{"id":"3746fd06-9b05-4029-9a41-4d1379a5a0ab","arxiv_id":"2508.06461","paper_version":1,"verdict":"UNVERDICTED","confidence":"LOW","novelty_score":6.0,"correctness_risk":"unknown","formal_verification":"none","parameter_count":2,"one_line_summary":"A continuum model shows low substrate friction allows collective cell motion to generate spiral flows that concentrate stress and spontaneously open persistent holes in cell monolayers.","lead":"This preprint presents simulations of a continuum model of cell monolayers, showing that when cells slide more easily over their substrate, their motion becomes more correlated and can create holes. The findings connect collective cell movement, tissue stress, and the spontaneous appearance of persistent gaps in tissue.","discovery_kind":"extension","skeptic_critique":{"model":"deepseek-v4-flash","headline":"Model's hole formation may be a parameter artifact; missing calibration to MDCK mechanics weakens the causal claim.","rationale":"The reader's weakest assumption is that the continuum model adequately captures MDCK mechanics. My concern sharpens this: even granting the model form, the predictions may be sensitive to uncalibrated parameter values, particularly the active stress and interfacial tension. Since only the abstract is available, the full derivation and parameter choices cannot be audited, so the verdict remains UNVERDICTED. However, the proposed calibration and passive-control checks would directly test whether the claimed emergent hole formation is robust and biologically representative. I partially agree with the reader because my concern is more specific about parameter dependence rather than the overall model form.","tokens_in":532,"tokens_out":4049,"duration_ms":47833,"concrete_test":"Rerun the simulations with the active dipolar force set to zero (passive tissue) across the same friction range; if holes still appear, the mechanism is not driven by active collective motion. Additionally, calibrate the model's interfacial tension, internal dissipation, and active stress to published MDCK measurements (e.g., micropipette aspiration, traction force microscopy, and cell rheology) and recompute the (friction, activity) phase diagram. If the low-friction hole regime lies outside the calibrated parameter range or disappears in the passive control, the central claim fails.","verdict_should_be":"UNCHANGED","load_bearing_attack":"The central claim that low friction + topological defects produce spiral flows that trigger holes rests on the balance between active dipolar stress and interfacial cohesion in the continuum multi-phase field model. The abstract does not report whether parameters (active force, internal dissipation, interfacial tension) are fitted to MDCK tissue measurements, nor any quantitative comparison with experimental hole densities or stability on soft substrates. If the active stress is set too high or the interfacial tension too low relative to measured values, holes can form by a purely mechanical dewetting that does not require collective cell motion as the essential mechanism. Thus the assertion that hole formation 'emerges from collective cell motion' may be an artifact of the chosen parameter regime rather than a robust biological insight.","agreement_with_reader":"partial"},"referee_report":{"model":"deepseek-v4-flash","summary":"The paper proposes a continuum multi-phase field model that incorporates internal dissipation and active dipolar forces to study spontaneous hole formation in cell monolayers. Based on simulations, the authors claim that reducing substrate friction increases cell-cell velocity correlations, and that in this low-friction regime topological defects generate spiral flow patterns that concentrate mechanical stress and trigger hole formation. The number and stability of holes are reported to depend on substrate friction and cellular activity. The abstract frames the central result as evidence that collective cell dynamics are critical for maintaining tissue integrity.","tokens_in":727,"tokens_out":1272,"duration_ms":15870,"significance":"If the claims are supported by quantitative validation, the work could provide a mechanistic bridge between active nematic defects and tissue-scale permeabilization, with implications for morphogenesis, wound healing, and tissue engineering. The strength of the claim, however, cannot be assessed from the abstract alone: no equations, parameter values, or experimental comparisons are provided. The paper's potential significance is therefore conditional on the full manuscript supplying the missing technical and quantitative support.","major_comments":[{"comment":"The abstract does not report any parameter values or ranges for the active dipolar stress, internal dissipation, interfacial tension, or substrate friction. This is load-bearing for the central claim: without evidence that these parameters fall within physiologically measured regimes for MDCK monolayers, the simulated hole formation could be an artifact of a dewetting-like parameter choice rather than a robust consequence of collective cell motion. The authors should provide the parameter values and, ideally, a sensitivity analysis showing that holes appear in a robust parameter region rather than only at a finely tuned boundary.","section":"Abstract"},{"comment":"The claim that hole formation 'emerges from collective cell motion' implies a causal mechanism that transcends mere mechanical dewetting. However, the abstract presents no quantitative comparison with experimental hole densities, hole sizes, or time scales on soft substrates. Without such validation, the causal attribution to collective motion remains unsupported. The