Papers

A central hypothesis in aging biology proposes that the gradual accumulation of stochastic molecular damage drives transcriptional deregulation (TD), ultimately leading to functional decline. However, existing single-cell analyses largely rely on static expression measurements and provide limited resolution of how regulatory responses change at the level of individual cells. Here, we leverage DKO, a deep learning framework that predicts cell-specific virtual gene perturbation effects from unperturbed transcriptomes, capturing cell-to-cell differences in regulatory context without requiring a reconstructed gene regulatory network or matched perturbation data. Applying DKO to single-cell transcriptomic datasets from humans, mice, Drosophila, and C. elegans revealed that the transcriptional consequences of perturbing the same gene became increasingly heterogeneous across cells with age, indicating that gene regulatory responses become less consistent and more dependent on cellular context. Furthermore, we find that cells with higher somatic mutation burdens have greater knockout-response variability, linking accumulated molecular damage to regulatory inconsistency. Within the same cellular populations, higher impact variability was also associated with higher senescence scores, linking transcriptional dysregulation to senescence-associated states. Our findings identify a progressive loss of regulatory robustness at both the gene and cell levels as a conserved feature of aging, linking stochastic molecular damage to increasing heterogeneity in cellular regulatory responses.

Adenoid cystic carcinoma (ACC) of the lacrimal gland is a rare and extremely life threatening malignant tumor with a high risk of recurrence and poor long-term outcomes. On the other hand, due to its complex molecular dynamics and low incidence rate, treatment strategies are very limited. In this study, a mathematical model is developed based on the biological phenomena of the tumor microenvironment using nonlinear ordinary differential equations. It is analyzed both analytically and numerically. According to the findings, the growth of tumor cells is associated with the depletion of oxygen and nutrients, while severe hypoxia promotes the development of abnormal blood vessels and makes tumor control more difficult. Surgery and postoperative radiotherapy have been considered as treatment strategies, and we have observed that surgery alone may not be sufficient to prevent the regrowth of residual tumor cells. In addition, postoperative radiotherapy provides better control of the residual tumor burden, particularly when the remaining tumor cells have higher radiosensitivity. Furthermore, different radiotherapy interruption scenarios have been investigated, and the results indicate that longer gaps between radiotherapy doses can adversely affect the overall treatment response, leading to increased overall toxicity and a higher number of residual tumor cells at the end of the observation period. Consequently, our results suggest that postoperative radiotherapy after surgery, combined with adequate radiosensitivity of the residual tumor cells and adherence to the prescribed treatment schedule without prolonged interruptions, may reduce the risk of tumor recurrence and potentially improve long term survival.

Spatial transcriptomics jointly captures molecular state, tissue morphology, and spatial organization, yet spatial-domain methods are typically compared only at late training checkpoints, obscuring differences in convergence efficiency. We introduce MP-MNCA, a morphology-prior masked neighbor cross-attention framework that preserves the full 3,000 dimensional highly-variable-gene representation while selectively routing molecular information across spatial neighbors, with histological similarity incorporated as a continuous attention prior under a self-supervised masked neighbor-contrastive objective. Across 12 heterogeneous human dorsolateral prefrontal cortex (DLPFC) sections, MP-MNCA is evaluated against established spatial-domain baselines using both convergence trajectories and epoch-wise spatial-domain visualizations. Our results show that MP-MNCA (i) reaches coherent spatial-domain structure in substantially fewer training epochs, as reflected quantitatively by convergence curves and qualitatively by progressive spatial grids, and (ii) maintains strong clustering quality, achieving a mean peak refined ARI of 0.546 versus 0.549 for the strongest baseline (STAIG), while attaining the highest mean refined NMI of 0.657 versus 0.640. Moreover, MP-MNCA outperforms STAIG on 7 of 12 sections in ARI and 11 of 12 in NMI, demonstrating faster convergence without sacrificing spatial-domain quality.

Automatic extraction and anatomical numbering (R01-R12, L01-L12) of all 24 rib centerlines in thoracic CT is essential for unfolded rib visualization, fracture detection, and surgical navigation, but remains challenging due to adjacent-bone confluence, calcified costal cartilage bridges, kyphotic pose variation, and partial visibility of terminal ribs. We present ribline, an open-source three-stage framework combining: (1) an automatically detected lung-apex and vertebral-midline coordinate frame with a kyphosis-aware azimuthal angle for point ordering along each rib; (2) a hybrid voxel detector fusing an anatomically anchored Semantic Context Forest (SCF) with a lightweight 3D U-Net; and (3) a global stage that decomposes the probability skeleton into candidate curves, assigns rib indices via a bilateral Viterbi dynamic program coupled across both hemithoraces, and refines curves via template recovery and normal-plane centering (RibSnake). On the Siemens Corporate Research 2 mm thoracic CT benchmark (47 training and 12 evaluation scans), our pipeline achieves a labeled Chamfer distance of 2.05 mm, labeled clDice of 0.886 (3 mm) and 0.945 (4 mm), 97.2% labeling accuracy (278/286 ribs), and zero false-positive curves on the evaluation split, and 3.64 mm (median 2.39 mm) with 91.8% labeling accuracy across all 59 annotated scans (1,402 ribs) in 5-fold cross-validation. Code: https://github.com/wq2012/ribline Pretrained Models: https://huggingface.co/collections/wq2012/ribline

