Biology and Life Sciences

Abstract: A physiological variable held by a controller with integral action cannot be moved by a sustained input. This is a theorem, not an observation: integral action drives the sensitivity function to zero at zero frequency, so a constant drug input produces zero steady-state deviation at any receptor occupancy. Potency cannot overcome it. What can move such a variable is a signal placed where the loop’s rejection is weakest, and Bode’s sensitivity integral guarantees that such a band exists. This paper derives that bound and shows by simulation that the drug-to-output path is a bandpass peaking at the loop’s natural frequency. Under an amplitude ceiling the effect of a pulsatile input peaks at a dosing period that is a fixed multiple of the loop’s natural period, the multiplier set by damping; the peak is broad, so what the model constrains sharply is the loss incurred by dosing faster than the loop. Four independent literatures retrodict the result: parathyroid hormone, gonadotropin-releasing hormone, adaptive deep brain stimulation, and conditioned dose reduction. Each shows a regulated system responding to the temporal pattern of exposure rather than its integral. The framework treats chronic symptom disorders as failures of active inference. That interpretation is assessed against what has actually been tested, which is less than the field’s confidence implies. Four predictions are stated, each with a criterion for failure.

Abstract: Background. In the final steps of the coagulation cascade, thrombin converts fibrinogen to fibrin, which polymerizes into a fibrin network that stabilizes blood clots. The concentration of these two proteins can affect network structure. The fibrin network is dissolved by plasmin, by cleaving fibrin peptide chains. In internal fibrinolysis, tissue plasminogen activator (tPA) activates endogenous plasminogen to plasmin, with activation efficiency much enhanced when tPA and plasminogen are bound to fibrin. The effect of varying fibrinogen and thrombin concentrations and the effect of the resulting varying network structure on fibrinolysis are convoluted, with contradictory trends reported in the literature. Objectives. Investigate how fibrinogen and thrombin concentration quantitatively affect fibrin network structure, and how fibrinogen, thrombin concentrations and the resulting, altered network structure affect fibrinolysis, at a given, rate-limiting tPA concentration. Methods. Fibrin clots were generated from diluted, platelet-poor plasma and purified PEAK 1 fibrinogen, at varying fibrinogen and exogenous thrombin concentrations. The effects of varying fibrinogen and thrombin concentrations on network structure were quantified using non-linear power-law equations derived from confocal images. Internal clot lysis time (CLT) was determined using turbidity-based assays as a function of fibrinogen and thrombin concentrations and network structure at fixed, rate-limiting tPA, and therefore fixed plasmin concentration. Results and Conclusions. Network structural features (fiber density, pore size) and CLT fit well to empirical equations of the form k([Fgn]^α× [Thr]^β). Generally, increasing fibrinogen resulted in higher fiber density and thicker fibers, whereas increasing thrombin resulted in higher fiber density and thinner fibers. Internal CLT showed strong dependence on fibrinogen, and negligible dependence on thrombin. This implies that fibrinogen is the main determinant of internal CLT in these systems, while thrombin and, thus, thrombin-dependent formation kinetics and network structure, per se, have a near-negligible effect.

Abstract: This article questions whether the predictive success of algorithmic descriptions warrants treating them as complete accounts of physical organisation. It distinguishes stability from organisation and argues that genuinely random fluctuations cannot, by themselves, explain the persistence of information-bearing structure whose coherence depends on information not already contained in the governing dynamics. Fluctuations treated as noise at one descriptive level may contain correlations or structure that become causally relevant at another. This possibility does not challenge established physical laws, but it questions the completeness of algorithmic explanation: predictive adequacy within a model should not be equated with the ontological completeness of the description. This framework is exemplified at the molecular scale, where Levinthal’s paradox and interfacial water dynamics suggest that protein folding relies on phase-correlated environmental fluctuations rather than isotropic stochastic search.

