Biology subjects

Schwarz, J. M.

Publications and source records attributed to Schwarz, J. M..

8 recordsLinked to original sources

bioRxiv2025

Differential Crosslinking and Contractile Motors Drive Nuclear Chromatin Compaction

During interphase, a typical cell nucleus features spatial compartmentalization of transcriptionally active euchromatin and repressed heterochromatin domains. In conventional nuclear organization, euchromatin predominantly occupies the nuclear interior, while heterochromatin, which is approximately 50% more dense than euchromatin, is positioned near the nuclear periphery. Peripheral chromatin organization can be further modulated by the nuclear lamina, which is itself a deformable structure. While a number of biophysical mechanisms for compartmentalization within rigid nuclei have been explored, we study a chromatin model consisting of an active, crosslinked polymer tethered to a deformable, polymeric lamina shell. Contractile motors, the deformability of the shell, and the spatial distribution of crosslinks all play pivotal roles in this compartmentalization. We find that a radial crosslink density distribution, even with a small linear differential of higher crosslinking density at the edge of the nucleus, combined with contractile motor activity, drives genomic segregation, in agreement with experimental observations. This arises from contractile motors preferentially drawing crosslinks into their vicinity at the nuclear periphery, forming high-density domains that promote heterochromatin formation. We also find an increased stiffness of nuclear wrinkles given the preferential heterochromatin compaction below the lamina shell, which is consistent with instantaneous nuclear stiffening under applied nanoindentation. We conclude with the potential for experimental validation of our model predictions.

biophysics↗

bioRxiv2024

Enhanced extracellular matrix remodeling due to embedded spheroid fluidization

Tumor spheroids are in vitro three-dimensional, cellular collectives consisting of cancerous cells. Embedding these spheroids in an in vitro fibrous environment, such as a collagen network, to mimic the extracellular matrix (ECM) provides an essential platform to quantitatively investigate the biophysical mechanisms leading to tumor invasion of the ECM. To understand the mechanical interplay between tumor spheroids and the ECM, we computationally construct and study a three-dimensional vertex model for a tumor spheroid that is mechanically coupled to a cross-linked network of fibers. In such a vertex model, cells are represented as deformable polyhedrons that share faces. Some fraction of the boundary faces of the tumor spheroid contain linker springs connecting the center of the boundary face to the nearest node in the fiber network. As these linker springs actively contract, the fiber network remodels. By toggling between fluid-like and solid-like spheroids via changing the dimensionless cell shape index, we find that the spheroid rheology affects the remodeling of the fiber network. More precisely, fluid-like spheroids displace the fiber network more on average near the vicinity of the spheroid than solid-like spheroids. We also find more densification of the fiber network near the spheroid for the fluid-like spheroids. These spheroid rheology-dependent effects are the result of cellular motility due to active cellular rearrangements that emerge over time in the fluid-like spheroids to generate spheroid shape fluctuations. These shape fluctuations lead to emergent feedback between the spheroid and the fiber network to further remodel the fiber network with, for example, lower radial alignment of the higher-tensioned fibers given the breaking of spheroidal radial symmetry, which can then further remodel the spheroid. Our results uncover intricate morphological-mechanical interplay between an embedded spheroid and its surrounding fiber network with both spheroid contractile strength and spheroid shape fluctuations playing important roles in the pre-invasion stages of tumor invasion.

biophysics↗

bioRxiv2023

How human-derived brain organoids are built differently from brain organoids derived of genetically-close relatives: A multi-scale hypothesis

How genes affect tissue scale organization remains a longstanding biological puzzle. As experimental efforts are underway to solve this puzzle via quantification of gene expression, chromatin organization, cellular structure, and tissue structure, computational modeling efforts remain far behind. To help accelerate the computational modeling efforts, we review two recent publications, the first on a cellular-based model for tissues and the second on a model of a cell nucleus that includes a lamina shell and chromatin. We then address how the two models can be combined to ultimately test multiscale hypotheses linking the chromatin scale and the tissue scale. To be concrete, we turn to an in vitro system for the brain known as a brain organoid. We provide a multiscale hypothesis to distinguish structural differences between brain organoids built from induced-pluripotent human stem cells and from induced-pluripotent gorilla and chimpanzee stem cells. Recent experiments discover that a cell fate transition from neuroepithelial cells to radial glial cells includes a new intermediate state that is delayed in human-derived brain organoids as compared to their genetically-close relatives, which significantly narrows and lengthens the cells on the apical side [1]. Additional experiments revealed that the protein ZEB2 plays a major role in the emergence of this new intermediate state with ZEB2 mRNA levels peaking at the onset of the emergence [1]. We postulate that the enhancement of ZEB2 expression driving this intermediate state is potentially due to chromatin reorganization. More precisely, there exists critical strain triggering the reorganization that is higher for human-derived stem cells, thereby resulting in a delay. Such a hypothesis can readily be tested experimentally within individual cells and within brain organoids as well as computationally to help work towards solving the gene-to-tissue organization puzzle.

developmental biology↗

bioRxiv2023

How cells wrap around virus-like particles using extracellular filamentous protein structures