Large language models (LLMs) are increasingly evaluated across ophthalmic tasks, yet the methodological quality of these evaluations has received little attention. Most studies report accuracy while overlooking design features required for valid and clinically meaningful inference. We critically reviewed published ophthalmic LLM evaluation studies covering knowledge assessment, patient education, diagnostic reasoning, triage, clinical documentation, multimodal image interpretation, and uncertainty estimation. We used the methodological weaknesses that recurred across study designs to develop the SIGHT framework, which has five domains: Sample and item provenance, Independence and blinding, Ground truth and comparator fairness, Handling of paired and repeated-measures data, and Transparency and trustworthiness. Current evaluations rely heavily on benchmark accuracy, synthetic clinical vignettes, and curated datasets, and real-world clinical validation remains rare. Common limitations include potential training-data contamination, inadequate handling of paired data, limited assessment of inter-rater reliability, inconsistent reference standards, insufficient evaluation of calibration and uncertainty, and frequent overinterpretation of benchmark performance as evidence of clinical readiness. SIGHT provides twenty structured appraisal items to evaluate internal validity, interpretability, and applicability across diverse ophthalmic LLM study designs. It offers a practical way to appraise ophthalmic LLM studies and may improve the methodological quality, interpretability, and clinical relevance of future evaluations.

Sliding-scale insulin is the default hospital response to high blood glucose. Its correction factor was designed for patients who make no insulin, yet it is routinely ordered for patients whose pancreas still works, including those on high-dose steroids. We treat the sliding scale as what it is, a proportional controller sampled every four hours, acting on a patient who already contains a working glucose controller of her own. We test it in a non-diabetic adolescent on high-dose corticosteroids and parenteral nutrition, and in 4,995 virtual patients. It fails for three structural reasons, and no choice of correction factor fixes any of them. First, the patient's own loop settles in 11.5 minutes while injected insulin takes 64 minutes to peak, so most of each dose simply replaces insulin she would have secreted; in simulation the ordered scale moved her mean glucose by less than 1.5 mg/dL. Second, one unit lowers glucose twice as much at 110 mg/dL as at 190, so any correction factor strong enough to work when glucose is high overshoots when it is low; in 99.5% of virtual patients no constant factor does both. Third, four-hour sampling is far below the Nyquist rate, so successive readings are uncorrelated and each dose responds to a value that does not persist. Even the argument that correction doses rest the beta cells, taken on its own terms, favors continuous delivery. We propose replacing the scale with a continuous insulin infusion co-delivered with the dextrose and adjusted once a day on mean glucose, the one quantity four-hour monitoring can measure.

Extracting patient-specific vascular trees from volumetric medical images is fundamental to computational angiography and non-invasive hemodynamic assessment. Conventional voxel segmentation models often sever delicate bifurcations, while heuristic Euclidean Minimum Spanning Trees introduce non-anatomical shortcuts. Moreover, linear Poiseuille flow neglects quadratic kinetic dissipation across arterial narrowings, underestimating ischemia. We formulate an end-to-end framework decoupling continuous geometric arborescence generation from non-linear hemodynamics. First, an autonomous 3D Ostium Landmark Localization Head with dual-sinus query channels and spherical-gated refinement eliminates centerline seeding dependency, achieving cohort mean localization error of 7.63 mm (7.43 mm LCA, 7.83 mm RCA; 71.4% <= 8.0 mm) from raw contrast context. Second, a Spatially-Grounded Deformable Step Flow Architecture queries continuous 3D feature pyramids via trilinear sampling, sequentially generating trajectories with anchor boundary enforcement (X(0) = P_start). Third, a Top-Down Recursive Arborescence State Machine detects bifurcation peaks via Tree-NMS and parameterizes predecessor parent pointers (p_k < k), guaranteeing single connected acyclic tree topology (beta_0 = 1, beta_1 = 0) with differentiable step termination. Fourth, an iterative Picard non-linear Kirchhoff solver with Young-Tsai / Gould quadratic dissipation enforces machine-precision mass conservation (residual 5.82e-11 mL/s). Across 14 development patients under standardized in-silico stenosis stress testing (Q_0 = 4.0 mL/s), linear Poiseuille flow misclassifies 75% diameter lesions as non-ischemic (FFR > 0.80) in 14/14 cases, whereas our non-linear solver captures functional ischemia (FFR = 0.5864, lesion disparity 32.89 mmHg, p = 6.10e-5) with 3.66x collateral shunting. Test set firewall isolation was maintained.

