions between H. pylori and different histological variables, log-linear analyses were used on a case–control study. To generate mathematically and biologically relevant statistical models, a designed algorithm and observed frequency tables were used. Results. The results show that patients with H. pylori infection need to present with proliferation and intestinal metaplasia to develop gastric cancer of the intestinal type. Proliferation and intestinal metaplasia interacted with the variables atrophy and foveolar hyperplasia. Intestinal metaplasia was the only variable with direct interaction with gastric cancer. Gender had no effect on the variables examined. Conclusion. The direct interactions observed in the final statistical model between H. pylori, changes of the mucosa and gastric cancer strengthens and supports previous theories about the progression towards gastric cancer. The results suggest that gastric cancer of the intestinal type may develop from H. pylori infection, proliferation and intestinal metaplasia, while atrophy and foveolar hyperplasia interplay with the other histological variables in the disease process.

Acylated homoserine lactones (AHLs) regulate a wide variety of phenotypes in Gram-negative bacteria. Most research suggests that AHL-mediated phenotypes are not expressed in populations until late logarithmic phase or stationary phase. Here, we model how the concentration of AHLs inside bacterial cells and in a biofilm changes over time as a function of population growth rate, diffusion of AHLs and the rate of autoinduction. Our theoretical results show that the concentration of AHLs inside a single bacterium (and by implication induction of a phenotype) has a non-trivial behaviour over time, and often exhibits a rapid increase early in population growth. This rapid increase is followed by a plateau, followed by another rise in the concentration of AHLs, to a second plateau. High concentrations of AHLs inside the bacterial cell early in population growth are positively affected by slow diffusion rates out of the cell and the biofilm, slow bacterial growth rates and fast autoinduction. In contrast, fast growth rates, slow autoinduction rates and high diffusion rates result in a high concentration plateau in stationary phase. More generally, the density-dependent nature of AHL regulation can be viewed as a trade-off between factors that dilute intracellular concentrations of AHLs (diffusion out of the cell, cell division), and those that increase concentrations (a slowing or restriction of diffusion or growth, or autoinduction). These results suggest that expression of AHL-mediated phenotypes can occur at relatively low cell densities and low external/environmental AHL concentrations.

The parental investment in angiosperms comprises the endosperm, a nutrient reserve that is used during seed development. The endosperm contains genes from both parents. The most common endosperm form is the 3n Polygonum-type with more maternal genetic influence than paternal, i.e. with two maternal nuclei and one paternal nucleus. The evolutionary original state is thought to be a diploid endosperm with equal influence of the parents. We focus on the evolution of the triploid endosperm and show that a gene for triploid endosperm would have an initial advantage in a population of diploid endosperm type plants, and increase to fixation. We assume that endosperm amount is controlled by endosperm genes. Then a gene causing triploid endosperm will increase the influence of the mother plant on parental investment. The production of endosperm with two copies of the maternal genes will modify the inheritance of endosperm amount and cause an increased production of seeds.

A mathematical model has been developed based on the fundamental properties of the control system formed by the lux genes and their products in Vibrio fischeri. The model Clearly demonstrates how the components of this system work together to create two, stable metabolic states corresponding to the expression of the luminescent and non-luminescent phenotypes. It is demonstrated how the cell can "switch" between these steady states due to changes in parameters describing metabolic processes and the extracellular concentration of the signal molecule N-3-oxohexanoyl-L-homoserine lactone. Ln addition, it is shown how these parameters influence how sensitive the switch mechanism is to cellular LuxR and N-3-oxohexanoyl-L-homoserine lactone and complex concentration. While these properties could lead to the collective phenomenon known as quorum sensing, the model also predicts that under certain metabolic circumstances, basal expression of the lux genes could cause a cell to luminesce in the absence of extracellular signal molecule. Finally, the model developed in this study provides a basis for analysing the impact of other levels of control upon lux regulation. (C) 2000 Academic Press.