Abstract: Synaptobrevin (Syb/VAMP) is the vesicular SNARE that drives synaptic vesicle fusion. Before fusion, Syb is located in the vesicle membrane. After fusion, Syb is translocated to the presynaptic plasma membrane and exposed to a different lipid environment. How its membrane-proximal juxtamembrane and transmembrane domains (JMD–TMDs) organ-ize these different surrounding membrane environments remains incompletely under-stood. Here, we used MARTINI coarse-grained molecular dynamics simulations to in-vestigate Syb1/2 membrane organization and collective behavior. Syb1 and Syb2 induced similar and robust local lipid disorder, whereas the spatial organization of lipid disorder and membrane mismatch depended more strongly on membrane lipid composition. Higher order Syb clustering was promoted by the presence of PIP₂ in the membrane, which is decreased in its absence and insensitive to PS depletion. Consistently, Syb cluster formation was associated with pronounced PIP₂ redistribution and enrichment, while PS showed substantially weaker enrichment and decreased association with Syb in the presence of PIP₂. Clustering spatially overlapped otherwise localized lipid-disordered regions without proportionally amplifying their magnitude. Together, these results dis-tinguish robust local membrane disorder from composition-dependent geometric re-modeling and identify PIP₂ as a prominent correlate of higher-order Syb organization that may contribute to post-fusion Syb reorganization before endocytic retrieval.

Abstract: Questions arise about how well early bacterial models of gene regulation generalize to eukaryotes and whether metazoan repetitive sequences are merely genomic spandrels. The repeats are recognized by sequence-specific RNA-binding proteins that play multiple roles in RNA biology. A subset, called flipons, adopts non-B-DNA conformations under physiological conditions without any sequence change or backbone cleavage. Other low-complexity sequences encode intrinsically disordered regions (IDRs) of proteins and promote the formation of membrane-less condensates with specific cellular functions. Here, I propose that metazoan repeats enable a fast readout of genetic information by facilitating massively parallel searches of large genomes, far exceeding that possible with diffusion alone. The locally transcribed repeats and flipon subsets seed condensates that display information about local DNA microstates on their surfaces, creating a 2-dimensional holographic hash of their contents. The hash enables transcription factors to rapidly discover critical cognate binding sites, facilitating rapid cellular responses to perturbation. The information displayed on condensate surfaces is constantly updated by both outward- and inward-directed processes. The rewrite further optimizes responses and increases the phenotypic variability on which natural selection acts. Applying the Principle of Least Action to the Lagrangian demonstrates that this strategy minimizes search times across arbitrary volumes.

Abstract: Chromatin spatial organization is commonly described through compaction, contact frequencies, chromosome territories, loops and polymer dynamics, yet these measures do not address how nuclear confinement shapes accessible genome configurations. We introduce the concept of chromatin congestion to describe changes in the geometrically, topologically and mechanically admissible chromatin configurations within a confined nucleus, integrating directional geometric constraints, topological obstruction, stochastic exploration, mechanical deformation and long-range dependence into a common description. We performed stochastic simulations of 480 nuclei across six microchannel widths from 14 to 4 micrometers, keeping chromatin content constant and quantifying collision-free path length, locus displacement, topological encounters, curvature, bending work, perturbation propagation and DNA-damage burden. As confinement progressed, chromatin displacement initially increased, consistent with exploration of the configurations still available, but declined under stronger restriction. Topological encounters, curvature and mechanical work increased, while perturbations extended across progressively larger nuclear regions and were associated with greater damage burden. Our simulations suggest that progressive confinement can drive transition from locally buffered chromatin dynamics to increasingly collective genome behaviour, characterized by stronger spatial interdependence among genomic regions. Potential applications include microfluidic migration experiments, single-cell nuclear phenotyping and the integration of imaging, mechanical and genome-organization measurements.

Abstract: The small GTPase Ras, a central switch in signal transduction of cell growth, is a crucial element in the development of many forms of cancer. Recent studies have shown that membrane association of Ras is essential to its downstream effector recruitment and signal transduction. Here we investigate the membrane association and interaction of K-Ras4B, the most frequently found Ras isoform in tumor cells, using all-atom molecular dynamics simulations totaling 8.5 µs. We find that the isoform-specific, farnesylated hypervariable region (HVR) of Ras plays an important role in the organization and oligomerization of its globular domain (G-domain) on the surface of the membrane. We show that the overall pose of the Ras G-domain on the membrane can be determined by its HVR. The HVR thus can control downstream effector binding by positioning the G-domain on the membrane in a specific orientation. Furthermore, we observe that the HVR alone already transiently dimerizes in the membrane and recruits negatively charged phosphatidylserine lipids around the K-Ras isoform specific poly-lysine region. The observed HVR dimerization potentially can initiate the dimerization of the full K-Ras, which is essential for downstream effector signaling via various pathways. These atomistic details behind the molecular mechanism of the HVR provide novel insight into Ras interaction with membrane and its availability for downstream effectors.

