scholarly journals Multi-scale dynamical modelling of T-cell development from an early thymic progenitor state to lineage commitment

2019 ◽  
Author(s):  
Victor Olariu ◽  
Mary A. Yui ◽  
Pawel Krupinski ◽  
Wen Zhou ◽  
Julia Deichmann ◽  
...  
Keyword(s):  
T Cell ◽  
Single Cell ◽  
Single Molecule ◽  
Network Architecture ◽  
Cell Model ◽  
Core Gene ◽  
Scale Model ◽  
Environmental Signals ◽  
Multi Scale ◽  
Clonal Proliferation

AbstractThymic development of committed pro-T-cells from multipotent hematopoietic precursors offers a unique opportunity to dissect the molecular circuitry establishing cell identity in response to environmental signals. This transition encompasses programmed shutoff of stem/progenitor genes, upregulation of T-cell specification genes, extensive proliferation, and commitment after a delay. We have incorporated these factors, as well as new single cell gene expression and developmental kinetics data, into a three-level dynamic model of commitment based upon regulation of the commitment gene Bcl11b. The first level is a core gene regulatory network architecture determined by transcription factor perturbation data, the second a stochastically controlled epigenetic gate, and the third a proliferation model validated by growth and commitment kinetics measured at single-cell levels. Using expression values consistent with single molecule RNA-FISH measurements of key transcription factors, this single-cell model exhibits state switching consistent with measured population and clonal proliferation and commitment times. The resulting multi-scale model provides a powerful mechanistic framework for dissecting commitment dynamics.

scholarly journals Direct observation of frequency modulated transcription in single cells using light activation

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Daniel R Larson ◽  
Christoph Fritzsch ◽  
Liang Sun ◽  
Xiuhau Meng ◽  
David S Lawrence ◽  
...  
Keyword(s):  
Single Cell ◽  
Single Molecule ◽  
Single Cell Analysis ◽  
Cell Model ◽  
Single Cells ◽  
Single Gene ◽  
Gene Activation ◽  
Light Activation ◽  
Dynamic Synthesis ◽  
Single Cell Model

Single-cell analysis has revealed that transcription is dynamic and stochastic, but tools are lacking that can determine the mechanism operating at a single gene. Here we utilize single-molecule observations of RNA in fixed and living cells to develop a single-cell model of steroid-receptor mediated gene activation. We determine that steroids drive mRNA synthesis by frequency modulation of transcription. This digital behavior in single cells gives rise to the well-known analog dose response across the population. To test this model, we developed a light-activation technology to turn on a single steroid-responsive gene and follow dynamic synthesis of RNA from the activated locus.

Volumetric compression develops noise-driven single-cell heterogeneity

2021 ◽  
Vol 118 (51) ◽  
pp. e2110550118
Author(s):  
Xing Zhao ◽  
Jiliang Hu ◽  
Yiwei Li ◽  
Ming Guo
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Single Molecule ◽  
Regulatory Network ◽  
Network Architecture ◽  
Cell Heterogeneity ◽  
Cell Lung Carcinoma ◽  
Homogeneous Population ◽  
Mesenchymal Transition ◽  
Signature Genes

Recent studies have revealed that extensive heterogeneity of biological systems arises through various routes ranging from intracellular chromosome segregation to spatiotemporally varying biochemical stimulations. However, the contribution of physical microenvironments to single-cell heterogeneity remains largely unexplored. Here, we show that a homogeneous population of non–small-cell lung carcinoma develops into heterogeneous subpopulations upon application of a homogeneous physical compression, as shown by single-cell transcriptome profiling. The generated subpopulations stochastically gain the signature genes associated with epithelial–mesenchymal transition (EMT; VIM, CDH1, EPCAM, ZEB1, and ZEB2) and cancer stem cells (MKI67, BIRC5, and KLF4), respectively. Trajectory analysis revealed two bifurcated paths as cells evolving upon the physical compression, along each path the corresponding signature genes (epithelial or mesenchymal) gradually increase. Furthermore, we show that compression increases gene expression noise, which interplays with regulatory network architecture and thus generates differential cell-fate outcomes. The experimental observations of both single-cell sequencing and single-molecule fluorescent in situ hybridization agrees well with our computational modeling of regulatory network in the EMT process. These results demonstrate a paradigm of how mechanical stimulations impact cell-fate determination by altering transcription dynamics; moreover, we show a distinct path that the ecology and evolution of cancer interplay with their physical microenvironments from the view of mechanobiology and systems biology, with insight into the origin of single-cell heterogeneity.

