The influence of trade-off shape on evolutionary behaviour in classical ecological scenarios

Trade-off shapes are crucial to evolutionary outcomes. However, due to different ecological feedbacks their implications may depend not only on the trade-off being considered but also the ecological scenario. Here, we apply a novel geometric technique, trade-off and invasion plots (TIPs), to examine in detail how the shape of trade-off relationships affect evolutionary outcomes under a range of classic ecological scenarios including Lotka-Volterra type and host-parasite interactions. We choose models of increasing complexity in order to gain an insight into the features of ecological systems that determine the evolutionary outcomes. In particular we focus on when evolutionary attractors, repellors and branching points occur and how this depends on whether the costs are accelerating (benefits become ‘increasingly’ costly), decelerating (benefits become ‘decreasingly’ costly) or constant. In all cases strongly accelerating costs lead to attractors while strongly decelerating ones lead to repellors, but with weaker relationships, this no longer holds. For some systems weakly accelerating costs may lead to repellors and decelerating costs may lead to attractors. In many scenarios it is weakly decelerating costs that lead to branching points, but weakly accelerating and linear costs may also lead to disruptive selection in particular ecological scenarios. Using our models we suggest a classification of ecological interactions, based on three distinct criteria, that can produce one of four fundamental TIPs which allow for different evolutionary behaviour. This provides a baseline theory which may inform the prediction of evolutionary outcomes in similar yet unexplored ecological scenarios. In addition we discuss the implications of our results to a number of specific life-history trade-offs in the classic ecological scenarios represented by our models.     

A Mechanochemical Model for Embryonic Pattern Formation: Coupling Tissue Mechanics and Morphogen Expression

Motivated by recent experimental findings, we propose a novel mechanism of embryonic pattern formation based on coupling of tissue curvature with diffusive signaling by a chemical factor. We derive a new mathematical model using energy minimization approach and show that the model generates a variety of morphogen and curvature patterns agreeing with experimentally observed structures. The mechanism proposed transcends the classical Turing concept which requires interactions between two morphogens with a significantly different diffusivity. Our studies show how biomechanical forces may replace the elusive long-range inhibitor and lead to formation of stable spatially heterogeneous structures without existence of chemical prepatterns. We propose new experimental approaches to decisively test our central hypothesis that tissue curvature and morphogen expression are coupled in a positive feedback loop.     

The evolutionary landscape of antifolate resistance in Plasmodium falciparum

Resistance to antifolates in Plasmodium falciparum is well described and has been observed in clinical settings for decades. At the molecular level, point mutations in the dhfr gene that lead to resistance have been identified, and the crystal structure of the wildtype and mutant dihydrofolate reductase enzymes have been solved in complex with native substrate and drugs. However, we are only beginning to understand the complexities of the evolutionary pressures that lead to the evolution of drug resistance in this system. Microbial systems that allow heterologous expression of malarial proteins provide a tractable way to investigate patterns of evolution that can inform our eventual understanding of the more complex factors that influence the evolution of drug resistance in clinical settings. In this paper we will review work in Escherichia coli and Saccharomyces cerevisiae expression systems that explore the fitness landscape of mutations implicated in drug resistance and show that (i) a limited number of evolutionary pathways to resistance are followed with high probability; (ii) fitness costs associated with the maintenance of high levels of resistance are modest; and (iii) different antifolates may exert opposing selective forces.     

Analysis of bone architecture sensitivity for changes in mechanical loading, cellular activity, mechanotransduction, and tissue properties

Bone has an architecture which is optimized for its mechanical environment. In various conditions, this architecture is altered, and the underlying cause for this change is not always known. In the present paper, we investigated the sensitivity of the bone microarchitecture for four factors: changes in bone cellular activity, changes in mechanical loading, changes in mechanotransduction, and changes in mechanical tissue properties. The goal was to evaluate whether these factors can be the cause of typical bone structural changes seen in various pathologies. For this purpose, we used an established computational model for the simulation of bone adaptation. We performed two sensitivity analyses to evaluate the effect of the four factors on the trabecular structure, in both developing and adult bone. According to our simulations, alterations in mechanical load, bone cellular activities, mechanotransduction, and mechanical tissue properties may all result in bone structural changes similar to those observed in various pathologies. For example, our simulations confirmed that decreases in loading and increases in osteoclast number and activity may lead to osteoporotic changes. In addition, they showed that both increased loading and decreased bone matrix stiffness may lead to bone structural changes similar to those seen in osteoarthritis. Finally, we found that the model may help in gaining a better understanding of the contribution of individual disturbances to a complicated multi-factorial disease process, such as osteogenesis imperfecta.     

