Browsing by Author "Xu, Chunrui"

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    Cell cycle control and environmental response by second messengers in Caulobacter crescentus
    Xu, Chunrui; Weston, Bronson R.; Tyson, John J.; Cao, Yang (2020-09-30)
    Background Second messengers, c-di-GMP and (p)ppGpp, are vital regulatory molecules in bacteria, influencing cellular processes such as biofilm formation, transcription, virulence, quorum sensing, and proliferation. While c-di-GMP and (p)ppGpp are both synthesized from GTP molecules, they play antagonistic roles in regulating the cell cycle. In C. crescentus, c-di-GMP works as a major regulator of pole morphogenesis and cell development. It inhibits cell motility and promotes S-phase entry by inhibiting the activity of the master regulator, CtrA. Intracellular (p)ppGpp accumulates under starvation, which helps bacteria to survive under stressful conditions through regulating nucleotide levels and halting proliferation. (p)ppGpp responds to nitrogen levels through RelA-SpoT homolog enzymes, detecting glutamine concentration using a nitrogen phosphotransferase system (PTS Ntr). This work relates the guanine nucleotide-based second messenger regulatory network with the bacterial PTS Ntr system and investigates how bacteria respond to nutrient availability. Results We propose a mathematical model for the dynamics of c-di-GMP and (p)ppGpp in C. crescentus and analyze how the guanine nucleotide-based second messenger system responds to certain environmental changes communicated through the PTS Ntr system. Our mathematical model consists of seven ODEs describing the dynamics of nucleotides and PTS Ntr enzymes. Our simulations are consistent with experimental observations and suggest, among other predictions, that SpoT can effectively decrease c-di-GMP levels in response to nitrogen starvation just as well as it increases (p)ppGpp levels. Thus, the activity of SpoT (or its homologues in other bacterial species) can likely influence the cell cycle by influencing both c-di-GMP and (p)ppGpp. Conclusions In this work, we integrate current knowledge and experimental observations from the literature to formulate a novel mathematical model. We analyze the model and demonstrate how the PTS Ntr system influences (p)ppGpp, c-di-GMP, GMP and GTP concentrations. While this model does not consider all aspects of PTS Ntr signaling, such as cross-talk with the carbon PTS system, here we present our first effort to develop a model of nutrient signaling in C. crescentus.
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    Feature selection of gene expression data for Cancer classification using double RBF-kernels
    Liu, Shenghui; Xu, Chunrui; Zhang, Yusen; Liu, Jiaguo; Yu, Bin; Liu, Xiaoping; Dehmer, Matthias (2018-10-29)
    Background Using knowledge-based interpretation to analyze omics data can not only obtain essential information regarding various biological processes, but also reflect the current physiological status of cells and tissue. The major challenge to analyze gene expression data, with a large number of genes and small samples, is to extract disease-related information from a massive amount of redundant data and noise. Gene selection, eliminating redundant and irrelevant genes, has been a key step to address this problem. Results The modified method was tested on four benchmark datasets with either two-class phenotypes or multiclass phenotypes, outperforming previous methods, with relatively higher accuracy, true positive rate, false positive rate and reduced runtime. Conclusions This paper proposes an effective feature selection method, combining double RBF-kernels with weighted analysis, to extract feature genes from gene expression data, by exploring its nonlinear mapping ability.
