Biophysical journal最新文献

{"title":"Diabetes-mediated changes in red blood cell biomechanics reorganize capillary network hemodynamics through altered cellular trafficking.","authors":"Shane LeCompte, Patrickalan Pangilinan, Yifu Ding, Phillip Bedggood, Andrew Metha, Prosenjit Bagchi","doi":"10.1016/j.bpj.2026.10.009","DOIUrl":"10.1016/j.bpj.2026.10.009","url":null,"abstract":"<p><p>Diabetes alters shape and deformability of red blood cells (RBCs), thereby potentially modifying their transport through capillary networks. Microvascular dysfunction-including impaired capillary perfusion, endothelial dysregulation, and vascular remodeling-is a hallmark of diabetes. However, the contribution of altered RBC biomechanics to network-scale changes in capillary hemodynamics and the cellular-scale mechanisms underlying such changes remain poorly understood. Current in vivo imaging techniques cannot directly quantify critical hemodynamic parameters including endothelial mechanical load, capillary pressure, and the cell-free layer in vessels less than 10 microns in diameter. Nor can they identify the cellular-scale mechanisms responsible for network-scale hemodynamic changes. To bridge these gaps, we combined anatomically reconstructed human retinal capillary networks with a high-fidelity three-dimensional fluid-structure interaction model that fully resolves RBC deformation and transport. The simulations predict that diabetes-mediated alterations in RBC shape and deformability redistribute capillary hemodynamics with bidirectional, highly localized, and spatially heterogeneous changes. Compared to healthy RBCs, diabetic RBCs resulted in hematocrit changes by ±40%, RBC velocity by -30% to +40%, vessel pressure drop by twofold, and local wall shear stress nearly fourfold. Diabetic RBCs also shifted the Fåhræus relationship where the concentration of cells decreases with vessel diameter through diameter-dependent changes in the cell-free layer. Analysis of individual bifurcations identified three cellular-scale mechanisms underlying these network-scale changes: reduced lingering, capillary obstruction, and slower lateral migration of diabetic RBCs that altered their partitioning into downstream vessels. Together, these mechanisms reorganized downstream cellular trafficking and redistributed capillary hemodynamics throughout the network. These findings establish how diabetes-mediated alterations in RBC biomechanics give rise to localized microvascular dysfunction by linking single-cell biomechanics to altered cellular trafficking and emergent capillary network hemodynamics.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantifying the biophysical properties of stomatocytes in health and disease","authors":"Zhaojie Chai,Jianlu Zheng,He Li,Ming Dao,George Em Karniadakis","doi":"10.1016/j.bpj.2026.10.007","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.10.007","url":null,"abstract":"Hereditary stomatocytosis (HSt) comprises red blood cell (RBC) disorders characterized by cup-shaped erythrocytes that share a nominal morphology yet respond oppositely to splenectomy: the procedure is often curative in overhydrated HSt (OHS) and intermediate phenotypes but can precipitate life-threatening thromboembolism in dehydrated HSt (DHS/xerocytosis). This “splenectomy paradox” persists because clinicians cannot predict which patients will benefit. A central obstacle is that RBC biomechanics is governed by several partly independent parameters—membrane shear modulus (μ), bending rigidity (kc), surface-to-volume ratio (S/V), and cytoplasmic viscosity (ηcyto)—that existing assays capture only piecemeal. Here we present an in silico dissipative particle dynamics (DPD) study that constructs a control discocyte (CTR-RBC) and three stomatocyte models (ST-RBC1–3) at fixed membrane area (A0 = 132.9 μm2) and decreasing volume (V = 109.7, 101.5, 89.8 fL), spanning the OHS-to-DHS hydration range. Lacking direct membrane-mechanics data for HSt, we anchor the models to published HSt morphometry, to mechanical measurements on healthy and simulated stomatocytic cells, and to matched brightfield imaging of cup-shaped RBCs used solely as a morphological reference. Tracing this single parameter set through five mechanically orthogonal assays, we find that interendothelial-slit (IES) traversal is geometry-dominated: overhydrated ST-RBC1 requires roughly an order of magnitude higher critical pressure than CTR-RBC, whereas dehydrated ST-RBC3 passes freely. ST-RBC3 nonetheless suppresses membrane tank-treading and raises low-shear whole-blood viscosity by ∼25% at physiological haematocrit, comparable to the hyperviscosity of Gaucher-disease blood. A funnel–obstacle chip amplifies these differences into a label-free centerline-offset signal predicted to separate all four RBC types (∼4.5σ between the extreme phenotypes). Together, these results unite single-cell mechanics, splenic filtration, and hemorheology in one framework, offer a mechanical account of the OHS-versus-DHS splenectomy paradox, and point toward a microfluidic route to pre-operative risk stratification in HSt.