We present field evidence for the induction of overcompensation, or increased fruit and seed yield as a consequence of damage, in the grassland biennial field gentian, Gentianella campestris (Gentianaceae). We compared equally sized clipped and unclipped plants in two populations in central Sweden during three years, 1992-1994, and plants clipped at different occasions, from 20 June to 2 August. Clipping once, by removing half of the biomass, significantly increased fruit production without affecting the number of seeds per fruit or seed mass. The degree of compensation was sensitive to the timing of clipping. Damage induced overcompensation only during a restricted inductive time period (ITP) in July. Plants clipped before about 1 July or after about 22 July achieved no overcompensation. The early limit of ITP was presumably determined by the availability of resources that could be mobilized for regrowth after damage. The late limit, on the other hand, depended primarily on the differentiation of meristems close to flowering in early August. The effects of clipping varied between years, presumably due to drought in 1994. During 1992-1993, plants consistently overcompensated for clipping on 1-20 July, whereas in 1994 only early clipping from 1 to 12 July induced overcompensation. In 1994, plants clipped in late July compensated less well, due to delayed fruit maturation leading to a high proportion of immature fruits at the end of the season. Because of this between-year variation, we used geometric mean fitness to calculate the expected long-term effects of damage over generations. The analysis suggests that the long-term effects can vary from positive to negative, depending on the frequency of bad fruiting years. The time limits of ITP fit well the hypothesis that predictable damage in July may have selected for a capacity of overcompensation in the field gentian. Because the ultimate limits of ITP are set by the length of the vegetation period, we expect overcompensation in this species to be more common in regions with a longer growing season.

We analyse the evolution of postponed seed germination in temporally and spatially homogenous habitats under the assumption that sibling seedlings compete because of clumped seed dispersal. The seed germination trait is assumed to be affected by two sets of autosomal genes. One set controls a germination factor that is expressed in young individuals, i.e. this factor determines the embryo's propensity to delay germination. The other set of genes controls a germination factor that is expressed in the seed coat, which, because this is maternal tissue, represents an adult trait. The two germination factors together determine the probability of a seed germinating as a function of time. The corresponding probability density function of germination times represents a seed's germination strategy. We investigate the evolutionary stability of such strategies by introducing rare mutant modifier alleles that give rise to small deviations with respect to germination strategies. The analysis shows that the coevolution of the two sets of genes leads to a joint ESS which is such that the embryonal trait favours a faster germination regime than does the adult one. We suggest that this joint ESS is best seen as a result of conflicting selection pressures acting upon genes with age-specific expression, rather than as a conflict between parents and their offspring.

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The presence of dormant buds allows grazed plants to compensate for destroyed active meristems. In this article we present a theoretical analysis of the adaptive significance of bud dormancy when the risk of herbivory varies from year to year. Under constant herbivore pressure, selection tends to favor either plants that have no dormant buds and hence no capacity of compensatory growth due to low risk of herbivory, or those that leave most of their buds in dormancy because of high risk of herbivory. We show that when the risk of herbivory varies from year to year, selection will favor intermediate phenotypes having both dormant and active meristems. The intermediate phenotypes represent bet-hedging strategies that have lower vari- ance of seed production than either of the extreme strategies. We also show that intensive herbivory can favor meristem allocation strategies that allow plants to overcompensate for herbivore damage. Our results suggest that two kinds of herbivores might cause selection pres- sures favoring compensatory growth: large ungulate herbivores that remove a large proportion of the aboveground parts of the attacked plants and that predictably attack fairly many plants (>50%) each year, and invertebrate herbivores that periodically cause extensive damage during years of mass attacks.