Abstract: Deltamethrin (DLT), a type-II pyrethroid insecticide, can interfere with voltage-gated Na⁺ currents (INa) in excitable cells; however, its effects on INa gating and neuronal discharge remain unclear. Using Neuro-2a motor neuron-like cells and whole-cell patch-clamp recordings, we found that DLT (10 μM) mildly increased transient INa (INa(T)) but markedly enhanced late INa (INa(L)) and tail INa (INa(Tail)). In the continued presence of DLT, dapagliflozin (Dapa) counteracted the DLT-induced increases in INa(L) and INa(Tail). We further incorporated modified INa(T), INa(L), and INa(Tail) kinetics mimicking DLT effects into a computational model of respiratory neurons. The simulations generated two distinct action potential (AP) bursting patterns characterized by either slow or fast intraburst firing. Both patterns exhibited progressively shortened AP intervals within bursts, indicating reverse spike-frequency adaptation. Molecular docking further predicted hydrophobic interactions between DLT and the NaV1.8 channel. Collectively, these findings demonstrate that DLT preferentially enhances INa(L) and INa(Tail), which may substantially alter bursting behavior in modeled respiratory neurons.

Abstract: L-asparaginase (L-ASNase) enzyme has found applications in medicine for treatment of various cancers. Herein, we report single-molecule study of thermal denaturation of L-ASNase within 25°C to 60°C temperature range by atomic force microscopy (AFM) and by single-molecule sensing with a (solid state nanopore)-based electrical detector (SSNPED). AFM has allowed us to reveal a thermally induced changes in aggregation state of L-ASNase and in its adsorbability on mica. At the same time, the configuration of the enzyme’s globule spatial conformation has been found to alter according to data obtained with the SSNPED. The results of AFM experiments have been confirmed by fluorescence spectroscopy. Our results reported open up opportunities for further development of anti-cancer drugs.

Abstract: Integrin-mediated adhesion is essential for leukocyte trafficking and contributes to hematogenous tumor metastasis. We recently showed that metastatic B16 melanoma cells undergo VLA-4-dependent rolling and rapid arrest on endothelial cells under physiological shear flow without classical chemokine-induced integrin activation. However, the molecular basis of this chemokine-independent adhesion remained unresolved. Here, atomic force microscopy (AFM)-based single-molecule force spectroscopy was used to characterize VLA-4-mediated adhesion between living B16 melanoma cells and bEnd.3 endothelial cells at the level of individual receptor–ligand interactions. Rupture-force histograms revealed a dominant population centered at approximately 33 pN, consistent with single VLA-4/VCAM-1 bonds. VLA-4 blockade reduced adhesion frequency, whereas VCAM-1 blockade shifted the rupture-force distribution toward lower forces; both effects support molecular specificity. VLA-4-directed antibody and pharmacological inhibition further indicated that regulation primarily affects bond-formation probability rather than the strength of individual receptor–ligand interactions. Homotypic VLA-4-mediated adhesion between melanoma cells was also detected. These findings provide a functional link between single-molecule receptor interactions and the rolling-to-arrest transition of metastatic melanoma cells under physiological flow. Together with our recent flow-chamber studies, they support a model in which VLA-4/VCAM-1 bond formation contributes to vascular arrest without requiring classical integrin activation, providing molecular insight into an early step of metastatic dissemination.

Abstract: The immune system delivers a highly diverse receptor repertoire while preserving self-tolerance, functional robustness and effective pathogen recognition. Although the mechanisms governing clonal selection are characterized, the mathematical principles potentially underlying repertoire-wide organization are less understood. We propose a geometric, probabilistic and spectral perspective in which immune repertoire selection could be interpreted as constrained sampling from a high-dimensional space of receptor configurations. Within this perspective, we connect developments in modern probability and combinatorics with distinct, testable aspects of repertoire organization: polynomial stability could define a global landscape of admissible repertoires; negative dependence could constrain simultaneous selection of similar or redundant clonotypes; entropy maximization could preserve the broadest receptor distribution compatible with self-tolerance and antigen recognition; log-concavity could organize compatible configurations into broad basins supporting gradual adaptation. Still, Kadison–Singer subset preservation could explain how comparatively small lymphocyte samples retain statistical and spectral properties of larger repertoires, whereas random-forest connectivity could quantify collective integration generated by local receptor relationships. Finally, spectral independence could constrain propagation of clonal perturbations, allowing local responses without uncontrolled repertoire-wide cascades. These mathematical issues could provide measurable descriptors of diversity, redundancy, representativeness, connectivity and perturbation propagation, generating falsifiable predictions accessible to repertoire sequencing and network analysis. Rather than replacing established immunological mechanisms, we introduce a complementary ensemble-level description shifting the mathematical object of interest from the individual clonotype to the organization of the repertoire as a whole.

