Jieling Zhao

Dynamic mechanical finite element model of biological cells for studying cellular pattern formation

Understanding the geometric, topologic, and mechanical properties of cells and their interactions... more Understanding the geometric, topologic, and mechanical properties of cells and their interactions is critical for studying tissue pattern formation and organ development. Computational model and tools for simulating cell pattern formation have broad implications in studying embryogenesis, blood-vessel development, tissue regeneration, and tumor growth. Although a number of cell modeling methods exist, they do not simultaneously account for detailed cellular shapes as well as dynamic changes in cell geometry and topology. Here we describe a dynamic finite element cell model (dFEMC) for studying populations of cells and tissue development. By incorporating details of cell shape, cell growth and shrinkage, cell birth and death, cell division and fusion, our method can model realistically a variety problems of cell pattern formation. We give two examples of applying our method to the study of cell fusion and cell apoptosis. The dFEMC model developed here provides a general computational...

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Cell–substrate mechanics guide collective cell migration through intercellular adhesion: a dynamic finite element cellular model

During the process of tissue formation and regeneration, cells migrate collectively while remaini... more During the process of tissue formation and regeneration, cells migrate collectively while remaining connected through intercellular adhesions. However, the roles of cell–substrate and cell–cell mechanical interactions in regulating collective cell migration are still unclear. In this study, we employ a newly developed finite element cellular model to study collective cell migration by exploring the effects of mechanical feedback between cell and substrate and mechanical signal transmission between adjacent cells. Our viscoelastic model of cells consists many triangular elements and is of high resolution. Cadherin adhesion between cells is modeled explicitly as linear springs at subcellular level. In addition, we incorporate a mechano-chemical feedback loop between cell–substrate mechanics and Rac-mediated cell protrusion. Our model can reproduce a number of experimentally observed patterns of collective cell migration during wound healing, including cell migration persistence, separ...

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Dynamic cellular finite-element method for modelling large-scale cell migration and proliferation under the control of mechanical and biochemical cues: a study of re-epithelialization

Computational modelling of cells can reveal insight into the mechanisms of the important processe... more Computational modelling of cells can reveal insight into the mechanisms of the important processes of tissue development. However, current cell models have limitations and are challenged to model detailed changes in cellular shapes and physical mechanics when thousands of migrating and interacting cells need to be modelled. Here we describe a novel dynamic cellular finite-element model (DyCelFEM), which accounts for changes in cellular shapes and mechanics. It also models the full range of cell motion, from movements of individual cells to collective cell migrations. The transmission of mechanical forces regulated by intercellular adhesions and their ruptures are also accounted for. Intra-cellular protein signalling networks controlling cell behaviours are embedded in individual cells. We employ DyCelFEM to examine specific effects of biochemical and mechanical cues in regulating cell migration and proliferation, and in controlling tissue patterning using a simplified re-epitheliali...

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Multiscale Modeling of Cellular Epigenetic States: Stochasticity in Molecular Networks, Chromatin Folding in Cell Nuclei, and Tissue Pattern Formation of Cells

Genome sequences provide the overall genetic blueprint of cells, but cells possessing the same ge... more Genome sequences provide the overall genetic blueprint of cells, but cells possessing the same genome can exhibit diverse phenotypes. There is a multitude of mechanisms controlling cellular epigenetic states and that dictate the behavior of cells. Among these, networks of interacting molecules, often under stochastic control, depending on the specific wirings of molecular components and the physiological conditions, can have a different landscape of cellular states. In addition, chromosome folding in three-dimensional space provides another important control mechanism for selective activation and repression of gene expression. Fully differentiated cells with different properties grow, divide, and interact through mechanical forces and communicate through signal transduction, resulting in the formation of complex tissue patterns. Developing quantitative models to study these multi-scale phenomena and to identify opportunities for improving human health requires development of theoret...

Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκB Signaling and Inflammatory Lung Injury

Ventilator-induced inflammatory lung injury (VILI) is mechanistically linked to increased NAMPT t... more Ventilator-induced inflammatory lung injury (VILI) is mechanistically linked to increased NAMPT transcription and circulating levels of nicotinamide phosphoribosyl-transferase (NAMPT/PBEF). Although VILI severity is attenuated by reduced NAMPT/PBEF bioavailability, the precise contribution of NAMPT/PBEF and excessive mechanical stress to VILI pathobiology is unknown. We now report that NAMPT/PBEF induces lung NFκB transcriptional activities and inflammatory injury via direct ligation of Toll–like receptor 4 (TLR4). Computational analysis demonstrated that NAMPT/PBEF and MD-2, a TLR4-binding protein essential for LPS-induced TLR4 activation, share ~30% sequence identity and exhibit striking structural similarity in loop regions critical for MD-2-TLR4 binding. Unlike MD-2, whose TLR4 binding alone is insufficient to initiate TLR4 signaling, NAMPT/PBEF alone produces robust TLR4 activation, likely via a protruding region of NAMPT/PBEF (S402-N412) with structural similarity to LPS. The ...

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Improving Accuracy of Functional Surfaces of Protein Structures Modeled From Sequences

Accurate models of protein functional surfaces are important for understanding enzyme mechanism, ... more Accurate models of protein functional surfaces are important for understanding enzyme mechanism, protein function prediction, compound-protein docking, and drug design. As the speed of rapid accumulation of protein sequence information far exceeds that of structures, it is important to construct models of proteins with accurate functional surfaces. A promising approach is to construct comparative models. We built three-dimensional comparative models of proteins using MODELLER and applied the pocket algorithm CASTp based on alpha shapes to compute functional surfaces for the modeled protein structures. To improve the accuracy of modeled functional surfaces, we have developed a new side-chain repacking algorithm based on an approximation algorithm that solves the optimization problem of finding compatible side chain rotamers with lowest energy, which is formulated as an integer programming problem. Our result showed that for 9 challenging modeled proteins (backbone sequence identity l...

Cell–substrate mechanics guide collective cell migration through intercellular adhesion: a dynamic finite element cellular model

Biomechanics and Modeling in Mechanobiology

During the process of tissue formation and regeneration, cells migrate collectively while remaini... more During the process of tissue formation and regeneration, cells migrate collectively while remaining connected through intercellular adhesions. However, the roles of cell-substrate and cell-cell mechanical interactions in regulating collective cell migration are still unclear. In this study, we employ a newly developed finite element cellular model to study collective cell migration by exploring the effects of mechanical feedback between cell and substrate and mechanical signal transmission between adjacent cells. Our viscoelastic model of cells consists many triangular elements and is of high-resolution. Cadherin adhesion between cells are modeled explicitly as linear springs at subcellular level. In addition, we incorporate a mechanochemical feedback loop between cell-substrate mechanics and Rac-mediated cell protrusion. Our model can reproduce a number of experimentally observed patterns of collective cell migration during wound healing, including cell migration persistence, separation distance between cell pairs and migration direction. Moreover, we demonstrate that cell protrusion determined by the cell-substrate mechanics plays important role in guiding persistent and oriented collective cell migration. Furthermore, this guidance cue can be maintained and transmitted to submarginal cells of long distance

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CASTp 3.0: computed atlas of surface topography of proteins

Nucleic acids research, Jan 2, 2018

Geometric and topological properties of protein structures, including surface pockets, interior c... more Geometric and topological properties of protein structures, including surface pockets, interior cavities and cross channels, are of fundamental importance for proteins to carry out their functions. Computed Atlas of Surface Topography of proteins (CASTp) is a web server that provides online services for locating, delineating and measuring these geometric and topological properties of protein structures. It has been widely used since its inception in 2003. In this article, we present the latest version of the web server, CASTp 3.0. CASTp 3.0 continues to provide reliable and comprehensive identifications and quantifications of protein topography. In addition, it now provides: (i) imprints of the negative volumes of pockets, cavities and channels, (ii) topographic features of biological assemblies in the Protein Data Bank, (iii) improved visualization of protein structures and pockets, and (iv) more intuitive structural and annotated information, including information of secondary str...

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Multiscale Modeling of Cellular Epigenetic States: Stochasticity in Molecular Networks, Chromatin Folding in Cell Nuclei, and Tissue Pattern Formation of Cells

Critical reviews in biomedical engineering, 2015

Genome sequences provide the overall genetic blueprint of cells, but cells possessing the same ge... more Genome sequences provide the overall genetic blueprint of cells, but cells possessing the same genome can exhibit diverse phenotypes. There is a multitude of mechanisms controlling cellular epigenetic states and that dictate the behavior of cells. Among these, networks of interacting molecules, often under stochastic control, depending on the specific wirings of molecular components and the physiological conditions, can have a different landscape of cellular states. In addition, chromosome folding in three-dimensional space provides another important control mechanism for selective activation and repression of gene expression. Fully differentiated cells with different properties grow, divide, and interact through mechanical forces and communicate through signal transduction, resulting in the formation of complex tissue patterns. Developing quantitative models to study these multi-scale phenomena and to identify opportunities for improving human health requires development of theoret...

Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκB Signaling and Inflammatory Lung Injury

Scientific Reports, 2015

Although VILI severity is attenuated by reduced NAMPT/PBEF bioavailability, the precise contribut... more Although VILI severity is attenuated by reduced NAMPT/PBEF bioavailability, the precise contribution of NAMPT/PBEF and excessive mechanical stress to VILI pathobiology is unknown. We now report that NAMPT/PBEF induces lung NFκB transcriptional activities and inflammatory injury via direct ligation of Toll-like receptor 4 (TLR4). Computational analysis demonstrated that NAMPT/PBEF and MD-2, a TLR4-binding protein essential for LPS-induced TLR4 activation, share ~30% sequence identity and exhibit striking structural similarity in loop regions critical for MD-2-TLR4 binding. Unlike MD-2, whose TLR4 binding alone is insufficient to initiate TLR4 signaling, NAMPT/PBEF alone produces robust TLR4 activation, likely via a protruding region of NAMPT/PBEF (S402-N412) with structural similarity to LPS. The identification of this unique mode of TLR4 activation by NAMPT/PBEF advances the understanding of innate immunity responses as well as the untoward events associated with mechanical stressinduced lung inflammation.

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Mechanical Model of Geometric Cell and Topological Algorithm for Cell Dynamics from Single-Cell to Formation of Monolayered Tissues with Pattern

PLOS ONE, 2015

Geometric and mechanical properties of individual cells and interactions among neighboring cells ... more Geometric and mechanical properties of individual cells and interactions among neighboring cells are the basis of formation of tissue patterns. Understanding the complex interplay of cells is essential for gaining insight into embryogenesis, tissue development, and other emerging behavior. Here we describe a cell model and an efficient geometric algorithm for studying the dynamic process of tissue formation in 2D (e.g. epithelial tissues). Our approach improves upon previous methods by incorporating properties of individual cells as well as detailed description of the dynamic growth process, with all topological changes accounted for. Cell size, shape, and division plane orientation are modeled realistically. In addition, cell birth, cell growth, cell shrinkage, cell death, cell division, cell collision, and cell rearrangements are now fully accounted for. Different models of cell-cell interactions, such as lateral inhibition during the process of growth, can be studied in detail. Cellular pattern formation for monolayered tissues from arbitrary initial conditions, including that of a single cell, can also be studied in detail. Computational efficiency is achieved through the employment of a special data structure that ensures access to neighboring cells in constant time, without additional space requirement. We have successfully generated tissues consisting of more than 20,000 cells starting from 2 cells within 1 hour. We show that our model can be used to study embryogenesis, tissue fusion, and cell apoptosis. We give detailed study of the classical developmental process of bristle formation on the epidermis of D. melanogaster and the fundamental problem of homeostatic size control in epithelial tissues. Simulation results reveal significant roles of solubility of secreted factors in both the bristle formation and the homeostatic control of tissue size. Our method can be used to study broad problems in monolayered tissue formation. Our software is publicly available.

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Dynamic mechanical finite element model of biological cells for studying cellular pattern formation

Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2013

Understanding the geometric, topologic, and mechanical properties of cells and their interactions... more Understanding the geometric, topologic, and mechanical properties of cells and their interactions is critical for studying tissue pattern formation and organ development. Computational model and tools for simulating cell pattern formation have broad implications in studying embryogenesis, blood-vessel development, tissue regeneration, and tumor growth. Although a number of cell modeling methods exist, they do not simultaneously account for detailed cellular shapes as well as dynamic changes in cell geometry and topology. Here we describe a dynamic finite element cell model (dFEMC) for studying populations of cells and tissue development. By incorporating details of cell shape, cell growth and shrinkage, cell birth and death, cell division and fusion, our method can model realistically a variety problems of cell pattern formation. We give two examples of applying our method to the study of cell fusion and cell apoptosis. The dFEMC model developed here provides a general computational...