Some plants can compensate, and even overcompensate, for the loss of productivity caused by herbivory. The presence of latent meristems, or dormant buds, is one of the basic prerequisites of such compensation mechanisms. We present a mathematical model in order to analyze compensation responses in relation to the intensity of herbivory. The model generates a number of qualitatively different kinds of compensation curves when seed production is plotted against the proportion of active meristems lost per grazed plant. The shape of the curves depends on the proportion of dormant buds and their activation sensitivity in relation to meristem loss. Overcompensation is most probable when dormant buds are easily activated. When plants are grazed only once, as assumed in our model, selection favors high bud sensitivity. However, we expect that repeated damage may select for a more restrained pattern of bud activation. When relatively few buds remain dormant, plants can overcompensate for low levels of damage only. On the other hand, when most buds remain dormant, they can overcompensate even for high levels of damage. We consider compensation capacity a potential benefit of bud dormancy when plants are subject to damage. However, bud dormancy may also imply costs on plant productivity and fecundity in the absence of herbivory. Still, intense herbivory may favor bud dormancy in spite of the potential costs. Selection for bud dormancy requires both that the risk of herbivory is high and that herbivores remove a large fraction of active meristems per plant. Consequently, overcompensation is a theoretically plausible possibility, and intense herbivory is a potential selective force that favors bud dormancy. None of these results, however, imply that herbivory is beneficial to plants. In our case, plants with bud dormancy never have higher seed production than plants that have no dormant buds and that are not grazed.

Seed dormancy has been considered, almost without exception, as a bet-hedging strategy in a temporally varying environment. However, in this paper we show that seed dormancy can improve the reproductive success of the mother plant when competition between sibling seedlings and adult plants is intense even if the environment is temporally invariable. We allow a cohort of sibling seeds to germinate simultaneously in the same patch and assume a density dependent survival and fecundity of seedlings. In the model, the mother plant is assumed to control the germination behaviour of the seeds, e.g. by enclosing the seeds in coats of different hardiness. When sib competition is intense, a postponed germination of her seeds can increase the reproductive success of the mother plant up to four times, measured in terms of the number of grandchildren. Consequently, our results suggest that postponed germination may function as a mechanism that alters local interactions in viscous plant populations with limited dispersal.

Biofilms are currently recognised as the predominant bacterial life-style and it has been suggested that biofilm development is influenced by a number of different processes such as adhesion, detachment, mass transport, quorum sensing, cell death and active dispersal. One of the least understood processes and its effects on biofilm development is cell death. However, experimental studies suggest that bacterial death is an important process during biofilm development and many studies show a relationship between cell death and dispersal in microbial biofilms. We present a model of the process of cell death during biofilm development, with a particular focus on the spatial localisation of cell death or cell damage. Three rules governing cell death or cell damage were evaluated which compared the effects of starvation, damage accumulation, and viability during biofilm development and were also used to design laboratory based experiments to test the model. Results from model simulations show that actively growing biofilms develop steep nutrient gradients within the interior of the biofilm that affect neighbouring microcolonies resulting in cell death and detachment. Two of the rules indicated that high substrate concentrations lead to accelerated cell death, in contrast to the third rule, based on the accumulation of damage, which predicted earlier cell death for biofilms grown with low substrate concentrations. Comparison of the modelling results with experimental results suggests that cell death is favoured under low nutrient conditions and that the accumulation of damage may be the main cause of cell death during biofilm development. © 2011 Elsevier Ltd.

Background Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide, but also a common colonizer of the upper respiratory tract. The emergence and spread of antibiotic resistant pneumococcal strains has threatened effective therapy. The long-term effects of measures aiming to limit pneumococcal spread are poorly understood. Computational modeling makes it possible to conduct virtual experiments that are impractical to perform in real life and thereby allows a more full understanding of pneumococcal epidemiology and control efforts. Methods We have developed a contact network model to evaluate the efficacy of interventions aiming to control pneumococcal transmission. Demographic data from Sweden during the mid-2000s were employed. Analyses of the model's parameters were conducted to elucidate key determinants of pneumococcal spread. Also, scenario simulations were performed to assess candidate control measures. Results The model made good predictions of previous findings where a correlation has been found between age and pneumococcal carriage. Of the parameters tested, group size in day-care centers was shown to be one of the most important factors for pneumococcal transmission. Consistent results were generated from the scenario simulations. Conclusion We recommend, based on the model predictions, that strategies to control pneumococcal disease and organism transmission should include reducing the group size in day-care centers.

