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
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.
Copyright (c) 2026 Jaba Tkemaladze (Author) https://creativecommons.org/licenses/by/4.0/
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.
A Vectorial Axiomatization of Space – Time Unity
This article presents a novel foundational framework for physics, grounded in a minimalist vectorial ontology. I propose that the unified fabric of reality is described by a fundamental abstract state space F, whose elements are normed vectors Ψ. From this single premise, a complete axiomatization of space-time and quantum phenomena is derived. The core innovation is the definition of space and time not as independent continua, but as complementary projections of the state vector: Ψ = (S, T). A set of nine axioms is introduced, imposing constraints on these components: their magnitudes are equal (|S| = c|T|), their directions are antiparallel (S = -T), and their evolution is a norm-preserving unitary redistribution. From these purely algebraic and geometric relations, I demonstrate the emergence of Minkowskian space-time with its Lorentzian metric, the invariant speed of light c, and a causal structure defined by the connectivity of F. The framework naturally incorporates quantum mechanics by identifying unitary evolution on F as the fundamental dynamical principle, with measurement and classicality arising via environmental decoherence and the dynamical selection of pointer states (Axiom IX). This work offers a path toward resolving the quantum gravity problem by suggesting that both geometry and quantum states are manifestations of a deeper vectorial substrate, thereby unifying relativity and quantum theory within a single, observer-independent mathematical structure.
Space and Time as Orthogonal Projections of a Conserved State Vector
This article presents a novel theoretical framework that reinterprets the fundamental nature of space and time. I propose that they are not independent, pre-existing continua but are emergent as orthogonal and anti-parallel projections of a single, conserved state vector in a higher-dimensional space. The model is built upon the core axiom of an invariant norm, ||Ψ||^2 = constant, and a strong geometric condition: the vectorial projections for space (S) and time (T) are equal in magnitude but opposite in direction, expressed as S = -κT, where κ is a fundamental constant. From this foundation, I demonstrate how key features of modern physics emerge naturally. The Lorentz transformations and phenomena of time dilation are derived from the compensatory exchange between the S and T components during state evolution. The mass-energy equivalence E=mc² is reformulated as a geometric conversion law, with the speed of light c acting as the exchange constant κ. Furthermore, the cosmological arrow of time is linked to a global drift of the state vector from an initial condition of high temporal potential toward increased spatial expression. The framework offers integrated explanations for causality, black hole structure, and provides pathways for unification with quantum mechanics, suggesting that spacetime itself is a quantum-informational construct.
Spelt (Triticum aestivum ssp. spelta) is frequently marketed as a more tolerable alternative to common wheat, particularly for individuals with gluten-related disorders. This study aimed to conduct a comprehensive comparative analysis of the gluten from spelt and modern wheat (Triticum aestivum ssp. vulgare) and its biological impact. Using standardized flour samples grown under identical conditions, we performed proteomic characterization, assessed immunoreactivity via ELISA with monoclonal and celiac disease (CeD) patient sera, evaluated effects on intestinal epithelial (Caco-2) barrier function and immune cell activation, and conducted a pilot randomized cross-over trial in subjects with non-celiac gluten sensitivity (NCGS). Results revealed that spelt gluten has a distinct proteomic signature with a lower relative abundance of specific immunogenic gliadins, leading to 15-25% lower immunoreactivity. In vitro, spelt peptides induced a slower and weaker disruption of epithelial tight junctions and a reduced pro-inflammatory cytokine release. In the NCGS trial, 60% of participants reported milder symptoms after spelt consumption compared to wheat, though objective inflammatory markers did not differ significantly. We conclude that while the quantitative and qualitative differences in spelt gluten attenuate its pathogenicity, it remains unsafe for individuals with CeD due to the presence of cross-reactive epitopes. For a subset of those with NCGS, spelt may be better tolerated, warranting a personalized dietary approach.