Abstract: Clonogenic survival under fractionated irradiation flattens after one to two weeks at a level that depends on fraction size. The linear–quadratic (LQ) model cannot reproduce this, because its exponent is a linear functional of delivered dose and therefore carries no memory of how the dose was given. We construct the smallest kill law that can, from six axioms: two clonogenic states, first-order kill in each, a constant ratio between their kill rates, a causal damage-driven transfer between them, conservation of total transfer, and one-way transfer over the interval considered. We prove the axioms independent, and prove that they determine the structural results without specifying either the hazard or the transfer kernel. These give a five-variable initial-value problem — a lethal hazard carrying a Lea–Catcheside repair memory, a two-stage cascade converting accumulated damage into transfer, and the two clonogenic compartments — which we solve in closed form for arbitrary dose rate. Two exact properties carry the results. The transfer term cancels identically when the two compartments are equally radiosensitive, so survival then depends only on the repair-weighted cumulative lethality; delivery order therefore changes cell kill if and only if a tolerance gap exists, provided repair is complete between deliveries. And once transfer is complete the per-fraction log-kill falls from L to rL, so late dose is devalued by r, tumour volume is amplified by 1/r, and cytoreduction is worth 1/r times its conventional value. For instantaneous fractions separated by intervals long compared with the repair and signal time constants, the system reduces exactly to a two-by-two linear map, verified to machine precision. Fitted to clonogenic survival at five fraction sizes the model returns a gate time constant of 1.75 fractions and a tolerance ratio of 0.063, with a held-out quantity implying 1.84 and excluding zero delay; we also report that it generalises slightly worse than a hand-added floor when whole fraction sizes are withheld. Away from that limit the formulation yields results a fraction-based law cannot express. Continuous low-dose-rate irradiation is penalised twice, by repair and by allowing the transfer time to act during delivery, and a seven-day implant delivering 60 Gy is predicted to be equivalent to thirty 2 Gy fractions. For radionuclide therapy, cell kill is predicted to rise by more than four log-kill as the effective half-life falls from thirty days to six hours at matched absorbed dose, so absorbed dose alone is an insufficient basis for comparing agents. The heterogeneity of uptake in radionuclide therapy also supplies the one configuration in which the tolerance ratio becomes measurable in vivo, because the dose-rate contrast between regions is known from the dosimetric imaging itself. The construction is calibrated on one cell line and the tolerance ratio has never been measured on a clonogenic endpoint; the claims that survive this are structural.

Abstract: Red blood cell (RBC) aggregation is an important hemorheological property that influences blood viscosity, microcirculation, and stored-blood quality. However, conventional measurements commonly require repeated flow cessation or flow-rate modulation, limiting continuous monitoring and providing little information on spatial heterogeneity. This study presents a microfluidic platform for spatiotemporal mapping of RBC aggregation during continuous blood flow. Multiple high-resistance side chambers connected to a main channel create low shear rate regions for aggregation while maintaining high shear in the main channel for RBC disaggregation. Flow rates and shear rates are evaluated using a hydraulic circuit model, numerical simulation, and micro-PIV measurements. An aggregation index (AI) map is introduced to quantify spatial and temporal changes in the side chambers. AI remains high and stable at flow rates of 0.5 ~ 1 mL/h. RBC aggregation increases significantly at concentrations of 15 mg/mL or higher. The proposed index shows an approximately 30% stronger response than a conventional aggregation index. Moreover, AI decreases progressively during four weeks of RBC storage. These findings demonstrate continuous and multiple-location detection of RBC aggregation and support the use of this platform for assessing hemorheological alterations and storage-induced RBC deterioration.