authors should specify which experimental observables from MDCK studies on soft substrates are reproduced by the model and with what accuracy.","section":"Abstract"},{"comment":"The statement that 'the number and stability of the holes, whether they close or persist, depends on both substrate friction and cellular activity' is presented without a phase diagram, threshold values, or quantitative trend. This is a key prediction of the model, but the abstract gives no indication of the magnitude of the effect or whether the dependence is monotonic, nonmonotonic, or bistable. The full manuscript should include such a characterization to allow the claim to be tested experimentally.","section":"Abstract"}],"minor_comments":[{"comment":"The abstract mentions 'recent studies on MDCK monolayers' without citations. In a published paper the full text will presumably cite these studies, but the abstract alone leaves the reader unable to connect the model to specific experimental observations.","section":"Abstract"}],"recommendation":"uncertain","confidential_remarks":"This review is based solely on the abstract, as the full text was not provided. The central claim is plausible and interesting, but the absence of equations, parameter values, and experimental validation makes it impossible to judge soundness. I cannot recommend acceptance or rejection without the full manuscript; the recommendation is 'uncertain' pending full review."},"author_rebuttal":null,"desk_editor":{"model":"deepseek-v4-flash","letter":"The one thing you should know: this is not another generic 'defects cause holes' paper. The new twist is that substrate friction controls whether spiral flows around topological defects concentrate stress enough to open holes, and whether those holes persist or heal. That is a concrete, mechanistic claim, and it goes beyond the prior work the authors cite. If it holds up, it gives experiments a handle: tune substrate stiffness and activity, watch hole density and lifetime.\n\nWhat the paper does well, even from the abstract: it names the physical ingredients — active dipolar forces, internal dissipation, cell shape anisotropy — and makes a falsifiable prediction that low friction enhances velocity correlations and promotes persistent holes. That is the right level of specificity for a simulation paper. The framing around tissue integrity is also sensible, not overstated.\n\nNow the soft spots, in proportion. The abstract gives no equations, no parameter values, and no comparison to MDCK data. That means the central claim is unverifiable from the abstract alone. The stress-test worry — that holes could be a parameter artifact, a mechanical dewetting that would happen even without collective motion as the essential cause — is legitimate. If the active stress is too high or interfacial tension too low relative to measured tissue values, you can get holes regardless of the spiral-flow mechanism. But that is exactly what referees are for. Nothing in the abstract signals dishonesty or hidden fitting; it simply doesn't show the calibration.\n\nI would not desk-reject this. The mechanism is novel enough and the authors are clearly competent. The full paper likely contains the phase-field equations and simulation details, so a referee can check whether the parameter regime is biological or just convenient. If the parameter scan is anchored to MDCK measurements, this is a solid contribution. If not, it's still a useful theoretical prediction that experiments can test.\n\nFor you: worth a reading-group slot to argue about how much weight to give a continuum model with internal dissipation. I'd cite it if I were working on active matter or tissue mechanics, granted the full text checks out.\n\nRecommendation: send it to peer review. A serious referee should spend time on it.","headline":"A plausible, specific mechanism linking substrate friction, spiral flows around defects, and hole stability; the abstract alone can't verify the parameter regime, but the claim is sharp enough to warrant a real referee.","tokens_in":1075,"tokens_out":1086,"would_cite":true,"duration_ms":15946,"reading_group":"yes","serious_thinker":"yes","would_accept_peer_review":true},"rs_alignment":null,"lean_confirmation":null,"pith_extraction":{"msc":[],"pacs":[],"model":"deepseek-v4-flash","headline":"Spontaneous holes in cell monolayers arise from collective cell motion: in the low-friction regime, topological defects generate spiral flows that concentrate stress and open holes, with hole number and persistence set by substrate friction","keywords":["cell monolayers","topological defects","active nematics","collective cell motion","hole formation","multi-phase field model","substrate friction","tissue integrity"],"falsifier":"Time-lapse tracking of the velocity field around topological defects in a low-friction monolayer: the model predicts a persistent spiral flow and a local stress peak at the defect core immediately before a hole opens. If imaging shows holes appearing without any preceding swirl or local stress concentration, the proposed triggering mechanism is wrong; equivalently, if the model still produces holes when active dipolar forces are switched off, the claim that collective motion is the cause would collapse.","tokens_in":522,"feed_emoji":"🕳️","tokens_out":4474,"duration_ms":51425,"temperature":0.7,"pith_summary":"This paper argues that spontaneous holes in cell monolayers are not random failures but a collective mechanical instability driven by cell motion. Using a continuum multi-phase field model with active dipolar forces and internal dissipation, the authors show that on low-friction substrates cells develop strong velocity correlations, and