Purpose: To evaluate the performance-feasibility tradeoffs of foundation models (FMs) and task-specific convolutional neural networks (CNNs) trained from scratch for breast implant classification in 2D mammography, with emphasis on suitability for near real-time clinical deployment. Methods: We evaluated four models: two FMs (RAD-DINO and MammoCLIP) and two CNNs trained from scratch for implant prediction (ResNet18 and our lightweight ResNetLite). Using the Emory Breast Imaging Dataset, 5,000 unilateral screening mammograms were used for training/validation and 1,000 manually reviewed unilateral images were held out for testing. For the FMs, global image embeddings from the pretrained encoder were classified using a support vector machine (SVM). The CNNs were trained end-to-end on 2D mammograms, with ResNetLite optimized via grid search over depth and width to balance accuracy and efficiency. Performance was evaluated using AUROC, sensitivity, specificity, accuracy, embedding visualization, and inference-latency. Results: All models demonstrated strong performance on held-out test data (n = 1,000). MammoCLIP achieved the highest AUROC (0.999) with the quickest training time of 493 seconds. RAD-DINO achieved the highest sensitivity (0.980; accuracy 0.989) but had the slowest inference and training times. ResNet18 and MammoCLIP achieved comparable accuracy (0.985). ResNetLite showed no statistically significant difference from ResNet18 (AUROC 0.993; accuracy 0.976) despite using only 1.4% of ResNet18's parameters, and had the fastest inference time. Conclusion: FMs and task-specific CNN models reliably detect breast implants on 2D mammography. Model selection is best guided by deployment context: MammoCLIP for GPU-equipped hospital settings requiring scalable integration, and lightweight CNNs such as ResNetLite for resource-constrained or edge deployments.

We study transient solute dispersion in pressure-driven micropolar flow through a concentric annulus representing a catheterized artery. The catheter is impermeable to solute, whereas the arterial wall combines irreversible removal with reversible surface retention. The exact steady micropolar velocity field is coupled to the Gill-Sankarasubramanian generalized-dispersion framework; the resulting bulk-surface hierarchy is advanced with Rannacher-damped Crank-Nicolson time stepping to determine $K_0(t)$, $K_1(t)$ and $K_2(t)$. The exchange coefficient is independent of the micropolar parameters and satisfies $-K_0(0^+)=2(\beta+\theta Da)/(1-\lambda^2)$, whereas $K_2-Pe^{-2}\sim\sigma_v^2t$ initially, so the leading short-time dispersion is hydrodynamic and independent of wall kinetics. In the weak-reaction regime, micropolarity modifies convection approximately linearly and shear dispersion quadratically through the velocity-amplitude factor. A narrow-gap analysis with $\varepsilon=1-\lambda$ gives $\bar v\sim(2-N_c)\varepsilon^2/6$ and $K_2-Pe^{-2}\sim(2-N_c)^2\varepsilon^6/7560$ for a fixed pressure gradient, revealing a sixth-power suppression of shear dispersion as the catheter approaches the arterial wall. Increasing $\lambda$ from $0.01$ to $0.30$ reduces effective convection by about a factor of $2.45$, while chemically passive shear-induced dispersion falls by a factor of $24$. The coupled formulation also yields the exact partition $\Phi_m+\Phi_s+\Phi_a=1$, separating mobile, reversibly retained and irreversibly absorbed solute. The reconstructed field quantifies reaction-modulated transverse non-uniformity, while the results distinguish hydrodynamic effects of confinement and microrotation from kinetic wall effects.

Truncus arteriosus (TA) is a rare, severe congenital heart disease in which the two main arteries exiting the heart fail to separate in utero resulting in one truncus and truncal valve, carrying mixed oxygenated and deoxygenated blood. About 25% of patients have a quadricuspid valve, which is prone to regurgitation and re-intervention. Despite its relevance for valve performance and mixing, fluid mechanics in TA are poorly understood. Patient-specific fluid-structure interaction simulations were performed based on CT imaging before and after TA repair. The quadricuspid valve was constructed using elasticity-based design with the patient's free edge length and geometric height extracted from echocardiography. Interaction between blood and valve was simulated with the Immersed Boundary Method. Boundary conditions were tuned to the patient's data. Mixing of oxygenated and deoxygenated blood and streaming were assessed via Lagrangian Coherent Structures (LCS) and Lagrangian Particle Tracing (LPT). Low pressures, forward flow and streamwise vortices in the one-sided pulmonary arteries (PAs) throughout the cardiac cycle affected leaflet motion, leading to asymmetric closure and regurgitation. Holodiastolic aortic flow reversal supplied PA flow and the regurgitant jet. LCS and LPT indicated favorable streaming of oxygenated blood from the LV to the aorta and deoxygenated blood from the RV to the PAs. After truncal surgery, normal hemodynamics were restored. This is the first study of fluid mechanics of TA. Using qualitative and quantitative flow analysis, we identified disrupted preoperative hemodynamics caused by one-sided PAs and showed how normal hemodynamics were re-established after repair. Favorable streaming was demonstrated aligned with patient reports. Thus, favorable streaming is plausible in total mixing lesions and patient-specific modeling may aid in its detection.

