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#cell

66 posts10 participants11 posts today
Public
Rxiv mechanobio

📰 "Protein diffusion controls how single cells respond to electric fields"
biorxiv.org/content/10.1101/20 #Dynamics #Cell

bioRxiv · Protein diffusion controls how single cells respond to electric fieldsCells sense and respond to electric fields, using these fields as a guidance cue in wound healing and development. This sensing is done by redistribution of charged membrane proteins on the cell's surface ("sensors") via electrophoresis and electroosmotic flow. If membrane proteins have to physically rearrange on the cell's surface, how quickly can a cell respond to an applied signal? What limits the cell's ability to respond? Are galvanotaxing cells, like chemotaxing cells, limited by stochasticity from the finite number of molecules? Here, we develop a model for the response dynamics of galvanotaxing cells and show that, for weak enough field strengths, two relevant timescales emerge: the time for the cell's sensors to rearrange, which depends on their diffusion across the cell, and the time for the cell's orientation to respond to an applied field, which may be very different. We fit this model to experimental measurements on the recently-identified sensor galvanin (TMEM154) in neutrophil-like HL-60 cells, finding that given the dynamics of a cell responding to an applied field, we can predict the dynamics of the cell after the field is turned off. This fit constrains the noise of the galvanotaxis process, demonstrating that HL-60 is not limited by the stochasticity of finite sensor number. Our model also allows us to explain the effect of media viscosity on cell dynamics, and predict how cells respond to pulsed DC fields. These results place constraints on the ability to guide cells with pulsed fields, predicting that a field on half of the time is no better than a field that is always on with half the magnitude. ### Competing Interest Statement The authors have declared no competing interest.
Public
Rxiv mechanobio

📰 "Whole-cell particle-based digital twin simulations from 4D lattice light-sheet microscopy data"
biorxiv.org/content/10.1101/20 #Dynamics #Cell

bioRxiv · Whole-cell particle-based digital twin simulations from 4D lattice light-sheet microscopy dataWe present a framework for performing whole-cell digital twin simulations which integrates 4D (x,y,z,t) lattice light-sheet microscopy (LLSM) data with particle-based reaction-diffusion modeling to capture intracellular organelle dynamics. Using imaging data from Cal27 cells, we construct digital twins that incorporate mitochondrial networks, microtubule networks, dynein and kinesin motors, the plasma membrane, and the nucleus. Passive diffusive mitochondrial dynamics are parameterized using stochastic reaction-diffusion simulations in ReaDDy, while active transport is modeled explicitly by incorporating motor-driven transport along a diffusing, polarized microtubule network. Our simulations accurately reproduce experimentally observed mitochondrial dynamics across pharmacological microtubule depolymerization conditions and reproduce the mitochondrial response to intermediate perturbations without explicit re-parameterization. This novel meso-scale digital twin framework offers a bridge between atomic-scale whole-cell simulations and experimental time and length scales. ### Competing Interest Statement The authors have declared no competing interest.
Public
Rxiv mechanobio

📰 "Phloem-Specific Translational Regulation of Soybean Nodulation: Insights from a Phloem-Targeted TRAP-Seq Approach"
biorxiv.org/content/10.1101/20 #Dynamics #Cell

bioRxiv · Phloem-Specific Translational Regulation of Soybean Nodulation: Insights from a Phloem-Targeted TRAP-Seq ApproachSoybean (Glycine max) root nodulation is a symbiotic process that requires complex molecular and cellular coordination. The phloem plays a crucial role not only in nutrient transport but also in long-distance signaling that regulates nodulation. However, the molecular mechanisms underlying phloem-specific regulation during nodulation remain poorly characterized. Here, we developed a phloem-specific Translating Ribosome Affinity Purification sequencing (TRAP-seq) system to investigate the translational dynamics of phloem-associated genes during nodulation. Using a phloem-specific promoter (Glyma.01G040700) combined with the GAL4-UAS amplification system, we successfully captured the translatome of soybean root phloem at early (72 hours post-inoculation, hpi) and late (21 days post-inoculation, dpi) nodulation stages. Differential expression analysis revealed dynamic translational reprogramming, with 2,636 differentially expressed genes (DEGs) at 72 hpi and 8,422 DEGs at 21 dpi. Gene ontology and pathway enrichment analyses showed stage-specific regulatory shifts, including early activation of ethylene and defense pathways and late-stage enhancement of nutrient transport and vascular development. Transcription factor analysis identified GmbHLH121 as a key phloem-specific regulator of nodulation. Functional validation using RNAi knockdown and overexpression experiments demonstrated that GmbHLH121 negatively regulates nodule formation, likely acting downstream of or independently from early nodulation signaling pathways. Additionally, we uncovered dynamic regulation of cell wall-modifying enzymes (PME and PMEI) in the phloem, implicating their role in modulating plasmodesmata permeability and facilitating symplastic connectivity during nodulation. Our findings highlight the critical role of phloem-mediated translational regulation in coordinating root nodulation, emphasizing the phloem as an active regulatory hub for long-distance signaling and symbiotic efficiency. ### Competing Interest Statement The authors have declared no competing interest.
Public
Rxiv mechanobio