Abstract: BACKGROUND: Malignant tumors remain a major threat to human health; however, the etiologies of most cancers remain elusive, highlighting the limitations of the dominant biological-reductionist and statistical paradigms in modern medicine. METHODS: To address these gaps, this study proposes a physics-informed conceptual model of the human organism from an organism-environment systems perspective. Positioned at the intersection of systems medicine and clinical oncology, the model is fundamentally immune-centric, resting on core tenets including​ the inherent high orderliness of living systems and the pivotal functional role of the immune system in tumorigenesis and treatment, thereby integrating biological, psychological, and environmental dimensions within a unified analytical framework. RESULTS: The model provides a coherent account of tumorigenesis, framing non-genetic tumors as a state of dysregulation in the internal environment that arises from persistent exogenous factors and compromised immune surveillance. It further delineates a comprehensive treatment framework targeting: (i) pathophysiological state correction, (ii) etiologic factor intervention, and (iii) psychosocial support. Notably, the inferences derived from this model align with the biopsychosocial model central to modern medicine and converge with the holistic imperative underpinning traditional medicine. CONCLUSION: This systems-based conceptual model bridges the gap between physics-informed reasoning and clinical practice, establishing a novel, axiomatic paradigm within clinical medicine. It offers a testable framework for future research, spanning biopsychosocial medicine to immuno-oncology and integrative oncology, and provides an intellectual scaffold to re-orient clinical practice toward etiologic diagnosis and integrated care, thereby holding considerable potential to refine cancer management.

Abstract: Whether life is an inevitable consequence of the laws of nature or an exceptional outcome of prebiotic evolution is unresolved. Origin-of-life hypotheses primarily seek to reconstruct molecular pathways linking prebiotic chemistry to the first evolving systems. Here, we introduce a theoretical framework inspired by the probabilistic reasoning of Paul Erdős, reformulating abiogenesis as a mathematical existence problem rather than a historical reconstruction problem. We define an abstract chemical configuration space comprising all chemically accessible prebiotic organizations and identify life as the subset of configurations simultaneously exhibiting compartmentalization, energy transduction, information persistence and heritable variation. Using probability theory and set theory, we aim to investigate whether this subset necessarily occupies a nonzero region of chemical configuration space. We establish the general conditions under which life-capable organizations have positive measure and derive an abiogenetic threshold beyond which the probability of life's emergence approaches unity. Our framework predicts threshold behavior, functional convergence and scaling relationships that are independent of any particular molecular substrate. In our setting, origin-of-life hypotheses like RNA-first, metabolism-first, compartment-based and autocatalytic models are interpreted as complementary mechanisms that either enlarge the life-capable subset or increase the exploration of chemical configuration space. Potential applications include quantitative analyses of prebiotic experimental systems, comparative assessment of planetary habitability and computational studies of chemical organization.

Abstract: Cardiolipin, the signature phospholipid of the inner mitochondrial membrane, is the ancestral Φ substrate: a gating variable that predates eukaryotes by one billion years. Applying the ARCH × Φ framework (R = Φ[A × D × C] ≥ θ) to four mitochondrial commitment systems—cardiolipin gating, PINK1/Parkin mitophagy, BCL-2/BAX apoptosis, and p16INK4a/Rb senescence—eight zero-term veto demonstrations establish Φ as formally distinct across all four. Three approved therapeutics—memantine, venetoclax, and elamipretide—converge on Φ-titration as a shared mechanism. The framework retrodicts 2025 integrated stress response trial failures in ALS and specifies five falsifiable predictions. τΦ spans minutes to a lifetime, tracking commitment cost.

Abstract: The linear–quadratic (LQ) model accumulates dose but carries no internal state, so it cannot represent how an earlier delivery conditions the response to a later one. We propose that radiation response is better treated as the trajectory of a single coupled state resolved into five layers ordered by relaxation time — redox, damage-stress signal, escape gate, radiation-tolerant persister, and population — read out through one kill kernel of which LQ is the exact frozen-state limit. Because the layer clocks separate by orders of magnitude the architecture is reducible: eliminating the fast layers leaves a two-compartment core of the lagged write that installs tolerance and the tolerance itself, on which the system is solved exactly. The resulting closed-form surviving fraction becomes independent of the entire delivery history on exactly two loci: an ablation locus, following from a left-eigenvector identity holding at every instant and therefore exact, all-orders, and independent of both the tolerance functional and the write; and an instantaneous-write locus, where the write becomes proportional to the kill. Cell-autonomy of the write is precisely the condition under which a closed form exists, and the ablation null survives even where it does not. Specialised to a fraction train under a delayed write, the same equation derives a survival floor previously added to LQ by hand; fitted to data at five fraction sizes it returns a consolidation window of 1.75 fractions and is preferred over the phenomenological alternative in sample, though not under held-out fraction sizes. The remaining results require layers the core does not contain, which is the argument for the framework and not only for the theorem. The falsifiable content is structural: a matched-dose, order-reversed contrast abolished by persister depletion.

