Stochastic modelling of collective motor protein transport through a crossing of microtubules.

The cytoskeleton in eukaryotic cells plays several crucial roles. In terms of intracellular transport, motor proteins use the cytoskeletal filaments as a backbone along which they can actively transport biological cargos such as vesicles carrying biochemical reactants. Crossings between such filaments constitute a key element, as they may serve to alter the destination of such payload. Although motor proteins are known to display a rich behaviour at such crossings, the latter have so far only been modelled as simple branching points. Here we explore a model for a crossing between two microtubules which retains the individual tracks consisting of protofilaments, and we construct a schematic representation of the transport paths. We study collective transport exemplified by the Totally Asymmetric Simple Exclusion Process (TASEP), and provide a full analysis of the transport features and the associated phase diagram, by a generic mean-field approach which we confirm through particle-based stochastic simulations. In particular we show that transport through such a compound crossing cannot be approximated from a coarse-grained structure with a simple branching point. Instead, it gives rise to entirely new and counterintuitive features: the fundamental current-density relation for traffic flow is no longer a single-valued function, and it furthermore differs according to whether it is observed upstream or downstream from the crossing. We argue that these novel features may be directly relevant for interpreting experimental measurements.

Novel mRNA-specific effects of ribosome drop-off on translation rate and polysome profile.

The well established phenomenon of ribosome drop-off plays crucial roles in translational accuracy and nutrient starvation responses during protein translation. When cells are under stress conditions, such as amino acid starvation or aminoacyl-tRNA depletion due to a high level of recombinant protein expression, ribosome drop-off can substantially affect the efficiency of protein expression. Here we introduce a mathematical model that describes the effects of ribosome drop-off on the ribosome density along the mRNA and on the concomitant protein synthesis rate. Our results show that ribosome premature termination may lead to non-intuitive ribosome density profiles, such as a ribosome density which increases from the 5' to the 3' end. Importantly, the model predicts that the effects of ribosome drop-off on the translation rate are mRNA-specific, and we quantify their resilience to drop-off, showing that the mRNAs which present ribosome queues are much less affected by ribosome drop-off than those which do not. Moreover, among those mRNAs that do not present ribosome queues, resilience to drop-off correlates positively with the elongation rate, so that sequences using fast codons are expected to be less affected by ribosome drop-off. This result is consistent with a genome-wide analysis of S. cerevisiae, which reveals that under favourable growth conditions mRNAs coding for proteins involved in the translation machinery, known to be highly codon biased and using preferentially fast codons, are highly resilient to ribosome drop-off. Moreover, in physiological conditions, the translation rate of mRNAs coding for regulatory, stress-related proteins, is less resilient to ribosome drop-off. This model therefore allows analysis of variations in the translational efficiency of individual mRNAs by accounting for the full range of known ribosome behaviours, as well as explaining mRNA-specific variations in ribosome density emerging from ribosome profiling studies.

Modeling cytoskeletal traffic: an interplay between passive diffusion and active transport.

We introduce the totally asymmetric simple exclusion process with Langmuir kinetics on a network as a microscopic model for active motor protein transport on the cytoskeleton, immersed in the diffusive cytoplasm. We discuss how the interplay between active transport along a network and infinite diffusion in a bulk reservoir leads to a heterogeneous matter distribution on various scales: we find three regimes for steady state transport, corresponding to the scale of the network, of individual segments, or local to sites. At low exchange rates strong density heterogeneities develop between different segments in the network. In this regime one has to consider the topological complexity of the whole network to describe transport. In contrast, at moderate exchange rates the transport through the network decouples, and the physics is determined by single segments and the local topology. At last, for very high exchange rates the homogeneous Langmuir process dominates the stationary state. We introduce effective rate diagrams for the network to identify these different regimes. Based on this method we develop an intuitive but generic picture of how the stationary state of excluded volume processes on complex networks can be understood in terms of the single-segment phase diagram.

Two-species totally asymmetric simple exclusion process model: From a simple description to intermittency and traveling traffic jams.

We extend the paradigmatic and versatile totally asymmetric simple exclusion process (TASEP) for stochastic 1D transport to allow for two different particle species, each having specific entry and exit rates. We offer a complete mean-field analysis, including a phase diagram, by mapping this model onto an effective one-species TASEP. Stochastic simulations confirm the results, but indicate deviations when the particle species have very different exit rates. We illustrate that this is due to a phenomenon of intermittency, and formulate a refined "intermittent" mean-field theory for this regime. We discuss how nonstationary effects may further enrich the phenomenology.

Totally asymmetric simple exclusion process on networks.

We study the totally asymmetric simple exclusion process (TASEP) on complex networks, as a paradigmatic model for transport subject to excluded volume interactions. Building on TASEP phenomenology on a single segment and borrowing ideas from random networks we investigate the effect of connectivity on transport. In particular, we argue that the presence of disorder in the topology of vertices crucially modifies the transport features of a network: irregular networks involve homogeneous segments and have a bimodal distribution of edge densities, whereas regular networks are dominated by shocks leading to a unimodal density distribution. The proposed numerical approach of solving for mean-field transport on networks provides a general framework for studying TASEP on large networks, and is expected to generalize to other transport processes.

Biomarkers of exercise-induced myocardial stress in relation to inflammatory and oxidative stress.