A path diagram relates observed, pairwise, variable correlations to a functional structure which describes the hypothesized causal relations between the variables. Here we combine path diagrams, heuristics and evolutionary search into a system which seeks to improve existing gene regulatory models. Our evaluation shows that once a correct model has been identified it receives a lower prediction error compared to incorrect models, indicating the overall feasibility of this approach. However, with smaller samples the observed correlations gradually become more misleading, and the evolutionary search increasingly converges on suboptimal models. Future work will incorporate publicly available sources of experimentally verified biological facts to computationally suggest model modifications which might improve the model's fitness.

Th-cell development has been suggested to include selective mechanisms in which certain cytokines select either Th1 or Th2 cells to proliferate and grow. The selective theory is based on the observation that Th2 cells secrete IL-4, a cytokine that promotes Th2 development, whereas Th1 cells secrete interferon-gamma (IFN-gamma) that favours Th1 development, and both positive and negative selective influences have been suggested to operate. In this study, we investigate the role of autocrine secretion and utilization of IL-4 by Th2 cells and address the question of whether an activated Th2 cell can be positively selected by IL-4 secreted from other Th2 cells. We present a spatial three dimensional (3D) modelling approach to simulate the interaction between the IL-4 ligand and its IL-4 receptors expressed on discrete IL-4 secreting cells. The simulations, based on existing experimental data on the IL-4 receptor-ligand system, illustrate how Th-cell development is highly dependent on the distance between cells that are communicating. The model suggests that a single Th2 cell is likely to communicate with possible target cells within a range of approximately 100 microm and that an activated Th2 cell manages to fill most of its own IL-4 receptors, even at a low secretion rate. The predictions made by the model suggest that negative selection against Th1 cells is more effective than positive selection by IL-4 for promoting Th2 dominance.

Information Fusion (IF) is about combining, or fusing, information from different sources in order to facilitate our understanding of a complex system and thereby provide insights that could not be gained from any of the individual data sources in isolation. We argue in this paper that there is a need for applying an IF approach in bioinformatics research, since the aim of bioinformatics is to understand complex biological systems using many different data sources providing complementary views of the system. We illustrate this argument with two application examples, where IF-based bioinformatics is applied to the study of stem cell differentiation and lipid digestion, respectively. We also discuss the use of automated information extraction from text sources, which is an essential component of a bioinformatics IF approach, given the abundant literature.

The virulence determinants of Staphylococcus aureus are expressed in a growth phase-dependent manner governed by the autoinducible quorum-sensing system agr. Activation of the agr system results in a rapid increase in the regulator RNAIII and occurs in response to accumulation of AIP. In order to activate the agr system, a basal transcription of agr components must be assumed. This basal transcription of agr components seems to be stimulated by sarA. To better understand how SarA would affect activation of the agr system by modulating the basal agr activity, a mathematical model for autoactivation of the agr system was set up. The model predicted that the agr system is hysteretic, meaning that the agr system is activated at a specific concentration of autoinducing peptide (AIP), whereas it is inactivated at a specific lower concentration of AIP. According to the model, changing the basal agr activity only had a marginal effect on steady-state levels of RNAIII but changed the sensitivity of the cells to AIP. This was supported by Northern blot analysis of RNAIII in S. aureus mutants with different levels of SarA expression. Since natural antagonistic AIPs have been demonstrated, the effect of adding inhibitors to the system was analyzed.

Quorum-sensing systems provide Pseudomonas aeruginosa with a sensitive regulatory mechanism that allows for the induction of several phenotypic genes in a cell density fashion. In this work, a mathematical model of the acylated homoserine lactones regulatory network system in P. aeruginosa has been developed. It is the first integrated model to consider both quorum-sensing systems. The model has allowed us to disentangle the complex behavior exhibited by the system as the concentration of extracellular OdDHL is increased. At either low or high levels of extracellular OdDHL, the bacterium remains in an uninduced or induced state, respectively. At moderate levels, the behavior is characterized by several states. Here, the bacteria can switch suddenly from an uninduced to an induced phenotype in response to small changes in the concentration of extracellular OdDHL. Additionally, we have been able to address the roles of RsaL and Vfr as regulators of the quorum-sensing system. An important result from this analysis suggests that RsaL will increase the concentration of extracellular OdDHL required to induce the system, and it is a key regulator of the inhibition of the quorum-sensing system under low cell densities. Most importantly, our results suggest that Vfr has strong regulatory effects on the system as an increased affinity between the LasR/OdDHL complex, and the lasR promoter leads to significant qualitative changes in induction patterns. We also show experimental data that demonstrate that Vfr is required for signal production in the early phase of growth, but that in the latter stages of growth, the vfr mutant is able to synthesize wild-type levels of signal.

