Nuclear Biophysics: A Decade of Composite Mechanics and Molecular Organization

1. The nucleus as a coupled physical system

A useful physical description separates the chromatin network, accessible nucleoplasmic spaces, concentrated nuclear bodies and the envelope-associated boundary, then asks how they interact. Each component supplies a different observable. Inert proteins report movement through accessible space; a labeled locus remains embedded in chromatin; a nuclear-body fusion event probes collective relaxation; stretching the nuclear boundary loads a composite structure. These differences explain why nuclear measurements can disagree numerically without contradicting one another. The measurements must first be matched by component, geometry and time scale before a common material interpretation is attempted. [12] [13] [2] [1]

The word composite also implies coupling. A force delivered to the envelope does not necessarily load all chromatin equally. A molecule concentrated in a nucleolus does not necessarily share the environment of a nearby soluble molecule. The mechanical and chemical connections between these components can change during perturbation. Attar and colleagues modeled peripheral chromatin links as a route for load transmission, while Zhao and colleagues observed regional condensate responses during nuclear deformation. The nucleus should therefore be described by component properties together with their connections, rather than by an average value that hides those connections. [8] [10] [2]

2. Structure identifies candidates, not mechanical constants

Cryo-electron structural analysis by Turgay and colleagues resolved lamin filament organization in a prepared somatic-cell system. Such work establishes molecular architecture at the lamina, whereas its mechanical contribution requires a separate perturbation or force experiment. Likewise, modern nuclear-pore structures distinguish scaffold, linker and cytoplasmic-face components but do not alone measure transport rates or stress response. Structural models narrow the plausible mechanisms and identify interfaces to test. They should not be used to infer a material modulus solely from an image or to assign a universal pore diameter to all cell types and mechanical states. [14] [15] [16] [11]

Genome-position measurements supply another structural level. Guelen and colleagues mapped broad lamina-associated domains in human fibroblasts, linking peripheral association with a characteristic genomic organization. These maps are evidence of association, not direct measurements of tether strength or permanent attachment in every cell. The associated corrigendum corrects the identity and provenance of a chromatin-mark dataset and should accompany the original reference. Recent tether-depletion studies make the distinction productive by testing which envelope proteins are necessary for positioning and what changes after short versus persistent loss. [17] [18] [9]

3. Chromatin and lamins contribute in different regimes

Stephens and colleagues used isolated-nucleus deformation to distinguish response regimes: chromatin contributed strongly at smaller extensions, whereas lamin A supported strain stiffening at larger extensions. This connects biochemical state to mechanical resistance without making one component the sole determinant of nuclear mechanics. The measured force–extension behavior depends on geometry and loading conditions. A slope in this assay is not directly interchangeable with an indentation modulus or a local viscosity. The useful mechanistic conclusion concerns how the relative load-bearing contributions change with deformation. [1]

Bergamaschi and colleagues extended the picture with optical-tweezer measurements accompanied by images of chromatin and the nuclear boundary, interpreting heterogeneous response through a hierarchical chain model. Attar and colleagues examined how peripheral tethering allows chromatin structure to affect force resistance in a polymer model constrained by experiments. These developments emphasize that internal organization and boundary coupling must be considered together. A chromatin change can alter global mechanics only to the extent that the imposed load engages that changed structure, and the form of engagement is itself an experimental variable. [7] [8]

4. Molecular mobility is another scale of physical organization

The eGFP-oligomer experiments of Dross and colleagues measured size-dependent mobility with calibrated FCS in living nuclear regions outside nucleoli. Erdel and colleagues combined tracer-size variation with modeling to identify intermediate-scale behavior consistent with obstacles and polymer organization. These observations show how the physical environment experienced by molecules depends on their dimensions and the scale of observation. They do not imply that every DNA-binding factor has the same mobility, because specific association with chromatin adds another process. Molecular search is consequently influenced by both the accessible environment and the binding chemistry of the searching protein. [12] [13] [19]

FRAP and single-particle tracking help resolve that distinction when their limitations are made explicit. Reaction–diffusion FRAP analysis separates transport and binding contributions only in identifiable model regimes. Spot-On demonstrated how blur and focal-volume escape bias apparent populations in tracking experiments. Such corrections matter when a mechanobiological perturbation changes the mobile fraction. A slower protein should not automatically be described as evidence of nuclear stiffening or increased viscosity; conversely, a mechanical softening need not accelerate a tightly bound factor. The two observations can be connected only by testing the relevant coupling. [20] [21] [19]