Increased concentrations of biomarkers reflecting myocardial stress such as cardiac troponin I and T and brain natriuretic peptide (BNP) have been observed following strenuous, long-lasting endurance exercise. The pathophysiological mechanisms are still not fully elucidated and the interpretations of increased post-exercise concentrations range from (i) evidence for exercise-induced myocardial damage to (ii) non-relevant spurious troponin elevations, presumably caused by assay imprecision or heterophilic antibodies. Several lines of evidence suggest that inflammatory processes or oxidative stress could be involved in the rise of NT-proBNP and Troponin observed in critically ill patients with sepsis or burn injury. We tested the hypothesis that inflammatory or oxidative stress is also responsible for exercise-induced cardiomyocyte strain in a large cohort of triathletes following an Ironman triathlon. However, the post-race increase in cardiac troponin T and NT-proBNP was not associated with several markers of exercise-induced inflammation, oxidative stress or antioxidant vitamins. Therefore, we clearly need more studies with other inflammatory markers and different designs to elucidate the scientific background for increases in myocardial stress markers following strenuous endurance events.

Role of network junctions for the totally asymmetric simple exclusion process.

We study the effect of local regulation mechanisms on stochastic network traffic, based on simple examples. Using the totally asymmetric simple exclusion process on a multiloop structure in which several segments share a single junction, we illustrate several mechanisms: (i) additional segments improve transport but the effect saturates due to blockage, (ii) bias reduces the overall transport and leads to several regimes, (iii) "pumping" particles out of the junctions, via a locally increased hopping rate, allows us to compensate the bottlenecks but becomes futile beyond a characteristic rate which we determine. We provide a generic discussion of combinations of these effects, including phase diagrams in terms of the control parameters.

Understanding totally asymmetric simple-exclusion-process transport on networks: generic analysis via effective rates and explicit vertices.

In this paper we rationalize relevant features of totally asymmetric simple-exclusion processes on topologies more complex than a single segment. We present a mean-field framework, exploiting the previously introduced notion of effective rates, which we express in terms of the average particle density on explicitly introduced junction sites. It allows us to construct the phase behavior as well as the current-density characteristic from well-known results for a linear totally asymmetric simple-exclusion-process segment in a very systematic and generic way. We validate the approach by studying a fourfold vertex in all variations in the number of entering/exiting segments and compare our predictions to simulation data. Generalizing the notion of particle-hole symmetry to take into account the topology at a junction shows that the average particle density at the junction constitutes a relevant directly observable parameter which gives detailed insight into the transport process. This is illustrated by a complete study of a simple network with figure-of-eight topology. Finally we generalize the approach to handle rate bias at a junction and discuss the surprisingly rich phenomenology of a biased figure-of-eight structure. This example highlights that the proposed framework is generic and readily extends to other topologies.

No indications of persistent oxidative stress in response to an ironman triathlon.

INTRODUCTION: Training for and competing in ultraendurance exercise events is associated with an improvement in endogenous antioxidant defenses as well as increased oxidative stress. However, consequences on health are currently unclear. PURPOSE: We aimed to examine the impact of training- and acute exercise-induced changes in the antioxidant capacity on the oxidant/antioxidant balance after an ironman triathlon and whether there are indications for sustained oxidative damage. METHODS: Blood samples were taken from 42 well-trained male triathletes 2 d before an ironman triathlon, then immediately postrace, 1, 5, and 19 d later. Blood was analyzed for conjugated dienes (CD), malondialdehyde (MDA), oxidized low-density lipoprotein (oxLDL), oxLDL:LDL ratio, advanced oxidation protein products (AOPP), AOPP:total protein (TP) ratio, Trolox equivalent antioxidant capacity (TEAC), uric acid (UA) in plasma, and activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in erythrocytes. RESULTS: Immediately postrace, there were significant increases in CD, AOPP, TEAC, UA (for all P < 0.001), and AOPP:TP (P < 0.01). MDA rose significantly (P < 0.01) 1 d postrace, whereas CD (P < 0.01), AOPP (P = 0.01), AOPP:TP (P < 0.05), and TEAC (P < 0.001) remained elevated. OxLDL:LDL trended to increase, whereas oxLDL significantly (P < 0.01) decreased 1 d postrace. Except for GSH-Px (P = 0.08), activities of SOD (P < 0.001) and CAT (P < 0.05) significantly decreased postrace. All oxidative stress markers had returned to prerace values 5 d postrace. Furthermore, several relationships between training status and oxidative stress markers, TEAC, and antioxidant enzyme activities were noted. CONCLUSIONS: This study indicates that despite a temporary increase in most (but not all) oxidative stress markers, there is no persistent oxidative stress in response to an ironman triathlon, probably due to training- and exercise-induced protective alterations in the antioxidant defense system.

The diffusive vesicle supply center model for tip growth in fungal hyphae.

We propose the diffusive vesicle supply center model for tip growth in fungal hyphae. The model is based on the three-dimensional vesicle supply center (VSC) model [Gierz, G., Bartnicki-García, S., 2001. A three-dimensional model of fungal morphogenesis based on the vesicle supply center concept: J. Theor. Biol. 208, 151-164], but incorporates two aspects of a more realistic vesicle delivery mechanism: vesicle diffusion from the VSC and a finite rate constant for vesicle fusion with the cell membrane. We develop a framework to describe tip growth for a general class of models based on the vesicle supply center concept. Combining this with a method for calculating the steady state distribution of diffusive vesicles we iteratively solve for stationary cell shapes. These show a blunter tip than predicted by the original VSC model, which we attribute to increased forward-directed vesicle delivery via diffusion. The predicted distance between the VSC and the utmost tip of the cell is set by the ratio between the diffusion constant and the rate constant for vesicle exocytosis. Combined with the cell radius, these define the only dimensionless parameter for our model.