Lead levels in long-tailed macaque (<Emphasis Type="Italic">Macaca fascicularis</Emphasis>) hair from Singapore

Nonhuman primates are potentially good sentinels of environmental toxicants because they share a similar physiology and life history with humans. In this report we present the results of an analysis of lead concentrations in hair from long-tailed macaques in Singapore. We hypothesized that because Singapore is highly urbanized, its macaque population may be exposed to higher levels of lead. The results of our study indicated that Singapore’s macaque population has not been exposed to high levels of environmental lead. Compared with previous studies of lead levels in human and nonhuman primate hair, the results of our analysis indicate a low level of exposure of monkeys to environmental lead (n = 27, arithmetic mean = 2.51 ppm, max = 6.45, min = 0.21 ppm). Hair lead concentrations varied both within social groups and by geographic location, with the highest concentrations observed in monkeys residing within an area containing a small-arms firing range and a manufacturing facility. Although lead exposure in this area seems to be low, additional monitoring and possible remediation may be warranted. Our study is among the first to illustrate how primates can serve as potential sentinels of environmental toxicants such as lead. Future research examining the efficacy of primates as sentinels of lead exposure should include monitoring of environmental lead levels, and comparison of hair lead levels with levels measured in blood samples.     

Formal modeling and analysis of the MAL-associated biological regulatory network: insight into cerebral malaria

The discrete modeling formalism of René Thomas is a well known approach for the modeling and analysis of Biological Regulatory Networks (BRNs). This formalism uses a set of parameters which reflect the dynamics of the BRN under study. These parameters are initially unknown but may be deduced from the appropriately chosen observed dynamics of a BRN. The discrete model can be further enriched by using the model checking tool HyTech along with delay parameters. This paves the way to accurately analyse a BRN and to make predictions about critical trajectories which lead to a normal or diseased response. In this paper, we apply the formal discrete and hybrid (discrete and continuous) modeling approaches to characterize behavior of the BRN associated with MyD88-adapter-like (MAL)--a key protein involved with innate immune response to infections. In order to demonstrate the practical effectiveness of our current work, different trajectories and corresponding conditions that may lead to the development of cerebral malaria (CM) are identified. Our results suggest that the system converges towards hyperinflammation if Bruton's tyrosine kinase (BTK) remains constitutively active along with pre-existing high cytokine levels which may play an important role in CM pathogenesis.     

Are time delays always destabilizing? Revisiting the role of time delays and the Allee effect

One of the main challenges in ecology is to determine the cause of population fluctuations. Both theoretical and empirical studies suggest that delayed density dependence instigates cyclic behavior in many populations; however, underlying mechanisms through which this occurs are often difficult to determine and may vary within species. In this paper, we consider single species population dynamics affected by the Allee effect coupled with discrete time delay. We use two different mathematical formulations of the Allee effect and analyze (both analytically and numerically) the role of time delay in different feedback mechanisms such as competition and cooperation. The bifurcation value of the delay (that results in the Hopf bifurcation) as a function of the strength of the Allee effect is obtained analytically. Interestingly, depending on the chosen delayed mechanism, even a large time delay may not necessarily lead to instability. We also show that, in case the time delay affects positive feedback (such as cooperation), the population dynamics can lead to self-organized formation of intermediate quasi-stationary states. Finally, we discuss ecological implications of our findings.     