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"53 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accounting for Missed Events in the Bayesian Modeling of IP3R2 Multimodal Gating","authors":"Schayma Ben marzougui,Audrey Denizot,Hugues Berry","doi":"10.1016/j.bpj.2026.10.004","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.10.004","url":null,"abstract":"The Inositol 1,4,5-trisphosphate receptor channel (IP3R) is an important calcium channel involved in calcium-induced calcium release, playing a prominent role in intracellular calcium signaling. However, accurately characterizing its gating behavior remains a challenge, particularly due to the temporal resolution of patch clamp techniques that is not large enough to detect all short-lived events. This limitation can significantly bias the inference of kinetic models describing the receptor activity. To address this issue, we focused on the quantitative analysis of IP3R2 gating behavior using patch clamp data, with particular attention to missed events. We modeled IP3R2 channel gating using Hierarchical Markov chains and used a Bayesian approach that integrates missed event correction directly into the likelihood function, enabling more accurate parameter inference and model evaluation. We show that accounting for missed events deeply clarifies the multi-modal model that emerges from model selection. In this new model, the Park and Drive modes both consist of the same 3-state Markov model, with mode-dependent kinetic parameters: the Drive mode stabilizes the closed state directly connected to the open one, whereas the Park mode stabilizes the other closed state, that is not connected to the open one. Intermediate Ca2+ concentrations are found to strongly depress the Drive to Park transition rate, so that the IP3R2 channel undergoes frequent transitions to the Park mode only for < 50 nM or micromolar Ca2+ concentrations. Overall, our approach provides a refined perspective on IP3R2 channel modeling and highlights the critical importance of accounting for missed events upon model selection based on single-channel recordings.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"9 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Mechanism of pH-Dependent Activation in Human Equilibrative Nucleoside Transporter 3","authors":"Thanh Tran,Jung-Hsin Lin","doi":"10.1016/j.bpj.2026.10.006","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.10.006","url":null,"abstract":"Human equilibrative nucleoside transporter 3 (hENT3) is a lysosomal transporter whose activity is strictly dependent on an acidic lumenal environment. Mutations in hENT3 lead to H syndrome and other metabolic disorders, yet the structural basis for its pH-sensitive gating remains poorly defined. Using multi-replica conventional MD simulations, we provide atomistic insight into the pH-dependent activation mechanism of hENT3 in the outward-facing state. Protonated Asp219 triggers a local hydrogen-bond reorganization that recruits conserved Ser229 and the TM6 helix-capping residue Asp225 and stabilizes TM5—an intrinsically flexible helix within the ENT family. Stabilization of TM5 in turn reinforces the neighboring helices including TM1, TM6 and TM8, reduces thin-gate fluctuations, and more frequently preserves the adenosine binding pose required for translocation. On the cytosolic side, Glu447 protonation modulates the interaction between the H-syndrome-associated Arg134 and loop 2. With an alignment-independent distance correlation analysis, we identified distinct state-dependent coupling patterns under acidic and neutral pH conditions. In particular, acidic ensembles that retained a transport-competent binding pose showed the strongest agreement with prior mutagenesis data, as site-centric distance correlation scores are consistent with experimentally observed loss of adenosine transport.