Abstract: Personalized glioma neoantigen vaccination requires a defensible way to prioritize candidate peptides when mutation, HLA presentation, biochemical, structural, manufacturability, and provenance signals are incomplete or discordant. We present TAMAVAQ/Q-TAMAVAQ, an audit-first computational framework that converts candidate triage from an opaque rank list into a replayable constrained decision process. Candidate dossiers are embedded with a Fubini-Study-style fidelity kernel, connected through a symmetrized 12-nearest-neighbour graph, and assigned CTQW neighborhood support. A deterministic MBHA boundary ledger records signed eligibility margins and preserves non-compensatory BIO, PHYS, GEOM, CMC, PROV, and VALID requirements. In the internal worksheet described in the source manuscript, the analysis contains n = 1,537 candidate records and a locked 65-candidate evidence-positive endpoint (4.23%). The full selector achieved AP = 0.552, AUROC = 0.962, and NDCG@100 = 0.693, compared with AP = 0.505 for graph-transport support alone and AP = 0.515 for a non-graph linear comparator. These findings establish internal computational feasibility and auditability only; biological validation remains prospective. The final proof schematic consolidates the quantum geometry, CTQW transport, PASS oracle and MBHA margin ledger into a single theorem-linked audit description.

Abstract: Cryogenic technologies have become an important catalyst for the development of sciece in the 20th century. They have played a significant role in biology (preservation of animal and plant gene pools and biological samples) and medicine (cryosurgery and cryotherapy). In photobiology, the use of deep cooling has deepened our understanding of the mechanisms of key processes: photosynthesis, vision, and photoregulation in plants. This review, based on the author's work, focuses on the characteristics and results of applying deep cooling methods in spectrofluorimetry of several major photoreceptor pigments. Two key effects of object cooling—a sharp narrowing of pigment spectral bands and an increase in their fluorescence quantum yield—have enabled, firstly, advances in the description of the multicomponent system of chlorophyll, phycobilins, and carotenoids, as well as the processes of light energy harvesting during photosynthesis. The system of chlorophyll forms and the energy migration between them and from accessory pigments are reproduced in model systems with aggregated pigments, indicating the important role of pigment-pigment interactions in the formation of the system of forms and during primary photoprocesses within them. Secondly, the fluorescence of visual and bacterial rhodopsins, and of phytochrome in its native state was detected in vivo; their primary photoprocesses were studied, and their general scheme was proposed. Structural and functionally distinct types of phytochrome A were discovered. The advantages of the application of cryotechnology in the spectroscopy of complex biological pigment systems are discussed.

Abstract: Is an ant colony conscious? What about a culture, an AI, or a planet? A conscious moment feels unified in time and space, yet signals take time to travel. Many theories bind an experience's parts within a window of duration θ, but leave other questions about time and space unanswered. Here I give a mathematical tool for answering some of those questions, narrowing down what is conscious under different theories. There are two possibilities, Arpeggio and Chord. Arpeggio says consciousness requires only that each ingredient occur somewhere in-window. Chord is harder to satisfy, requiring ingredients coexist in time and influence one another. This limits the size of conscious unity. For a system of diameter D and signal-speed ceiling v, its exchange architecture sets a factor ε, giving D ≤ εvθ. Primate data constrain θ. Chord can augment the likes of Orch-OR, IIT 4.0 and GWT with size bounds, time constraints and two-way exchange requirements. Within Stack Theory, Chord completes the temporal aspect of the Psychophysical Principle of Causality. Given a theory and parameters Chord can, for example, rule out ant colonies or certain AI, or give latency limits for human–AI hybrids. In contrast, under Arpeggio all theories collapse toward panpsychism.