📰 "Characterization of a Novel FKS1 Mutation in Candida lusitaniae Shows a Potential Critical Role for MKC1 in Echinocandin Resistance"
biorxiv.org/content/10.1101/20 #Force #Cell

bioRxiv · Characterization of a Novel FKS1 Mutation in Candida lusitaniae Shows a Potential Critical Role for MKC1 in Echinocandin ResistanceCaspofungin is an echinocandin antifungal that inhibits glucan synthesis in the fungal cell wall. A Candida parapsilosis bloodstream isolate resistant to echinocandins was recovered from a patient who had undergone allogeneic hematopoietic stem cell transplantation. The FKS1 gene, encoding the target glucan synthase, contained a heterozygous mutation resulting in an I1380T amino acid change, in addition to the naturally occurring P660A polymorphism. When expressed at the equivalent position in the Fks1p protein of C. lusitaniae, P642A and I1359T, alone and in combination, led to 6-, 12-, and ≥256-fold increases in the minimal inhibitory concentration (MIC) of caspofungin, respectively. The caspofungin concentration needed to inhibit 50% of glucan synthase activity was increased 3-, 37-, and 270-fold, respectively. At high drug concentrations, and also in drug-free medium, infrared spectroscopy revealed a decrease in β-glucan content and an increase in chitin in the cell wall of the I1359T Fks1p mutants. Atomic force microscopy showed cell wall damage and cell swelling in both susceptible and resistant strains under caspofungin exposure. Analysis of susceptibility to cell-wall stressors and key factors in cell wall integrity (CWI) and high-osmolarity glycerol (HOG) pathways showed that all strains activated these pathways under caspofungin stress. In the I1359T Fks1p mutants, Mkc1p was constitutively activated even without caspofungin. Deletion of MKC1 restored caspofungin susceptibility, indicating that activation of the CWI pathway is a key molecular determinant of resistance in vitro to caspofungin in these mutants.
Public
Rxiv mechanobio

📰 "Mechanical properties of adherent cell sheets analyzed by deflection of supporting membrane"
biorxiv.org/content/10.1101/20 #Mechanical #Cell

bioRxiv · Mechanical properties of adherent cell sheets analyzed by deflection of supporting membraneMulticellular structures, including cell sheets, are actively used as model systems to study intercellular interactions and can be applied in different areas of regenerative medicine. In this paper, we present a novel approach for measuring mechanical properties of cell sheets based on a simple experimental setup and numerical simulations. The advantage of the present approach is the relative ease of the sample preparation, while previous systems for the tensile tests required specialized and sensitive equipment. With the developed approach, the cell sheet on a polymer membrane is mounted in the holder on one side, and then deflection of the free end of the membrane is measured. The deflection of this cantilever-like construction depends on the elastic modulus of the membrane (which is known) and cell sheet, and also from the traction force generated by the cell sheet. By involving an experimental step with relaxing the traction force and by conducting finite element simulations, both traction force and elastic properties of the cell sheet can be estimated. We performed such measurements on cell sheets from keratocytes from corneal explants and confirmed that the developed approach is applicable for measurement of both traction force and elastic modulus of cell sheets. ### Competing Interest Statement The authors have declared no competing interest.
Public
Rxiv mechanobio

📰 "Reducing phenotype-structured PDE models of cancer evolution to systems of ODEs: a generalised moment dynamics approach"
arxiv.org/abs/2406.01505 #Dynamics #Q-Bio.Pe #Cell

arXiv logo
arXiv.orgReducing phenotype-structured PDE models of cancer evolution to systems of ODEs: a generalised moment dynamics approachIntratumour phenotypic heterogeneity is nowadays understood to play a critical role in disease progression and treatment failure. Accordingly, there has been increasing interest in the development of mathematical models capable of capturing its role in cancer cell adaptation. This can be systematically achieved by means of models comprising phenotype-structured nonlocal partial differential equations, tracking the evolution of the phenotypic density distribution of the cell population, which may be compared to gene and protein expression distributions obtained experimentally. Nevertheless, given the high analytical and computational cost of solving these models, much is to be gained from reducing them to systems of ordinary differential equations for the moments of the distribution. We propose a generalised method of model-reduction, relying on the use of a moment generating function, Taylor series expansion and truncation closure, to reduce a nonlocal reaction-advection-diffusion equation, with general phenotypic drift and proliferation rate functions, to a system of moment equations up to arbitrary order. Our method extends previous results in the literature, which we address via two examples, by removing any \textit{a priori} assumption on the shape of the distribution, and provides a flexible framework for mathematical modellers to account for the role of phenotypic heterogeneity in cancer adaptive dynamics, in a simpler mathematical framework.
Public
Rxiv mechanobio