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    Mathematical Model of the Cell Cycle Control and Asymmetry Development in Caulobacter crescentus
    Xu, Chunrui (Virginia Tech, 2022-06-23)
    Caulobacter crescentus goes through a classic dimorphic cell division cycle to adapt to the stringent environment and reduce intraspecific competition. Caulobacter mother cell gives rise to two progenies with distinct morphology - a motile swarmer cell equipped with a flagellum and a sessile stalked cell equipped with a stalk. Because of the nature of dimorphic lifestyle, Caulobacter becomes a model bacterium to study the cell differentiation, signalling transduction, stress response, and asymmetry development of prokaryotes. The dimorphic cell cycle of Caulobacter is driven by the elaborate spatiotemporal organization of regulatory molecules through regulations of synthesis, degradation, phosphorelay, and localization. There is a wealth of experimental observations about gene/protein interactions and localizations accumulated in recent decades, while several mathematical models have been proposed to study the cell cycle progression in Caulobacter. However, the specific control mechanisms of stress response and spatial asymmetry establishment are yet clearly elucidated, while these mechanisms are of fundamental importance to understanding the bacterial survival strategy and developing the microbial industry. Here we utilize mathematical modeling to study the regulatory network of cell cycle control in C. crescentus, focusing on the stress response and asymmetry development. First, we investigate the starvation response of Caulobacter through the connection of phosphotransferase systems (PTS) and guanine nucleotide-based second messenger system. We have developed a mathematical model to capture the temporal dynamics of vital regulatory second messengers, c-di-GMP (cdG) and guanosine pentaphosphate or tetraphosphate (pppGpp or ppGpp), under normal and stressful conditions. This research suggests that the RelA-SpoT homolog enzymes have the potential to effectively influence the cell cycle in response to nutrition changes by regulating cdG and (p)ppGpp levels. We further integrate the second messenger network into a temporal cell cycle model to investigate molecular mechanisms underlying responses of Caulobacter to nutrition starvation. Our model suggests that the cdG-relevant starvation signal is essential but not sufficient to robustly arrest the cell cycle of Caulobacter. We also demonstrate that there may be unknown pathway(s) reducing CtrA under starvation conditions, which results in delayed cytokinesis in starved stalked cells. The cell cycle development of Caulobacter is determined by the periodical activation and deactivation of the master regulator CtrA. cdG is an essential component of the ClpXP pro- tease complex, which is specifically responsible for the degradation of CtrA. We propose a mathematical model for the hierarchical assembly of ClpXP complexes, together with modeling DNA replication, transcription, and protein interactions, to characterize the Caulobacter cell cycle. Our model suggests that the ClpXP-based proteolysis system contributes to the timing and robustness of the cell cycle progression. Furthermore, we construct a spatiotemporal model with Turing-pattern mechanism to study the morphogenesis and asymmetry establishment during the cell cycle of Caulobacter. We apply reaction-diffusion equations to capture the spatial dynamics of scaffolding proteins PodJ, PopZ, and SpmX, which organize two distinct poles of Caulobacter. The spatial regulations influence the activity and distribution of key cell cycle regulators, governing the dimorphic lifestyle of Caulobacter. Our model captures major spatiotemporal experimental observations of wild-type and mutant cells. It provides predictions of novel mutant strains and explains the spatial regulatory mechanisms of bacterial cell cycle progression.
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    Turing-pattern model of scaffolding proteins that establish spatial asymmetry during the cell cycle of Caulobacter crescentus
    Xu, Chunrui; Tyson, John J.; Cao, Yang (Cell Press, 2023-04)
    The crescent-shaped bacterium Caulobacter crescentus divides asymmetrically into a sessile (stalked) cell and a motile (flagellated) cell. This dimorphic cell division cycle is driven by the asymmetric appearance of scaffolding proteins at the cell's stalk and flagellum poles. The scaffolding proteins recruit enzyme complexes that phosphorylate and degrade a master transcription factor, CtrA, and the abundance and phosphorylation state of CtrA control the onset of DNA synthesis and the differentiation of stalked and flagellated cell types. In this study, we use a Turing-pattern mechanism to simulate the spatiotemporal dynamics of scaffolding proteins in Caulobacter and how they influence the abundance and intracellular distribution of CtrA similar to P. Our mathematical model captures crucial features of wild-type and mutant strains and predicts the distributions of CtrA similar to P and signaling proteins in mutant strains. Our model accounts for Caulobacter polar morphogenesis and shows how spatial localization and phosphosignaling cooperate to establish asymmetry during the cell cycle.