Predicting the formation of different tissue types during Achilles tendon healing using mechanoregulated and oxygen-regulated frameworks

During Achilles tendon healing in rodents, besides the expected tendon tissue, also cartilage-, bone- and fat-like tissue features have been observed during the first twenty weeks of healing. Several studies have hypothesized that mechanical loading may play a key role in the formation of different tissue types during healing. We recently developed a computational mechanobiological framework to predict tendon tissue production, organization and mechanical properties during tendon healing. In the current study, we aimed to explore possible mechanobiological related mechanisms underlying formation of other tissue types than tendon tissue during tendon healing. To achieve this, we further developed our recent framework to predict formation of different tissue types, based on mechanobiological models established in other fields, which have earlier not been applied to study tendon healing. We explored a wide range of biophysical stimuli, i.e., principal strain, hydrostatic stress, pore pressure, octahedral shear strain, fluid flow, angiogenesis and oxygen concentration, that may promote the formation of different tissue types. The numerical framework predicted spatiotemporal formation of tendon-, cartilage-, bone- and to a lesser degree fat-like tissue throughout the first twenty weeks of healing, similar to recent experimental reports. Specific features of experimental data were captured by different biophysical stimuli. Our modeling approach showed that mechanobiology may play a role in governing the formation of different tissue types that have been experimentally observed during tendon healing. This study provides a numerical tool that can contribute to a better understanding of tendon mechanobiology during healing. Developing these tools can ultimately lead to development of better rehabilitation regimens that stimulate tendon healing and prevent unwanted formation of cartilage-, fat- and bone-like tissues.

     

Artifactual phylogenies caused by correlated distribution of substitution rates among sites and lineages: the good, the bad, and the ugly

Despite the advances in understanding molecular evolution, current phylogenetic methods barely take account of a fraction of the complexity of evolution. We are chiefly constrained by our incomplete knowledge of molecular evolutionary processes and the limits of computational power. These limitations lead to the establishment of either biologically simplistic models that rarely account for a fraction of the complexity involved or overfitting models that add little resolution to the problem. Such oversimplified models may lead us to assign high confidence to an incorrect tree (inconsistency). Rate-across-site (RAS) models are commonly used evolutionary models in phylogenetic studies. These account for heterogeneity in the evolutionary rates among sites but do not account for changing within-site rates across lineages (heterotachy). If heterotachy is common, using RAS models may lead to systematic errors in tree inference. In this work we show possible misleading effects in tree inference when the assumption of constant within-site rates across lineages is violated using maximum likelihood. Using a simulation study, we explore the ways in which gamma stationary models can lead to wrong topology or to deceptive bootstrap support values when the within-site rates change across lineages. More precisely, we show that different degrees of heterotachy mislead phylogenetic inference when the model assumed is stationary. Finally, we propose a geometry-based approach to visualize and to test for the possible existence of bias due to heterotachy.     

Cadmium and Lead Accumulation in the Earthworm Eisenia fetida (Savigny) and its Impact on Cholinesterase and Metabolic Pathway Enzyme Activity

The uptake of cadmium and lead was studied in the earthworm Eisenia fetida (Annelida: Oligochaeta) using an artificial soil exposure. Although cadmium and lead are bioconcentrated in Eisenia fetida tissue, bioaccumulation is not shown for concentrations below 100 ppm for lead, individuals eliminating as much metal as they ingest or the interactions between lead and organic matter in our substratum reduce the bioavailability of lead at low concentration. The cholinesterase activity was not inhibited when individuals were exposed for 8 weeks to either 8 or 80 ppm of cadmium or 100 or 2,000 ppm of lead. Results are different from those reported in another species Eisenia fetida andrei (= E. andrei) showing an inhibitory effect of lead on ChE activity; thus, differences in cholinesterase inhibition reflects the existence of two separate species. No effect of cadmium and lead on the activity of esterases, malate dehydrogenase, phosphoglucomutase and glutamate oxalate transferase was found in our experimental conditions, but we observed the disappearance of the fast moving band after electrophoretic separation for phosphoglucose isomerase.     

