At Longevity Horizon (Online ISSN: 3088-4063), we unite leading researchers and innovators to advance transformative technologies that will shape the future. Bringing together experts from diverse fields, we cultivate an environment where impactful ideas and scientific breakthroughs can emerge. Our mission is to support collaboration and make cutting-edge knowledge accessible to the global community, promoting research that improves lives and contributes to a sustainable, thriving future. Our platform provides high-quality, peer-reviewed articles that drive scientific progress. These contributions help turn such visions as expanded living space, optimal health, food security, and even the pursuit of radical longevity into realistic possibilities. This is an open access journal, meaning all content is freely available to read, download, copy, distribute, print, search, or link, in accordance with the BOAI definition of open access. Immortalitas in Hac Vita
Ze theory assigns a binary-stream counter Ze = (Zₛ, Zₜ) to any binary observable, where Zₛ counts stasis events and Zₜ counts transition events. We investigate which subatomic particles can possess a well-defined Ze and establish two distinct classes: Ze-autonomous particles, whose binary degree of freedom evolves independently of the measurement apparatus (neutrinos via flavor oscillation; nucleons via isospin in nuclei), and Ze-observable particles, whose Ze is defined only relative to a measurement protocol (electrons via spin; photons via polarization). The W± boson is reclassified as a Zₜ-carrier that mediates transition events in quark and lepton Ze streams rather than possessing its own Ze. We show that CP violation in the K⁰–K̄⁰ system implies a measurable Ze-impedance asymmetry ΔZ_Ze = 2ε/(1−p₀)² ≈ 4.5×10⁻³. The quantum Zeno effect is identified as the Z_Ze → 0 limit and NMR resonance as the Z_Ze = 1 condition. Five falsifiable predictions are derived. Particles without a binary degree of freedom (Higgs boson, gluon) are excluded from Ze classification.
Copyright (c) 2026 Jaba Tkemaladze (Author) https://creativecommons.org/licenses/by/4.0/
I present a Popperian falsification protocol for Ze theory, a framework that derives the Minkowski metric ds2 = Zs2 - k2*Zt2 from a dual-channel binary event counter. Five ordered kill criteria are defined: (Kill-0/1) the normalized Euclidean invariant I_norm = (Zs2+Zt2)/(N-1)2 must be stable across window sizes with std ~ 1/sqrt(N); (Kill-2) the Minkowski form must be preserved under the Ze Lorentz transform; (Kill-3) the Ze velocity limit k = <Zs>/<Zt> must be consistent within the same physical stream; (Kill-4) the Lorentz gamma-factor must be recoverable from counting data; (Kill-5) Ze-derived ds2 must agree with relativistic time dilation from atomic clocks or GPS. Kill-0 through Kill-4 are run numerically on N=10^6 event streams. Ze passes all four: I_norm is flat to <0.6% across window sizes, ds2 is preserved to <5x10^-13%, and gamma is recovered to <3x10^-13%. Non-stationary streams correctly fail Kill-1. Kill-5 remains open. Two errors in the original falsification theses are corrected: the invariant must be normalized by (N-1)2, and the kill condition must compare std(I_norm) to the 1/sqrt(N) baseline.
The Lorentz Group as an Automorphism of Ze Counting
We demonstrate that the Lorentz group O(1,1) acts naturally and exactly on the dual-channel output of a Ze binary event counter. For any binary stream analyzed in a sliding window of width W, the stasis count Z_s (T-events) and transition count Z_t (S-events) define a pseudo-Euclidean quadratic form ds² = Z_s² − k²Z_t² on the Ze counting plane R^{1,1}. We prove analytically that the transformation T_v: (Z_s, Z_t) → (γ(Z_s − vZ_t), γ(Z_t − (v/k²)Z_s)) with γ = (1 − v²/k²)^{−1/2} preserves ds² exactly, constituting an element of the Lorentz group O(1,1). The parameter k plays the role of the speed of light: it is the Ze impedance limit separating timelike (v_Ze < k, ds² > 0) from spacelike (v_Ze > k, ds² < 0) intervals. Numerical simulations with up to 500,000-event streams and 2,495 sliding windows confirm: (i) ds² is preserved to within 5 × 10⁻¹³% under all tested Lorentz transforms; (ii) the γ-factor is recovered exactly as γ = Z_s'/(Z_s − vZ_t); (iii) the causal transition from timelike to spacelike occurs precisely at p = 0.5 (v_Ze = k = 1), which corresponds to the Minkowski lightcone. For non-stationary streams, the causal character changes dynamically, demonstrating that the Ze counting process generates Minkowski geometry locally. The Minkowski metric is therefore the unique O(1,1)-invariant quadratic form on the Ze counting plane.
Ze Impedance and the Emergence of the Minkowski Metric
We propose a derivation of the Minkowski spacetime metric that proceeds entirely from the combinatorial structure of a dual-channel binary event counter—the Ze system. A Ze system partitions any binary observation stream into T-events (stasis) and S-events (change), defining a Ze impedance Z_Ze ≡ N_S/N_T and the Ze proper time τ = √(N_T² − N_S²). The resource constraint N_T + N_S = N − 1 forces N_T and N_S into anti-phase: any increase in N_S must reduce N_T, generating the quadratic invariant τ² = N_T² − N_S². In the continuous limit, assigning coordinate differentials dN_T → dt and dN_S → dx/Z_Ze and imposing Z_Ze = const yields the line element ds² = Z_Ze²dt² − dx², which coincides with the Minkowski metric upon the identification Z_Ze ≡ c. The speed of light thus emerges as a structural impedance limit of the counting process, not as an independently postulated constant. Numerical simulations with N up to 5 × 10⁶ confirm the invariant τ² = N_T² − N_S² with relative error below 0.01% for N > 10⁵. Extension to variable Z_Ze(x) reproduces the Schwarzschild metric form, suggesting that curved spacetime corresponds to spatially modulated Ze impedance. Five falsifiable predictions are provided.
