Biology subjects

Cytrynbaum, E. N.

Publications and source records attributed to Cytrynbaum, E. N..

7 recordsLinked to original sources

bioRxiv2025

Improving dosage and timing of radiopharmaceutical therapies using computational modeling of tumor and radioligand dynamics

Radiopharmaceutical therapies (RPTs) offer targeted radiation delivery to tumour cells, yet treatment outcomes vary substantially across patients while dosing protocols remain largely uniform. Translating mechanistic insight into improved protocols requires models that couple radioligand (RL) pharmacokinetics, spatial tumour biology, and radiation response -- a combination that existing models have not yet fully achieved. We coupled a cellular automaton for spatially resolved tumour dynamics to a pharma-cokinetic compartment model that tracks RL from injection through receptor binding and internalization. We estimate the energy deposited by radiation emitted from RL within the tumour and use a linear-quadratic radiobiological survival probability to determine the impact of the treatment. Simulating heterogeneous tumours across a range of conditions, we find that treatment outcome is governed primarily by tumour size and receptor expression levels and is relatively insensitive to the injected amount per cycle but highly dependent on inter-injection time intervals. The models uniform RL delivery separates radiobiological resistance from delivery effects -- two mechanisms that are spatially correlated in real tumours -- and the simulations suggest that compromised RL delivery may play a larger role in hypoxic treatment failure than radioresistance alone. These findings provide a mechanistic basis for patient stratification by receptor expression, yield a new size-based rationale for multi-injection protocols, and demonstrate that spatially resolved modelling can reveal treatment principles inaccessible to non-spatial approaches.

cancer biology↗

bioRxiv2024

Cell geometry, microtubule anchoring and anisotropic dynamic instability: challenges and solutions to transverse cortical array organization

The self-organization of cortical microtubule arrays within plant cells is an emergent phenomenon with important consequences for the synthesis of the cell wall, cell shape, and subsequently the structure of plants. Mathematical modelling and experiments have elucidated the underlying processes involved. There has been recent interest in the influence of geometric cues on array orientation, be it direct (cell shape) or indirect (tension in the membrane). However, the mechanical influence of membrane curvature on these elastic filaments has largely been ignored. A previous model was proposed to describe how the anchoring process may control the deflection of individual microtubules seeking to minimize bending on a cylindrical cell. We incorporate this process into a model of interacting microtubules and find the cell curvature influence to be significant: the array favours orientations parallel to the direction of elongation rather than the expected transverse direction. Even without elasticity, the geometry of large cells hinders robust microtubule organization. These results suggest the necessity of additional processes to overcome these factors. We propose an orientation-dependent catastrophe rate, hypothetically caused by cellulose microfibrils impeding microtubule polymerization. We find a combination of anchoring and impedance to be sufficient to generate transverse arrays despite the geometric influences. Significance StatementThe organization of microtubule (MT) polymers into parallel arrays along the two-dimensional cortex of plant cells is crucial for directional cell growth and plant development. Despite decades of experimentation and more recent computational modelling, understanding the mechanisms that orient cortical MTs remains incomplete. With computational modelling, we have re-examined an assumption common to many models: that MTs grow along straight (geodesic) paths rather than minimizing bending. We model MT bending, and find a significant disruption of transverse MT ordering, especially in larger cells. We find that angle-dependent MT behaviour can counteract the effect of bending in certain contexts.

plant biology↗

bioRxiv2022

Evolutionarily conserved waves of tooth replacement in the gecko are dependent on local signaling

The fossil record contains dinosaur jaws with rows of unerupted successional teeth that are arranged in a variety of elegant patterns. The remnants of these patterns are visible in modern dentate reptiles but the mechanism for generating and maintaining these rows of teeth is unknown. The biology underlying the tooth replacement pattern was hypothesized to either be stimuli transmitted across tooth families in the jaws (Edmund) or secretion of local inhibitory molecules that would stagger development of adjacent tooth families (Osborn). To test these hypotheses and generate new ones, we completed a study on 6 treated adult geckos in which one side of the jaw had teeth removed. Wax bites were used to record the maxillary teeth 2 times a week. Tooth presence or absence was recorded and transformed mathematically. The time between eruption at each tooth position was measured as was the relative phase compared to the immediate adjacent teeth over successive bites. The period between eruption events at each tooth position was approximately 30 days with some lengthening over time. The average relative phase showed there was a tilt in the data that fit the observation that alternating teeth were being shed. This tilt was opposite on the left and right sides of the jaw. The asymmetry of the right and left sides was consistent across the dentition. After plucking, the pattern recovers after 3 periods fitting with the consistent finding that there are 3 teeth in each tooth family. Ablated areas did not recover tooth formation even after 14 months. The plucked animals showed evidence of fixed, local signaling that restores the pattern. Two models based on Osborns concept of a "zone of inhibition" deviate from the observed data. The ablated animals show no change in patterns of tooth eruption anterior and posterior to the gap. Thus there is no support for the Wave stimulus theory of Edmund. Finally, we propose a new Phase Inhibition Model. This model assumes fixed initiation sites at which teeth are initiated at some phase within a month-long cycle and that, as a tooth is initiated, the cycles of nearby initiation sites are inhibited in their progress. This inhibition causes nearest neighbours to erupt in anti-synchrony. This model best maintained the tilt, spacing timing of the real biological data. Mathematical modeling was sensitive enough to measure the normal developmental instability and the resilience of the gecko to restore homeostasis after tooth removal.

developmental biology↗

bioRxiv2022

A stochastic model of cortical microtubule anchoring and mechanics provides regulatory control of microtubule shape