Circular DNA molecules—mitochondrial DNA (mtDNA) and extrachromosomal circular DNA (ecDNA)—are fundamental genetic elements whose structural integrity is essential for cellular homeostasis. Pathological alterations in their length, caused by deletions or duplications, are directly implicated in a broad spectrum of human diseases, from inherited mitochondrial disorders to aggressive cancers. This review provides a comprehensive methodological guide for detecting these specific structural changes. We systematically evaluate classical techniques (long-range PCR, Southern blotting, electron microscopy) that offer direct visualization and validation, and modern high-throughput approaches (short- and long-read sequencing) that enable genome-wide discovery. Special emphasis is placed on quantitative clinical tools like digital droplet PCR (ddPCR) for ultrasensitive monitoring. By presenting a comparative framework, we guide the selection of optimal methods based on resolution, throughput, and clinical applicability. We conclude that an integrated, multi-method strategy is indispensable for robust analysis, positioning the precise detection of circular DNA length alterations as a cornerstone of emerging precision diagnostics and therapeutic strategies.
Copyright (c) 2026 Zurab Abashidze (Author) https://creativecommons.org/licenses/by/4.0/
De novo centriole formation and the assembly of differentiation inducing molecular complexes in embryonic cells
Early embryonic development requires the transformation of a single cell into a complex, patterned organism. This process critically depends on the de novo formation of centrioles, which, unlike the canonical templated duplication in somatic cells, occurs without pre-existing organelles in oocytes and zygotes. This review synthesizes evidence from a systematic analysis of studies across model organisms to propose that de novo centriole biogenesis serves a dual, integrative function. It not only ensures the assembly of the mitotic apparatus but also acts as a fundamental organizing principle for the spatial assembly and asymmetric segregation of macromolecular complexes that induce cell differentiation. We delineate a stage-dependent model, from oogenic predetermination through the first cleavages, demonstrating how the nascent centriole acts as a scaffold for liquid-liquid phase separation (LLPS), co-condensing fate determinants like transcription factors, repressors, and localized mRNAs. Comparative and functional analyses from C. elegans to mice establish a causal link: disrupting centriole assembly or its association with determinants leads to defective asymmetric division and cell fate transformation. We conclude that de novo centriologenesis is the architectonic event that couples cell division with lineage specification, a deeply conserved mechanism whose disruption underpins severe human developmental disorders. The presented integrative model reframes the centrosome as an active conductor of embryonic patterning.
Identifying Centriole-associated Factors That Induce Differentiation
The centrosome is fundamentally recognized for its role in cell division and ciliogenesis. However, emerging evidence suggests a non-canonical function: the centriole, particularly the mother centriole, acts as a regulatory hub for cellular differentiation. This article synthesizes data from 65 studies (2010–2024) to test the hypothesis that centrioles are associated with unique sets of regulatory molecules which, upon specific cues, can act as local inducers of cell fate. We systematically identify and classify such Centriole-Associated Fate Determinants (CAFDs), including transcription factors (STAT3, YAP/TAZ, Gli), RNA regulators (Prospero mRNA), kinases (PLK4), and ubiquitin ligase components. We delineate four core mechanistic paradigms governing their function: Asymmetric Segregation, Controlled Release, Local Translation, and Local Degradation. A comparative analysis across neurogenesis, gliogenesis, myogenesis, and mesenchymal differentiation reveals both conserved principles and lineage-specific adaptations of these mechanisms. We further review critical methodological approaches—from centrosomal proteomics to proximity ligation (BioID/APEX) and mRNA-trapping—essential for discovering CAFDs. Finally, we propose an integrative "Centriolar Decision-Making Conveyor" model, positioning this organelle as an active processing station that integrates signals and dispatches instructive cues to the nucleus. This refines our understanding of cell fate specification and highlights the therapeutic potential of manipulating centriolar signaling to direct differentiation in regenerative medicine and oncology.
