Biology subjects

Garikipati, K.

Publications and source records attributed to Garikipati, K..

7 recordsLinked to original sources

bioRxiv2023

Patterning and folding of intestinal villi by active mesenchymal dewetting

Tissue folding generates structural motifs critical to organ function. In the intestine, bending of a flat epithelium into a periodic pattern of folds gives rise to villi, the numerous finger-like protrusions that are essential for nutrient absorption. However, the molecular and mechanical mechanisms driving the initiation and morphogenesis of villi remain a matter of debate. Here, we identify an active mechanical mechanism that simultaneously patterns and folds intestinal villi. We find that PDGFRA+ subepithelial mesenchymal cells generate myosin II-dependent forces sufficient to produce patterned curvature in neighboring tissue interfaces. At the cell-level, this occurs through a process dependent upon matrix metalloproteinase-mediated tissue fluidization and altered cell-ECM adhesion. By combining computational models with in vivo experiments, we reveal these cellular features manifest at the tissue-level as differences in interfacial tensions that promote mesenchymal aggregation and interface bending through a process analogous to the active de-wetting of a thin liquid film.

developmental biology↗

bioRxiv2022

Cell-to-cell variability of dynamic CXCL12-CXCR4 signaling and morphological processes in chemotaxis

Chemotaxis drives critical processes in cancer metastasis. While commonly studied at the population scale, metastasis arises from small numbers of cells that successfully disseminate, underscoring the need to analyze chemotaxis at single-cell resolution. Here we focus on chemotaxis driven by the CXCL12-CXCR4 pathway, a signaling network that promotes metastasis in more than 20 different human cancers. CXCL12-CXCR4 activates ERK and Akt, kinases known to promote chemotaxis, but how cells couple signaling to chemotaxis remain poorly defined. To address this challenge, we implemented single-cell analysis of MDA-MB-231 breast cancer cells migrating in a chemotaxis device towards chemokine CXCL12. We integrated live, single-cell imaging with advanced computational analysis methods to discover processes defining subsets of cells that move efficiently toward a CXCL12 gradient. We identified dynamic oscillations in ERK and Akt signaling and associated morphological transitions as key determinants of successful chemotaxis. Cells with effective chemotaxis toward CXCL12 exhibit faster and more persistent movement than non-migrating cells, but both cell populations show similar random motion. Migrating cells exhibit higher amplitude fluctuations in ERK and Akt signaling and greater frequencies of generating lateral cell membrane protrusions. Interestingly, computational analysis reveals less correlated network coupling of signaling and morphological changes in migrating cells. These data reveal processing events that enable cells to convert a signaling input to chemotaxis and highlight how cells in a uniform environment produce heterogeneous responses.

cancer biology↗

bioRxiv2021

Biomembranes undergo complex, non-axisymmetric deformations governed by Kirchhoff-Love kinematics and revealed by a three dimensional computational framework

Biomembranes play a central role in various phenomena like locomotion of cells, cell-cell interactions, packaging and transport of nutrients, transmission of nerve impulses, and in maintaining organelle morphology and functionality. During these processes, the membranes undergo significant morphological changes through deformation, scission, and fusion. Modeling the underlying mechanics of such morphological changes has traditionally relied on reduced order axisymmetric representations of membrane geometry and deformation. Axisymmetric representations, while robust and extensively deployed, suffer from their inability to model symmetry breaking deformations and structural bifurcations. To address this limitation, a three-dimensional computational mechanics framework for high fidelity modeling of biomembrane deformation is presented. The proposed framework brings together Kirchhoff-Love thin-shell kinematics, Helfrich-energy based mechanics, and state-of-the-art numerical techniques for modeling deformation of surface geometries. Lipid bilayers are represented as spline-based surface discretizations immersed in a three-dimensional space; this enables modeling of a wide spectrum of membrane geometries, boundary conditions, and deformations that are physically admissible in a 3D space. The mathematical basis of the framework and its numerical machinery are presented, and their utility is demonstrated by modeling three classical, yet non-trivial, membrane deformation problems: formation of tubular shapes and their lateral constriction, Piezo1-induced membrane footprint generation and gating response, and the budding of membranes by protein coats during endocytosis. For each problem, the full three dimensional membrane deformation is captured, potential symmetry-breaking deformation paths identified, and various case studies of boundary and load conditions are presented. Using the endocytic vesicle budding as a case study, we also present a "phase diagram" for its symmetric and broken-symmetry states.

biophysics↗

bioRxiv2020

CRIMSON: An Open-Source Software Framework for Cardiovascular Integrated Modelling and Simulation