The organization of cortical microtubule arrays play an important role in the development of plant cells. Until recently, the direct mechanical influence of cell geometry on the constrained microtubule (MT) trajectories have been largely ignored in computational models. Modelling MTs as thin elastic rods constrained on a surface, a previous study examined the deflection of MTs using a fixed number of segments and uniform segment lengths between MT anchors. It is known that the resulting MT curves converge to geodesics as the anchor spacing approaches zero. In the case of long MTs on a cylinder, buckling was found for transverse trajectories. There is a clear interplay between two factors in the problem of deflection: curvature of the membrane and the lengths of MT segments. We examine the latter in detail, in the backdrop of a circular cylinder. In reality, the number of segments are not predetermined and their lengths are not uniform. We present a minimal, realistic model treating the anchor spacing as a stochastic process and examine the net effect on deflection. We find that, by tuning the ratio of growth speed to anchoring rate, it is possible to mitigate MT deflection and even prevent buckling for lengths significantly larger than the previously derived critical buckling length. We suggest that this mediation of deflection by anchoring might provide cells with a means of preventing arrays from deflecting away from the transverse orientation.

biophysics↗

bioRxiv2021

A Multiscale computational model of YAP signaling in epithelial fingering behaviour

In epithelial-mesenchymal transition (EMT), cells organized into sheets break away and become motile mesenchymal cells. EMT plays a crucial role in wound healing, embryonic development, and cancer metastasis. Intracellular signaling in response to mechanical, topographic, or chemical stimuli can promote EMT. We present a multiscale model for EMT downstream of the protein YAP, which suppresses the cell-cell adhesion protein E-cadherin and activates the GTPase Rac1 that enhances cell migration. We first propose an ODE model for YAP/Rac1/E-cadherin interactions. The model dynamics are bistable, accounting for motile loose cells as for adherent slower cells. We implement this model in a cellular Potts model simulation of 2D wound-healing using the open source platform Morpheus. We show that, under suitable stimuli (depicting topographic cues) the sheet exhibits finger-like projections and EMT. Morphological, as well as quantitative differences in YAP levels as well as cell speed across the sheet are consistent with preexisting experimental observations of epithelial sheets grown on topographic features in vitro. The simulation is also consistent with experiments that knockdown or over-express YAP, inhibit Rac1, or block E-cadherin. SIGNIFICANCEIn normal wound-healing, cell in an epithelium divide, grow, and migrate so as to seal a gap. In some pathological states, epithelial-mesenchymal transition (EMT) can lead to abnormal morphology, including fingering, breakage of single cells or multicellular clusters from the sheet edge. The mechanochemical control of this behaviour by cell signaling circuits (YAP, Rac1, and E-cadherin) reveals how the competition between cell adhesion and cell migration contributes to the process. We use the open-source computational platform Morpheus to investigate a multiscale model for the interactions of the proteins inside cells and the resulting morphology of the cell sheet. Results are consistent with experimental results in the literature.

cell biology↗

bioRxiv2021

The mechanism of MinD stability modulation by MinE in Min protein dynamics

The patterns formed both in vivo and in vitro by the Min protein system have attracted much interest because of the complexity of their dynamic interactions given the apparent simplicity of the component parts. Despite both the experimental and theoretical attention paid to this system, the details of the biochemical interactions of MinD and MinE, the proteins responsible for the patterning, are still unclear. For example, no model consistent with the known biochemistry has yet accounted for the observed dual role of MinE in the membrane stability of MinD. Until now, a statistical comparison of models to the time course of Min protein concentrations on the membrane has not been carried out. Such an approach is a powerful way to test existing and novel models that are difficult to test using a purely experimental approach. Here, we extract time series from previously published fluorescence microscopy time lapse images of in vitro experiments and fit two previously described and one novel mathematical model to the data. We find that the novel model, which we call the Asymmetric Activation with Bridged Stability Model, fits the time-course data best. It is also consistent with known biochemistry and explains the dual MinE role via MinE-dependent membrane stability that transitions under the influence of rising MinE to membrane instability with positive feedback. Our results reveal a more complex network of interactions between MinD and MinE underlying Min-system dynamics than previously considered.

biochemistry↗

bioRxiv2020

Beta-cell specific insulin resistance promotes glucose-stimulated insulin hypersecretion

Abstract Insulin receptor (Insr) protein can be found at higher levels in pancreatic {beta}-cells than in most other tissues, but the consequences of {beta}-cell insulin resistance remain enigmatic. Ins1cre allele was used to delete Insr specifically in {beta}-cells of both female and male mice. Experimental mice were compared to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of purified recombined {beta}-cells revealed transcriptomic consequences of Insr loss, which differed between female and male mice. Action potential and calcium oscillation frequencies were increased in Insr knockout {beta}- cells from female, but not male mice, whereas only male {beta}InsrKO mice had reduced ATP-coupled oxygen consumption rate and reduced expression of genes involved in ATP synthesis. Female {beta}InsrKO and {beta}InsrHET mice exhibited elevated insulin release in perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr did not alter {beta}-cell area up to 9 months of age, nor did it impair hyperglycemia-induced proliferation. Based on our data, we adapted a mathematical model to include {beta}-cell insulin resistance, which predicted that {beta}-cell Insr knockout would improve glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance was significantly improved in female {beta}InsrKO and {beta}InsrHET mice when compared to controls at 9, 21 and 39 weeks, and also in insulin-sensitive 4-week old males. We did not observe improved glucose tolerance in older male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of {beta}-cell specific insulin resistance. The propensity for hyperinsulinemia was associated with mildly reduced fasting glucose and increased body weight. We further validated our main in vivo findings using the Ins1-CreERT transgenic line and found that male mice had improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that loss of {beta}-cell Insr contributes to glucose-induced hyperinsulinemia, thereby improving glucose homeostasis in otherwise insulin sensitive dietary and age contexts.

physiology↗