Methods for Tracking Individual Centrioles in Living Cells
The ability to track individual centrioles in living cells represents a pivotal methodology for advancing our understanding of centrosome biology, cell division, and ciliogenesis. This article provides a comprehensive review of the current methodological landscape for centriole tracking, bridging historical approaches with cutting-edge innovations. We begin by outlining the fundamental challenges—including the organelle's sub-diffraction size, dynamic life cycle, and close pairing—that have historically limited observation. The review then details a hierarchical progression of techniques, from foundational static methods like immunofluorescence and electron microscopy to the direct live-cell imaging enabled by fluorescent protein fusions and advanced microscopy platforms such as spinning-disk confocal and Total Internal Reflection Fluorescence (TIRF) microscopy. A significant focus is placed on super-resolution methods, particularly Stimulated Emission Depletion (STED) microscopy, which allows for the resolution of individual centrioles within a pair in real time. We further explore critical genetic manipulation and labeling strategies, including CRISPR/Cas9-mediated endogenous tagging and photoactivatable proteins for pulse-chase experiments. Practical, detailed protocols for long-term tracking, super-resolution imaging, and lineage analysis are presented, followed by an in-depth discussion of the computational pipeline for data analysis, encompassing object detection, trajectory linking, and quantitative kinetic measurements. Finally, we address common artifacts and mitigation strategies, and conclude by highlighting emerging technologies like correlative light-electron microscopy (CLEM) and lattice light-sheet microscopy (LLSM) that promise to further revolutionize the field by linking dynamic behavior with ultrastructure and enabling studies within complex 3D tissues.
Mother and Daughter Centrioles Are Not Equivalent
For decades, centrioles were viewed as symmetrical, semi-conservatively duplicated organelles. This review synthesizes contemporary evidence to establish a fundamental paradigm shift: mother (mature) and daughter (newly formed) centrioles are intrinsically non-equivalent, serving as distinct cellular compartments with specialized roles. We systematically analyze data from super-resolution microscopy, comparative proteomics, live-cell tracking, and functional genetics to delineate a multi-layered hierarchy of asymmetry. This encompasses profound differences in ultrastructure (possession of appendages), molecular composition, functional capacity (as microtubule-organizing centers and basal bodies), dynamic properties, and fate during asymmetric cell divisions. We explore the sequential biochemical maturation program and post-translational modifications that establish this asymmetry and examine its critical manifestations across diverse cellular systems, from fibroblasts and stem cells to epithelia and sperm. Furthermore, the pathological consequences of disrupting this hierarchy are detailed, linking failures in centriole maturation to ciliopathies, neurodevelopmental disorders like microcephaly, and oncogenic processes driven by centrosomal amplification and chromosomal instability. We propose an integrative "Master-Apprentice" model, wherein the mother centriole acts as a stable organizing and signaling hub instructing its dynamic daughter counterpart. This inherent non-equivalence is not a minor detail but a core organizing principle essential for cellular polarity, accurate division, and tissue homeostasis.
Centrioles as Intracellular Timers of the Cell Cycle and Cell Fate
The centrosome, and specifically its core centriolar components, is classically known for its structural roles in cell division and ciliogenesis. However, emerging evidence suggests a far more integrative function: centrioles may act as autonomous intracellular timers that encode cellular history and influence future decisions. This review synthesizes data from 41 studies (2010–2024) to evaluate the hypothesis that centrioles function as biological “clocks” for the cell cycle and determinants of cell fate. We present empirical evidence showing that centriole age, number, and structural state serve as quantifiable metrics that cells utilize to count divisions, time cell cycle phases, and determine division symmetry. The molecular basis of this timing involves the accumulation of age-specific post-translational modifications on mother centrioles, dynamic changes in pericentriolar material composition, and physical linkage to the nuclear lamina. A comparative analysis across embryonic stem cells, neural progenitors, senescent fibroblasts, and cancer cells reveals context-specific manifestations of this timer function, from safeguarding pluripotency to driving genomic instability. While alternative viewpoints on causality and universality exist, an integrative “Centriolar Regulatory Clock” model positions these organelles as critical information-processing hubs that compute temporal and spatial data to guide cell cycle progression, division mode, and ultimate fate. This reframing of centrioles from structural elements to computational timers opens novel therapeutic avenues in regenerative medicine, oncology, and research into aging.