The vacuum impedance Z₀ = √(μ₀/ε₀) ≈ 376.73 Ω and the speed of light c = 1/√(μ₀ε₀) are two complementary invariants derived from the same pair of electromagnetic constants {μ₀, ε₀}: one encodes dynamics, the other kinematics. This paper shows that an identical structural duality arises within the Ze framework (Tkemaladze, 2026a), where a binary event stream is partitioned into N_T T-events and N_S S-events. We define Ze permittivity ε_Ze = N_T/T = 1 − v (temporal accumulation, analogous to ε₀) and Ze permeability μ_Ze = N_S/T = v (spatial flow, analogous to μ₀). Two invariants follow: Ze impedance Z_Ze = √(μ_Ze/ε_Ze) = √(v/(1−v)) and Ze speed c_Ze = τ/T = √(1−v²). We show that Z_Ze is universal: it is independent of stream type (i.i.d. Bernoulli, Markov, deterministic) when v is held fixed. The Ze generation map v₁ → v₂ = 2(1−v₁)/(2−v₁)² (Tkemaladze, 2026b) translates into an impedance map Z₁ → Z₂, with a unique stable fixed point Z* = 0.9161 (corresponding to v* = 0.4563). The matching condition Z_Ze = 1 (v = 0.5) coincides exactly with the Nash equilibrium of Ze competition (Tkemaladze, 2026c): the maximum-entropy state. The paper proposes five falsifiable predictions connecting Ze impedance to measurable properties of causal event streams.
The Ze framework models any binary observation stream as a causal counter whose proper time is the Minkowski interval τ = √(T² − X²), where T = N_T + N_S counts total events and X = N_S counts state-change events. This paper addresses the multi-Ze scenario: what happens when two or more Ze systems co-exist, compete for causal dominance, and interact through adversarial mechanisms? We formalize τ-dominance (Ze_k dominates Ze_j iff τ_k > τ_j), identify two primary strategies—T-amplification (inserting redundant T-events) and S-injection (inserting random S-events into a rival)—and derive their quantitative effects. T-amplification by factor m+1 boosts τ proportionally, with ×10 amplification raising τ by a factor of 11.53. S-injection at rate r = 40% degrades the rival's τ by 10.9%. Game-theoretic analysis shows that symmetric mutual attack converges to a Nash equilibrium at v = 0.5 (maximum entropy), destroying τ for both parties—a causal Prisoner's Dilemma. For three or more Ze systems, a τ-dominance hierarchy emerges whose stability depends on pairwise velocity differences. We present falsifiable predictions and discuss the ontological interpretation: competing Ze systems generate distinguishable experiential realities, with the dominant system experiencing slower, richer time.
The Ze framework represents spacetime as a statistical partitioning of a binary event stream into T-events (state repetitions) and S-events (state transitions), from which proper time tau = sqrt(T^2 - X^2) and velocity v = N_S / N are derived in direct analogy with the Minkowski interval. This paper investigates a new phenomenon: a Ze system Ze1 can generate a daughter Ze system Ze2 by re-encoding the run-length parities of its S-events. We derive the analytical formula v2 = 2(1-v1)/(2-v1)^2 and verify it against simulation data (N = 5 x 10^6, nine velocity values) with residuals below 5 x 10^-4. The map f(v) = 2(1-v)/(2-v)^2 has a unique stable fixed point v* = 0.45631 governed by the cubic equation u^3 - 2u^2 + 2u - 2 = 0 (u = 2 - v*). The Ze cascade Ze1 -> Ze2 -> Ze3 -> ... converges numerically to v*, confirming the fixed-point prediction. An exact algebraic conservation law holds for any partition of Ze1: tau1^2 = tau2^2 + tau3^2 + 2 T2 T3 (1 - v2 v3), verified with relative error < 10^-6. The paper presents four falsifiable predictions of the cascade theory.
Falsifiable Predictions of the Ze Framework
The Ze Framework proposes that relativistic and quantum effects emerge from the statistics of causal event updates rather than from the fundamental geometry of spacetime. This paper presents eight falsifiable predictions (FP-1 through FP-8) of the Ze Framework, formally restated in precise mathematical language. Four predictions are verified computationally: FP-1 (universal Lorentz scaling τ(v)/τ₀ = √(1−v²), confirmed to residuals < 10⁻⁵ across 21 velocity values and N = 10⁷ events); FP-2 (implementation equivalence — i.i.d., Markov, and deterministic streams with identical (N_T, N_S) yield identical τ); FP-3 (acceleration independence — four p-profiles with equal effective velocity produce equal τ/τ₀); FP-5 (causal chain length determines proper time — τ = √(L_c² + 2L_c·N_S) matches the Minkowski interval exactly). FP-6 (twin paradox) is verified to agree with the SR prediction to within statistical fluctuations O(1/√N). FP-4, FP-7, and FP-8 are critically assessed: FP-4 is reformulated as an analytic limit statement; FP-7 and FP-8 are identified as theoretical programme goals requiring future formal development. All computationally tested predictions pass their pre-specified falsifiability thresholds. The Ze Framework is found to be self-consistent within its defined domain and fully compatible with the established structures of special relativity at the level of counter dynamics.