Ovarian follicle development has been modeled either by compartmental models, where developmental stages are represented by discrete compartments, or by physiologically structured population models (PSPMs), formulated as transport PDEs describing follicles along a continuous maturation variable. Compartmental models reproduce full-cycle hormonal and follicular dynamics but cannot describe cellular features. PSPMs capture multiscale behavior, yet lack a direct link to compartmental descriptions, making hormonal feedback difficult to incorporate. Here, we introduce a class of ODE systems derived as finite-dimensional reductions of PSPMs via a perturbative moment closure. These systems provide backbone approximations of the structured dynamics, retaining key nonlinear mechanisms governing recruitment, selection for dominance, and atresia while projecting maturation onto macroscopic variables. Zero- and first-order moments, derived from phenomenological assumptions regarding follicular maturation, allow us to realistically model follicle sizes and blood estradiol concentrations over one follicular wave. This application is supported by bovine data and likely generalizable to other mammalian species.

Pneumonia is difficult to diagnose in older long-term care residents; multimorbidity and atypical presentations obscure signs, motivating operationally efficient objective testing. We analyzed multi-channel digital stethoscope recordings from 185 Japanese residents (73 pneumonia, 112 symptomatic without), using radiologist-confirmed chest X-rays and clinician diagnoses as supervisory signals that train convolutional neural networks, multimodal fusion, and channel-based variants with time-domain Grad-CAM interpretability. Models were evaluated with repeated patient-level cross-validation showing models with X-ray supervision outperformed clinician supervision (F1 0.729, accuracy 0.783 vs. F1 0.637, accuracy 0.711). Additionally, a three-channel selection protocol maintained performance (F1 0.736; accuracy 0.803), with two mid-thoracic sites ranking highest and Grad-CAM attention overlapping adventitious sounds. These findings indicate automated multi-channel lung-sound analysis can aid long-term care pneumonia diagnosis, with X-ray supervision being more reliable than clinical, and fewer channels preserving performance while lowering acquisition times.

The lymphatic system (LS), a body-wide network of vessels and lymphoid organs governing fluid homeostasis and immune surveillance, has so far not been investigated as a domain for diagnostic and therapeutic molecular communications (MC) applications, despite several properties that make it a promising, complementary alternative to the cardiovascular system. These favorable properties include slower flow, simpler and less dense molecular fluid composition, and direct anatomical access to lymph nodes. Realizing this potential, however, requires a quantitative understanding of how solutes propagate through the LS, a problem that, unlike lymph flow itself, remains largely unaddressed in the literature. As a first step towards narrowing this gap, we develop a particle-based simulation (PBS) framework of solute transport through a three-dimensional chain of valve-separated, concatenated vessel segments, called lymphangions. We simulate the spatiotemporal evolution of solute concentration and qualitatively validate the resulting transport dynamics against existing in vivo measurements of fluorescent tracer propagation in multi-lymphangion lymphatic vessels. Our simulations show that the valve-gated nature of solute transport in lymphatic vessels leads to bursty solute concentrations over time, a characteristic that can also be observed in vivo. Additionally, we find that, within one pumping period, peak timing is dictated by the valves' synchronizing effect rather than the particle release time, while diffusivity and receiver placement determine peak sharpness. Overall, the proposed PBS framework provides a first quantitative basis for solute transport modeling in the LS and several concrete application scenarios for MC in this underexplored domain. Supplementary video material illustrating the PBS is publicly available on Zenodo [DOI: 10.5281/zenodo.21888066].

Electrocardiograms (ECGs) carry subject-specific patterns enabling reliable individual discrimination, forming the basis of ECG biometrics. Beyond authentication, this paradigm holds significant potential to secure sensitive cardiac data and to serve as a pretext task in self-supervised learning. Yet, most studies remain confined to singlesession, resting data, leaving robustness to temporal and physiological variations largely untested. We address this gap by evaluating ECG biometrics under realistic conditions involving exercise-induced stress and cross-session variability. A Siamese ResNet with late multi-lead fusion strategy is trained on a large ECG dataset extracted from cardiopulmonary exercise tests and evaluated with a exercise-and time-aware protocol, as well as on public benchmarks. This first extensive assessment of ECG biometrics under combined physiological and temporal variability achieves an intra-session rest-to-peak EER of 1.7% and stateof-the-art 3.9% on the CYBHi dataset. Findings support the presence of an intrinsic cardiac signature resilient to physiological and temporal drift.