Pseudomonas aeruginosa is a gram-negative bacterium that causes serious illnesses, particularly in immunocompromised individuals, often with a fatal outcome. The finding that the acylated homoserine lactone quorum sensing (QS) system controls the production of virulence factors in P. aeruginosa makes this system a possible target for antimicrobial therapy. It has been suggested that an N-(3-oxododecanoyl)-homoserine lactone (3O-C12-HSL) antagonist, a QS blocker (QSB), would interfere efficiently with the quorum sensing system in P. aeruginosa and thus reduce the virulence of this pathogen. In this work, a mathematical model of the QS system in P. aeruginosa has been developed. The model was used to virtually add 3O-C12-HSL antagonists that differed in their affinity for the receptor protein and for their ability to mediate degradation of the receptor. The model suggests that very small differences in these parameters for different 3O-C12-HSL antagonists can greatly affect the success of QSB based inhibition of the QS system in P. aeruginosa. Most importantly, it is proposed that the ability of the 3O-C12-HSL antagonist to mediate degradation of LasR is the core parameter for successful QSB based inhibition of the QS system in P. aeruginosa. Finally, this study demonstrates that QSBs can shift the system to a low steady state, corresponding to an uninduced state and thus, suggests that the use of 3O-C12-HSL antagonists may constitute a promising therapeutic approach against P. aeruginosa involved infections.

Swedish University of Agricultural Sciences, Department of Conservation Biology, Section of Conservation Botany, Box 7072, 750 07 Uppsala, Sweden; University of Oulu, Department of Biology, Linnanmaa, 90 570 Oulu, Finland, and University of Lund, Department for Theoretical Ecology, Ecology Building, 223 62 Lund, Sweden; University of Lund, Department for Theoretical Ecology, Ecology Building, 223 62 Lund, Sweden

In angiosperm plants the parental investment consists mainly of the endosperm, a nutritive tissue formed by genetic elements from both parents and used upon germination. We analyze a one-locus model of the evolution of the endosperm assuming that the alleles expressed in the endosperm determine the seed provisioning. In the model, we assume that large endosperm increases the probability of survival when young, but decreases seed set when the plant has reached the reproductive stage. We show that there is an evolutionarily stable strategy (ESS) of endosperm amount which is influenced by mating system, ploidy of the endosperm, paternity and genomically imprinted genes with parent-specific expression. The ESS value is higher than the value which maximizes the reproductive success of the plant. When the maternal genetic contribution is higher than the paternal (e.g. Polygonum plants), the ESS is almost always lower than when the parents have equal influence over the endosperm as in Oenothera plants. In both types, increasing the number of pollen donors to a seed crop selects for higher levels of endosperm. Accordingly, genes expressed only when inherited from the father are selected for higher endosperm amounts than genes expressed only when inherited from the mother, except when all seed have the same pollen parent. ESS values for imprinted genes do not differ between Polygonum and Oenothera types of plants. The ESS values are shown to be both locally and globally stable. The results are discussed in relation to evolutionary conflicts between the sexes.

