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#dynamics

42 posts11 participants5 posts today
Rxiv mechanobio

📰 "Cell-Free Protein Crystallization Enables Rapid Structure Determination of Disaccharides and Trisaccharides Using Galectin-10 Crystals"
biorxiv.org/content/10.1101/20 #Dynamics #Cell

bioRxiv · Cell-Free Protein Crystallization Enables Rapid Structure Determination of Disaccharides and Trisaccharides Using Galectin-10 CrystalsIt is critical to understand the conformational selection and dynamics of flexible saccharides via protein-ligand interactions in efforts to elucidate their biofunctional roles. Protein crystals can serve as scaffolds to immobilize small molecules, enabling structural and dynamic analysis of saccharides that are difficult to study by conventional approaches. However, constructing versatile scaffold crystals for high-throughput structural analysis remains challenging because this work involves laborious protein production and crystallization workflows. Here, we report rapid crystallization and structural analysis of saccharide-bound scaffolds by applying cell-free protein crystallization (CFPC) to galectin-10 (Gal-10), a lectin known to crystallize spontaneously in vivo. Using CFPC-generated Gal-10 crystals, we obtained the first atomic-resolution structures of melezitose, one of the trisaccharide, bound to the protein scaffold, revealing binding modes inaccessible by conventional approaches. Normalized B-factor analysis combined with molecular dynamics simulations reveals how the binding-site architecture modulates saccharide flexibility and immobilization. This platform can be extended to other flexible ligands and fragment-based screening. ### Competing Interest Statement The authors have declared no competing interest. Japan Society for the Promotion of Science, https://ror.org/00hhkn466, JP22H00347, JP25H02254, JP22K19266
Rxiv mechanobio

📰 "Thermodynamics and unbinding kinetics of A22 at multiple actin binding sites revealed by enhanced sampling simulations"
biorxiv.org/content/10.1101/20 #Cytoskeletal #Dynamics #Actin

bioRxiv · Thermodynamics and unbinding kinetics of A22 at multiple actin binding sites revealed by enhanced sampling simulationsThe cytoskeletal protein plays a major role in various cellular processes. Understanding the interactions of small molecules with cytoskeletal protein therefore might help in the development of therapeutics. Employing combined molecular docking, all-atom molecular dynamics (MD) and infrequent well-tempered metadynamics (iWT-MetaD) we studied bacterial inhibitor A22 and actin protein interaction. Five probable A22 binding sites (S1-S5) were observed in actin and unbiased MD simulations of 100 ns - 500 ns showed structural stability at these sites. Interaction analyses showed A22 to mostly forms transient interactions except at sites S4 and S5 where long-lives interactions were present. Enhanced sampling simulations quantitatively estimated ligand dissociation free energy ~ - 2 kcal/mol to -3.5 kcal/mol for sites S1-S4 with residence times ~ microseconds to milliseconds. For site S5, we observed the highest binding affinity (~ - 6.05 kcal/mol) and longest residence time ~ 0.75 sec. Analyses of the dissociation trajectories predict multiple dissociation pathways for A22 and found key gatekeeper residues at specific-sites facilitating ligand dissociation. Comparison of A22 with other known inhibitors suggest that A22 binds actin with relatively lower affinity, however, exhibits site-specific unbinding kinetics. Thus, our study provides a detailed mechanistic overview of A22-actin interaction, its various binding modes, and unbinding kinetics. It also shows the importance and usage of infrequent metadynamics in exploring rare events like ligand-protein interaction. Deeper insights gained from this study expands our understanding of cytoskeletal ligand dynamics. These knowledges will be paramount in designing drug targeting cytoskeletal protein actin. ### Competing Interest Statement The authors have declared no competing interest.
Rxiv mechanobio