5. Nuclear bodies combine composition and material response

Feric and colleagues demonstrated coexisting nucleolar subcompartments and component-specific dynamics in living systems and reconstituted droplets. The in-vitro tracer-viscosity experiment and the in-vivo fusion experiment measured different quantities, including viscosity and viscosity relative to surface tension. This supports a physically organized nucleolus while retaining preparation and component specificity. A spherical shape, exchange of fluorescent molecules or fusion event alone should not substitute for a complete material characterization. Different molecular mechanisms can produce some similar imaging behaviors, and the surrounding chromatin can also constrain collective motion. [2] [22] [10]

The 2024 confined-migration work of Zhao, Xia and Brangwynne makes that surrounding environment explicit. Chromatin became regionally heterogeneous as nuclei passed through microfluidic constrictions, with different opportunities for condensate formation in advancing and trailing regions. Endogenous-body deformation and model-assembly behavior were both studied, supplying complementary observations. The result connects nuclear mechanics with compartment organization without requiring a uniform global crowding change or a universal phase-separation mechanism. Local protein concentration and mechanical permissiveness jointly define the relevant physical conditions. [10]

6. Active remodeling and persistent responses

Rashid and colleagues directly loaded chromatin with approximately 200-nm-diameter targeted magnetic particles and connected local deformation with persistent changes in mobility and regulatory readouts. Their CHO chromatin-reporter and induced-pluripotent-stem-cell polymerase experiments are distinct biological arms. The lasting response after force cessation is not identical to the immediate viscoelastic phase response during oscillatory loading. It supplies a mechanism-oriented example of nuclear mechanomemory whose generality must be tested in other cell types and genomic contexts. [4]

Byfield and colleagues used metabolically active karyoplasts to probe dissipation and large deformation, with ATP-production and BRM/BRG1-remodeling perturbations. The work argues that active internal processes can permit nuclear fluidization and shape change. It also shows why loading hysteresis should not be assigned exclusively to passive viscosity. The preparation preserves a membrane-enclosed active nuclear system; it differs from detergent-isolated nuclei and from a nucleus still coupled to the full cell. Such preparation differences are biological differences in the system, rather than nuisance details to remove from the discussion. [5] [23]

7. Envelope coupling, transport and failure

The SUN–nesprin experiments of Crisp and colleagues established a molecular route linking inner and outer nuclear-membrane proteins across the perinuclear space, supporting the LINC-complex model. This gives external force a plausible connection to nuclear structure, while specific mechanical and transport experiments are needed to establish its functional consequences. Elosegui-Artola and colleagues showed force-dependent YAP nuclear entry and changes in import behavior in defined cell systems. The result demonstrates a regulated cargo response rather than a universal rule that every protein crosses more rapidly whenever the nucleus flattens. [24] [25]

Envelope rupture presents a different physical and biological state. Denais and colleagues observed loss of compartmentalization during constrained migration and studied ESCRT-III-dependent resealing alongside damage-associated responses. This does not mean every deformed nucleus ruptures, or that restoration of a localization reporter proves all DNA lesions have been repaired. The mechanical challenge and the subsequent recovery involve membrane integrity, molecular redistribution and genome consequences that need distinct readouts. A current account of nuclear function should preserve those stages rather than collapsing them into a binary healthy-versus-damaged shape classification. [3] [26]

8. Current advances connect density, pores and genome tethers

The density-homeostasis study of Biswas and colleagues connects nuclear volume to imported macromolecules and chromatin through a pressure-balance model supported by measurements in several systems. Hoffmann and colleagues studied pressure-dependent nucleocytosolic flow in Dictyostelium and related it to pore dilation. These are complementary physical questions: one concerns volume and concentration, the other flow under a pressure difference. Neither is identical to passive protein exchange or receptor-mediated cargo transport. Together they broaden nuclear biophysics beyond structural stiffness to include composition, osmotic balance and membrane-crossing mechanics. [6] [27]