We formulate and analyze a system of non-linear ordinary differential equations that describe key metabolic and immunological interactions between butyrate produced by fiber-fermenting gut microbiota, colorectal cancer cells and host cell populations. The model is studied both independently and in conjunction with a pre-existing carbohydrate fermentation model. The parameter space is explored through sensitivity analyses. Simulation experiments are conducted to illustrate the emergence of varying dynamical behaviour driven by butyrate availability. Our model predicts that butyrate production is driven by fiber consumption and further supported by probiotics in the case of microbial dysbiosis. It also suggests that butyrate may help in suppressing tumour growth. We also show that by adding noise with sufficiently high intensity, cancer elimination occurs almost surely in infinite time and that this threshold level of noise intensity decreases with increasing butyrate concentrations.

The diversity of brain size and organization across mammals reflects how evolutionary and ecological pressures have shaped neural architecture through time. Yet, how these selective pressures translated into measurable variation in the proportions and overall shape of the brain across species remains poorly understood. In this study, we used high-resolution virtual endocasts from 41 musteloid species (e.g. otters, skunks, raccoons) to quantify variation in endocranial composition and shape. We analyzed both the complete endocast and its principal subdivisions (olfactory bulbs, cerebrum, and hindbrain) using a combination of compositional data analysis and 3D geometric morphometrics. Phylogenetically informed regressions (PGLS) and model comparisons were used to assess the effects of endocranial size, locomotion, diet, and taxonomy on both the regional proportions and the overall shape of the endocranial cast. Musteloid brain organization is mostly driven by size-dependent scaling: larger brains have enlarged cerebra, reduced olfactory and hindbrain regions, and rounder endocasts. However, some lineages markedly deviate from this largely conserved allometry: otters (Lutrinae) exhibit proportionally enlarged cerebra and strongly reduced olfactory bulbs, whereas skunks (Mephitidae) show the reverse pattern, emphasizing enhanced olfactory investment. Feeding ecology also contributes to variation in brain organization, as piscivores show disproportionately smaller olfactory bulbs compared with other feeding guilds. In contrast, locomotor mode has little explanatory power for either endocranial composition or shape. Brain evolution in musteloids is therefore not uniform: a common scaling pattern dominates, but lineage-and diet-specific adjustments modify how brain regions are proportioned.

Video capsule endoscopy offers a non-invasive way to examine the small bowel, however, the rare but clinically important findings that appear only in less than 1% of labelled frames, provide very less signal for detection. As a result, while models can achieve high overall performance, they almost completely miss these rare findings. We condition each frame's decision on evidence from the rest of that patient's video, not on the frame's own posterior alone, supplying information a single frozen frame can never contain. Building upon Expected Gain Arbitration, a per-frame, macro-F1-optimal correction over the confusion matrix, we further compose it with video-disease-presence conditional resulting in our decoding method Hierarchical Conditional-Expected-gain (HCE). We evaluate HCE on two independent VCE datasets, Kvasir-Capsule and GALAR, against a static temporal-smoothing baseline and an optimal-transport (OT) frame-level correction. HCE significantly improves rare-class recall over a temporal-smoothing baseline on GALAR (2.7–3.1x; 95% CI excludes zero in both scopes) and shows a similar, though not statistically confirmed, gain on Kvasir-Capsule (up to 3.4x). Against OT, HCE still improves rare-class recall in all four evaluation settings (+0.016 to +0.029), and additionally improves macro-F1 and MCC.

Biological tissues grow by continuously producing, transporting, and reorganizing multiple interacting constituents. These processes are intrinsically coupled to finite deformation and residual stress. Existing models typically capture either finite growth kinematics or multi-constituent transport, but rarely both within a thermodynamically consistent setting. In particular, existing approaches do not consistently link the volume created by finite growth to the mass produced for each individual constituent. In this work, we develop a general continuum framework that unifies finite growth kinematics and multiphase mixture theory for fully saturated multi-constituent mixtures containing an arbitrary number of dilute dissolved solutes. Formulated in a solid-skeleton-based description, the framework rests on constituent-wise balance laws and a free-energy dissipation principle, from which thermodynamically admissible constitutive closures are derived for all mass-exchange, transport, reaction, and growth processes. The central novelty of the framework is a coupling between growth-induced volume creation and constituent mass production, expressed through volume accumulation fractions that distribute the newly created volume among the constituents while preserving saturation. We cast the resulting model in a total Lagrangian mixed weak form and specialize the general theory to a four-constituent, two-solute model of avascular tumor growth that couples nutrient transport, waste production, phenotype transitions between proliferative, hypoxic, and necrotic cells, volume growth, elastic deformation, and growth-induced residual stress. The model is implemented within a finite element setting and its capabilities are demonstrated on representative benchmark problems.