📰 "Real-time visualisation of the intracellular dynamics of Shigella virulence plasmid"
biorxiv.org/content/10.1101/20 #Dynamics #Cell

bioRxiv · Real-time visualisation of the intracellular dynamics of Shigella virulence plasmidBacterial plasmids play critical roles in horizontal gene transfer, antibiotic resistance, virulence, and in shaping the interaction of bacteria with their environment, including those encountered in their hosts. They are integral to bacterial evolution as they act as vectors for rapid genetic change and adaptation. Shigella sonnei is a human-adapted pathogen that is a leading cause of bacillary dysentery and a significant threat to public health. In common to all species of Shigella , S. sonnei harbours an ~ 210 kb virulence plasmid, pINV, which is essential for its virulence. pINV encodes a Type III secretion system that mediates bacterial invasion of epithelial cells. Understanding the dynamics of replication and segregation of pINV is therefore necessary to define how Shigella retains the plasmid and thence virulence. In this study, we used three fluorescent tagging approaches to detect the presence of pINV in live S. sonnei to allow tracking of the plasmid during cell division. Conclusively, we found that tagging the plasmid with the parS -ParB partitioning system sequences from Caulobacter crescentus chromosome, allowed suitable visualization of the single copy pINV in S. sonnei . This comprehensively enabled us to monitor the location and segregation of the plasmid during bacterial growth. ### Competing Interest Statement The authors have declared no competing interest.
Rxiv mechanobio

📰 "Convergent Evolution of Sociality Causes Reduction of Mutation Rates in Spiders"
biorxiv.org/content/10.1101/20 #Dynamics #Cell

bioRxiv · Convergent Evolution of Sociality Causes Reduction of Mutation Rates in SpidersGermline mutations play a crucial role in determining the rate of molecular evolution. In the spider genus Stegodyphus, sociality has independently evolved three times within the past million years, each transition accompanied by major life history shifts, including obligate inbreeding, highly female biased sex ratios, reduced fecundity, and drastically lowered effective population sizes. We conducted whole genome sequencing of 202 parent-offspring trios from 34 families across three social and four subsocial species to estimate mutation rates in a phylogenetic comparative framework. Strikingly, each independent transition to sociality is associated with an approximately 50% reduction in germline mutation rate. This reduction has persisted over evolutionary timescales and suggests that mutation rates can decline rapidly, even in lineages with small effective population sizes, departing from predictions of the drift barrier hypothesis, which posits that mutation rates should increase under stronger genetic drift. We propose that the observed decline arises from life history mediated changes in germline dynamics such as slower development and fewer germline cell divisions, rather than direct selection on DNA repair efficiency. Our results highlight how social evolution can reshape fundamental genomic parameters and caution against assuming static mutation rates in evolutionary inference, underscoring the importance of ecological and developmental context in interpreting mutation rate variation. ### Competing Interest Statement The authors have declared no competing interest. Danmarks Frie Forskningsfond, https://ror.org/05svhj534, 0135-00201B Novo Nordisk Foundation, NNF20OC0060118
Rxiv mechanobio

📰 "Cell-Free DNA Reveals the Longitudinal Effects of Temozolomide Treatment and Host Co-Culture in Glioblastoma Models"
biorxiv.org/content/10.1101/20 #Dynamics #Cell

bioRxiv · Cell-Free DNA Reveals the Longitudinal Effects of Temozolomide Treatment and Host Co-Culture in Glioblastoma ModelsGlioblastoma (GBM) is a highly aggressive brain tumor with limited options for longitudinal monitoring. We evaluated the potential of cell-free DNA (cfDNA) as a real-time biomarker of tumor burden under tightly controlled conditions. We measured the cfDNA release dynamics, fragmentation sizes, and variant allele frequencies (VAF) in patient-derived GBM cell cultures. Time series of cfDNA were collected and analyzed in treatment-naive monocultures, during temozolomide (TMZ) treatment, and in co-culture with normal human astrocyte (NHA) cells. Longitudinal collection of media from individual cultures demonstrated that cfDNA yield increased, indicating the ability to use cfDNA to track tumor burden over time. Using a co-culture system, we deconvoluted cfDNA admixtures by analyzing yield, fragment size patterns, and cell line-specific variants. The exclusive detection of NHA- and GBM-specific mutations confirmed the distinct contributions of each cell type. Finally, TMZ treatment of GBM cells prompted an increase in cfDNA yield and VAF, suggesting that the effects of therapy could be measured using cfDNA. These findings support cfDNA as a non-invasive biomarker for real-time monitoring of GBM progression and treatment response, with clinical potential as a liquid biopsy tool in glioblastoma management. ### Competing Interest Statement The authors have declared no competing interest. American Brain Tumor Association, https://ror.org/03w32n732
Rxiv mechanobio