Pore plasticity and genome positioning are also becoming more experimentally resolved. Morgan and colleagues used pan-expansion microscopy to examine NPC diameter distributions, surface biases and perturbations. Lewis and colleagues identified redundant contributions from LBR and membrane-bound LAP2 isoforms to peripheral heterochromatin positioning in mammalian cells. These studies show that neither pore geometry nor chromatin attachment should be regarded as a fixed universal boundary condition. Understanding their dynamic regulation will require linking structural measurements to matched transport, force and transcription assays in the same biological context. [11] [9] [8]

A recent biological example comes from McCreery and colleagues’ study of human embryo and primed-pluripotent-cell models. Growth-factor state was linked to nuclear deformation, osmotic stress and chromatin regulation during fate transitions. Mechanical or osmotic priming could accelerate transitions, while sustained biochemical signals remained necessary for robust lineage induction. This connects nuclear physical organization to a regulated developmental context and shows why a mechanical response should be interpreted together with the signaling state in which it occurs. [29]

An integrated account also needs to distinguish reversible adaptation from loss of compartment integrity. Regional condensate changes during confinement can accompany deformation without being identical to envelope rupture, while the restoration of a leakage reporter after rupture does not establish that chromatin organization is fully restored. Following both body organization and boundary integrity can identify which response comes first and whether it persists after migration. This temporal information helps connect the immediate mechanical event to subsequent nuclear function rather than treating every endpoint image as the same biological state. [10] [3]

The link between density and active response remains especially promising. A transport-driven change in imported macromolecules can alter the pressure balance and nuclear volume, while remodeling activity can change how chromatin accommodates load. These mechanisms could interact during a state transition, but their relationship is not established simply because both respond to substrate or growth-factor conditions. A joint experiment should track composition, nuclear geometry, loading response and regulatory state. Such an approach can test whether changes in nuclear volume are a cause, consequence or partner of changes in mechanical behavior. [6] [5] [4]

9. An evidence map for integrated nuclear biophysics

The most informative comparisons preserve both the observable and the state of the cell. A nuclear mechanics phenotype can coexist with an unchanged soluble-probe diffusivity, and a pore diameter change can coexist with cargo-specific regulation. Matched studies should report location, scale, loading regime, specimen preparation and the exact molecular reporter. A disagreement then becomes a concrete question about component recruitment or regulation. Without that information, a collection of numerical stiffness or viscosity values can create apparent precision while comparing physically different systems. [23] [1] [12] [11] [25]

10. Synthesis and research priorities

The past decade established that nuclear structure, transport and mechanics are coupled while retaining distinct physical descriptions. Current work is beginning to identify the connections: peripheral tethering recruits chromatin into force response, active remodeling contributes dissipation, spatial heterogeneity affects condensates, and transport helps set nuclear density. The next step is joint causal measurement across these levels. Tracking the sequence of structural, mechanical and regulatory changes in one biological transition will be more revealing than assigning a universal nuclear material label or treating a single assay as sufficient for all mechanisms. [8] [5] [10] [6] [9]

References

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   Evidence and source scope

   Source type: primary. Access: Primary abstract and bibliographic metadata; complete body unavailable through connector..

   Chromatin and lamins contribute in separate isolated-nucleus extension regimes; spring constants are not universal moduli or viscosity.

   No indexed notice in retrieved result is not a guarantee of no correction/retraction. New records lacked complete Scite notice check after monthly quota.

2. [2] Marina Feric, Nilesh Vaidya, Tyler S. Harmon et al. (2016). Coexisting Liquid Phases Underlie Nucleolar Subcompartments. Cell. 10.1016/j.cell.2016.04.047
   Evidence and source scope

   Source type: primary. Access: Primary main-text Results subsection on in-vitro viscoelasticity, Fig2E and main Experimental Procedures, independently checked in root browser; source detail received as collaborator evidence. No supplements/raw-data reanalysis..

   Component-specific nucleolar coexistence and dynamics; in-vitro 50nm-radius tracer values belong to reconstituted NPM1/FIB1 droplets.

   No indexed notice in retrieved result is not a guarantee of no correction/retraction. New records lacked complete Scite notice check after monthly quota.

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   NLS-reporter rupture, defined in-vitro and mouse-dermis models, deformation-associated damage foci and ESCRT-III-dependent resealing independently match primary main Results/Figures. Mixed-topic Scite opening excluded.