CDATA Computational Validation and Mechanics
The Centriolar Damage Accumulation Theory of Aging (CDATA) proposes that the mother centriole in adult stem cells functions as an irreversible molecular damage accumulator, whose progressive deterioration drives the decline of tissue homeostasis and organismal aging. While theoretically compelling, CDATA has faced valid criticisms regarding the correlation-vs.-causation problem, the non-universality of asymmetric centriole inheritance, the specificity of the centriole over other long-lived organelles, and an internal contradiction regarding cancer biology. Here I present the Cell DT platform — a computational digital twin of CDATA — that provides the first mechanistic, quantitative, and internally consistent model of centriolar aging. Implemented in Rust using an Entity-Component-System (ECS) architecture, the platform models five molecular damage types (protein carbonylation, tubulin hyperacetylation, protein aggregation, phosphorylation dysregulation, and distal appendage loss), two downstream failure tracks (Track A: ciliary signaling failure; Track B: asymmetric division failure), and a positive ROS feedback loop. Simulations of 36,500 daily time steps reproduce a human lifespan of approximately 78–83 years under normal conditions, approximately 15–20 years under progeria-like parameters (5× damage rates), and approximately 130 years under longevity-associated parameters (0.6× rates). I systematically address each major critique of CDATA, showing that: (1) the digital twin provides mechanistic causal evidence beyond correlation; (2) stochastic asymmetric division suffices to drive CDATA dynamics even in tissues with predominantly symmetric divisions; (3) the centriole is uniquely positioned as a non-renewable, template-replicated hub integrating both ciliary and spindle functions; and (4) the cancer-aging paradox is resolved by two distinct failure modes of the same underlying mechanism. I conclude that CDATA is a falsifiable, computationally validated hypothesis that warrants experimental testing with the priority experiments outlined herein.
Emergent Lorentz Time Dilation from a Ze Counter-Based Information - Processing Experiment
I present the Ze experiment — a minimal counter-based information-processing framework in which the Lorentz time-dilation factor emerges without invoking spacetime geometry, a metric tensor, or any relativistic postulate. A binary event stream of N elements is partitioned into temporal updates (sequential correlations, x_k = x_{k−1}) and spatial updates (inverse correlations, x_k ≠ x_{k−1}). Coordinate time is defined as the total event count T = N; spatial displacement as X = N_S; and proper time as the Minkowski interval τ = √(T² − X²). The velocity parameter v = X/T then satisfies τ(v)/τ₀ = √(1 − v²) — the Lorentz time-dilation factor — with residuals below 10⁻⁵ across 21 velocity values and N = 10⁷ events per point. Three independent falsifiability tests (stream independence, monotonicity, Lorentz-factor consistency) are all passed within their pre-specified thresholds. This constitutes the experimental arm of the Ze System theoretical programme (Tkemaladze, 2026a, 2026b) and provides a direct informational derivation of the relativistic time-dilation structure from pure counting dynamics.
The Ze framework proposes that proper time is not a geometric parameter but a count of effective information updates, with relativistic kinematics emerging statistically from the dynamics of event processing rather than from assumed spacetime structure. This paper presents a comprehensive experimental programme to test four core Ze postulates across multiple domains. The foundational digital experiment employs identical processors receiving identical input streams operating in maximally sequential versus maximally parallel modes, predicting update count ratios τ_B/τ_A = √(1 - v²) where v represents the proportion of parallel correlations—a functional form identical to the Lorentz factor of special relativity. Physical clock experiments compare internal transition counts in systems with different internal complexity (trapped ions, molecular clocks, optical lattice clocks) under identical relativistic conditions, testing whether proper time correlates with update statistics rather than merely with velocity. Non-inertial experiments subject systems to periodic correlation modulation without changing average velocity, predicting that proper time accumulation depends on causal structure rather than path length alone. Quantum-level experiments leverage programmable quantum computers (IBM, IonQ) to test whether interference corresponds to parallel update distribution and whether the quantum Zeno effect reflects mode switching with measurable update deficits. The Ze framework does not claim special relativity is incorrect but seeks to show it arises as an effective theory from deeper informational principles. Structural convergence with causal set theory, twistor theory, and emergent spacetime frameworks provides indirect support. The digital experiment offers the most direct test: if the relativistic curve emerges from pure information dynamics, it demonstrates that relativistic kinematics are not unique to physics but reflect universal constraints on information processing. Independent replication by multiple groups and derivation of relativity without assuming it would constitute sufficient evidence to attract serious scientific engagement. All proposed experiments are feasible with current technology, and their falsification conditions are clearly specified, ensuring the Ze framework meets the highest standards of empirical testability.
This paper presents the Ze → Twistor → Spin Network framework, a unified conceptual pathway from a primitive discrete ontology to the emergence of relativistic spacetime. The framework begins with fundamental events, denoted ΔC_i, each characterized by dual aspects: a temporal component C_i^{temporal} governing participation in sequential causal chains, and a spatial component C_i^{spatial} governing participation in parallel structural configurations. The first transition, Ze → Twistor, encodes these aspects in a complex representation Z_i = C_i^{temporal} + i C_i^{spatial}, drawing on Penrose's twistor theory. The Hermitian norm |Z_i|^2 = (ΔC_i^{spatial})^2 - γ(ΔC_i^{temporal})^2 carries the Minkowski signature intrinsically, emerging from the SU(2,2) invariant structure of twistor space rather than being inserted by hand. This addresses the fundamental question of how a discrete substrate can give rise to a Lorentzian manifold without violating Lorentz invariance. The second transition, Twistor → Spin Network, discretizes the twistor representation into a labeled graph. Nodes correspond to events (antichains representing spatial slices), edges correspond to causal links, and each edge carries a spin label j determined by j(j+1) ∝ |Z_i|^2, connecting directly to loop quantum gravity where spin networks provide an orthonormal basis for kinematical states. From this structure, relativistic spacetime emerges in the continuum limit: proper time along a worldline is given by the sum of spin labels τ = Σ √[j(j+1)] × τ_Planck, velocity emerges from the ratio of accumulated spatial to temporal increments, and the twin paradox resolves combinatorially through different total spin sums along distinct worldlines. The framework synthesizes insights from causal set theory, twistor theory, and loop quantum gravity, demonstrating how these approaches complement rather than compete with one another. It offers resolutions to long-standing puzzles including the origin of the Lorentzian signature, the compatibility of discreteness with Lorentz invariance, and the combinatorial definition of proper time. Open questions regarding dynamics, the quantum measure, and phenomenological predictions are discussed as directions for future investigation.