📰 "CaMKIIβ-mediated phosphorylation enhances protein stability of spastin to promote neurite outgrowth"
doi.org/doi:10.1523/JNEUROSCI.
pubmed.ncbi.nlm.nih.gov/406457
#Cytoskeleton #Dynamics

Journal of Neuroscience · CaMKIIβ-mediated phosphorylation enhances protein stability of spastin to promote neurite outgrowthNeurite outgrowth is critically controlled by calcium influx-mediated cytoskeleton dynamics. Spastin, a AAA ATPase microtubule severing protein, also plays an important role in neurite outgrowth. However, the detailed mechanisms underlying post-transcriptional fine-tuning spastin activity, particularly in the context of calcium signaling, remain elusive. Here, we identified Ca2+/calmodulin-dependent protein kinase II beta isoform (CaMKIIβ) acted as an upstream kinase to mediate the phosphorylation of spastin. CaMKIIβ interacted with and phosphorylated spastin on Ser233 and Ser562 amino acids. Moreover, CaMKIIβ-mediated phosphorylation reduced the poly-ubiquitination level of spastin and suppressed its proteasomal degradation. This enhanced protein stability by CaMKIIβ increased the microtubule severing activity of spastin and coordinately promoted the neurite outgrowth in hippocampal neurons. Inhibition of spastin or CaMKIIβ impaired synaptic activity, as evidenced by reduced frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs). Behaviorally, treatment with spastin or CaMKIIβ inhibitors led to deficits in short-term working memory and spatial learning, as assessed by Y-maze and Morris water maze tests in male mice, respectively. In general, this study unveils a novel mechanism whereby CaMKIIβ-mediated phosphorylation of spastin connects extracellular calcium signaling to the regulation of cytoskeleton dynamics and neurite outgrowth. Significance Statement This work uncovers a novel molecular mechanism that links calcium signaling to cytoskeletal remodeling and neural function. We demonstrate that CaMKIIβ phosphorylates spastin, enhancing its stability by reducing polyubiquitination and proteasomal degradation. This post-transcriptional regulation increases spastin’s microtubule-severing activity, thereby promoting neurite outgrowth in hippocampal neurons. Furthermore, inhibition of CaMKIIβ or spastin impairs synaptic transmission and cognitive performance, highlighting their critical roles in neuronal development and function. Overall, the study identifies CaMKIIβ as a key upstream regulator of spastin, offering new insights into how calcium influx governs neurite extension and memory-related behavior, with potential implications for neurological disease mechanisms and therapeutic strategies.
Rxiv mechanobio

📰 "Dynamical analysis of a model of BCL-2-dependent cellular decision making"
biorxiv.org/content/10.1101/20 #Dynamics #Cell

bioRxiv · Dynamical analysis of a model of BCL-2-dependent cellular decision makingThe BCL-2 protein family governs critical cell-fate decisions between survival, senescence, and apoptosis, yet the dynamical principles underlying these choices remain poorly understood. Here, we integrate mathematical modeling, bifurcation analysis, and stochastic simulations to dissect how BCL-2 network architecture encodes multistability and fate plasticity. Our coarse-grained model reveals tristable regimes requiring cooperative BH3-only and anti-apoptotic BCL-2 interactions, with stochastic fluctuations driving heterogeneous fate commitments in genetically identical cells. Comparative analysis of mechanistic models demonstrates that while bistability emerges from canonical BCL-2 interactions, robust tristability requires additional regulatory constraint, explaining the metastability of senescence in stress responses. Hybrid models further show that BH3-only binding cooperativity enables multistability, but physiological senescence likely depends on additional control mechanisms. These results establish a unified framework linking molecular interactions to cell-fate dynamics, with implications for targeting apoptosis resistance in disease. ### Competing Interest Statement The authors have declared no competing interest. Agencia Estatal de Investigación, PID2021-127896OB-I00 Fundación Severo Ochoa, CEX2020-001084-M
Rxiv mechanobio

