@article{nosbisch_rahman_mohan_elston_bear_haugh_2020, title={Mechanistic models of PLC/PKC signaling implicate phosphatidic acid as a key amplifier of chemotactic gradient sensing}, volume={16}, ISSN={["1553-7358"]}, DOI={10.1371/journal.pcbi.1007708}, abstractNote={Chemotaxis of fibroblasts and other mesenchymal cells is critical for embryonic development and wound healing. Fibroblast chemotaxis directed by a gradient of platelet-derived growth factor (PDGF) requires signaling through the phospholipase C (PLC)/protein kinase C (PKC) pathway. Diacylglycerol (DAG), the lipid product of PLC that activates conventional PKCs, is focally enriched at the up-gradient leading edge of fibroblasts responding to a shallow gradient of PDGF, signifying polarization. To explain the underlying mechanisms, we formulated reaction-diffusion models including as many as three putative feedback loops based on known biochemistry. These include the previously analyzed mechanism of substrate-buffering by myristoylated alanine-rich C kinase substrate (MARCKS) and two newly considered feedback loops involving the lipid, phosphatidic acid (PA). DAG kinases and phospholipase D, the enzymes that produce PA, are identified as key regulators in the models. Paradoxically, increasing DAG kinase activity can enhance the robustness of DAG/active PKC polarization with respect to chemoattractant concentration while decreasing their whole-cell levels. Finally, in simulations of wound invasion, efficient collective migration is achieved with thresholds for chemotaxis matching those of polarization in the reaction-diffusion models. This multi-scale modeling framework offers testable predictions to guide further study of signal transduction and cell behavior that affect mesenchymal chemotaxis.}, number={4}, journal={PLOS COMPUTATIONAL BIOLOGY}, author={Nosbisch, Jamie L. and Rahman, Anisur and Mohan, Krithika and Elston, Timothy C. and Bear, James E. and Haugh, Jason M.}, year={2020}, month={Apr} }
 @article{pirone_elston_2004, title={Fluctuations in transcription factor binding can explain the graded and binary responses observed in inducible gene expression}, volume={226}, ISSN={["0022-5193"]}, DOI={10.1016/j.jtbi.2003.08.008}, abstractNote={Inducible genes are expressed in the presence of an external stimulus. Individual cells may exhibit either a binary or graded response to such signals. It has been hypothesized that the chemical kinetics of transcription factor/DNA interactions can account for both these scenarios (EMBO J. 9(9) (1990) 2835; BioEssays 14(5) (1992) 341). To explore this question, we have conducted work based on the experimental results of Fiering et al. (Genes Dev. 4 (10) (1990) 1823). In these experiments, three upstream NF-AT binding sites control transcription of the lacZ gene, which codes for the enzyme β-Galactosidase. The experimental data show a binary response for this system. We consider the effects of fluctuations in NF-AT binding on the response of the system. Our modeling results are in good qualitative agreement with the experimental data, and illustrate how the binary and graded responses can stem from the same underlying mechanism.}, number={1}, journal={JOURNAL OF THEORETICAL BIOLOGY}, author={Pirone, JR and Elston, TC}, year={2004}, month={Jan}, pages={111–121} }
 @article{elston_2002, title={The Brownian ratchet and power stroke models for posttranslational protein translocation into the endoplasmic reticulum}, volume={82}, ISSN={["0006-3495"]}, DOI={10.1016/S0006-3495(02)75480-5}, abstractNote={A quantitative analysis of experimental data for posttranslational translocation into the endoplasmic reticulum is performed. This analysis reveals that translocation involves a single rate-limiting step, which is postulated to be the release of the signal sequence from the translocation channel. Next, the Brownian ratchet and power stroke models of translocation are compared against the data. The data sets are simultaneously fit using a least-squares criterion, and both models are found to accurately reproduce the experimental results. A likelihood-ratio test reveals that the optimal fit of the Brownian ratchet model, which contains one fewer free parameter, does not differ significantly from that of the power stroke model. Therefore, the data considered here cannot be used to reject this import mechanism. The models are further analyzed using the estimated parameters to make experimentally testable predictions.}, number={3}, journal={BIOPHYSICAL JOURNAL}, author={Elston, TC}, year={2002}, month={Mar}, pages={1239–1253} }
 @article{elston_kepler_2001, title={A linear two-state model with complex dynamics}, volume={280}, ISSN={["0375-9601"]}, DOI={10.1016/S0375-9601(01)00052-4}, abstractNote={We study the dynamics of a stochastic two-state model in which all forces are linear. While conceptually simple, we show that the behavior of this system is surprisingly complex. The moments of the system undergo a series of bifurcations as either the overall fluctuation rate or the ratio between the two transition rates is varied. The system displays the very counterintuitive behavior in which all its spatial moments diverge in time, and yet the mean time to escape from a region that includes the origin is infinite. Finally, the system displays resonant activation in a particularly transparent way.}, number={4}, journal={PHYSICS LETTERS A}, author={Elston, TC and Kepler, TB}, year={2001}, month={Feb}, pages={204–208} }