   No indexed notice in retrieved result is not a guarantee of no correction/retraction. New records lacked complete Scite notice check after monthly quota.

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   200-nm-diameter targeted magnetic particles in CHO DHFR reporter nuclei; 0.1–5 Hz force response and separate hiPSC Pol II arm; local perturbation and injection limitations.

   No independent experimental replication or raw-data reanalysis. Source interpretation confined to the stated access depth.

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   Evidence and source scope

   Source type: primary. Access: Published PDF front matter, main preparation/treatment Methods, Results around Figure 9 and Discussion read; supplementary data not appraised..

   Metabolically active karyoplast compression/dissipation and BRM-014 inhibition; BRM-014 inhibits BRM and BRG1, so pharmacology is not exclusive genetic proof for BRG1. Karyoplasts are not bare detergent-isolated nuclei.

   No independent experimental replication or raw-data reanalysis. Source interpretation confined to the stated access depth.

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   Evidence and source scope

   Source type: primary. Access: Fetched primary abstract and publisher Results excerpts on Xenopus assembly and density model; Crossmark publication date and author metadata checked. Complete body and supplements not appraised..

   Nuclear/cytoplasmic density differences and pressure-balance model constrained by transport, chromatin and embryo observations. Erroneous2023 provider year corrected to publisher15August2025.

   No independent experimental replication or raw-data reanalysis. Source interpretation confined to the stated access depth.

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   Evidence and source scope

   Source type: primary. Access: Fetched Consensus primary abstract/record, cross-checked with SciSpace where available; complete body not appraised..

   Bergamaschi and colleagues measured isolated-nucleus force responses together with chromatin and nuclear-envelope deformation. Chromatin was more compliant than the envelope below the reported 30% strain regime, and chromatin digestion softened nuclei. The joint readouts strengthen component interpretation in the tested preparation without defining one elastic modulus or viscosity for every nucleus. Bergamaschi et al. (2024) .

   No indexed notice in retrieved result is not a guarantee of no correction/retraction. New records lacked complete Scite notice check after monthly quota.

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   Evidence and source scope

   Source type: primary. Access: Fetched Consensus primary abstract/record, cross-checked with SciSpace where available; complete body not appraised..

   Attar and colleagues used polymer simulations compared with micromechanical and chromosome-contact measurements. In that model, peripheral chromatin attachment transmitted imposed nuclear forces to chromatin, and internal crosslinks stiffened the nucleus only when that peripheral coupling was present. This is a model-constrained account of load transfer; a mapped lamina association by itself does not establish the strength or permanence of every molecular tether. Attar et al. (2025) .

   No indexed notice in retrieved result is not a guarantee of no correction/retraction. New records lacked complete Scite notice check after monthly quota.

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   Evidence and source scope

   Source type: primary. Access: Publisher primary Abstract and main Results through heterochromatin-tether deconvolution, membrane LAP2 rescue and short/long-term transcription effects read; complete Methods and supplements not appraised. Published 24 February 2026..

   Redundant LBR/membrane LAP2 tethering in mammalian cell models, distinction between short-term release and persistent loss; not universal instant repression by peripheral position.

   No independent experimental replication or raw-data reanalysis. Source interpretation confined to the stated access depth.

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    Evidence and source scope

    Source type: primary. Access: Primary publisher Abstract and main Results/Figures1–4 read; complete Methods and supplements not appraised..

    MDA-MB-231 microfluidic confinement, differential leading/trailing chromatin heterogeneity and endogenous/synthetic condensate behavior; reporter expression and phase-boundary context matter.

    No independent experimental replication or raw-data reanalysis. Source interpretation confined to the stated access depth.

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    Evidence and source scope

    Source type: primary. Access: Fetched primary abstract and publication record; full Methods and Results not yet appraised..

    Expanded fixed-cell NPC diameter distributions, nuclear-surface bias, hyperosmotic constriction and LINC perturbation; one patient-derived neuronal comparison does not establish all ALS.

    No independent experimental replication or raw-data reanalysis. Source interpretation confined to the stated access depth.

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    Evidence and source scope

    Source type: primary. Access: Primary PLOS main Abstract, Methods data analysis/acquisition/calibration and selected Results/Discussion; no raw data reanalysis..

    eGFP oligomer FCS outside nucleoli: calibrated two-normal-diffusion components plus triplet term; cell/model/probe constraints retained.