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Accuracy of functional surfaces on comparatively modeled protein structures

Journal of Structural and Functional Genomics, 2011

Identification and characterization of protein functional surfaces are important for predicting p... more Identification and characterization of protein functional surfaces are important for predicting protein function, understanding enzyme mechanism, and docking small compounds to proteins. As the rapid speed of accumulation of protein sequence information far exceeds that of structures, constructing accurate models of protein functional surfaces and identify their key elements become increasingly important. A promising approach is to build comparative models from sequences using known structural templates such as those obtained from structural genome projects. Here we assess how well this approach works in modeling binding surfaces. By systematically building three-dimensional comparative models of proteins using Modeller, we determine how well functional surfaces can be accurately reproduced. We use an alpha shape based pocket algorithm to compute all pockets on the modeled structures, and conduct a largescale computation of similarity measurements (pocket RMSD and fraction of functional atoms captured) for 26,590 modeled enzyme protein structures. Overall, we find that when the sequence fragment of the binding surfaces has more than 45% identity to that of the tempalte protein, the modeled surfaces have on average an RMSD of 0.5 Å, and contain 48% or more of the binding surface atoms, with nearly all of the important atoms in the signatures of binding pockets captured.

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Identification of Functional Surfaces of Proteins from Sequences

Biophysical Journal, 2010

It is known that bone and tendon are piezoelectric, and it is believed that the piezoelectric cha... more It is known that bone and tendon are piezoelectric, and it is believed that the piezoelectric charges produced under mechanical deformation in these tissues have a potential role in mechanoelectric transduction leading to their growth and remodeling. With high resolution PFM we probe piezoelectric properties in bone and show that single collagen fibrils are responsible for piezoelectric behavior of bone and behave predominantly as shear piezoelectric materials. Furthermore, we show that there is an intrinsic electromechanical heterogeneity in axial direction of individual fibrils that holds even for the collagen fibrils embedded in bone matrix. Such heterogeneity may have implications in regulating the ionic environment in bone responsible for bone remodeling.

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Improving Accuracy of Functional Surfaces of Protein Structures Modeled From Sequences

Biophysical Journal, 2011

Dynamic cellular finite-element method for modelling large-scale cell migration and proliferation under the control of mechanical and biochemical cues: a study of re-epithelialization

Computational modelling of cells can reveal insight into the mechanisms of the important processe... more Computational modelling of cells can reveal insight into the mechanisms of the important processes of tissue development. However, current cell models have limitations and are challenged to model detailed changes in cellular shapes and physical mechanics when thousands of migrating and interacting cells need to be modelled. Here we describe a novel dynamic cellular finite-element model (DyCelFEM), which accounts for changes in cellular shapes and mechanics. It also models the full range of cell motion, from movements of individual cells to collective cell migrations. The transmission of mechanical forces regulated by intercellular adhesions and their ruptures are also accounted for. Intra-cellular protein signalling networks controlling cell behaviours are embedded in individual cells. We employ DyCelFEM to examine specific effects of biochemical and mechanical cues in regulating cell migration and proliferation, and in controlling tissue pat-terning using a simplified re-epithelialization model of wound tissue. Our results suggest that biochemical cues are better at guiding cell migration with improved directionality and persistence, while mechanical cues are better at coordinating collective cell migration. Overall, DyCelFEM can be used to study developmental processes when a large population of migrating cells under mechanical and biochemical controls experience complex changes in cell shapes and mechanics.

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Zhao Cao Di Pietro Liang2017 Final Interface

Computational modeling of cells can reveal insight into mechanism of important processes of tissu... more Computational modeling of cells can reveal insight into mechanism of important processes of tissue development. However, current cell models have limitations, and are challenged to model detailed changes in cellular shapes and physical mechanics when thousands of migrating and interacting cells need to be modeled. Here we describe a novel dynamic cellular finite element model (dyCelFEM), which accounts for changes in cellular shapes and mechanics. It also models the full range of cell motion, from motilities of individual cells to collective cell migrations. The transmission of mechanical forces regulated by intercellular adhesions and their ruptures are also accounted for. Intra-cellular protein signaling networks controlling cell behaviors are embedded in individual cells. We employ dyCelFEM to examine specific effects of biochemical and mechanical cues in regulating cell migration and proliferation, and in controlling tissue patterning using a simplified re-epithelialization model of wound tissue. Our results suggest that biochemical cues are better at guiding cell migration with improved directionality and persistence, while mechanical cues are better at coordinating collective cell migration. Overall, dyCelFEM can be used to study developmental processes when a large population of migrating cells under mechanical and biochemical controls experience complex changes in cell shapes and mechanics.

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