scholarly journals Probing red blood cell mechanics, rheology and dynamics with a two-component multi-scale model

2014 ◽  
Vol 372 (2021) ◽  
pp. 20130389 ◽  
Author(s):  
Xuejin Li ◽  
Zhangli Peng ◽  
Huan Lei ◽  
Ming Dao ◽  
George Em Karniadakis
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Cell Model ◽  
Microfluidic Channel ◽  
Scale Model ◽  
Cross Sectional ◽  
Whole Cell ◽  
Multi Scale ◽  
Rbc Membrane ◽  
Two Component

This study is partially motivated by the validation of a new two-component multi-scale cell model we developed recently that treats the lipid bilayer and the cytoskeleton as two distinct components. Here, the whole cell model is validated and compared against several available experiments that examine red blood cell (RBC) mechanics, rheology and dynamics. First, we investigated RBC deformability in a microfluidic channel with a very small cross-sectional area and quantified the mechanical properties of the RBC membrane. Second, we simulated twisting torque cytometry and compared predicted rheological properties of the RBC membrane with experimental measurements. Finally, we modelled the tank-treading (TT) motion of a RBC in a shear flow and explored the effect of channel width variation on the TT frequency. We also investigated the effects of bilayer–cytoskeletal interactions on these experiments and our simulations clearly indicated that they play key roles in the determination of cell membrane mechanical, rheological and dynamical properties. These simulations serve as validation tests and moreover reveal the capabilities and limitations of the new whole cell model.

scholarly journals Multicellular Models Bridging Intracellular Signaling and Gene Transcription to Population Dynamics

Processes ◽  
2018 ◽  
Vol 6 (11) ◽  
pp. 217 ◽  
Author(s):  
Mohammad Islam ◽  
Satyaki Roy ◽  
Sajal Das ◽  
Dipak Barua
Keyword(s):  
Single Cell ◽  
Gene Transcription ◽  
Intracellular Signaling ◽  
Message Passing Interface ◽  
Cell Model ◽  
Parallel Process ◽  
Biochemical Network ◽  
Scale Model ◽  
Bacterial Cells ◽  
Growth Environment

Cell signaling and gene transcription occur at faster time scales compared to cellular death, division, and evolution. Bridging these multiscale events in a model is computationally challenging. We introduce a framework for the systematic development of multiscale cell population models. Using message passing interface (MPI) parallelism, the framework creates a population model from a single-cell biochemical network model. It launches parallel simulations on a single-cell model and treats each stand-alone parallel process as a cell object. MPI mediates cell-to-cell and cell-to-environment communications in a server-client fashion. In the framework, model-specific higher level rules link the intracellular molecular events to cellular functions, such as death, division, or phenotype change. Cell death is implemented by terminating a parallel process, while cell division is carried out by creating a new process (daughter cell) from an existing one (mother cell). We first demonstrate these capabilities by creating two simple example models. In one model, we consider a relatively simple scenario where cells can evolve independently. In the other model, we consider interdependency among the cells, where cellular communication determines their collective behavior and evolution under a temporally evolving growth condition. We then demonstrate the framework’s capability by simulating a full-scale model of bacterial quorum sensing, where the dynamics of a population of bacterial cells is dictated by the intercellular communications in a time-evolving growth environment.

scholarly journals Arrhythmia Mechanisms and Spontaneous Calcium Release: I - Multi-scale Modelling Approaches

2018 ◽  
Author(s):  
Michael A. Colman
Keyword(s):  
Single Cell ◽  
Calcium Release ◽  
Cell Model ◽  
Single Cells ◽  
Computational Modelling ◽  
Calcium Handling ◽  
Spontaneous Release ◽  
Multi Scale ◽  
Cellular Models ◽  
Tissue Models