📰 "Collective Gene Expression Fluctuations Encode the Regulatory State of Cells"
biorxiv.org/content/10.1101/20 #Dynamics #Cell

bioRxiv · Collective Gene Expression Fluctuations Encode the Regulatory State of CellsGene expression is inherently stochastic, but how fluctuations propagate at the macroscopic scale of gene networks and whether they play a functional role remains unclear. Here, we develop a theoretical and statistical learning framework that shows how collective gene expression fluctuations encode the regulatory state of cells. Specifically, we map fluctuations in gene expression to a disordered, non-equilibrium system and derive the macroscopic phase behaviour of these fluctuations. Applying our theory to single-cell RNA sequencing data, we show that cells operate close to a dynamical transition separating strongly correlated fluctuations, reminiscent of glassy dynamics, from weakly correlated, disordered regimes. Drawing on these experiments, we adapt Restricted Boltzmann Machines to infer cell states by the structure of their collective gene expression fluctuations. This shows that strongly correlated fluctuations characterize cells with the ability to differentiate into more specialised cell types. Our results point to the emergence of collective fluctuations as a layer of regulation in cells and as a hallmark of high regulatory flexibility. They also demonstrate how physical principles can yield functional insights into cell states from widely used single-cell data. ### Competing Interest Statement The authors have declared no competing interest.
Rxiv mechanobio

📰 "Beyond Static Screens: A High-Throughput Pooled Imaging CRISPR Platform for Dynamic Phenotype Discovery"
biorxiv.org/content/10.1101/20 #Dynamics #Cell

bioRxiv · Beyond Static Screens: A High-Throughput Pooled Imaging CRISPR Platform for Dynamic Phenotype DiscoveryUnderstanding the dynamic regulation of signaling pathways requires methods that capture cellular responses in real time. While high-content imaging-based genetic screens have transformed functional genomics, they have remained largely limited to static or binary phenotypes. Here, we present DynaScreen, an imaging-based, pooled CRISPR screening platform that enables high-throughput investigation of dynamic cellular phenotypes at single-cell resolution. By integrating Forster resonance energy transfer (FRET)-fluorescence lifetime imaging microscopy (FLIM) biosensors with photoactivation-based single-cell tagging and pooled CRISPR screening technology, we establish a scalable system to identify genes that regulate the timing, amplitude, and duration of signaling responses. As proof of principle, we applied this approach to the cAMP signaling pathway, a key regulator of cellular physiology. Using a custom guide RNA (gRNA) library, we tracked real-time cAMP dynamics in response to agonist stimulation and identified genes that modulate its basal levels and response kinetics. Cells with aberrant signaling were selectively photoactivated, isolated by fluorescence-activated cell sorting (FACS), and subjected to next-generation sequencing to pinpoint causal genetic perturbations. This strategy successfully uncovered known and novel regulators of cAMP dynamics. In conclusion, the integration of FLIM microscopy, CRISPR technology and open-source software to handle image analysis, automated hit identification and data representation, enables real-time exploration of dynamic phenotypes in a wide range of biological settings. ### Competing Interest Statement The authors have declared no competing interest. NWO, TTW 14691 Marie Skłodowska-Curie Grant, 101073507 (flIMAGIN3D – HORIZON-MSCA-DN-2021 NWO National Roadmap for Large-Scale Research Infrastructure, NWO 184.036.012 ScreeninC Infrastructure KWF, KWF 12539
Rxiv mechanobio

📰 "Measure Sodium Transport in Cells with NMR"
biorxiv.org/content/10.1101/20 #Dynamics #Cell

bioRxiv · Measure Sodium Transport in Cells with NMRSodium ions (Na⁺) are fundamental to numerous physiological functions, such as maintaining electrolyte balance, enabling nerve impulse transmission, and facilitating muscle contraction. Dysregulation of Na⁺ transport across cell membranes is implicated in a range of health issues, including metabolic syndromes, neurological conditions, and cardiovascular diseases. However, current methods for assessing cellular Na⁺ activity often face limitations; they can be invasive or fail to capture dynamic changes. In this study, we introduce a non-invasive 23Na nuclear magnetic resonance (NMR) methodology designed to directly quantify the transport rate of sodium ions in living cells. Our technique integrates relaxation exchange spectroscopy (REXSY) with a multi-site exchange model, enabling the investigation of Na⁺ transport dynamics on a timescale of sub-seconds. A key advantage is its ability to differentiate between intracellular and extracellular Na⁺ pools based on the endogenous NMR relaxation difference, thereby avoiding the need for potentially disruptive exogenous reagents. Experiments conducted on human cell lines successfully demonstrated the technique's capacity to distinguish between various physiological states, such as when ion channels are pharmacologically blocked or activated. The resulting measurements of Na⁺ transport rates and intracellular Na⁺ fractions show a clear correlation with cellular metabolic activity, offering valuable quantitative markers for monitoring transmembrane ion dynamics in vitro. ### Competing Interest Statement The authors have declared no competing interest. the National Natural Science Foundation of China, 22425402, 22275159 Cyrus Tang Foundation, 202523 the Fundamental Research Funds for the Central Universities, YG2025ZD30
Rxiv mechanobio