Evolution of branched regulatory genetic pathways: directional selection on pleiotropic loci accelerates developmental system drift

Developmental systems are regulated by a web of interacting loci. One common and useful approach in studying the evolution of development is to focus on classes of interacting elements within these systems. Here, we use individual-based simulations to study the evolution of traits controlled by branched developmental pathways involving three loci, where one locus regulates two different traits. We examined the system under a variety of selective regimes. In the case where one branch was under stabilizing selection and the other under directional selection, we observed "developmental system drift": the trait under stabilizing selection showed little phenotypic change even though the loci underlying that trait showed considerable evolutionary divergence. This occurs because the pleiotropic locus responds to directional selection and compensatory mutants are then favored in the pathway under stabilizing selection. Though developmental system drift may be caused by other mechanisms, it seems likely that it is accelerated by the same underlying genetic mechanism as that producing the Dobzhansky-Muller incompatibilities that lead to speciation in both linear and branched pathways. We also discuss predictions of our model for developmental system drift and how different selective regimes affect probabilities of speciation in the branched pathway system.     

The Tumorgenicity of Glioblastoma Cell Line U87MG Decreased During Serial In Vitro Passage

Established cancer cell lines are routinely used to study cancer. Several factors such as serial passage may affect the reproducibility of experiments with cancer cell lines, but few researches focused on these changes. In the present study, different morphology and decreased tumorigenicity were observed in late passage U87MG cells. In vitro experiments further revealed that late passage U87MG cells possessed lower invasion properties than early passage, whereas no significant differences of proliferation and migration were found between early and late passage U87MG cells. In particular, we confirmed that late passage U87MG cells exhibited more epithelial phenotype with decreased PI3K/Akt pathway and TGF-β pathway expressions at protein level. In summary, our results focused on the changes of U87MG cells during serial in vitro passage, suggested that passage-induced changes may lead to notable changes of biological characteristics and several molecular transitions in cancer cell lines, indicating the necessity to shorten experiment-span and accomplish experiments with the same or similar passage cancer cell strains.     

Role of Oxidative Damage in Friedreich's Ataxia

Plasma malondialdehyde (MDA) levels were raised in Friedreich's ataxia (FRDA) patients. These levels correlated with increasing age and disease duration, suggesting lipid peroxidation increased with disease progression. Using fibroblasts from FRDA patients we observed that GSH levels and aconitase activities were normal, suggesting their antioxidant status was unchanged. When exposed to various agents to increase free radical generation we observed that intracellular superoxide generation induced by paraquat caused enhanced oxidative damage. This correlated with the size of the GAA1 expansion, suggesting decreased frataxin levels may render the cells more vulnerable to mild oxidative stress. More severe oxidative stress induced by hydrogen peroxide caused increased cell death in FRDA fibroblasts but was not significantly different from control cells. We propose that abnormal respiratory chain function and iron accumulation may lead to a progressive increase in oxidative damage, but increased sensitivity to free radicals may not require detectable respiratory chain dysfunction.     

Preferences for phosphorylation sites in the retinoblastoma protein of D-type cyclin-dependent kinases, Cdk4 and Cdk6, in vitro

D-type cyclin-dependent kinases (Cdk4 and Cdk6) regulate the G1 to S phase progression of the mammalian cell cycle. It has been suggested that Cdk4 and Cdk6 may have distinct functions in vivo, even though they are indistinguishable biochemically. Here we show that although these Cdks phosphorylate multiple residues in pRB, they do so with different residue selectivities in vitro; Thr821 and Thr826 are preferentially phosphorylated by Cdk6 and Cdk4, respectively. This raises the possibility different substrate specificities lead to their different roles in the regulation of cellular events. Furthermore, our results indicate the new concept that Cdk itself contributes to substrate recognition.     

The Role of Cellular Coupling in the Spontaneous Generation of Electrical Activity in Uterine Tissue