📰 "Retinotopic Mechanics derived using classical physics"
arxiv.org/abs/2109.11632 #Physics.Bio-Ph #Mechanics #Q-Bio.Nc #Dynamics #Cell

arXiv logo
arXiv.orgRetinotopic Mechanics derived using classical physicsThe concept of a cell$'$s receptive field is a bedrock in systems neuroscience, and the classical static description of the receptive field has had enormous success in explaining the fundamental mechanisms underlying visual processing. Borne out by the spatio-temporal dynamics of visual sensitivity to probe stimuli in primates, I build on top of this static account with the introduction of a new computational field of research, retinotopic mechanics. At its core, retinotopic mechanics assumes that during active sensing receptive fields are not static but can shift beyond their classical extent. Specifically, the canonical computations and the neural architecture that supports these computations are inherently mediated by a neurobiologically inspired force field (e.g.,$R_s\propto \sim 1 /ΔM$). For example, when the retina is displaced because of a saccadic eye movement from one point in space to another, cells across retinotopic brain areas are tasked with discounting the retinal disruptions such active surveillance inherently introduces. This neural phenomenon is known as spatial constancy. Using retinotopic mechanics, I propose that to achieve spatial constancy or any active visually mediated task, retinotopic cells, namely their receptive fields, are constrained by eccentricity dependent elastic fields. I propose that elastic fields are self-generated by the visual system and allow receptive fields the ability to predictively shift beyond their classical extent to future post-saccadic location such that neural sensitivity which would otherwise support intermediate eccentric locations likely to contain retinal disruptions is transiently blunted.
Public
Rxiv mechanobio

📰 "Predicting Treatment Outcomes from Adaptive Therapy -- A New Mathematical Biomarker"
biorxiv.org/content/10.1101/20 #Dynamics #Cell

bioRxiv · Predicting Treatment Outcomes from Adaptive Therapy — A New Mathematical BiomarkerStandard-of-care cancer therapy regimens are characterized by continuous treatment at the maximum tolerated dose; however, this approach often fails on metastatic cancers due to the emergence of drug resistance. An evolution-based treatment paradigm known as 'Adaptive Therapy' has been proposed to counter this, dynamically adjusting treatment to control, rather than minimize, the tumor burden, thus suppressing the growth of treatment-resistant cell populations and hence delaying patient relapse. Promising clinical results in prostate cancer indicate the potential of adaptive treatment protocols, but demonstrate broad heterogeneity in patient response. This naturally leads to the question: why does this heterogeneity occur, and is a 'one-size-fits-all' protocol best for patients across this spectrum of responses? Using a Lotka – Volterra representation of drug-sensitive and -resistant tumor populations' dynamics, we obtain a predictive expression for the expected benefit from Adaptive Therapy and propose two new mathematical biomarkers (the Delta AT Score and the eTTP) that can identify the best responders in a clinical dataset after the first cycle of treatment. Based on prior theoretical analyses, we derive personalized and clinically-feasible optimal treatment strategies, based on individual patient's tumor dynamics. These strategies vary significantly between patients, and so we present a framework to generate individual treatment schedules based on a patient's response to the first treatment cycle. Finally, we develop metrics to identify which patients have the greatest sensitivity to unplanned schedule changes, such as delayed appointments, allowing clinicians to identify high-risk patients that need to be monitored more closely and potentially more frequently. Overall, the proposed strategies offer personalized treatment schedules that consistently outperform clinical standard-of-care protocols. ### Competing Interest Statement The authors have declared no competing interest.
Public
Rxiv mechanobio