The Ze framework proposes a fundamental ontology of discrete counters whose updates constitute primitive events, from which the geometric structure of spacetime emerges relationally. This paper develops the correspondence between Ze dynamics, twistor theory, and spin networks, demonstrating a natural unification of continuous and discrete descriptions of physics. Each event in Ze is associated with a complex counter C = C_temporal + i C_spatial, which is shown to admit a direct interpretation as a point in projective twistor space, following Penrose (1967). The temporal component encodes the event's location along a causal chain, while the spatial component encodes its relational coupling to other events, together forming a twistor coordinate that satisfies the Minkowski norm |C|²_η. Causal sequences of events form a directed graph, which maps naturally onto a spin network wherein edges carry quantized spin labels derived from accumulated counter increments, satisfying j(j+1) ∝ n². This mapping preserves the causal structure while providing a discrete, background-independent representation of quantum geometry in the sense of Penrose (1971) and Rovelli & Smolin (1995). Proper time emerges as the sum of spin labels along causal chains, yielding a combinatorial definition τ = Σ f(j_edge) that reproduces relativistic time dilation and the twin paradox without additional postulates. The discrete Ze Lagrangian L_Ze = Σ [(dC_spatial/dt)² - γ(dC_temporal/dt)²] converges in the continuum limit to the twistor Lagrangian L_twistor = Σ (Ż)ηŻ, confirming that relativistic kinematics are encoded in the counter dynamics. The Ze framework thus achieves a synthesis wherein twistor space provides the continuous, complex-geometric representation of events, spin networks provide the discrete, combinatorial projection, and relativistic effects arise from the internal structure of counters rather than from postulated symmetries. This unification offers a promising foundation for quantum gravity by deriving both quantum discreteness and relativistic spacetime from a single causal ontology.
Reconstructing Special Relativity from Ze
This paper presents a reconstruction of special relativity from a fundamentally discrete framework called Ze, in which physical reality is composed of discrete events eₖ and local counters Cᵢ with increments ΔCᵢ. Two primitive modes of change are distinguished: temporal mode (sequential updates) and spatial mode (configurational changes across channels). From these elements, a fundamental invariant I = Σᵢ (ΔCᵢˢᵖᵃᵗⁱᵃˡ)² – γ Σᵢ (ΔCᵢᵗᵉᵐᵖᵒʳᵃˡ)² is constructed, which serves as the discrete precursor to the Minkowski interval. The discrete Ze Lagrangian Lₖᶻᵉ emerges naturally from the counter dynamics, with spatial updates contributing positively and temporal updates negatively to the invariant. In the continuous limit, where counter increments become field derivatives, the Lagrangian takes the form Lᶻᵉ = (∂C/∂x)² – c²(∂C/∂t)² with γ identified as c². For a single central counter representing a particle, this yields L_Ze-particle = –(1/2) m c² (1 – v²/c²)—exactly the relativistic free particle Lagrangian. Velocity is interpreted operationally as the fraction of counter activity allocated to spatial versus temporal modes: v² = (∂C/∂x)²/(∂C/∂t)². From this, proper time is derived as dτ = dt √(1 – v²/c²), corresponding to the count of temporal mode increments accumulated by a moving clock. Time dilation and Lorentz invariance thus emerge as statistical features of the discrete counter distribution rather than imposed postulates. The Minkowski metric arises from the relative weighting of spatial and temporal counter modes, with the light cone structure reflecting the balance between stabilizing (spatial) and destabilizing (temporal) updates. The Ze framework provides an operational, discrete foundation for special relativity, demonstrating that relativistic spacetime is not fundamental but emerges from the collective dynamics of primitive counters and their increments. This approach aligns with spacetime functionalism and offers new perspectives on the nature of time, velocity, and the speed of light.
Digital Twins of Cell Differentiation Integrating Centrosomal Dynamics
The integration of centrosomal dynamics into digital twins (DTs) of cell differentiation represents a paradigm shift from descriptive, empirical protocols to predictive, mechanism-based engineering of cell fate. Digital twins in biomedicine act as dynamic, multi-scale virtual systems that integrate experimental data and generate testable predictions, yet most models overlook the centrosome—an organelle increasingly recognized as an active signal-integration hub rather than a passive microtubule-organizing center. This review synthesizes evidence that centrosomes orchestrate cell fate decisions through asymmetric inheritance, CAFD (cell fate determinant) docking, primary ciliogenesis, and coordination with polarity complexes. We propose a six-layer digital twin architecture that incorporates the centrosome as a mandatory computational module at the perception–integration level and CAFD logistics at the intracellular transport level. Data acquisition analysis shows that super-resolution live-cell imaging, APEX2 proximity proteomics, FRET-based biosensors, and imaging mass cytometry provide multiparametric data to parameterize centrosome-specific dynamics. Computational frameworks include agent-based modeling with explicit centrosomal state vectors, hybrid LSTM–CNN architectures for multimodal time-series integration, graph neural networks for CAFD–centrosome interactomes, and reinforcement learning for closed-loop protocol optimization. A case study optimizing cortical neuron differentiation from iPSCs via Aurora A kinase inhibition illustrates implementation from data acquisition through hybrid model training. Key challenges include dimensionality, computational demands, incomplete CAFD inventories, and validation costs. Ethical issues of data sovereignty, liability, and reproducibility remain. Over three to five years, protocol twins will enable pharmaceutical in silico screening; within five to ten years, cloud platforms with pretrained centrosomal modules will democratize access; beyond ten years, integrated virtual cells may support Human Digital Twin initiatives. This interdisciplinary effort will accelerate predictable, safe cell therapies by transforming trial-and-error into centrosome-informed engineering.