The spontaneous emergence of contraction-inducing electrical activity in the uterus at the beginning of labor remains poorly understood, partly due to the seemingly contradictory observation that isolated uterine cells are not spontaneously active. It is known, however, that the expression of gap junctions increases dramatically in the approach to parturition, by more than one order of magnitude, which results in a significant increase in inter-cellular electrical coupling. In this paper, we build upon previous studies of the activity of electrically excitable smooth muscle cells (myocytes) and investigate the mechanism through which the coupling of these cells to electrically passive cells results in the generation of spontaneous activity in the uterus. Using a recently developed, realistic model of uterine muscle cell dynamics, we investigate a system consisting of a myocyte coupled to passive cells. We then extend our analysis to a simple two-dimensional lattice model of the tissue, with each myocyte being coupled to its neighbors, as well as to a random number of passive cells. We observe that different dynamical regimes can be observed over a range of gap junction conductances: at low coupling strength, corresponding to values measured long before delivery, the activity is confined to cell clusters, while the activity for high coupling, compatible with values measured shortly before delivery, may spread across the entire tissue. Additionally, we find that the system supports the spontaneous generation of spiral wave activity. Our results are both qualitatively and quantitatively consistent with observations from in vitro experiments. In particular, we demonstrate that the increase in inter-cellular electrical coupling observed experimentally strongly facilitates the appearance of spontaneous action potentials that may eventually lead to parturition.     

Phylogenetic incongruence in the Drosophila melanogaster species group

Drosophila melanogaster and its close relatives are used extensively in comparative biology. Despite the importance of phylogenetic information for such studies, relationships between some melanogaster species group members are unclear due to conflicting phylogenetic signals at different loci. In this study, we use twelve nuclear loci (eleven coding and one non-coding) to assess the degree of phylogenetic incongruence in this model system. We focus on two nodes: (1) the node joining the Drosophila erecta-Drosophila orena, Drosophila melanogaster-Drosophila simulans, and Drosophila yakuba-Drosophila teissieri lineages, and (2) the node joining the lineages leading to the melanogaster, takahashii, and eugracilis subgroups. We find limited evidence for incongruence at the first node; our data, as well as those of several previous studies, strongly support monophyly of a clade consisting of D. erecta-D. orena and D. yakuba-D. teissieri. By contrast, using likelihood based tests of congruence, we find robust evidence for topological incongruence at the second node. Different loci support different relationships among the melanogaster, takahashii, and eugracilis subgroups, and the observed incongruence is not easily attributable to homoplasy, non-equilibrium base composition, or positive selection on a subset of loci. We argue that lineage sorting in the common ancestor of these three subgroups is the most plausible explanation for our observations. Such lineage sorting may lead to biased estimation of tree topology and evolutionary rates, and may confound inferences of positive selection.     

Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives — A molecular dynamics study

Amphotericin B (AmB) is an effective but very toxic antifungal antibiotic. In our laboratory a series of AmB derivatives of improved selectivity of action was synthesized and tested. To understand molecular basis of this improvement, comparative conformational studies of amphotericin B and its two more selective derivatives were carried out in an aqueous solution and in a lipid membrane. These molecular simulation studies revealed that within a membrane environment the conformational behavior of the derivatives differs significantly from the one observed for the parent molecule. Possible reasons for such a difference are analyzed. Furthermore, we hypothesize that the observed conformational transition within the polar head of AmB derivatives may lead to destabilization of antibiotic-induced transmembrane channels. Consequently, the selective toxicity of the derivatives should increase as ergosterol-rich liquid-ordered domains are more rigid and conformationally ordered than their cholesterol-containing counterparts, and as such may better support less stable channel structure.     

Social Origins of Rhythm? Synchrony and Temporal Regularity in Human Vocalization

Humans have a capacity to perceive and synchronize with rhythms. This is unusual in that only a minority of other species exhibit similar behavior. Study of synchronizing species (particularly anurans and insects) suggests that simultaneous signal production by different individuals may play a critical role in the development of regular temporal signaling. Accordingly, we investigated the link between simultaneous signal production and temporal regularity in our own species. Specifically, we asked whether inter-individual synchronization of a behavior that is typically irregular in time, speech, could lead to evenly-paced or “isochronous” temporal patterns. Participants read nonsense phrases aloud with and without partners, and we found that synchronous reading resulted in greater regularity of durational intervals between words. Comparison of same-gender pairings showed that males and females were able to synchronize their temporal speech patterns with equal skill. These results demonstrate that the shared goal of synchronization can lead to the development of temporal regularity in vocalizations, suggesting that the origins of musical rhythm may lie in cooperative social interaction rather than in sexual selection.