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"67 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell Geometry and Mechanics Slow Gaucher Red Blood Cells","authors":"Elif Dursun,Hanxun Jin","doi":"10.1016/j.bpj.2026.10.003","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.10.003","url":null,"abstract":"","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"56 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thermodynamic Drivers of LINC Complex Clustering in the Nuclear Envelope","authors":"Nya Domkam,Joshua Adenugba,Anahi Barasso,Mohammad R.K. Mofrad","doi":"10.1016/j.bpj.2026.10.005","DOIUrl":"https://doi.org/10.1016/j.bpj.2026.10.005","url":null,"abstract":"The Linker of Nucleus to Cytoskeleton (LINC) complex is a central mechanical element of the nuclear envelope, transmitting cytoskeletal forces to the nucleus and coordinating nuclear mechanics. While individual LINC complex units (LCUs) are well characterized structurally, growing experimental evidence suggests that LCUs assemble into higher-order clusters whose organization may critically influence force transmission. However, the molecular drivers of LINC complex clustering and their stability in the absence of externally applied forces remain poorly understood.\u0000Here, we use all-atom molecular dynamics simulations to investigate the thermodynamic and structural determinants of LINC complex clustering within the nuclear envelope. Using SUN2–KASH2 assemblies as building blocks, we generated and analyzed ten distinct higher-order cluster configurations derived from protein–protein docking, AI-based structure prediction, and biologically motivated geometric placement. Across these models, we quantified cluster stability, relative motion, interaction energetics, interacting surface area, hydrogen bond density, and per-residue effective free energy contributions.\u0000Our results reveal that LINC clustering can be stabilized through distinct interaction modes, including electrostatic, hydrogen-bond–rich, and hydrophobic interfaces, depending on cluster geometry. Stable clusters exhibit correlated motion between LCUs, minimal translational separation, and interaction energies dominated by either van der Waals or Coulombic contributions. Importantly, clustering emerges as a thermodynamically favorable property of specific LINC architectures even in the absence of applied force.\u0000Together, these findings provide a mechanistic framework for understanding LINC complex superstructure formation and suggest that LINC clustering may serve as a tunable architectural feature for regulating nuclear mechanotransduction under physiological and pathological conditions.","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":"16 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conformational ensembles of flexible multidomain proteins: How close are we to accurate and reliable predictions?","authors":"Santiago Rodriguez, Aurélie Fournet, Simon Bartels, Mátyás Pajkos, Ilinka Clerc, Laure Carrière, Aurélien Thureau, Cédric Montanier, Claire Dumon, Frédéric Allemand, Juan Cortés, Pau Bernadó","doi":"10.1016/j.bpj.2026.08.018","DOIUrl":"10.1016/j.bpj.2026.08.018","url":null,"abstract":"<p><p>Multidomain proteins connected by flexible linkers populate conformational ensembles that are challenging to characterize using conventional structural biology methods. In domain-linker-domain proteins, linker-mediated inter-domain relative positions and orientations are functionally relevant, yet their dynamical behavior in solution normally remains poorly described. Small-angle X-ray scattering (SAXS) provides ensemble-averaged structural information for such systems; however, coupling with computational modeling is required to accurately describe the dynamic behavior of this family of proteins in solution. Here, we present a systematic evaluation of five ensemble-generation strategies applied to a set of eighteen proteins sharing the same two globular domains, connected by naturally occurring linkers of varying length and composition. Modeling methods based on different underlying principles are compared by assessing their agreement to experimental SAXS data, showing a large disparity and systematic structural biases among them. Furthermore, for each approach, we examine the effect of refinement against SAXS restraints and assess its capacity to describe the experimental data, as well as the induced biases in global dimensions and inter-domain distance distributions. This analysis underlines the importance of the initial conformational pool for deriving experimentally compatible ensembles. Overall, this work provides a high-quality benchmark for SAXS-driven ensemble modeling of flexible, multidomain proteins and establishes a framework for the critical interpretation of solution scattering data in systems with pronounced conformational heterogeneity.