topological defects in their nematic alignment seed spiral flows. These spiral flows concentrate mechanical stress, which can open holes in the monolayer. The model further shows that hole number and whether holes close or persist depend on the balance between substrate friction and cellular activity, pointing to collective dynamics as a key regulator of tissue integrity.","feed_headline":"Spiral cell flow opens holes in low-friction monolayers","feed_subtitle":"A continuum model shows defects in cell alignment create spiral stress that triggers persistent holes.","key_machinery":"The key object is a continuum multi-phase field model in which each cell is represented by a phase field, and cell shape anisotropy is driven by active dipolar forces; internal dissipation controls how the mechanical work of these forces is converted into deformation. The model produces local nematic order whose topological defects are the active sites of the mechanism. In the low-friction regime, these defects organise the surrounding velocity field into spirals, and the resulting stress concentration is what triggers hole formation.","core_discovery":"The central claim is that topological defects in the locally aligned cell orientation act as mechanical singularities: when the substrate friction is low, each defect generates a spiral flow pattern that pumps stress into its core, and sufficiently active cells convert that stress into the opening of a hole. The holes are therefore a direct consequence of collective cell motion rather than of chemical signalling or external damage. In the model, the fate of a hole—whether it heals or persists—is controlled by two parameters: substrate friction and the strength of the active dipolar force driving cell shape anisotropy. Low friction and high activity favour persistent holes; higher friction or","pith_inferences":["The mechanism suggests a threshold in the activity-to-friction ratio: holes should appear only above a critical value. Measuring this ratio across substrates of different stiffness would provide a direct experimental test.","The predicted spiral flows imply that cells rotate coherently around defect cores before a hole opens; time-lapse tracking of the velocity field near defects could detect these swirls as precursors.","If the mechanism is generic, similar hole formation should occur in other confluent active nematic tissues, such as confined organoids or epithelial sheets under low adhesion, not only in the specific cell line studied.","The role of internal dissipation suggests that treatments that increase effective friction or reduce active contraction could preserve confluence, a testable implication for wound healing."],"forward_implications":["Substrate friction acts as a control parameter for monolayer integrity: lowering friction strengthens cell-cell velocity correlations and makes hole formation more likely.","Cellular activity sets the fate of a hole: high active dipolar forcing favours persistent holes, while lower activity allows holes to close.","Topological defects in cell alignment should be viewed as mechanically active locations, not just orientational texture, because they are the sites where spiral flow and stress concentrate.","The continuum model offers a mechanistic explanation for the spontaneous, persistent holes seen in experiments on soft substrates.","Tissue integrity is not a static property but an outcome of the balance between collective motion and dissipative coupling to the environment."],"supporting_citations":[],"fun_headline_variants":["Spiral cell flow carves holes in low-friction monolayers","Low friction turns cell swirls into monolayer hole punchers","Collective motion, not damage, opens holes in cell sheets","Topological defects detonate spiral stress to rip holes","Persistent holes in soft monolayers come from active swirls"],"cache_read_input_tokens":2816,"weakest_assumption_plain":"The load-bearing premise is that the continuum multi-phase field model with internal dissipation and active dipolar forces reproduces the actual mechanics of cell monolayers on soft substrates, so that the holes it produces are the same phenomenon seen in experiments.","fun_headline_variants_meta":{"raw":{"variants":["Spiral cell flow carves holes in low-friction monolayers","Low friction turns cell swirls into monolayer hole punchers","Collective motion, not damage, opens holes in cell sheets","Topological defects detonate spiral stress to rip holes","Persistent holes in soft monolayers come from active swirls"]},"model":"deepseek-v4-flash","effort":"low","cost_usd":0.000751,"raw_usage":{"total_tokens":3135,"prompt_tokens":652,"completion_tokens":2483,"prompt_tokens_details":{"cached_tokens":256},"prompt_cache_hit_tokens":256,"prompt_cache_miss_tokens":396,"completion_tokens_details":{"reasoning_tokens":2408}},"tokens_in":396,"tokens_out":2483,"duration_ms":19018,"temperature":1.0,"reasoning_tokens":2408,"cache_read_input_tokens":256,"cache_creation_input_tokens":0},"cache_creation_input_tokens":0},"created_at":"2026-08-05T22:40:31.319393+00:00","model_set":{"reader":"deepseek-v4-flash"},"falsifier":"Time-lapse tracking of the velocity field around topological defects in a low-friction monolayer: the model predicts a persistent spiral flow and a local stress peak at the defect core immediately before a hole opens. If imaging shows holes appearing without any preceding swirl or local stress concentration, the proposed triggering mechanism is wrong; equivalently, if the model still produces holes when active dipolar forces are switched off, the claim that collective motion is the cause would collapse.","supporting_citations":[],"review_version":1}