In this work, we describe the CRIMSON (CardiovasculaR Integrated Modelling and SimulatiON) software environment. CRIMSON provides a powerful, customizable and user-friendly system for performing three-dimensional and reduced-order computational haemodynamics studies via a pipeline which involves: 1) segmenting vascular structures from medical images; 2) constructing analytic arterial and venous geometric models; 3) performing finite element mesh generation; 4) designing, and 5) applying boundary conditions; 6) running incompressible Navier-Stokes simulations of blood flow with fluid-structure interaction capabilities; and 7) post-processing and visualizing the results, including velocity, pressure and wall shear stress fields. A key aim of CRIMSON is to create a software environment that makes powerful computational haemodynamics tools accessible to a wide audience, including clinicians and students, both within our research laboratories and throughout the community. The overall philosophy is to leverage best-in-class open source standards for medical image processing, parallel flow computation, geometric solid modelling, data assimilation, and mesh generation. It is actively used by researchers in Europe, North and South America, Asia, and Australia. It has been applied to numerous clinical problems; we illustrate applications of CRIMSON to real-world problems using examples ranging from pre-operative surgical planning to medical device design optimization. CRIMSON binaries for Microsoft Windows 10, documentation and example input files are freely available for download from www.crimson.software, and the source code with compilation instructions is available on GitHub https://github.com/carthurs/CRIMSONFlowsolver (CRIMSON Flowsolver) under the GPL v3.0 license, and https://github.com/carthurs/CRIMSONGUI (CRIMSON GUI), under the AGPL v3.0 license. Support is available on the CRIMSON Google Groups forum, located at https://groups.google.com/forum/#!forum/crimson-users.

bioengineering↗

bioRxiv2020

Discovery of deformation mechanisms and constitutive response of soft material surrogates of biological tissue by full-field characterization and data-driven variational system identification

We present a novel, fully three-dimensional approach to soft material characterization and constitutive modeling with relevance to soft biological tissue. Our approach leverages recent advances in experimental techniques and data-driven computation. The experimental component of this approach involves in situ mechanical loading in a magnetic field (using MRI), yielding the entire deformation tensor field throughout the specimen regardless of the possible irregularities in its three-dimensional shape. Characterization can therefore be accomplished with data at a reduced number of deformation states. We refer to this experimental technique as MR-u. Its combination with powerful approaches to inverse modelling, specifically methods of model inference, would open the door to insightful mechanical characterization for soft materials. In recent computational advances that answer this need, we have developed new, data-driven inverse techniques to infer the model that best explains the physics governing observed phenomena from a spectrum of admissible ones, while maintaining parsimony of representation. This approach is referred to as Variational System Identification (VSI). In this communication, we apply the MR-u approach to characterize soft polymers regarding them as surrogates of soft biological tissue, and using VSI, we infer the physically best-suited and parsimonious mathematical models of their mechanical response. We demonstrate the performance of our methods in the face of noisy data with physical constraints that challenge the identification of mathematical models, while attaining high accuracy in the predicted response of the inferred models.

biophysics↗

bioRxiv2020

An inverse modelling study on the local volume changes during early growth of the fetal human brain

We take a data-driven approach to deducing the local volume changes accompanying early development of the fetal human brain. Our approach uses fetal brain atlas MRI data for the geometric changes in representative cases. Using a nonlinear continuum mechanics model of morphoelastic growth, we invert the deformation obtained from MRI registration to arrive at a field for the growth deformation gradient tensor. Our field inversion uses a combination of direct and adjoint methods for computing gradients of the objective function while constraining the optimization by the physics of morphoelastic growth. We thus infer a growth deformation gradient field that obeys the laws of morphoelastic growth. The errors between the MRI data and the forward displacement solution driven by the inverted growth deformation gradient field are found to be smaller than the reference displacement by well over an order of magnitude, and can be driven even lower. The results thus reproduce the three-dimensional growth during the early development of the fetal brain with controllable error. Our findings confirm that early growth is dominated by in plane cortical expansion rather than thickness increase.

developmental biology↗

bioRxiv2019

A mechanical model reveals that non-axisymmetric buckling lowers the energy barrier associated with membrane neck constriction

Membrane neck formation is essential for scission, which, as recent experiments on tubules have demonstrated, can be location dependent. The diversity of biological machinery that can constrict a neck such as dynamin, actin, ESCRTs and BAR proteins, and the range of forces and deflection over which they operate, suggest that the constriction process is functionally mechanical and robust to changes in biological environment. In this study, we used a mechanical model of the lipid bilayer to systematically investigate the influence of location, symmetry constraints, and helical forces on membrane neck constriction. Simulations from our model demonstrated that the energy barriers associated with constriction of a membrane neck are location-dependent. Importantly, if symmetry restrictions are relaxed, then the energy barrier for constriction is dramatically lowered and the membrane buckles at lower values of forcing parameters. Our simulations also show that constriction due to helical proteins further reduces the energy barrier for neck formation compared to cylindrical proteins. These studies establish that despite different molecular mechanisms of neck formation in cells, the mechanics of constriction naturally leads to a loss of symmetry that can lower the energy barrier to constriction. Significance statementMembrane tubule constriction is a critical step of cellular membrane trafficking processes and is thought to be mechanically regulated. Mechanical modeling techniques employing the Helfrich Hamiltonian and axisymmetric continuum frameworks have previously described energy barriers to constriction as a function of location along a 26 membrane tubule. Recent advances in numerical modeling using spline basis functions (Isogeometric Analysis) enable us to conduct our analyses of membrane mechanics in a generalized 3D framework. Here, we implement a novel 3D Isogeometric Analysis framework and juxtapose it against an axisymmetric model to study the influence of location, symmetry constraints and helical collars on the constriction pathway. We show that an unsymmetric, "crushed soda can" neck consistently displays a lower energy barrier than a symmetric neck.

biophysics↗