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"5662-5675"},"PeriodicalIF":3.7,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polymorphic structures of rapidly twisting 40-residue amyloid-β fibrils.","authors":"Motahareh G Larimi, Kent R Thurber, Robert Tycko","doi":"10.1016/j.bpj.2026.08.003","DOIUrl":"10.1016/j.bpj.2026.08.003","url":null,"abstract":"<p><p>Fibrils formed by 40- and 42-residue amyloid-β peptides (Aβ40 and Aβ42) are polymorphic, containing molecular structures that vary with growth conditions in ways that are not fully understood. Here, we use cryoelectron microscopy to characterize the structure of rapidly twisting Aβ40 fibrils, for which the distance between apparent width minima in electron microscope images (\"cross-over distances\") is approximately 25 nm. From samples grown under a single set of growth conditions, we obtain high-resolution structures for three different rapidly twisting polymorphs. Although their cross-over distances are similar, the three rapidly twisting polymorphs differ in twist handedness, symmetry, molecular conformations, and intermolecular contacts. Two of the rapidly twisting polymorphs resemble Aβ40 polymorphs with longer cross-over distances that have been described previously, including polymorphs extracted from brain tissue of patients with Alzheimer's disease or created by seeded growth from amyloid in brain tissue, but have shorter conformationally ordered segments and other specific conformational differences. These results contribute to our understanding of amyloid polymorphism, connections between morphology and molecular structure, and relationships between brain-derived and in-vitro-grown fibrils.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"5526-5541"},"PeriodicalIF":3.7,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148688503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Label-free microrefractometry of interfacial processes using fluorescent smart coverslips.","authors":"Hodaya Klimovsky, Amitay Ginsberg, Dmytro Ohorodniichuk, Maria Shehadeh, Ilya Olevsko, Gerardo Byk, Martin Oheim, Adi Salomon","doi":"10.1016/j.bpj.2026.08.022","DOIUrl":"10.1016/j.bpj.2026.08.022","url":null,"abstract":"<p><p>Molecular dipoles near interfaces emit highly directional radiation due to near-field interactions, making surface-bound fluorophores sensitive probes of local physicochemical changes. We introduce \"smart coverslips,\" standard microscope substrates, which are stably coated with uniform, brightly fluorescent nanobead films, that exploit refractive-index-dependent shifts in the radiation pattern for sensitive microrefractometry in small volumes. Supercritical angle fluorescence refractometry uses single back focal plane images to allow us real-time refractive index sensing and nanometric thin-film height measurements without the need for multi-angle or multi-wavelength acquisition. Our fast, label-free, and noninvasive approach allows measurements of thin-film properties and monitoring of interfacial dynamics on a standard inverted microscope and is broadly applicable to nano-biophotonics, chemical sensing, and in situ materials analysis. Applied to membrane biophysics, these findings establish a versatile approach for resolving the nanoscale organization of membrane-proximal or -associated structures.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"5706-5717"},"PeriodicalIF":3.7,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-dimensional energetic landscape governing Ca²⁺ binding in troponin C.","authors":"Abdul Basit","doi":"10.1016/j.bpj.2026.09.002","DOIUrl":"10.1016/j.bpj.2026.09.002","url":null,"abstract":"<p><p>Ca²⁺ binding regulates muscle contraction through coupled structural and dynamical mechanisms, yet a unified description of mutation-induced perturbations in binding energetics remains incomplete. Mutational effects on proteins are often high dimensional and difficult to interpret mechanistically. Here, we develop a physically interpretable low-dimensional reaction coordinate that captures coordination environment, electrostatic features, and dynamical coupling. Structural, electrostatic, and dynamical descriptors correlate with experimental binding free energies with Pearson coefficients of R_p = 0.83, 0.83, and 0.85, respectively. Integration of these domains improves agreement with experiment (R_p = 0.90), indicating substantial dimensional compression of the underlying descriptor space. This framework provides a physically grounded description of how mutations reshape Ca²⁺-binding energetics in a minimal EF-hand system.</p>","PeriodicalId":8922,"journal":{"name":"Biophysical journal","volume":" ","pages":"5739-5751"},"PeriodicalIF":3.7,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}