Centrioles as Determinants of Asymmetric Stem Cell Division
Asymmetric stem cell division (ASCD) is a fundamental process for generating cellular diversity while maintaining the stem cell pool. This review synthesizes evidence from diverse model systems to establish a paradigm-shifting hypothesis: centrioles are not passive microtubule-organizing centers but active determinants that orchestrate ASCD. We argue that centrioles function as integrative hub-organelles, executing four coordinated roles: as a Compass that fixes the division axis via cortical linkages, a Dispatcher that asymmetrically recruits and segregates fate determinants, a Sensor that transduces niche signals through the primary cilium, and a Chronometer that regulates division timing. The molecular asymmetry between the mother and daughter centriole, established during interphase, is a prerequisite for correct spindle orientation and asymmetric cargo partitioning. Disruption of centriolar integrity, as seen in human "centriolopathies" like primary microcephaly and ciliopathies, leads to randomized divisions and tissue malformation. Conversely, in cancer, centrosome amplification disrupts this intrinsic asymmetry, promoting symmetric, expansive divisions of stem-like cells. This integrative model positions the centriole as the central architect of cell fate, translating extrinsic polarity into intrinsic asymmetry. Understanding this centriole-centric program opens novel avenues in regenerative medicine, by controlling differentiation in vitro, and in oncology, by targeting the self-renewal of cancer stem cells.
Centriole Biogenesis Constrains Whole Body Regeneration in Planarians
Whole-body regeneration in planarians represents the ultimate challenge in restoring a complete organism from a fragment, requiring coordinated mass proliferation, global repatterning, de novo organogenesis, and tissue remodeling. This review synthesizes evidence from recent functional studies to argue that centriole biogenesis acts as a fundamental constraint on every phase of this complex process. Disruption of centriole duplication or function leads to a hierarchical failure: early blockage of neoblast proliferation results in fragment lethality, while partial impairment yields specific defects in brain regeneration, eye formation, and axial patterning. These phenotypes stem from the centriole's multifunctional role as the orchestrator of mitotic fidelity, asymmetric cell divisions, primary cilia-based signaling, and cytoskeletal organization. A comparative analysis reveals that while centriole dependency is a conserved theme in regeneration, planarians present a uniquely stringent model due to their absolute reliance on a stem cell-driven morphogenetic program. The findings imply that "centriolar health" is a critical determinant of regenerative potential and suggest that evolutionary trade-offs involving centrosome regulation may underlie the loss of regenerative capacity in complex animals. For regenerative medicine, this underscores the necessity of ensuring centriole integrity in stem cell-based strategies.
Centriole Biogenesis Disruption Impairs Regenerative Patterning in Planarians
Centrioles are classically known for their role in mitotic spindle formation, yet their broader function in complex tissue regeneration remains poorly defined. Using the planarian Schmidtea mediterranea as a model, this review synthesizes findings from recent studies employing targeted RNAi and pharmacological inhibition to disrupt centriole biogenesis during pharyngeal regeneration. The analysis reveals that centrioles are indispensable, multi-functional organelles governing a hierarchical cascade of regenerative events. Complete inhibition of centriole duplication (e.g., via Plk4 or SAS-6 knockdown) abolishes neoblast proliferation, preventing blastema formation. Partial impairment of centriolar function (e.g., via CEP120 or Centrin knockdown), which spares proliferation, uncovers critical non-mitotic roles. These include directing cell migration via primary cilia-dependent morphogen signaling (e.g., Wnt, Hedgehog) and orchestrating the cytoskeletal remodeling necessary for epithelial polarization and lumenogenesis. Consequently, pharyngeal regeneration fails due to ectopic patterning, tissue disorganization, and functional non-integration. We propose a model wherein centrioles act as central integrators, sequentially ensuring proliferative expansion, spatial coordination, and morphogenetic execution. These findings elevate centrioles from passive structural components to active regulators of regenerative patterning and suggest that centriolar competence may be a critical, yet overlooked, determinant of stem cell efficacy in regenerative contexts.