Nanoparticles, such as viruses, can enter cells via endocytosis. During endocytosis, the cell surface wraps around the nanoparticle to effectively eat it. Prior focus has been on how nanoparticle size and shape impacts endocytosis. However, inspired by the noted presence of extracellular vimentin affecting viral and bacteria uptake, as well as the structure of coronaviruses, we construct a computational model in which both the cell-like construct and the virus-like construct contain filamentous protein structures protruding from their surfaces. We then study the impact of these additional degrees of freedom on viral wrapping. We find that cells with an optimal density of filamentous extracellular components (ECCs) are more likely to be infected as they uptake the virus faster and use relatively less cell surface area per individual virus. At the optimal density, the cell surface folds around the virus, and folds are faster and more efficient at wrapping the virus than crumple-like wrapping. We also find that cell surface bending rigidity helps generate folds, as bending rigidity enhances force transmission across the surface. However, changing other mechanical parameters, such as the stretching stiffness of filamentous ECCs or virus spikes, can drive crumple-like formation of the cell surface. We conclude with the implications of our study on the evolutionary pressures of virus-like particles, with a particular focus on the cellular microenvironment that may include filamentous ECCs.

biophysics↗

bioRxiv2021

Vimentin binds to SARS-CoV-2 spike protein and antibodies targeting extracellular vimentin block in vitro uptake of SARS-CoV-2 virus-like particles

Infection of human cells by pathogens, including SARS-CoV-2, typically proceeds by cell surface binding to a crucial receptor. In the case of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) has been identified as a necessary receptor, but not all ACE2-expressing cells are equally infected, suggesting that other extracellular factors are involved in host cell invasion by SARS-CoV-2. Vimentin is an intermediate filament protein that is increasingly recognized as being present on the extracellular surface of a subset of cell types, where it can bind to and facilitate pathogens cellular uptake. Here, we present evidence that extracellular vimentin might act as a critical component of the SARS-CoV-2 spike protein-ACE2 complex in mediating SARS-CoV-2 cell entry. We demonstrate direct binding between vimentin and SARS-CoV-2 pseudovirus coated with the SARS-CoV-2 spike protein and show that antibodies against vimentin block in vitro SARS-CoV-2 pseudovirus infection of ACE2-expressing cells. Our results suggest new therapeutic strategies for preventing and slowing SARS-CoV-2 infection, focusing on targeting cell host surface vimentin.

biophysics↗

bioRxiv2020

Dynamic nuclear structure emerges from chromatin crosslinks and motors

The cell nucleus houses the chromosomes, which are linked to a soft shell of lamin filaments. Experiments indicate that correlated chromosome dynamics and nuclear shape fluctuations arise from motor activity. To identify the physical mechanisms, we develop a model of an active, crosslinked Rouse chain bound to a polymeric shell. System-sized correlated motions occur but require both motor activity and crosslinks. Contractile motors, in particular, enhance chromosome dynamics by driving anomalous density fluctuations. Nuclear shape fluctuations depend on motor strength, crosslinking, and chromosome-lamina binding. Therefore, complex chromatin dynamics and nuclear shape emerge from a minimal, active chromosome-lamina system.

biophysics↗

bioRxiv2018

Brain folding is initiated by mechanical constraints without a cellular pre-pattern

During human brain development the cerebellum and cerebral cortex fold into robust patterns that increase and compartmentalize neural circuits. Although differential expansion of elastic materials has been proposed to explain brain folding, the cellular and physical processes responsible at the time of folding have not been defined. Here we used the murine cerebellum, with 8-10 folds, as a tractable model to study brain folding. At folding initiation we considered the cerebellum as a bilayer system with a fluidlike outer layer of proliferating precursors and an incompressible core. We discovered that there is no obvious cellular pre-pattern for folding, since when folding initiates, the precursors within the outer layer have uniform sizes, shapes and proliferation, as well as a distribution of glial fibers. Furthermore, although differential expansion is created by the outer layer expanding faster than the core at folding initiation, thickness variations arise in the outer layer that are inconsistent with elastic material models. A multiphase model was applied that includes radial and circumferential tension and mechanical constraints derived from in vivo measurements. Our results demonstrate that cerebellar folding emerges from mechanical forces generated by uniform cell behaviors. We discuss how our findings apply to human cerebral cortex folding.

developmental biology↗

bioRxiv2018

Phenotero: annotate as you write

Controlled vocabularies and ontologies have become a valuable resource for knowledge representation, data integration, and downstream analyses in the biomedical domain. In precision medicine, especially in clinical genetics, the Human Phenotype Ontology (HPO) as well as disease ontologies like the Orphanet Rare Disease Ontology (ORDO) or Medical Subject Headings (MeSH) are often used for deep phenotyping of patients and coding of clinical diagnoses. However, the process of assigning ontology classes (annotating) to patient descriptions is often disconnected from the process of writing patient reports or manuscripts in word processing software such as Microsoft Word or LibreOffice. This additional workload and the requirement to install dedicated software may discourage usage of ontologies for parts of the target audience.\n\nTo improve this situation, we present Phenotero, a freely available and simple solution to annotate patient phenotypes and diseases at the time of writing clinical reports or manuscripts. We adopt Zotero, a well-established, actively developed citation management software to generate a tool which allows to reference classes from ontologies within clinical reports or manuscripts at the time of writing. We expect this approach to decrease the additional workload to a minimum while ensuring high quality associations with ontology classes. Standardised collection of phenotypic information at the time of describing the patient allows for streamlining of clinic workflow, efficient data entry, and will subsequently promote clinical and molecular diagnosis, remove ambiguousness from manuscripts, and allow sharing of anonymised patient phenotype data with ultimate goal of a better understanding of the disease. Thus, we hope that our integrated approach will further promote the usage of ontologies and controlled vocabularies in the clinical setting and in the biomedical domain.

bioinformatics↗