In the nematodes Caenorhabditis elegans and Pristionchus pacificus, a modular library of small molecules control behavior, lifespan, and development. However, little is known about the final steps of ...their biosynthesis, in which diverse building blocks from primary metabolism are attached to glycosides of the dideoxysugar ascarylose, the ascarosides. We combine metabolomic analysis of natural isolates of P. pacificus with genome-wide association mapping to identify a putative carboxylesterase, Ppa-uar-1, that is required for attachment of a pyrimidine-derived moiety in the biosynthesis of ubas#1, a major dauer pheromone component. Comparative metabolomic analysis of wild-type and Ppa-uar-1 mutants showed that Ppa-uar-1 is required specifically for the biosynthesis of ubas#1 and related metabolites. Heterologous expression of Ppa-UAR-1 in C. elegans yielded a non-endogenous ascaroside, whose structure confirmed that Ppa-uar-1 is involved in modification of a specific position in ascarosides. Our study demonstrates the utility of natural variation-based approaches for uncovering biosynthetic pathways.
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•GWAS identifies a gene required for modular ascaroside biosynthesis•Ppa-UAR-1 is required for attachment of a nucleobase-derived moiety to ascarylose•Heterologous expression of Ppa-UAR-1 in C. elegans produced a non-natural ascaroside•Natural variation-based approaches can uncover unanticipated biosynthetic pathways
A small-molecule library, the ascarosides, regulates the life history of Caenorhabditis elegans and Pristionchus pacificus. GWAS combined with metabolomics of P. pacificus natural isolates revealed a putative carboxylesterase, Ppa-uar-1, involved in attaching a pyrimidine-derived moiety in the biosynthesis of a major dauer pheromone component.
We simulate currents and concentration profiles generated by Ca
2+
release from the endoplasmic reticulum (ER) to the cytosol through IP
3
receptor channel clusters. Clusters are described as ...conducting pores in the lumenal membrane with a diameter from 6 nm to 36 nm. The endoplasmic reticulum is modeled as a disc with a radius of 1–12
μ
m and an inner height of 28 nm. We adapt the dependence of the currents on the
trans
Ca
2+
concentration (intralumenal) measured in lipid bilayer experiments to the cellular geometry. Simulated currents are compared with signal mass measurements in
Xenopus
oocytes. We find that release currents depend linearly on the concentration of free Ca
2+
in the lumen. The release current is approximately proportional to the square root of the number of open channels in a cluster. Cytosolic concentrations at the location of the cluster range from 25
μ
M to 170
μ
M. Concentration increase due to puffs in a distance of a few micrometers from the puff site is found to be in the nanomolar range. Release currents decay biexponentially with timescales of <1 s and a few seconds. Concentration profiles decay with timescales of 0.125–0.250 s upon termination of release.
Intracellular calcium release is a prime example for the role of stochastic effects in cellular systems. Recent models consist of deterministic reaction-diffusion equations coupled to stochastic ...transitions of calcium channels. The resulting dynamics is of multiple time and spatial scales, which complicates far-reaching computer simulations. In this article, we introduce a novel hybrid scheme that is especially tailored to accurately trace events with essential stochastic variations, while deterministic concentration variables are efficiently and accurately traced at the same time. We use finite elements to efficiently resolve the extreme spatial gradients of concentration variables close to a channel. We describe the algorithmic approach and we demonstrate its efficiency compared to conventional methods. Our single-channel model matches experimental data and results in intriguing dynamics if calcium is used as charge carrier. Random openings of the channel accumulate in bursts of calcium blips that may be central for the understanding of cellular calcium dynamics.
Currents through ion channels are determined (among other parameters) by the concentration difference across the membrane containing the channel and the diffusive transport of the conducted ion ...toward the channel and away from it. Calculation of the current requires solving the diffusion equation around the channel. Here, we provide a quasi-steady approximation for the current and the local concentrations at the channel together with formulas linking the current and local concentrations at the channel to bulk concentrations and diffusion properties of the compartments.
Models of the inositol trisphosphate receptor Sneyd, J.; Falcke, M.
Progress in Biophysics and Molecular Biology/Progress in biophysics and molecular biology,
11/2005, Letnik:
89, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The inositol (1,4,5)-trisphosphate receptor (IPR) plays a crucial role in calcium dynamics in a wide range of cell types, and is often a central feature in quantitative models of calcium oscillations ...and waves. We review deterministic and stochastic mathematical models of the IPR, from the earliest ones of the 1970s and 1980s, to the most recent. The effects of IPR stochasticity on
Ca
2
+
dynamics are briefly discussed.