    No indexed notice in retrieved result is not a guarantee of no correction/retraction. New records lacked complete Scite notice check after monthly quota.

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    Evidence and source scope

    Source type: primary. Access: Published identity and primary abstract from author-manuscript repository; full main text not appraised..

    Differently sized inert GFP probes and polymer simulations; size-dependent intermediate-scale viscoelastic behavior and obstacle-network model; not universal fixed fractal organization.

    No independent experimental replication or raw-data reanalysis. Source interpretation confined to the stated access depth.

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    Evidence and source scope

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    Prepared vimentin-null mouse-fibroblast lamina filament structure; approximately3.5nm filaments are not live-lamina thickness.

    No indexed notice in retrieved result is not a guarantee of no correction/retraction. New records lacked complete Scite notice check after monthly quota.

15. [15] Stefan Petrovic, Dipanjan Samanta, Thibaud Perriches et al. (2022). Architecture of the linker-scaffold in the nuclear pore. Science. 10.1126/science.abm9798
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    Linker/scaffold structural integration and flexible ring-spoke models; model architecture not universal transport threshold.

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    Evidence and source scope

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    Composite human/fungal cytoplasmic-face architecture and approximate composition; not one atomic image of a functioning pore.

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17. [17] Lars Guelen, Ludo Pagie, Émilie Brasset et al. (2008). Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature. 10.1038/nature06947
    Evidence and source scope

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    LAD association map, domain scales and low expression in human fibroblasts; no universal permanent tether or repression causality.

    No indexed notice in retrieved result is not a guarantee of no correction/retraction. New records lacked complete Scite notice check after monthly quota.

18. [18] Lars Guelen, Ludo Pagie, Émilie Brasset et al. (2013). Correction: Corrigendum: Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature. 10.1038/nature12316
    Evidence and source scope

    Source type: editorial notice. Access: Primary correction abstract/citation record containing full correction statements; original full Methods not reappraised..

    Official corrected H3K9me3 identity and Methods data sources; no inferred change to uncorrected abstract-level LAD conclusions.

    No indexed notice in retrieved result is not a guarantee of no correction/retraction. New records lacked complete Scite notice check after monthly quota.

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    Evidence and source scope

    Source type: primary. Access: Primary abstract and bibliographic metadata; complete body unavailable through connector..

    Tracer exclusion/hindrance and transient chromatin-protein trapping; fractal interpretation remains model dependent.

    No indexed notice in retrieved result is not a guarantee of no correction/retraction. New records lacked complete Scite notice check after monthly quota.

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    Evidence and source scope

    Source type: primary. Access: Primary abstract and bibliographic metadata; complete body unavailable through connector..

    Reaction-diffusion FRAP solutions constrain binding inference; not every recovery curve identifies every parameter.

    No indexed notice in retrieved result is not a guarantee of no correction/retraction. New records lacked complete Scite notice check after monthly quota.

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    Source type: primary. Access: Primary indexed main Introduction and selected Results/model/simulation evaluation, first8000char source excerpt; not complete article..

    Spot-On model/testing distinguishes localization, defocalization, density and motion-blur biases with steady-state Brownian populations.

    No indexed notice in retrieved result is not a guarantee of no correction/retraction. New records lacked complete Scite notice check after monthly quota.

22. [22] Todd M. Squires, Thomas G. Mason (2010). Fluid Mechanics of Microrheology. Annual Review of Fluid Mechanics. 10.1146/annurev-fluid-121108-145608
    Evidence and source scope

    Source type: seminal review. Access: Publisher bibliographic identity and abstract; established mathematical relationships independently checked dimensionally. Detailed review body not appraised..

    Foundational synthesis of probe/bulk coupling, passive thermal-fluctuation and active-force microrheology assumptions; not a nuclear measurement.

    No independent experimental replication or raw-data reanalysis. Source interpretation confined to the stated access depth.

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    Evidence and source scope

    Source type: primary. Access: Root independently read primary PMC12173521 Abstract and selected main Methods/Results paragraphs, including oscillatory preparation, hydrodynamic drag correction, morphology and Jeffreys analysis; primary Scite webpage identity corroborated. Supplement and raw-data reanalysis excluded..

