Searcharxiv⌕ Search

SEARCH · Searcharxiv

Results for “q-bio.SC”

Search indexed arXiv papers on artificial intelligence, large language models, computer vision and robotics. Read source abstracts and follow links to arXiv.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 559 records · Page 31Linked to original sources
arXiv2024

Dynein-driven self-organization of microtubules: An entropy- and network-based analysis

Microtubules self-organize to form part of the cellular cytoskeleton. They give cells their shape and play a crucial role in cell division and intracellular transport. Strikingly, microtubules driven by motor proteins reorganize into stable mitotic/meiotic spindles with high spatial and temporal precision during successive cell division cycles. Although the topic has been extensively studied, the question remains: What defines such microtubule networks' spatial order and robustness? Here, we aim to approach this problem by analyzing a simplified computational model of radial microtubule self-organization driven by a single type of motor protein -- dyneins. We establish that the spatial order of the steady-state pattern is likely associated with the dynein-driven microtubule motility. At the same time, the structure of the microtubule network is likely linked to its connectivity at the beginning of self-organization. Using the continuous variation of dynein concentration, we reveal hysteresis in microtubule self-organization, ensuring the stability of radial filament structures.

nlin.AO↗
arXiv2023

Tube geometry controls protein cluster conformation and stability on the endoplasmic reticulum surface

The endoplasmic reticulum (ER), a cellular organelle that forms a cell-spanning network of tubes and sheets, is an important location of protein synthesis and folding. When the ER experiences sustained unfolded protein stress, IRE1 proteins embedded in the ER membrane activate and assemble into clusters as part of the unfolded protein response (UPR). We use kinetic Monte Carlo simulations to explore IRE1 clustering dynamics on the surface of ER tubes. While initially growing clusters are approximately round, once a cluster is sufficiently large a shorter interface length can be achieved by `wrapping' around the ER tube. A wrapped cluster can grow without further interface length increases. Relative to wide tubes, narrower tubes enable cluster wrapping at smaller cluster sizes. Our simulations show that wrapped clusters on narrower tubes grow more rapidly, evaporate more slowly, and require a lower protein concentration to grow compared to equal-area round clusters on wider tubes. These results suggest that cluster wrapping, facilitated by narrower tubes, could be an important factor in the growth and stability of IRE1 clusters and thus impact the persistence of the UPR, connecting geometry to signaling behavior. This work is consistent with recent experimental observations of IRE1 clusters wrapped around narrow tubes in the ER network.

physics.bio-ph↗
arXiv2024

Chromatin remodeling due to transient-link-and-pass activity enhances subnuclear dynamics

Spatiotemporal coordination of chromatin and subnuclear compartments is crucial for cells. Numerous enzymes act inside nucleus\textemdash some of those transiently link and pass two chromatin segments. Here we study how such an active perturbation affects fluctuating dynamics of an inclusion in the chromatic medium. Using numerical simulations and a versatile effective model, we categorize inclusion dynamics into three distinct modes. The transient-link-and-pass activity speeds up inclusion dynamics by affecting a slow mode related to chromatin remodeling, viz., size and shape of the chromatin meshes.

physics.bio-ph↗
arXiv2023

Active thermodynamic force driven mitochondrial alignment

Mitochondria are critical organelles in eukaryotes that produce the energy currency ATP. In nerve axons, mitochondria are known to align at almost regular intervals to maintain a constant ATP concentration, but little is known about the mechanism. In this letter, we show theoretically that ATP production and ATP-dependent non-directional movement of mitochondria are sufficient for alignment, even in the absence of an explicit repulsive force between them. This is similar to thermodynamic forces driven by thermal fluctuations, even generated by non-equilibrium processes, and demonstrates the diversity of mechanisms governing the motion of biological matter.

physics.bio-ph↗
arXiv2024

AI-based analysis of super-resolution microscopy: Biological discovery in the absence of ground truth

Super-resolution microscopy, or nanoscopy, enables the use of fluorescent-based molecular localization tools to study molecular structure at the nanoscale level in the intact cell, bridging the mesoscale gap to classical structural biology methodologies. Analysis of super-resolution data by artificial intelligence (AI), such as machine learning, offers tremendous potential for discovery of new biology, that, by definition, is not known and lacks ground truth. Herein, we describe the application of weakly supervised paradigms to super-resolution microscopy and its potential to enable the accelerated exploration of the nanoscale architecture of subcellular macromolecules and organelles.