Communities of microscopic dinoflagellates are omnipresent in aquatic ecosystems. Consequently, their traits drive community processes with profound effects on global biogeochemistry. Species traits ...are however not necessarily static but respond to environmental changes in order to maintain fitness and may differ with cell size that scales physiological rates. Comprehending such trait characteristics is necessary for a mechanistic understanding of plankton community dynamics and resulting biogeochemical impacts. Here we used information theory to analyze metatranscriptomes of micro- and nano-dinoflagellate communities in three ecosystems. Measures of gene expression variations were set as a proxy to determine conserved and plastic community traits and the environmental influence on trait changes. Using metabarcoding, we further investigated if communities with a more similar taxon composition also express more similar traits. Our results indicate that plastic community traits mainly arise from membrane vesicle associated processes in all the environments we investigated. A specific environmental influence on trait plasticity was observed to arise from nitrogen availability in both size classes. Species interactions also appeared to be responsible for trait plasticity in the smaller-sized dinoflagellates. Additionally, the smaller-sized dinoflagellate communities are characterized by a large pool of habitat specific genes despite being taxonomically more similar across the habitats, in contrast to the microplanktonic assemblages that adapted to their environments by changing species composition. Our data highlight the functional diversification as a signature of smaller sized dinoflagellates, nitrogen availability and species interactions as drivers of trait plasticity, and traits most likely linked to fitness and community performance.
Adaptivity in space and time for the numerical simulation of stochastic and deterministic equations for intracellular calcium dynamics is presented. The modeling of diffusion, reaction and membrane ...transport of calcium ions in cells leads to a system of reaction–diffusion equations. We describe the modulation of cytosolic and ER calcium concentrations close to the membrane of the cell organelle.
A conforming piecewise linear finite element method is used for the spatial discretization. Linearly implicit methods of Rosenbrock type are used for the time integration. We adopt a hybrid algorithm to solve the stochastic part. The space grid is adjusted to the strong localization of the calcium release following stochastic channel transitions. By automatically adapting the spatial meshes and time steps to the proper scales during the transition of channel states, the method accurately resolves the evolution of intracellular calcium concentrations as well as buffer concentrations. This article emphasizes adaptive and efficient hybrid numerical simulations in two space dimensions. The presented work establishes the basis for future simulations in a realistic 3D geometry.
We present a novel approach to the dynamics of reactions of diffusing chemical species with species fixed in space, e.g., by binding to a membrane. The nondiffusing reaction partners are clustered in ...areas with a diameter smaller than the diffusion length of the diffusing partner. The activated fraction of the fixed species determines the size of an active subregion of the cluster. Linear stability analysis reveals that diffusion is one of the major determinants of the stability of the dynamics. We illustrate the model concept with Ca2+ dynamics in living cells, which has release channels as fixed reaction partners. Our results suggest that spatial and temporal structures in intracellular Ca2+ dynamics are caused by fluctuations due to the small number of channels per cluster.
Ca
2+
is one of the most important messengers. It transmits signals inside living cells and takes part in intercellular coordination. The dynamics of the Ca
2+
concentration shows a transition from ...elemental, stochastic events to global events like waves and oscillations. This transition renders it an ideal tool for studying basic concepts of pattern formation, especially since access to the most important experimental parameters is given. Ca
2+
dynamics in living cells has been a major topic of biophysical modelling in the last 15 years. Modelling has reached the level of predictive power. The theoretical analysis of waves provided new insight into the mechanisms of Ca
2+
signaling and led to new concepts of analysis of wave equations with concentration dependent diffusion and novel wave bifurcations. Modelling of oscillations provided understanding especially of complex oscillations and allowed to extract information about the underlying cellular parameters and mechanisms. The investigation of the stochastic aspects of intracellular Ca
2+
dynamics demonstrated the fundamental role of fluctuations arising from the control of the release channel by Ca
2+
and IP
3
. This review presents an overview of current theoretical research on Ca
2+
dynamics in living cells driven by the inositol 1,4,5-trisphosphate receptor channel.
We investigate the key characteristics of Ca(2+) puffs in deterministic and stochastic frameworks that all incorporate the cellular morphology of IP(3) receptor channel clusters. In the first step, ...we numerically study the Ca(2+) liberation in a three-dimensional representation of a cluster environment with reaction-diffusion dynamics in both the cytosol and the lumen. These simulations reveal that Ca(2+) concentrations at a releasing cluster range from 80 to 170 microM and equilibrate almost instantaneously on the time scale of the release duration. These highly elevated Ca(2+) concentrations eliminate Ca(2+) oscillations in a deterministic model of an IP(3)R channel cluster at physiological parameter values as revealed by a linear stability analysis. The reason lies in the saturation of all feedback processes in the IP(3)R gating dynamics, so that only fluctuations can restore experimentally observed Ca(2+) oscillations. In this spirit, we derive master equations that allow us to analytically quantify the onset of Ca(2+) puffs and hence the stochastic time scale of intracellular Ca(2+) dynamics. Moving up the spatial scale, we suggest to formulate cellular dynamics in terms of waiting time distribution functions. This approach prevents the state space explosion that is typical for the description of cellular dynamics based on channel states and still contains information on molecular fluctuations. We illustrate this method by studying global Ca(2+) oscillations.
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