Elastic buckling has explained shape formation in growing tissues, yet the role of tissue fluidity remains elusive. We derive a minimal fluidized growth-elasticity model as a nonlinear analogue of Maxwell rheology. Analysis of a growing strip reveals a different picture of growth-induced morphogenesis: rather than emerging at a critical stress, symmetry breaking develops continuously during growth. Fluidity regulates stress evolution, the rate of shape-symmetry breaking, and flow patterns, establishing it as an active regulator of morphogenesis beyond its intuitive role in stress relaxation.

Interstitial flow plays a key role in drug delivery, angiogenesis, cancer, and edema. Recent studies have identified connected interstitial pathways that can transport material over long distances. However, the spatial scale of physiological interstitial flow remains unclear: despite the existence of connected pathways, flow may be dominated by nearby vascular filtration or extend over longer distances. Here, we identify organ-scale interstitial flow patterns in the chick yolk sac and elucidate the mechanisms that determine their spatial scale. The yolk sac contains an organ-scale interstitial region that enables large-scale flow patterns to be identified without truncation. Our approach combines experimental imaging with computational modeling of coupled blood and interstitial flow in the whole yolk sac. Scaling analysis identifies a hydraulic conductivity ratio that controls the transition from small-scale to organ-scale flow. In organ-scale patterns, we find interstitial flow speed to be substantially greater than the transvascular flow speed. Mechanistically, the organ-scale patterns arise from the spatial segregation of the leakage and drainage of interstitial fluid from the vessels. These findings have important implications for biological transport by interstitial flow, suggesting that flow-mediated cues may be sensed locally but generated nonlocally.

Sampling error yields exclusively reactive, non-lesional brain parenchyma in a significant proportion of intracranial biopsies, leaving the underlying disease undiagnosed. We benchmark four pathology foundation models (UNI2-h, Virchow2, Prov-GigaPath, H-optimus-0) as frozen patch encoders within a shared attention-based multiple-instance learning framework using 245 whole-slide images from 186 patients with confirmed downstream diagnoses. We first show that coarse disease-category prediction can be reproduced largely from slide size alone. After restricting classification to three finer diagnostic distinctions within common tissue categories, this confound no longer explains performance, yet disease labels remain predictable above chance under permutation testing (p $\le 10^{-4}$ throughout). Surprisingly, performance is statistically indistinguishable across all foundation-model encoders, suggesting that recovering these weak morphological signatures is not limited by current patch representations. Signed instance-contribution maps and expert review further test whether predictive evidence localizes to reactive parenchyma rather than sampling-induced bias like blood introduced during tissue sampling. These results position acquisition-shortcut auditing via a provenance-only baseline as a necessary control in computational-pathology benchmarks, and show, once that confound is removed, that weakly supervised models still recover disease signal from tissue conventionally regarded as non-diagnostic.

The extracellular matrix (ECM) is a fibrous and dynamic network that plays a critical role in development, homeostasis, and disease. Cells both respond to and remodel the ECM, engaging in a mechanical reciprocity that shapes tissues. To study these interactions, computational models have been developed that simulate either ECM mechanics or cell behavior. The Cellular Potts Model (CPM) is a flexible cell-based framework that has been extended to many biological processes, including coupling to a discrete deformable fiber network. So far, however, this extension has only been applied in two dimensions, even though a three-dimensional setting is biologically more relevant. Here, we present a 3D hybrid framework that couples the CPM with a discrete and deformable representation of the ECM. This model enables explicit simulation of cell-induced ECM remodeling, including fiber reorientation and matrix densification. By incorporating contractile forces through static adhesion points, the model captures how ECM elasticity and fiber stiffness influences cell shape. The simulations show that ECM stiffness, controlled by fiber crosslinking, resists contraction and reaches equilibrium, while crosslink density modulates fiber alignment and local matrix accumulation. This framework provides a versatile platform for studying cell-ECM mechanics and supports future studies of multicellular behavior in realistic 3D environments.