Embryonic Developmental Disruptions via Centriole Inhibition
The centriole, a key organelle for cell division and ciliogenesis, is indispensable for embryonic development. The advent of specific pharmacological inhibitors targeting distinct stages of centriole biogenesis—so-called “centriole blockers”—has provided powerful tools to dissect its spatiotemporal functions. This review synthesizes findings from experimental models (mouse, zebrafish, Xenopus, and human stem cell-derived organoids) exposed to three major inhibitor classes: specific PLK4 inhibitors (e.g., centrinone), centriole assembly disruptors (e.g., Bril), and multi-kinase inhibitors (e.g., CFI-400945). Our comparative meta-analysis reveals a fundamental dichotomy in developmental disruption mechanisms. PLK4 inhibition primarily triggers p53-dependent apoptotic depletion of rapidly proliferating progenitors, modeling microcephaly and causing pre-implantation arrest. In contrast, assembly inhibitors predominantly cause structural ciliary defects, disrupting Sonic Hedgehog and Wnt signaling to produce classic ciliopathy phenotypes (polydactyly, renal cysts, laterality defects). The multi-kinase inhibitor CFI-400945 demonstrates compounded toxicity from off-target effects. These phenotypes directly mirror human “centriolopathies,” including autosomal recessive primary microcephaly (MCPH) and syndromic ciliopathies (e.g., Meckel-Gruber syndrome), validating the pathological mechanisms. The analysis establishes the embryo's extreme vulnerability to “centriolar stress,” where checkpoints eliminate defective cells, and highlights the dual role of the centriole as both a mitotic licensor and a ciliary organizer. These insights carry significant translational implications, warning of high teratogenic risk for anticancer therapies targeting this pathway while endorsing these inhibitors as precise tools for disease modeling and therapeutic screening.
For decades, centrioles have been studied primarily for their canonical roles in organizing the mitotic spindle and templating cilia. However, a paradigm shift is underway. This meta-analysis synthesizes contemporary evidence to argue that centrioles are, in fact, pivotal regulatory hubs that directly govern cellular differentiation and fate specification. Moving beyond their structural functions, centrioles influence differentiation through a multi-faceted framework: (1) by ensuring precise spindle geometry and orientation to execute asymmetric cell divisions that segregate fate determinants; (2) by serving as the mandatory platform for the primary cilium, a signaling compartment essential for transducing Hedgehog, Wnt, and other developmental pathways; (3) by acting as sensors of homeostatic integrity, where aberrations in their number or structure trigger p53-dependent signaling to influence cell cycle exit and differentiation; and (4) by modulating cellular competence through "centrosomal maturity," which dictates cytoskeletal polarization and responsiveness to differentiation cues. This integrative role resolves the apparent paradox of an organelle central to cell division being crucial for post-mitotic specialization. The findings redefine centrioles as dynamic information processors, linking their dysfunction to developmental centriolopathies and cancer, and positing them as novel targets for controlling stem cell fate in regenerative medicine.
Ze Systems Generate Entropy to Forge Truth
Initially, the Ze system resides in a high-entropy "wave" state of multiple potential futures, described by a probability distribution P(X) with high Shannon entropy H(X) = - Σ P(x_i) log₂ P(x_i). The cheating model's goal is to collapse this distribution into a low-entropy spike, a definite outcome aligned with its prediction. The Ze System framework proposes a radical epistemological shift from passive observation to active provocation as the basis for scientific discovery. It posits that a substantial portion of reality exists in a latent, wave-like state of unmanifested potentialities. Traditional methods are insufficient for probing this domain, as they merely record already-localized facts. The Ze paradigm introduces a methodology centered on predictive pressure, where scientific inquiry is redefined as the engineering of controlled dilemmas. By deploying competing predictive models and applying precise interventions (Ze probes), these systems force latent structures into a crisis of choice, compelling them to localize into observable phenomena. This process is fundamentally entropic: it expends energy, increases disorder, and irrevocably annihilates alternative potentials to forge a singular, co-created fact. Consequently, truth is not discovered but extracted, emerging from the structured, interpretable failure of expectations rather than their confirmation. The Ze System thus redefines the scientist's role from a detached observer to an accountable architect of reality, establishing entropy not as waste but as the essential currency paid for knowledge. This manifesto outlines the ontological, methodological, and ethical foundations of this second-order science, inviting a deliberate experimentation with the very architecture of knowledge production.