q-bio.SC↗
arXiv2023

Cooperation of myosin II in muscle contraction through nonlinear elasticity

Myosin II plays a pivotal role in muscle contraction by generating force through the cooperative action of multiple motors on actin filaments. In this study, we integrate the nonlinear elasticity of the neck linker in individual myosin II and comprehensively investigate the evolution of cooperativity and dynamics at {\it microstate} and {\it mesostate} levels using a combined model of single and multiple motors. We find that a substantial proportion of actin-bound motors reside in the {\it mid-} and {\it post-power stroke} states, and our nonlinear model reveals their increased capacity for load sharing. Additionally, we systematically explore the impact of mechanical load and ATP concentration on myosin II motors. Notably, we observe that the average net distance of actin undergoes a transition from a weak load-sensitive regime at low ATP concentrations to a load-sensitive regime at higher ATP concentrations. Furthermore, increasing the load or raising the ATP concentration to saturation can enhance the efficiency and output power of myosin filament. Moreover, the efficiency of the myosin filament increases with the power stroke strength, reaching a maximum at a specific range, and subsequently declining beyond that threshold. Finally, we explore the mean run time/length and mean existence probability of myosin filament, shedding light on its overall behavior.

physics.bio-ph↗
arXiv2024

Signature of (anti)cooperativity in the stochastic fluctuations of small systems: application to the bacterial flagellar motor

The cooperative binding of molecular agents onto a substrate is pervasive in living systems. To study whether a system shows cooperativity, one can rely on a fluctuation analysis of quantities such as the number of substrate-bound units and the residence time in an occupancy state. Since the relative standard deviation from the statistical mean monotonically decreases with the number of binding sites, these techniques are only suitable for small enough systems, such as those implicated in stochastic processes inside cells. Here, we present a general-purpose grand canonical Hamiltonian description of a small one-dimensional (1D) lattice gas with either nearest-neighbor or long-range interactions as prototypical examples of cooperativity-influenced adsorption processes. First, we elucidate how the strength and sign of the interaction potential between neighboring bound particles on the lattice determine the intensity of the fluctuations of the mean occupancy. We then employ this relationship to compare the theoretical predictions of our model to data from single molecule experiments on bacterial flagellar motors (BFM) of E. coli. In this way, we find evidence that cooperativity controls the mechano-sensitive dynamical assembly of the torque-generating units, the so-called stator units, onto the BFM. Furthermore, in an attempt to quantify fluctuations and the adaptability of the BFM, we estimate the stator-stator interaction potential. Finally, we conclude that the system resides in a sweet spot of the parameter space (phase diagram) suitable for a smoothly adaptive system while minimizing fluctuations.

physics.bio-ph↗
arXiv2023

Emergent Spatiotemporal Organization in Stochastic Intracellular Transport Dynamics

The interior of a living cell is an active, fluctuating, and crowded environment. Yet, it maintains a high level of coherent organization, which is readily apparent in the intracellular transport network. Membrane-bound compartments called endosomes play a key role in carrying cargo, in conjunction with myriad components including cargo adaptor proteins, membrane sculptors, motor proteins, and the cytoskeleton. These components coordinate to effectively navigate the crowded cell interior and transport cargo to specific intracellular locations, even though the underlying protein interactions and enzymatic reactions exhibit stochastic behavior. A major challenge is to measure, analyze, and understand how, despite the inherent stochasticity of the constituent processes, the collective outcomes show an emergent spatiotemporal order that is precise and robust. This review focuses on this intriguing dichotomy, providing insights into the known mechanisms of noise suppression and noise utilization in intracellular transport processes, and also identifies opportunities for future inquiry.

physics.bio-ph↗
arXiv2023

Modelling cargo transport in crowded environments: effect of motor association to cargos

In intracellular transports, motor proteins transport macromolecules as cargos to desired locations by moving on biopolymers such as microtubules. Recent experiments suggest that cargos that can associate motor proteins during their translocation have larger run-length, association time and can overcome the motor traffic on microtubule tracks. Here, we model the dynamics of a cargo that can associate at the most m free motors present on the track as obstacles to its motion. The proposed models display competing effects of association and crowding, leading to a peak in the run-length with the free motor density. This result is consistent with past experimental observations. For m=2 and 3, we show that this feature is governed by the largest eigenvalue of the transition matrix describing the cargo dynamics. In all the above cases, free motors are assumed to be present as stalled obstacles. We finally compare simulation results for the run-length for general scenarios where the free motors undergo processive motion in addition to binding and unbinding to or from the microtubule.