Digital twin technologies could transform neuroscience and biomedicine by creating predictive computational representations of living organisms. However, most animal digital twins model neural circuits, anatomy, or biomechanics separately rather than integrating the processes that generate behavior. We argue that animal digital twins should instead be conceived as embodied dynamical systems that unify neural activity, body mechanics, sensory feedback, and environmental interactions. We propose a neuro-musculoskeletal digital twin of the mouse that combines multimodal anatomical reconstruction from X-ray CT, high-resolution white-light sections, and Scx-GFP imaging with biomechanical simulation, Bonhoeffer–van der Pol neural dynamics, and tactile feedback. This framework forms a closed sensorimotor loop in which behavior emerges through continuous interactions among the nervous system, musculoskeletal system, and environment. The Bonhoeffer–van der Pol model provides a computationally tractable dynamical foundation for large-scale simulation of these interactions. Neuro-musculoskeletal digital twins could provide a convergence point for computational neuroscience, biomechanics, artificial intelligence, and robotics. When coupled with adaptive learning and autonomous experimentation, they may develop from passive simulations into active scientific instruments that generate hypotheses, predict interventions, and guide experiments. Such embodied digital twins could advance the study of biological intelligence and support new adaptive biomedical and robotic systems.

This study presents a theoretical investigation of generalized solute dispersion in magnetohydrodynamic multiphase tube flow with porous layers. A two-fluid analytical model is developed for applications in biofluid and environmental fluid dynamics. The model comprises a micropolar (non-Newtonian) fluid core representing the rotational behaviour of red blood cells and a Newtonian plasma periphery embedded with Brinkman and Darcy porous structures, corresponding to the glycocalyx and endothelial layers with distinct permeability characteristics. A transverse magnetic field is incorporated to investigate how magnetic-field-induced modifications of the carrier flow influence solute localisation, with potential relevance to magnetic nanoparticle-mediated drug delivery. Using the generalised dispersion framework of Sankarasubramanian & Gill, analytical solutions are derived to investigate how the coupled axial velocity field and associated microrotational dynamics influence solute transport. The analytical predictions are independently validated through Brownian dynamics simulations, demonstrating excellent agreement for the temporal evolution of the zeroth and first transport moments. The results reveal the previously unexplored influence of microrotational dynamics on solute concentration, convection coefficients and effective dispersion, providing new insights into the coupled roles of translational and rotational fluid motion in biofluid transport. This work bridges an important gap in the literature and establishes a generalized theoretical framework linking magnetic fields, micropolar fluids and porous arterial structures for biofluid transport, targeted drug delivery and clinical engineering applications.

In the present study, we investigated a large dataset of normal adult corneal topographies in an exploratory attempt to identify the natural groupings of their 3D shapes, with the practical clinical aim of categorizing the shape of a future generation of biosynthetic corneal implants. Because of the wide range of shapes among normal corneas, we needed to identify a limited number of normal corneal shape categories to guide the conception of different implants to match the patient's own corneal shape category. At this stage of our research, we focused on the anterior surface, which exhibits greater variation in a normal population and is responsible for most of the refractive power of the eye. The corneal surface 3D data used were the anterior elevation maps taken from corneal topographies. Clustering corneal topography elevation maps was performed to reveal the normal corneal shape categories. To facilitate groupings, corneal data had their dimensionality reduced by Zernike polynomial modeling. The resulting clusters were evaluated using different clustering scores, representations and statistical cluster comparisons. While several hard and soft linear and nonlinear clustering methods were tested in this way, k-means proved to be sufficient for this task. The best number of clusters was three and they were primarily differentiated according to corneal curvature (Zernike defocus coefficient). These clusters were related to established clinical parameters, confirming that the algorithm extracted relevant information based solely on the normal 3D shape of corneas.

Growth may cease at a target size or continue throughout life: the determinate and indeterminate phenotypes. We develop an active viscoelastic continuum model of a tissue growing along one axis, in which cell division and death generate active stresses. We find two asymptotic states: one in which the tissue reaches a relative size fixed by its material parameters, and one in which it elongates linearly without bound. Which state is realised is set by the ratio of active stress to elastic modulus. The transition originates in a bound on the elastic stress the tissue can support: a sufficiently large activity can never be balanced. In a tissue made of parts with different material properties, the growing phase settles into fixed length proportions, set by the mechanical impedances of the parts rather than inherited; matching impedances to initial lengths preserves the proportions the tissue began with. Determinate, indeterminate and proportionate growth thus appear as regimes of one continuum mechanical framework.

Adaptive therapy has emerged as a promising treatment strategy that exploits within-tumour competition to delay disease progression. Implementation, however, typically relies on indirect measurements of tumour burden and must account for potentially substantial patient heterogeneity. In this work, we capture patient-to-patient variability, parameter uncertainty, and imperfect biomarker measurements with a mathematical and statistical model that we calibrate to clinical prostate cancer data using a Bayesian inference framework. We use the resulting virtual cohort to demonstrate that, within the simple but now well-established Lotka-Volterra-based model, adaptive therapy robustly improves time-to-progression for the subset of patients that are predicted to eventually progress by the model. To account for other risk factors associated with larger tumour volumes, we introduce a new metric based on the risk of metastasis that demonstrates how adaptive therapy may be disadvantageous when sustained tumour burden is also considered. Given the ubiquity of uncertainty in oncology, we then describe several future modelling directions that also capture uncertainty in the temporal evolution of the underlying tumour or biomarker dynamics. Finally, we demonstrate how model misspecification and non-identifiability can lead to unreliable predictions, especially if uncertainty is inadequately captured.