Ex Vivo Manipulation Strategies for Directed Stem Cell Differentiation
Directed differentiation of stem cells into functional somatic cell types ex vivo remains a cornerstone of regenerative medicine, yet conventional approaches relying solely on soluble factor modulation have reached a plateau in efficiency, homogeneity, and functional maturation. This review synthesizes classical and emerging manipulation strategies, with emphasis on the centrosome as an underappreciated but critical regulator of cell fate decisions. Classical methods—including growth factor-mediated chemical induction, matrix-engineered scaffolds, and coculture systems—are systematically evaluated for their strengths and limitations. Genetic engineering approaches utilizing transcription factor overexpression and CRISPR/Cas9-mediated reporter generation are discussed as tools for enhancing purity and enabling real-time fate monitoring. Physical stimulation through bioreactors delivering pulsatile flow, mechanical stretch, and electrical fields is examined for its capacity to engage mechanotransductive pathways that converge on the centrosome. The core of this review introduces pioneering strategies targeting centrioles and associated cell fate determination systems (CAFDs), including pharmacological modulation of centriolar kinases (PLK4, NEK2, Aurora A), optogenetic control of CAFD localization, nanoparticle-mediated delivery to centrosomes, magnetic manipulation of centrosome position, and pharmacological stimulation of ciliogenesis. An integrative protocol for generating functional dopaminergic neurons is presented as a proof-of-concept, sequentially incorporating centriole priming, dual SMAD inhibition, ciliogenesis-enhanced ventral specification, mechanical maturation, and reporter-based purification. Critical quality assessment methodologies—super-resolution imaging, ciliogenesis assays, spindle orientation analysis, single-cell omics, and transplantation validation—are outlined. Finally, key challenges including safety validation, persistent heterogeneity, scalability limitations, and ethical considerations are addressed. The emerging paradigm positions the centriole not as a static structural element but as a dynamic, manipulable target for biotechnological engineering of cell fate. Integration of centrosome-directed approaches with predictive digital twin modeling promises to accelerate the transition from generating incompletely differentiated populations toward creating truly functional, mature, and safe transplantable products for regenerative medicine.
Pharmacological Control of Cell Fate via Centriole-Associated Determinants
The centriole has evolved from a structural microtubule-organizing center to a dynamic signaling hub that integrates mechanical, biochemical, and spatial information to regulate cell identity. Centriole-Associated Fate Determinants (CAFDs) comprise a diverse class of proteins—including transcription factors, signaling effectors, and structural regulators—whose physical interaction with the centriole governs their activity, stability, and inheritance. This review synthesizes recent advances in the pharmacological targeting of CAFD-centriole interactions as a strategy for precise intervention in cell fate decisions. We analyze four target classes: (1) direct CAFD-centriolar adaptor interfaces (YAP-AMOTL2-CEP83, LGN-NuMA, STAT3-centriole); (2) kinases regulating CAFD availability (PLK4, NEK2, GSK3β); (3) the ubiquitin-proteasome system at the centrosome (SCF^FBXW7^, COP9 signalosome, USP9X); and (4) liquid-liquid phase separation (LLPS) condensates that concentrate CAFDs within the pericentriolar material. Methodological platforms including PROTACs, peptidomimetics, allosteric modulators, and nanoparticle-based delivery systems are critically evaluated. PLK4 inhibitors represent the most clinically advanced approach, with RP-1664 having entered Phase 1 trials, though on-target toxicity and the need for biomarker-driven patient selection (e.g., TRIM37-amplified tumors) remain significant challenges. PROTAC technology offers unprecedented potential for eliminating oncogenic CAFDs, but achieving pool-specific degradation—selectively targeting the centriolar population while sparing essential nuclear or junctional pools—remains an unresolved hurdle. The LGN-NuMA complex, despite structural elucidation, is likely therapeutically intractable due to its essential role in all mitotic cells. LLPS modulation, while mechanistically illuminating, awaits discovery of centrosome-specific phase regulators. We conclude that the most realistic near-term applications lie in biomarker-selected oncology (PLK4/NEK2 inhibitors) and ex vivo stem cell manipulation, where controlled culture environments circumvent systemic delivery and toxicity challenges. Elegant in vivo regulation of specific CAFD pools awaits breakthroughs in targeted protein degradation, structural biology, and precision delivery technologies.