    Oscillatory AFM on live and isolated MCF7 nuclei, hydrodynamic-drag validation, modulus/loss-tangent distinction and Jeffreys model. The published author list supersedes incomplete Consensus authors.

    No independent experimental replication or raw-data reanalysis. Source interpretation confined to the stated access depth.

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    Evidence and source scope

    Source type: primary. Access: Primary abstract and bibliographic identity through author institutional repository; full Methods not appraised..

    SUN1/SUN2–nesprin2 localization and depletion/overexpression in HeLa cells, perinuclear spacing and LINC model.

    No independent experimental replication or raw-data reanalysis. Source interpretation confined to the stated access depth.

25. [25] Alberto Elosegui-Artola, Ion Andreu, Amy E. M. Beedle et al. (2017). Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores. Cell. 10.1016/j.cell.2017.10.008
    Evidence and source scope

    Source type: primary. Access: Publisher primary selected Results on force application and import/export plus AFM Methods excerpt read; complete body and supplements not appraised..

    Force-dependent YAP entry in defined fibroblast/MCF10A systems, nuclear deformation and import-rate assays; not all cargo or universal pore-mechanics explanation.

    No independent experimental replication or raw-data reanalysis. Source interpretation confined to the stated access depth.

26. [26] Yolanda Olmos, Lorna Hodgson, Judith Mantell, Paul Verkade, Jeremy G. Carlton (2015). ESCRT-III controls nuclear envelope reformation. Nature. 10.1038/nature14503
    Evidence and source scope

    Source type: primary. Access: Fetched primary abstract and identity; full Methods not accessible..

    CHMP2A/CHMP4B/UFD1-dependent postmitotic envelope sealing and compartmentalization in human cells, not all envelope-repair routes.

    No independent experimental replication or raw-data reanalysis. Source interpretation confined to the stated access depth.

27. [27] Patrick C. Hoffmann, Hyuntae Kim, Aleksandra Obarska-Kosińska et al. (2024). Nuclear pore permeability and fluid flow are modulated by its dilation state. Molecular Cell. 10.1016/j.molcel.2024.11.038
    Evidence and source scope

    Source type: primary. Access: Consensus fetched primary record and search-returned primary abstract; full Results inaccessible. Online 2024; issue year should not replace online publication date..

    Dictyostelium osmotic adaptation, dilation-dependent pressure-driven nucleocytosolic fluid flow and viral blockage; not identical to diffusion or receptor-driven transport.

    No independent experimental replication or raw-data reanalysis. Source interpretation confined to the stated access depth.

28. [28] Benjamin L. Timney, Barak Raveh, Roxana Mironska et al. (2016). Simple rules for passive diffusion through the nuclear pore complex. Journal of Cell Biology. 10.1083/jcb.201601004
    Evidence and source scope

    Source type: primary. Access: Primary abstract and bibliographic metadata; complete body unavailable through connector..

    Gradual size-dependent passive NPC reporter exchange in yeast; not a hard universal mass cutoff or whole-nucleoplasm diffusion law.

    No indexed notice in retrieved result is not a guarantee of no correction/retraction. New records lacked complete Scite notice check after monthly quota.

29. [29] Kaitlin P. McCreery, Aki Stubb, Rebecca Stephens et al. (2025). Mechano-osmotic signals control chromatin state and fate transitions in pluripotent stem cells. Nature Cell Biology. 10.1038/s41556-025-01767-x
    Evidence and source scope

    Source type: primary. Access: Primary abstract, publication identity and main Figures1–5 captions through PubMed read; complete main Results/Methods not appraised..

    Human embryo/primed-pluripotency models connect growth-factor state, nuclear deformation, crowding and chromatin regulation. Mechanical/osmotic priming is not sufficient for robust lineage induction without sustained biochemical signals.

    No independent experimental replication or raw-data reanalysis. Source interpretation confined to the stated access depth.

Evidence scope

This review integrates published primary research with a foundational methods review where needed. Source access ranges from primary abstracts to the selected main Results and Methods identified in each reference record. It is a scholarly synthesis rather than an independent reanalysis of experimental data. Conclusions retain the biological system, measurement scale and model assumptions of the cited studies.