Preterm birth remains a major cause of neonatal morbidity and mortality worldwide. Electrohysterography (EHG), a noninvasive measure of uterine myoelectrical activity, has been studied for preterm-birth prediction, but performance estimates may be biased when segments from the same maternal record are split across training and validation data. We formalized the distinction between segment-level and patient-independent record-grouped validation, established a patient-independent benchmark on the Term-Preterm Electrohysterogram Database, and evaluated class-conditional conformal selective prediction. All 300 records (38 preterm) were analyzed across three prespecified regimes. A 92-feature elastic-net logistic model was evaluated with record-grouped nested cross-validation; preprocessing, model fitting, Platt calibration, and conformal estimation were confined to training data, and performance was calculated from strictly out-of-fold record-level predictions with 1,000 bootstrap resamples. Under patient-independent evaluation, AUROC was 0.493 (95% CI 0.467-0.520), AUPRC 0.122 (0.095-0.152), and Brier score 0.115 (0.094-0.137). AUROC was 0.514 at or before 26 weeks and 0.469 thereafter. At miscoverage alpha=0.10, marginal coverage was 0.897, abstention 72.7%, and singleton-prediction accuracy 0.624. These findings establish a record-separated reference benchmark for EHG prediction and a broader validation principle for segmented physiological data: the unit of resampling should correspond to the unit at which predictive performance is intended to generalize. Conformal prediction further quantifies when the available information supports a singleton classification and when uncertainty warrants deferral.

In this study, we develop a novel integrated framework that links the impact response with cellular dynamics using a live-neuron cell-integrated biomechanical full-body surrogate model. The impact event is simulated by allowing the surrogate model to fall from controlled seated release angles of 30-degree, 60-degree, and 90-degree. Three vertically stacked cell-culture Petri dishes, each containing live SH-SY5Y neuroblastoma cells, were placed inside the head of a commercially available surrogate model. The dynamic response of the impact event was evaluated using acceleration measurements from six accelerometers, comprising three sensors mounted on the head surface and three embedded in series with the cell stacks, along with kinematic measurements of the fall and deformation of the head model. In parallel, an OpenSim-based modified musculoskeletal model was used to simulate the fall experiment. We found that variation in contact stiffness produced the largest change in the predicted head acceleration in the simulation. When the cellular response and the measured accelerations are compared, oxidative stress and cell viability showed trends consistent with the regional acceleration and angle of fall. At the 90-degree fall, where median peak linear accelerations ranged from 170-258g, and the maximum headform deformation was approximately 9.4 mm, oxidative stress increased to approximately twice that of the control sample. We also quantified the cellular drift of SH-SY5Y cells, which is focal in nature for the 90-degree impact condition. The corresponding fall scenarios were also simulated in OpenSim and a preliminary calibration relationship was developed to compare the kinematic responses of the physical surrogate and musculoskeletal model. Finally, the framework provides a basis for relating experimental surrogate measurements to human head-neck response during impact.

Multimodal Large Language Models (MLLMs) can generate pathological descriptions from histological images, but gigapixel Whole Slide Images (WSIs) exceed their visual context limits. The standard tiling workaround makes WSIs tractable yet severs the tissue neighborhoods that define tumor-stroma interfaces and morphology. We introduce Spatial Language Message Passing (SLMP), a framework that performs spatial reasoning entirely in language space, human-readable by construction. SLMP represents a WSI region as a spatial text graph: tiles are nodes initialized with MLLM descriptions, and edges encode spatial adjacency. For each tile, an LLM refines its description by integrating language messages from adjacent tiles under a shared aggregation policy that, on the tile grid, acts as an adaptive local kernel operating on text rather than learned embeddings. This policy is an inspectable prompt that can be refined from model-observed tissue phenotypes via textual gradients, enabling automatic semantic optimization from local cellular context to broader tissue morphology without fine-tuning MLLM weights. On representative HER2 and CAMELYON16 regions, SLMP improves tile-level tumor description accuracy in settings spanning general-purpose and pathology-specialized backbones, with gains of +3.3 to +19.6 percentage points. Random-neighbor ablations confirm that these gains stem from spatial context rather than additional text alone, and inspecting the optimized policies reveals interpretable, tissue-specific decision rules. Besides, without any weight updates or fine-tuning the backbone MLLM, SLMP substantially improves general-purpose MLLMs and narrows its gap to pathology-specialized counterparts, offering a transparent and flexible mechanism for incorporating spatial reasoning into MLLM-based pathology analysis.