physics.bio-ph↗
arXiv2023

Membrane Thickness Sensitivity of Avian Prestin: Implications

Avian prestin is sensitive to membrane thickness as much as mammalian prestin, which undergoes conformational transitions in membrane area and thereby drives length changes of the cylindrical cell body of outer hair cells. The membrane thickness dependence of mammalian prestin stems from changes in hydrophobic profile in conformational states, accompanied by changes in their membrane area. Even though such area changes are not detected for avian prestin, it nonetheless bends hair bundles of avian short hair cells. Here it is suggested that the motile function of avian prestin can be based on conformational transitions involving shearing deformation of the membrane protein, which also leads to membrane thickness sensitivity.

physics.bio-ph↗
arXiv2024

Solving stochastic gene expression models using queueing theory: a tutorial review

Stochastic models of gene expression are typically formulated using the chemical master equation, which can be solved exactly or approximately using a repertoire of analytical methods. Here, we provide a tutorial review of an alternative approach based on queueing theory that has rarely been used in the literature of gene expression. We discuss the interpretation of six types of infinite server queues from the angle of stochastic single-cell biology and provide analytical expressions for the stationary and non-stationary distributions and/or moments of mRNA/protein numbers, and bounds on the Fano factor. This approach may enable the solution of complex models which have hitherto evaded analytical solution.

q-bio.SC↗
arXiv2023

High-density single-molecule maps reveal transient membrane receptor interactions within a dynamically varying environment

Over recent years, super-resolution and single-molecule imaging methods have delivered unprecedented details on the nanoscale organization and dynamics of individual molecules in different contexts. Yet, visualizing single-molecule processes in living cells with the required spatial and temporal resolution remains highly challenging. Here, we report on an analytical approach that extracts such information from live-cell single-molecule imaging at high-labeling densities using standard fluorescence probes. Our high-density-mapping (HiDenMap) methodology provides single-molecule nanometric localization accuracy together with millisecond temporal resolution over extended observation times, delivering multi-scale spatiotemporal data that report on the interaction of individual molecules with their dynamic environment. We validated HiDenMaps by simulations of Brownian trajectories in the presence of patterns that restrict free diffusion with different probabilities. We further generated and analyzed HiDenMaps from single-molecule images of transmembrane proteins having different interaction strengths to cortical actin, including the transmembrane receptor CD44. HiDenMaps uncovered a highly heterogenous and multi-scale spatiotemporal organization for all the proteins that interact with the actin cytoskeleton. Notably, CD44 alternated between periods of random diffusion and transient trapping, likely resulting from actin-dependent CD44 nanoclustering. Whereas receptor trapping was dynamic and lasted for hundreds of milliseconds, actin remodeling occurred at the timescale of tens of seconds, coordinating the assembly and disassembly of CD44 nanoclusters rich regions. Together, our data demonstrate the power of HiDenMaps to explore how individual molecules interact with and are organized by their environment in a dynamic fashion.

physics.bio-ph↗
arXiv2023

Understanding AKT-mediated chemoresistance: the relationship between ion channels and AKT activation

Overcoming chemoresistance is a challenge for multiple chemotherapeutics agents like cisplatin. ABC transporters such as MDR1 or MRPs and PI3K/AKT pathway have been proposed as actors of chemoresistance in several cancers. In this review we describe two downstream targets of Akt: c-myc and p53 in the chemoresistance. We suggest a potential link between p53, c-myc and ABC transporters expression. Consequently a link between Akt and ABC transporters-mediated chemoresistance may exist. Finally we show that Akt activation may be Orai-dependent and/or TRPC-dependent, suggesting that these ion channels could constitute a therapeutic target in cancer.

q-bio.SC↗
arXiv2023

Involvement of calcium channels Orai3 in the chemoresistance to cisplatin in non-small cell lung cancer (NSCLC)

This is the second part of the previous review. In the previous review we suspected that Orai3 channels were involved in lung cancer and more precisely in several cancers. Here we confirm that calcium dysregulation is important for cancer development. in this paper we show that Orai3 is an upstream activator of AKT and we prove that AKT is involved in chemoresistance in NSCLC.

q-bio.TO↗
arXiv2023

Unravelling the fluorescence kinetics of light-harvesting proteins with simulated measurements