📰 "Investigation of the global translational response to oxidative stress in the model archaeon Haloferax volcanii reveals untranslated small RNAs with ribosome occupancy"
biorxiv.org/content/10.1101/20 #Dynamics #Cell

bioRxiv · Investigation of the global translational response to oxidative stress in the model archaeon Haloferax volcanii reveals untranslated small RNAs with ribosome occupancyOxidative stress induces a wide range of cellular damage, often causing disease and cell death. While many organisms are susceptible to the effects of oxidative stress, haloarchaea have adapted to be highly resistant. Several aspects of the haloarchaeal oxidative stress response have been characterized, however little is known about the impacts of oxidative stress at the translation level. Using the model archaeon Haloferax volcanii , we performed RNA-seq and ribosome profiling (Ribo-seq) to characterize the global translation landscape during oxidative stress. We identified 281 genes with differential translation efficiency (TE). Downregulated genes were enriched in ribosomal and translation proteins, in addition to peroxidases and genes involved in the TCA cycle. We also observed upregulated TE for several transporters and membrane-bound proteases, highlighting the importance of membrane dynamics during oxidative stress. We additionally identified 42 small noncoding RNAs (sRNAs) with ribosome occupancy. Size distributions of ribosome footprints revealed distinct patterns for coding and noncoding genes, with 12 sRNAs matching the pattern of coding genes, and mass spectrometry confirming the presence of seven small proteins originating from these sRNAs. However, the majority of sRNAs with ribosome occupancy had no evidence of coding potential. Of these ribosome-associated sRNAs, 12 had differential ribosome occupancy or TE during oxidative stress, suggesting that they may play a regulatory role during the oxidative stress response. In combination with the evidence of regulation at the translation level during oxidative stress, this demonstrates the complexity of gene regulation in response to stress.
Public
Rxiv mechanobio

📰 "A local composition of peptidoglycan drives the division site selection by MapZ in Streptococcus pneumoniae"
biorxiv.org/content/10.1101/20 #CellDivision #Cell

bioRxiv · A local composition of peptidoglycan drives the division site selection by MapZ in Streptococcus pneumoniaeAccurate division site placement is essential for bacterial cells to produce viable daughter cells with proper size and appropriate functional features. In the opportunistic pathogen bacterium Streptococcus pneumoniae, the positioning of the division site has been shown to depend on both the protein MapZ and chromosome segregation. However, the nature of this interplay and the molecular determinants guiding division site localization remained unclear. Here we demonstrated that the division site is positioned at the cell equator, the widest part of the cell body, rather than at mid-cell. In addition, we observed that the localization of MapZ and/or the divisome remain unaffected even in the absence of properly segregated DNA, indicating that chromosome segregation does not contribute to division site selection. Our findings further reveal that MapZ localization depends on the activities of two PG hydrolases DacA and DacB, whose sequential recruitment to the division site during early PG synthesis drives the formation of a distinctive PG signature required for MapZ binding. These results support a model in which MapZ identifies the division site by recognizing a specific PG composition produced only during the early stages of cell division. This PG composition becomes enriched at the cell equators which will eventually serve as the division site of the daughter cells. ### Competing Interest Statement The authors have declared no competing interest.
Public
Rxiv mechanobio

📰 "Infinite Boundary Terms and Pairwise Interactions: A Unified Framework for Periodic Coulomb Systems"
arxiv.org/abs/2504.06023 #Physics.Plasm-Ph #Physics.Chem-Ph #Physics.Comp-Ph #Pressure #Cell

arXiv logo
arXiv.orgInfinite Boundary Terms and Pairwise Interactions: A Unified Framework for Periodic Coulomb SystemsThe introduction of the infinite boundary terms and the pairwise interactions [J. Chem. Theory Comput., 10, 5254, (2014)] enables a physically intuitive approach for deriving electrostatic energy and pressure for both neutral and non-neutral systems under the periodic boundary condition. For a periodic system consisting of $N$ point charges (with charge $q_j$ located at ${\mathbf r}_j$ where $j=1,2,\cdots N$) and one charge distribution of density $ρ({\mathbf r})$ within a primary cell of volume $V$, the derived electrostatic energy can be expressed as, \[ {\mathcal U} = \sum_{i<j}^N q_iq_jν({\mathbf r}_{ij} ) + \sum_{j=1}^N q_j \int_V d{\mathbf r}_0\,ρ({\mathbf r}_0) ν({\mathbf r}_{0j} ) + \frac{1}{2}\int_V d{\mathbf r}_0 \int_V d{\mathbf r}_1\,ρ({\mathbf r}_0)ρ({\mathbf r}_1) ν({\mathbf r}_{01}), \] where ${\mathbf r}_{ij}={\mathbf r}_i - {\mathbf r}_j$ is the relative vector and $ν({\mathbf r})$ represents the effective pairwise interaction. The charge density $ρ({\mathbf r})$ is free of Delta-function-like divergence throughout the volume but may exhibit discontinuity. This unified formulation directly follows that of the isolated system by replacing the Coulomb interaction $1/\lvert {\mathbf r} \rvert$ or other modified Coulomb interactions with $ν({\mathbf r})$. For a particular system of one-component plasma with a uniform neutralizing background, the implementation of various pairwise formulations clarifies the contribution of the background and subsequently reveals criteria for arbitrary volume-dependent potentials that preserve the simple relation between energy and pressure.
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