Toward Integral Field Tomography of Living Systems
Modern medical diagnostics relies on modality-specific approximations—CT for density, MRI for proton environments, ultrasound for mechanical impedance, and PET for metabolic proxies—each observing a projection of the organism rather than the organism itself. Disease, however, is not merely a structural anomaly but a loss of system stability, often established long before macroscopic changes become detectable. This article introduces the concept of Integral Field Tomography (IFT), a novel framework for reconstructing the internal physiological state of a living organism by solving the inverse problem of its externally measurable physical fields. Living systems are conceptualized as unified, multi-field entities: electrodynamic, magnetodynamic, mechanical continua, metabolic dissipative structures, and information-processing systems far from equilibrium. These processes continuously generate electrical, magnetic, mechanical, and photonic fields that propagate beyond tissue boundaries, serving as fundamental expressions of physiological state. IFT proposes to capture these fields simultaneously using ultra-sensitive detectors—including optically pumped magnetometers, laser vibrometers, and quantum-limited photonic sensors—and to reconstruct the organism's internal state through multi-scale, multi-physics inverse modeling. Artificial intelligence plays an intrinsic role in learning personalized priors, enforcing physical constraints, integrating heterogeneous data, and maintaining a living digital twin of the organism. The framework aligns naturally with active inference, reconceptualizing diagnosis as the estimation of how well the organism minimizes its own variational free energy. This shift from episodic structural imaging to continuous state inference enables detection before structural damage, monitoring of aging as loss of system coherence, evaluation of interventions at the level of state recovery, and the establishment of individualized baselines instead of population norms. Fundamental physical limits—quantum noise, thermal fluctuations, and information-theoretic constraints—lie far above current clinical thresholds, confirming that the primary obstacles are conceptual and computational, not physical. Integral Field Tomography represents not merely a new device but a new epistemology of medicine, transforming diagnostics from looking at bodies to reading living systems as coherent, measurable, dynamic wholes.
Centriole-Associated Fate Determinants (CAFDs)
Emerging evidence, however, reveals that this organelle plays a far more expansive role as a dynamic platform for cell fate determination. We propose the concept of Centriole-Associated Fate Determinants (CAFDs)—a class of biomolecules, including proteins, RNAs, and ribonucleoprotein complexes, that physically localize to the centriole or pericentriolar material and whose function in specifying cell identity is directly modulated by this association. Unlike core structural components, CAFDs are "guests" at the centriole, with primary biochemical roles in transcription, signaling, translation, or proteostasis. This review provides a comprehensive framework for understanding CAFDs, including their conceptual basis, classification by chemical nature and mechanism of action, and a detailed catalogue of key examples across model systems. We examine the regulatory mechanisms that control CAFD activity at the centriole—post-translational modifications, conformational changes, competitive binding, and signal-dependent release—and survey the advanced methodologies for their identification and study, from proximity-dependent biotinylation to super-resolution imaging and induced tethering. An evolutionary perspective reveals that primitive CAFD-like functions likely originated in unicellular eukaryotes to coordinate life cycle transitions, later co-opted in metazoans for asymmetric division and differentiation. Disruption of CAFDs or their centriolar adapters underlies a spectrum of human pathologies, including microcephaly, ciliopathies, and cancer. We conclude with an integrative model positioning the centriole as a strategic command post that integrates cytoskeletal architecture with gene regulatory programs, and pose the central question for future therapeutic exploration: Can cell fate be controlled by pharmacologically modulating specific CAFD-centriole interactions?
Interference is Controlled by Prediction
Interference phenomena are commonly understood as consequences of path indistinguishability and coherence constrained by the availability of which-path information. While delayed-choice and quantum eraser experiments have demonstrated that interference can be restored or suppressed depending on measurement context, such effects are typically implemented through discrete, externally imposed experimental configurations. In this work, propose a delayed-choice interferometric scheme in which interference visibility is regulated adaptively via predictive estimates of informational accessibility. The proposed architecture introduces an operational measure of predictability derived from ensemble-level intensity statistics, which is used to control downstream interferometric elements after the system has traversed the interferometer. This design preserves the delayed-choice character of the experiment while avoiding any modification of standard quantum mechanical formalism or assumptions of retrocausality. Predictability is treated as an informational control parameter rather than as an intrinsic property of the system’s past evolution. The scheme builds upon established complementarity relations and information-theoretic approaches to coherence and decoherence, extending them toward adaptive, feedback-based control of interference. The proposal is experimentally accessible using classical or semi-classical optical components and does not rely on single-particle detection. By reframing interference as a dynamically regulated informational regime, the work provides a bridge between foundational concepts of quantum measurement and practical architectures for coherence control.
The Hidden Mutational Landscape of Extrachromosomal Circular DNA
The human genome is not confined to chromosomes. Extrachromosomal circular DNA—eccDNA and its megabase-scale counterpart ecDNA—is a persistent, transcriptionally active, and mutationally accelerated compartment present in normal and neoplastic cells. Yet every stage of genomic analysis, from DNA extraction to variant annotation, is engineered for linear, diploid templates. This review argues that circular DNA mutations are not rare events; they are systematically erased by methodologies that mistake the map for the territory. We synthesize evidence that circular DNA exhibits a mutational spectrum fundamentally distinct from chromosomal DNA: microhomology-driven indels, complex structural rearrangements within single molecules, and interchromosomal chimeric fusions that generate novel oncogenic reading frames. Its mutation rate is accelerated by rolling-circle replication, suppressed homologous recombination, and torsional stress—quantified as μ_eff = μ_bp × CN × f_rep, exceeding chromosomal rates by two orders of magnitude. Experimental isolation and detection methods each carry specific biases that distort mutational discovery. Computational reconstruction requires graph-based assembly and copy-number-normalized burden metrics. Validation by inverse PCR, mutation-specific FISH, and single-cell sequencing reveals that ecDNA mutations exhibit non-Mendelian inheritance yet drive transient transcriptional dominance. Major barriers include the absence of a circular reference genome, indistinguishable replication errors, and zero clinical standardization. Nevertheless, ecDNA amplifications occur in 14% of cancers, confer prognosis independent of chromosomal status, and serve as privileged sites for resistance mutations. eccDNA burden tracks cellular age and genotoxic stress. Emerging therapies targeting ecDNA segregation or transcription are plausible but lack specificity. The central conclusion is not that circular DNA matters—it is that the genome is not what we thought it was.