 @article{kepler_elston_2001, title={Stochasticity in transcriptional regulation: Origins, consequences, and mathematical representations}, volume={81}, ISSN={["0006-3495"]}, DOI={10.1016/S0006-3495(01)75949-8}, abstractNote={Transcriptional regulation is an inherently noisy process. The origins of this stochastic behavior can be traced to the random transitions among the discrete chemical states of operators that control the transcription rate and to finite number fluctuations in the biochemical reactions for the synthesis and degradation of transcripts. We develop stochastic models to which these random reactions are intrinsic and a series of simpler models derived explicitly from the first as approximations in different parameter regimes. This innate stochasticity can have both a quantitative and qualitative impact on the behavior of gene-regulatory networks. We introduce a natural generalization of deterministic bifurcations for classification of stochastic systems and show that simple noisy genetic switches have rich bifurcation structures; among them, bifurcations driven solely by changing the rate of operator fluctuations even as the underlying deterministic system remains unchanged. We find stochastic bistability where the deterministic equations predict monostability and vice-versa. We derive and solve equations for the mean waiting times for spontaneous transitions between quasistable states in these switches.}, number={6}, journal={BIOPHYSICAL JOURNAL}, author={Kepler, TB and Elston, TC}, year={2001}, month={Dec}, pages={3116–3136} }
 @article{elston_2000, title={A macroscopic description of biomolecular transport}, volume={41}, ISSN={["0303-6812"]}, DOI={10.1007/s002850000043}, abstractNote={We present a general algorithm for computing the effective diffusion coefficient of a general class of biomolecular transport processes. The method can be applied to spatially discrete and continuous processes and takes into account the effects of thermal diffusion and chemical kinetics. To provide an illustration of the algorithm, the problem of protein translocation is considered.}, number={3}, journal={JOURNAL OF MATHEMATICAL BIOLOGY}, author={Elston, TC}, year={2000}, month={Sep}, pages={189–206} }
 @article{elston_2000, title={Models of post-translational protein translocation}, volume={79}, ISSN={["0006-3495"]}, DOI={10.1016/S0006-3495(00)76471-X}, abstractNote={Organellar Hsp-70 is required for post-translational translocation into the endoplasmic reticulum and mitochondria. The functional role played by Hsp-70 is unknown. However, two operating principles have been suggested. The power stroke model proposes that Hsp-70 undergoes a conformational change, which pulls the precursor protein through the translocation pore, whereas, in the Brownian ratchet model, the role of Hsp-70 is simply to block backsliding through the pore. A mathematical analysis of both mechanisms is presented and reveals that qualitative differences between the models occur in the behavior of the mean velocity and effective diffusion coefficient as a function of Hsp-70 concentration. An experimental method is proposed for measuring these two quantities that only relies on current experimental techniques.}, number={5}, journal={BIOPHYSICAL JOURNAL}, author={Elston, TC}, year={2000}, month={Nov}, pages={2235–2251} }
 @article{elston_peskin_2000, title={Protein flexibility and the correlation ratchet}, volume={61}, number={3}, journal={SIAM Journal on Applied Mathematics}, author={Elston, T. C. and Peskin, C. S.}, year={2000}, pages={842–867} }
 @article{elston_peskin_2000, title={The role of protein flexibility in molecular motor function: Coupled diffusion in a tilted periodic potential}, volume={60}, ISSN={["0036-1399"]}, DOI={10.1137/S0036139998345343}, abstractNote={Biomolecular motors are tiny engines that transport material at the microscopic level within biological cells. It has been proposed that many such motors operate, at least in part, by a Brownian ratchet mechanism. Since biomolecular motors typically transport cargo that are much larger than themselves, one would expect the speed of such a motor to be severely limited by the small diffusion coefficient of its enormous cargo. It has been suggested by Berg and Kahn [Mobility and Recognition in Cell Biology, H. Suns and C. Veeger, eds., de Gruyter, Berlin, 1983, pp. 485--497] and Meister, Caplan, and Berg [ Biophys. J. 55 (1989), pp. 905--914] that this limitation can be overcome if the tether that connects the motor to its cargo is sufficiently elastic. This paper evaluates the influence of the elasticity of the tether on the speed of an imperfect Brownian ratchet. This is done in two limiting cases: (1) large diffusion coefficient of the motor and (2) large potential barrier against reverse motion at each r...}, number={3}, journal={SIAM JOURNAL ON APPLIED MATHEMATICS}, author={Elston, TC and Peskin, CS}, year={2000}, month={Mar}, pages={842–867} }