📰 "Wave propagation enhances extracellular signal strength in small excitable tissues"
biorxiv.org/content/10.1101/20 #Extracellular #Dynamics #Cell

bioRxiv · Wave propagation enhances extracellular signal strength in small excitable tissuesHuman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer new opportunities to study cardiac dynamics and drug responses. High-throughput platforms often rely on extracellular potential (EP) recordings as a proxy for transmembrane voltage, making EP signal strength critical for analysis. EPs arise from spatial inhomogeneities — either intrinsic or induced by wave propagation. Using a computational model, we show that uniform simultaneous stimulation of all cells suppresses wave propagation and results in weak signals. In contrast, localized stimulation that initiates a traveling wave generates much stronger EPs, improving the robustness of biomarker extraction from extracellular recordings. ### Competing Interest Statement Both authors are shareholders in Organos Inc., a start-up company specializing in measuring drug effects in microphysiological systems. The authors hold the following patents/patent applications: (a) US011846631B2 (2023) - Methods for determining drug effects on a mature cardiomyocyte. Tveito, A., Wall, S., and Jaeger, K.H. (granted), (b) WO2021236535 (2021) - Determining drug effects using combination of measurements. Tveito, A., Jaeger, K.H., and Wall, S. (application being processed), (c) WO2022264096 (2022) - Combination of existing drugs to repair the action potentials of cells. Jaeger, K.H., and Tveito, A. (application being processed).
Rxiv mechanobio

📰 "Controlling quantum entanglement with classical non-separable light"
arxiv.org/abs/2507.06462 #Physics.Optics #Dynamics #Quant-Ph #Matrix

arXiv logo
arXiv.orgControlling quantum entanglement with classical non-separable lightHere we investigate the quantum frequency conversion of entangled photons driven by a classically non-separable laser beam. We show that the frequency conversion dynamics is described by a quantum channel that stems from the classical drive field through the channel-state duality - the quantum channel is dual to the classical coherence matrix of the drive field. This implies that the evolution of entanglement in the conversion process is bound by the classical non-separability of the drive field, a result that we confirm experimentally. Furthermore, we show that the conversion dynamics can be understood as a swapping operation between classical non-separability and entanglement, unveiling a physical connection between two fundamentally different concepts.
Rxiv mechanobio

📰 "Targeting Melanoma-Specific Tyrosinase: Cyclic Peptide Disrupts Actin Dynamics for Precision Apoptosis Induction"
arxiv.org/abs/2507.06534 #Dynamics #Q-Bio.Bm #Actin

arXiv logo
arXiv.orgTargeting Melanoma-Specific Tyrosinase: Cyclic Peptide Disrupts Actin Dynamics for Precision Apoptosis InductionMelanoma is an aggressive and highly metastatic cancer that exhibits stubborn resistance to conventional therapies, highlighting the need for novel treatments. Existing therapeutic strategies often suffer from systemic toxicity, poor efficacy and fast-gained drug resistance. In this study, we designed a cyclic peptide system (c-RGDKYQ) that takes the advantage of the overexpression of tyrosinase in melanoma cells to trigger enzyme-mediated oxidation and self-assembly. The assembled peptide nanostructures can selectively disrupt the actin cytoskeleton, impairing cancer cellular functions, e.g., motility, adhesion, and proliferation, ultimately leading to apoptosis. This approach does not rely on external drug payloads or complex delivery mechanisms. c-RGDKYQ exhibits high selectivity for melanoma cells, strongly suppressing tumor growth in a murine model with minimal systemic toxicity. Our findings illuminate that, through targeting tyrosinase, c-RGDKYQ may be an enzyme-responsive alternative to conventional treatments for melanoma.
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