Copyright (c) 2026 Lali Latsabidze (Author) https://creativecommons.org/licenses/by/4.0/
The twin paradox is generally regarded as a consequence of the geometry of Minkowski spacetime: the traveling twin follows a shorter worldline and therefore accumulates less proper time. While mathematically consistent, this explanation leaves a conceptual gap—it stipulates that clocks measure the metric interval without specifying why such a relation holds. The Ze interpretation closes this gap by reconstructing proper time from purely operational primitives. Time is defined not as a geometric coordinate but as a local count: tau = alpha * N, where N is the number of causally connected coincidence events registered by a stable counter and alpha is a conventional normalization coefficient. Motion redistributes a finite event budget between two orthogonal channels: temporal self-correlation (aging) and spatial cross-correlation (displacement). The total event count satisfies dN_total^2 = dN_temporal^2 + dN_spatial^2, from which the Lorentz factor gamma = dN_total / dN_temporal and the Minkowski interval ds^2 = dt^2 - dx^2/c^2 emerge as derived continuum approximations. Velocity is redefined as the event allocation ratio v/c = dN_spatial / dN_total. Within this framework, the twin scenario reduces to a comparison of two distinct causal chains sharing common endpoints. The traveling twin’s chain contains the same number of temporal self-correlations interspersed with additional spatial correlation events required by motion; these spatial events consume event budget without contributing to causal distance. Upon reunion, the counter comparison yields N_T < N_E directly and without paradox. The asymmetry is not a puzzle requiring reconciliation with a symmetric description—it is the empirical fact from which theorizing begins. The Ze interpretation is empirically equivalent to special relativity but provides a constructive mechanism for time dilation, eliminates the clock hypothesis as an independent postulate, aligns time ontology with metrological practice, and dissolves the twin paradox by reducing it to trivial arithmetic. The paradox vanishes not because it is resolved but because it was never there.
Direct Derivation of Time Dilation from Ze Counters
Special relativity postulates time dilation as a consequence of the Lorentz transformation derived from the light postulate and the principle of relativity. This paper presents a fundamentally different approach. I introduce the Ze counter framework, in which time is not a background coordinate but a countable quantity: proper time τ is defined as the total number of effective sequential state updates performed by a system. Motion, in this framework, corresponds to the allocation of finite update resources to parallel (spatial) processing rather than sequential (temporal) evolution. Using only discrete counting rules, I define velocity as the ratio of accumulated parallel update squares to sequential update squares, and I postulate conservation of total update squared magnitude. From these purely combinatorial assumptions, I derive the invariant interval ΔS² − c²ΔT² = constant and the exact Lorentz factor τ(v) = τ₀/√(1 − v²/c²). No geometric postulates, no light postulate, and no coordinate time are assumed. Time dilation is thus not a stretching of time but a deficit of update events: moving systems update their internal states less frequently because their update budget is partially consumed by spatial translation. I demonstrate that this derivation is not a reinterpretation of special relativity but an independent foundation that explains why relativity has the form it does. A readily executable numerical experiment, implementable in under 100 lines of code, exhibits relativistic time dilation from pure prediction-error statistics without any relativistic axioms. The Ze framework predicts discrete granularity of proper time at sufficiently high resolution and suggests that Lorentz invariance is not fundamental but emergent from the resource economics of finite-speed update propagation. This work unifies relativistic kinematics with information theory, computational mechanics, and active inference, revealing time dilation as a universal property of resource-constrained predictive systems.
Emergence of the Minkowski Metric from Ze Dynamics
This paper presents a novel derivation of the Minkowski metric from first principles within the framework of Ze dynamics. I demonstrate that the fundamental structure of spacetime, characterized by the Lorentzian interval ds² = –c²dt² + dx², emerges not as an a priori geometric postulate but as a statistical invariant of a discrete, information-theoretic substrate. The primitive elements are counters updated by a stream of events, governed by a statistically conserved quadratic sum. A critical functional bifurcation separates the dynamics into a temporal channel, defined by sequential, order-dependent prediction error, and a spatial channel, defined by parallel, order-invariant structural differences. The inherent antagonism between these channels—where spatial stabilization is paid for by temporal destabilization—forces their contributions to combine with opposite signs in the conserved quantity, thereby deriving the minus sign of the metric signature. The constant c emerges as a conversion factor between the natural scales of the two counting processes. The resulting interval, computed via a concrete numerical algorithm, recovers the kinematics of Special Relativity in the continuum limit, with the light cone arising as a numerical stability boundary for coherent signal propagation within the network. This work reframes Minkowski spacetime as an effective geometry, positing that space and time are emergent operational modes of information processing rather than fundamental dimensions.
This paper presents a unified physical interpretation of the Ze framework, positioning it not as a computational algorithm but as a foundational ontological theory. We argue that Ze is built upon a single primitive: a fundamental state whose norm is conserved. This state admits a dual representation—continuous for analysis and discrete for dynamics—where integer-valued counters constitute the physical substrate. From this basis, all conventional physical concepts are derived. Quantization emerges from the discreteness of counter updates, replacing wave-particle duality with a minimal unit of registration. Causality and the arrow of time arise from the principle of directional stabilization, where the causal order is the sequence that maximizes global state predictability. Space and time are not independent continua but emerge as antiparallel modes of processing the state: time as sequential accumulation and space as parallel comparison. Their competition yields the kinematic structure of Special Relativity, while gradients in the state's stable orientation manifest as effective curvature, reproducing General Relativity. Consequently, matter is interpreted as a stabilized pattern, motion as its reorientation, and forces as stabilization gradients. The interpretation leads to a monistic ontology where the universe is a single, conserved state undergoing structured redistribution, offering a parsimonious path to unifying quantum and relativistic phenomena without dualistic postulates.