The plant light-harvesting pigment-protein complex LHCII is the major antenna sub-unit of PSII and is generally (though not universally) accepted to play a role in photoprotective energy dissipation under high light conditions, a process known Non-Photochemical Quenching (NPQ). The underlying mechanisms of energy trapping and dissipation within LHCII are still debated. Various proposed models differ considerably in their molecular and kinetic detail, but are often based on different interpretations of very similar transient absorption measurements of isolated complexes. Here we present a simulated measurement of the fluorescence decay kinetics of quenched LHCII aggregates to determine whether this relatively simple measurement can discriminate between different potential NPQ mechanisms. We simulate not just the underlying physics (excitation, energy migration, quenching and singlet-singlet annihilation) but also the signal detection and typical experimental data analysis. Comparing this to a selection of published fluorescence decay kinetics we find that: (1) Different proposed quenching mechanisms produce noticeably different fluorescence kinetics even at low (annihilation free) excitation density, though the degree of difference is dependent on pulse width. (2) Measured decay kinetics are consistent with most LHCII trimers becoming relatively slow excitation quenchers. A small sub-population of very fast quenchers produces kinetics which do not resemble any observed measurement. (3) It is necessary to consider at least two distinct quenching mechanisms in order to accurately reproduce experimental kinetics, supporting the idea that NPQ is not a simple binary switch switch.

q-bio.MN↗
arXiv2023

Strategies for targeting chondrosarcomas in vivo and molecular dissection of oncogenic events in chondrosarcomas: is epigenetics the culprit?

It is obvious that both epigenetic and non-epigenetic actors contribute to tumorigenesis in chondrosarcomas and more generally in other cancers. Thus, the main altered pathways in chondrosarcomas are now well established and include both epigenetic and non-epigenetic pathways such as the PI3K-AKT signaling, EGFR overexpression, SPARC overexpression, c-myc overexpression, IHH/GLI1 axis, loss of Rb function, HIF1-alpha stabilization, IDH1 mutations, hypermethylation and SIRT1. This review aims to provide a detailed analysis of these pathways and highlights recurrent interactions between non-epigenetic and epigenetic actors in chondrosarcomas, raising the intriguing possibility of developing therapeutics targeting both epigenetic and non-epigenetic actors and supporting data from previous studies. Finally, we propose some strategies for targeting chondrosarcomas in vivo based on properties of this tumor.

q-bio.MN↗
arXiv2026

UQSA -- An R-Package for Uncertainty Quantification and Sensitivity Analysis for Biochemical Reaction Network Models

Biochemical reaction models describing subcellular processes generally come with a large uncertainty. To be able to account for this during the modeling process, we have developed the R-package UQSA, performing uncertainty quantification and sensitivity analysis in an integrated fashion. UQSA is designed for fast sampling of complicated multi-dimensional parameter distributions, using efficient Markov chain Monte Carlo (MCMC) sampling techniques and Vine-copulas to model complicated joint distributions. We perform MCMC sampling both from stochastic and deterministic models, in either likelihood-free or likelihood-based settings. In the likelihood-free case, we use Approximate Bayesian Computation (ABC), while for likelihood-based sampling we provide different algorithms, including the fast geometry-informed algorithm SMMALA (Simplified Manifold Metropolis-Adjusted Langevin Algorithm). The uncertainty quantification can be followed by a variance decomposition-based global sensitivity analysis. We are aiming for biochemical models, but UQSA can be used for any type of reaction networks. VineCopula: The use of Vine-copulas allows us to describe, evaluate, and sample from complicated parameter distributions, as well as adding new datasets in a sequential manner without redoing the previous parameter fit. The code is written in R, with C as a back-end to improve speed. We use the SBtab table format for Systems Biology projects for the model description as well as the experimental data. An event system allows the user to model complicated transient input, common within, e.g., neuroscience. UQSA has an extensive documentation with several examples describing different types of models and data. The code has been tested on up to 2000 cores on several nodes on a computing cluster, but we also include smaller examples that can be run on a laptop. Source code: https://github.com/icpm-kth/uqsa

q-bio.QM↗
arXiv2023

Geometry-sensitive protrusion growth directs confined cell migration

The migratory dynamics of cells can be influenced by the complex micro-environment through which they move. It remains unclear how the motility machinery of confined cells responds and adapts to their micro-environment. Here, we propose a biophysical mechanism for a geometry-dependent coupling between cellular protrusions and the nucleus that leads to directed migration. We apply our model to geometry-guided cell migration to obtain insights into the origin of directed migration on asymmetric adhesive micro-patterns and the polarization enhancement of cells observed under strong confinement. Remarkably, for cells that can choose between channels of different size, our model predicts an intricate dependence for cellular decision making as a function of the two channel widths, which we confirm experimentally.

physics.bio-ph↗