AbstractMotivationSpontaneous sub-cellular calcium release events (SCRE), controlled by microscopic stochastic fluctuations of the proteins responsible for intracellular calcium release, are conjectured to promote the initiation and perpetuation of rapid arrhythmia associated with conditions such as heart failure and atrial fibrillation: SCRE may underlie the emergence of spontaneous excitation in single cells, resulting in arrhythmic triggers in tissue. However, translation of single-cell data to the tissue scale is non-trivial due to complex substrate considerations. Computational modelling provides a viable approach to dissect these multi-scale mechanisms, yet there remains a significant challenge in accurately and efficiently modelling this probabilistic behaviour in large-scale tissue models. The aim of this study was to develop an approach to overcome this challenge.MethodsThe dynamics of SCRE under multiple conditions (pacing rate, beta-stimulation, disease remodelling) in a computational model of stochastic, spatio-temporal calcium handling were analysed in order to develop Spontaneous Release Functions, which capture the variability and properties of SCRE matched to the full cell model. These functions were then integrated with tissue models, comprising idealised 2D sheets as well as full reconstructions of ventricular and atrial anatomy.ResultsThe Spontaneous Release Functions accurately reproduced the dynamics of SCRE and its dependence on environment variables under multiple different conditions observed in the full single-cell model. Differences between cellular models and conditions where enhanced at the tissue scale, where the emergence of a focal excitation is largely an all-or-nothing response. Generalisation of the approaches was demonstrated through integration with an independent cell model, and parameterisation to an experimental dataset.ConclusionsA novel approach has been developed to dynamically model SCRE at the tissue scale, in-line with behaviour observed in detailed single-cell models. Such an approach allows evaluation of the potential importance of SCRE in arrhythmia in both general mechanistic and disease-specific investigation.

Assessing tensile behavior of open-hole variable angle tow composites using a general gradient property simulation methodology

2020 ◽  
Vol 39 (19-20) ◽  
pp. 742-757
Author(s):  
Yingdan Zhu ◽  
Shijie Qi ◽  
Hongli Jia ◽  
Pengcheng Shi ◽  
Youqiang Yao ◽  
...  
Keyword(s):  
Tensile Strength ◽  
Failure Modes ◽  
Cell Model ◽  
Failure Process ◽  
Tensile Behavior ◽  
Scale Model ◽  
Multi Scale ◽  
Variable Angle ◽  
Open Hole ◽  
Curvilinear Fibers

Variable Angle Tow placement is a way to steer individual curvilinear fibers. This work presents the assessment of tensile behavior of open-hole composite laminates with Variable Angle Tow reinforcement. A new multi-scale finite element method, consisting of a microscale unit cell model and a macroscale gradient property model, is developed to simulate Variable Angle Tow structures with various fiber trajectories. The tensile strength and the failure process of open-hole reinforced laminates with Variable Angle Tow reinforcement under tensile loading are predicted and analyzed. Experiments are also conducted to investigate reinforcing efficiency and failure modes of the open-hole laminates. The comparison of predicted and experimental results for the tensile strength and failure modes of T700/Epoxy laminates demonstrates clearly that the mechanical behavior of Variable Angle Tow structure can be simulated very well by the proposed multi-scale model. Moreover, it is found that the tensile strength of Variable Angle Tow laminates is closely related to the eccentricity and it reaches the maximum value only when the trajectories of curvilinear fibers keeps consistent with maximum principal stress trajectories of the open-hole plate.

scholarly journals Robust coordination of collective oscillatory signaling requires single-cell excitability and fold-change detection

2021 ◽  
Author(s):  
Chuqiao Huyan ◽  
Alexander Golden ◽  
Xinwen Zhu ◽  
Pankaj Mehta ◽  
Allyson E. Sgro
Keyword(s):  
Single Cell ◽  
Network Architecture ◽  
Single Cells ◽  
Full Range ◽  
Network Models ◽  
Fold Change ◽  
Relay Network ◽  
Recent Experimental Data ◽  
Cell Dynamics ◽  
Environmental Signals

Complex multicellular behaviors are coordinated at the level of biochemical signaling networks, yet how this decentralized control mechanism enables robust coordination in variable environments and over many orders of magnitude of spatiotemporal scales remains an open question. A stunning example of these behaviors is found in the microbe Dictyostelium discoideum, which uses the small molecule cyclic AMP (cAMP) to drive the propagation of collective signaling oscillations and spatial waves leading to multicellular development. The critical design features of the Dictyostelium signaling network remain unclear despite decades of mathematical modeling and experimental research because the mathematical models make different assumptions about the network architecture. To resolve this discrepancy, we use recent experimental data to normalize the time and response scales of five major signal relay network models to one another and assess their ability to recapitulate experimentally-observed population and single-cell dynamics. We find that to successfully reproduce the full range of observed behaviors, single cells must be excitable and respond to the relative fold-change of environmental signals, suggesting that these features represent robust principles for controlling cellular populations and that single-cell excitable dynamics are a generalizable route for controlling population behaviors.

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