This paper presents the complete axiomatic foundation of the Ze Vector Theory (ZVT), a unified framework for fundamental physics. ZVT posits a single ontological primitive—the Ze State—which inherently admits both a continuous (vector) and a discrete (counter) representation. From this basis, the theory derives space and time as antiparallel, co-equal projections of the State, rather than assuming them as a background manifold. Physical dynamics are defined as the norm-preserving redistribution of the State's measure, from which causality and quantum phenomena emerge naturally. Quantum discreteness is shown to be a consequence of the discrete substrate, while interference patterns arise from the superposition of statistical pathways for state transitions, eliminating the need for a physical collapse postulate. The theory intrinsically defines an observer as an autonomous subsystem capable of stable registration. Crucially, ZVT demonstrates that Special Relativity, General Relativity, standard Quantum Theory, and Causal Set Theory arise as specific limiting regimes of its general formalism. By deriving, rather than postulating, the core concepts of modern physics and seamlessly integrating the continuous and discrete, ZVT offers a coherent, monistic, and relational foundation for a unified description of reality.
The geometric-differential paradigm of spacetime, while foundational to modern physics, faces intrinsic challenges in quantum gravity and provides a limited framework for understanding state evolution as a computational process. This article proposes a shift in ontological foundations, presenting Ze, a discrete computational framework that implements the dynamics of a fundamental state vector Ψ. We argue that Ze is not merely an algorithm but a model of physical becoming, where space and time are not pre-existing coordinates but emerge as anti-parallel channels for the redistribution of information flow. Within Ze, the state vector is represented by a global configuration of statistical counters, and its evolution is driven by a process of passive learning through the minimization of prediction error. The framework naturally maps key physical entities: the temporal component corresponds to the sequential, irreversible flow of events and counter growth, while the spatial component corresponds to the synchronous, correlational structure of the internal model. This anti-parallelism is formalized in a discrete Ze-Lagrangian, a variational principle balancing structural stabilization against predictive error. We demonstrate how this setup allows for the emergence of relativistic invariants, a statistical and vector-based causality akin to causal sets, and quantum phenomena such as quantization (from discrete accounting) and interference (from superposition of predictive contexts). The theory reframes the observer as a self-norm-preserving system and suggests that Special and General Relativity are limiting descriptions of stable regimes in the Ze dynamics. The work offers a unified, vector-based ontology that derives physics from first principles of information processing.
This paper introduces a novel ontological framework, termed the Ze model, which reframes the foundations of Einstein's relativity. It posits a unified vectorial substance, the state vector Ψ, as the fundamental entity, with its invariant norm ‖Ψ‖² serving as the primary conserved quantity. Space and time are not independent dimensions but emerge as antiparallel projections of Ψ. I demonstrate that Special Relativity (STR)—its invariant interval, time dilation, and the role of the speed of light c—arises as the kinematic limit of the dynamics governing the reallocation of Ψ's magnitude. General Relativity (GR) is recovered as the classical continuum limit, where spacetime curvature is reinterpreted as a smooth gradient in the orientation field of Ψ vectors, effectively unifying matter and geometry into manifestations of a single substrate. The framework exhibits deep conceptual affinities with pre-geometric approaches: it shares the primacy of a deeper space with Twistor Theory and grounds causality in vector directionality, paralleling Causal Set Theory. This synthesis suggests that STR and GR are not fundamental descriptions of an arena but are highly effective theories emergent from a monistic, vector-based reality. The model provides a new pathway for conceptualizing quantum gravity through the proposed quantization of Ψ's orientation.
The centrosome, classically defined as the primary microtubule-organizing center of the animal cell, is here reconceptualized as a critical organelle for non-genomic cellular memory. We propose the Centrosomal Ledger hypothesis, which posits that the mother centriole encodes a high-dimensional molecular state vector. This distributed memory integrates proteomic composition, post-translational modification (PTM) landscapes, and macromolecular stoichiometries accumulated over a cell’s history. Rather than being a passive structural hub, the centrosome actively utilizes this integrated record to guide future cell fate decisions, such as the choice between symmetric and asymmetric division. Crucically, this hypothesis is untestable by traditional bulk-cell molecular biology, as it requires the discrimination of centriole-age-specific molecular signatures. Its rigorous falsification necessitates centrosome-resolved, multi-omic approaches. Furthermore, we argue that dysregulation of this ledger—through corruption or erosion—constitutes a fundamental mechanistic axis underlying oncogenic transformation, where fate instruction is scrambled, and age-associated stem cell decline, where instructive fidelity is lost. This reframing of the centrosome from a cytoskeletal architect to an information-processing device opens novel translational avenues for diagnosing and treating cancer and degenerative diseases by targeting organelle memory.
Space–Time from a Conserved State Vector
This paper develops a foundational theory in which the geometry of spacetime and the dynamics of matter emerge from the evolution of a conserved real state vector, Ψ^μ, in an abstract four-dimensional internal space endowed with a Minkowski metric η_{μν}. The theory is constructed from two core axioms: the strict conservation of the state vector's Minkowski norm and the condition of anti-parallelism between its temporal and spatial components. We derive the minimal and covariant action principle consistent with these axioms, which takes the form of a worldline action for a relativistic particle, S = -m c ∫ √(-η_{μν} dΨ^μ dΨ^ν). We demonstrate that the equations of motion describe a Lorentz-rotation of Ψ^μ, with its components Ψ^μ ≡ (c t, x^i) directly identifiable as physical spacetime coordinates. This identification recovers standard relativistic mechanics, with mass m reinterpreted as the frequency of the state vector's internal oscillation. The framework provides a unified geometric interpretation where physical time, space, motion, and mass are seen as derived, phenomenological aspects of a more fundamental, conserved dynamics in state space. The formulation suggests a natural pathway toward a field-theoretic generalization where the spacetime metric emerges as an induced quantity from the gradients of the state vector field.