The presence of an overcompensatory response to damage in some plant species has recently created a debate concerning whether this trait is an adaptation to herbivory, or simply a physiological consequence of adaptations to competition for light. According to the latter hypothesis, competition for light favors fast vertical growth and strong apical dominance. The removal of apical dominance by damaging the primary shoot allows the growth of secondary shoots and hence increases productivity. We compare predictions of these two hypotheses in a model-system where plants are exposed to both a risk of damage and a risk of competition. Compensatory seed production is assumed to depend on the number of dormant buds that can be activated by damage, and on the seed production of surviving shoots. In accordance with earlier theoretical analyses, we expect that intensive herbivory can favor overcompensatory seed production. In contrast, competition for light should at best lead to exact compensation when the competitive environment remains unchanged. Competition acts against overcompensation for two reasons. First, competitive plants should have poor resource reserves to support compensatory growth. Second, competition for light is assumed to favor unbranched architecture and thus. activation of many secondary shoots should not increase the seed yield. However, we cannot exclude the possibility that plants adapted to competition may overcompensate when grown singly. In spite of this caveat, it is likely that overcompensation requires damage related adaptations that may evolve only under intensive and relatively predictable risk of damage.

The regular cyclic population dynamics of herbivores has frustrated naturalists since the middle of the 16th century. Olaus Magnus, archbishop of Uppsala, Sweden, concluded already 1555 that the lemming populations showed oscillatory population changes (Olaus Magnus 1555) Furthermore, he suggested that the cyclic outbreaks of stoats and weasels could be caused by the 3-4-yr lemming cycle. Since then, several ecologists have speculated about the causes of these spectacular phenomena. For cyclic microtine populations, the hypotheses presented, may, according to Stenseth and Ims (1993) be divided into four main categories: (1) abiotic hypotheses (e.g. Elton 1924, Moran 1953a, b), (2) intrinsic factor hypotheses (e.g. Chitty 1967, Charnov and Finerty 1980), (3) prey-predator/pathogen interactions (e.g. Stenseth 1980, Ydenberg 1987, Anderson and May 1991), and (4) vegetation-herbivore interactions (e.g. Schultz 1969, Haukioja and Hakala 1975, Haukioja 1980). Obviously, this is a general classification that could be valid for all kinds of cyclic herbivore populations. Among the vegetation-herbivore hypotheses, we find the ones concerning food quality especially interesting. Green and Ryan (1972) suggested that plants could respond to herbivory by the production of proteinase inhibitors with adverse effects on herbivore performance (growth, survival and reproduction). These defence responses may, according to Haukioja and Hakala (1975), be a driving force of fluctuating herbivore populations. In a recent contribution, Seldal et al. (1994) propose that an inducible defence mechanism can be the cause of the population cycles exhibited by the lemming in the tundras of America, Fennoscandia and Russia. Their main findings are: (1) Physical damage to those plants that constitute the bulk of the lemmings' diet will induce the synthesis of large amounts of proteinase inhibitors, proteins that form irreversible complexes with trypsin and other proteolytic enzymes. This does not only effectively inhibit the protein digestion in the gut of most mammals, birds and insects, but also drain their reserves of essential amino acids that are excreted into the faeces (reviewed by e.g. Gallaher and Schneeman 1986, Ryan 1990). (2) Experiments have shown that proteinase inhibitors, when introduced with artificial food, have adverse effects on the growth and can eventually cause the death of mammals, birds and insects (reviewed by e.g. Gallaher and Schneeman 1986, Ryan 1990). Similar effects could be observed when young lemmings were given food collected in their natural habitat, if the samples were taken during the decline and trough phases of the lemming population cycle. The phytochemical induction by herbivory has been studied extensively by other workers. In the case of proteinase inhibitors, the general conclusion that can be drawn from these studies is that a plant can exhibit different levels of induction, depending on the size and number of damages (Green and Ryan 1972). A single damage event will trigger the production of inhibitors, but without further damages, the synthesis will cease and the concentration of these substances will decline in the plant tissue (Seldal et al. 1994). Repeated damages do, however, cause high levels of proteinase inhibitors that will last for extended periods (Green and Ryan 1972, Gustafson and Ryan 1976). Seldal et al. (1994) argue that this effect might cause a delay in the lemming population regulation, and that this could be sufficient for causing cyclic population dynamics. The more a plant has been damaged through grazing, the higher will its defence level be, and the longer will it remain in this induced state. In this note we propose a fairly simple mathematical model that encapsulate these properties, in order to investigate the hypothesis that inducible defences can cause oscillations in herbivore populations.