For over a century, centrioles have been defined by their role as architects of the mitotic spindle. This review synthesizes contemporary evidence to propose a paradigm shift: centrioles are strategic timekeepers of the cell. They function not as simple clocks but as custodians of cellular time, encoding a history of divisions and stresses through accumulating post-translational modifications and proteomic changes. This molecular archive, stored on one of the cell's most stable structures, is subsequently interpreted by the cell via mechanical, signaling, and proteostatic pathways to dictate fundamental fate decisions—proliferation, differentiation, senescence, or apoptosis. This centriolar timekeeping function operates across a hierarchy, interacting with circadian oscillators, telomeric and epigenetic clocks, and crucially influencing organismal aging through its role in stem cell fate and asymmetric division. We develop an integrative "Centriolar Timeline" model, describing how the accrual of neutral (maturity) and pathological (damage) marks directs cellular trajectories. This model positions the centriole as a unique bio-physical interface that transforms linear chronological time into non-linear biological fate. Re-conceptualizing centrioles as central processors of temporal information has profound implications for understanding development, aging, and diseases like cancer, and suggests novel therapeutic avenues in regenerative medicine and gerontology aimed at modulating this deep-time cellular memory. The Centrosomal Ledger hypothesis is inherently untestable without omics-based approaches, as it posits that cellular memory is encoded not in single molecular markers but in distributed, multivariate structural states of the centrosome. Only system-level omics analyses can capture the weak yet coordinated molecular patterns, temporal integration, and state-dependent signatures required to render this model experimentally falsifiable
Multiparametric Paradigm from Molecular Assessment to Clinical Translation
Mitochondrial health is a critical determinant of cellular vitality, extending far beyond ATP production to encompass regulation of apoptosis, calcium homeostasis, redox signaling, and dynamic network integrity. Its dysfunction underpins a vast spectrum of age-related and metabolic diseases. However, quantifying this multifaceted concept remains a central challenge due to the absence of a universal "gold standard." This review synthesizes the contemporary methodological arsenal for assessing mitochondrial health in human cells, detailing techniques for evaluating bioenergetics, membrane potential, redox state, morphology, and molecular underpinnings. We critically examine the principles, advantages, and limitations of each approach, highlighting the interpretive pitfalls arising from mitochondrial heterogeneity, the necessity of stress tests to probe functional reserve, and the profound context-dependence of healthy parameters. We argue that accurate assessment necessitates a multiparametric, integrative strategy. Consequently, we outline future frontiers focused on developing integrated real-time platforms, standardized diagnostic panels for personalized medicine, and advanced screening for mitochondria-targeted therapeutics (mitocans, mitohormetic inducers). Advancing from univariate assays to systems-level analysis is essential for unlocking the diagnostic and therapeutic potential of mitochondrial health.
Copyright (c) 2026 Veronika Nadareidze (Author) https://creativecommons.org/licenses/by/4.0/
The measurement problem in quantum mechanics challenges our understanding of reality, demanding explanations beyond both Copenhagen's "collapse" and the Many-Worlds' ontological multiplicity. This paper introduces and formalizes the Ze framework as a novel synthesis of Relational Quantum Mechanics (RQM) and the Active Inference paradigm from theoretical neuroscience. Ze posits that quantum states are relational, defined by the posterior beliefs of interacting generative models engaged in variational free energy minimization. Within this framework, quantum superposition is formalized as high compatibility (ℐ ≈ 1) between competing models, characterized by low free-energy conflict (ΔF < θ). Conversely, the transition to a localized state—the physical correlate of "collapse"—is reconceived not as a metaphysical event but as an optimization-driven phase transition. This occurs when model conflict exceeds a critical threshold (ΔF > θ), a process objectively driven by interactions like which-path marking. We demonstrate that matter-wave interferometry with complex molecules provides a direct experimental testbed for these principles, where which-path information and quantum erasure actively manipulate ΔF. Extending the isomorphism, we propose that transitions in human cognition—from focused wakefulness to dreaming and psychedelic states—are governed by analogous shifts in the brain's inferential threshold (θ). Thus, Ze offers a unified, testable architecture bridging quantum foundations, statistical physics, and the neuroscience of consciousness.
Quantum Behavior as a Consequence of Ze Systems
This paper proposes a novel theoretical framework that reinterprets quantum behavior—superposition, interference, and wavefunction collapse—not as fundamental properties of matter but as emergent epistemic properties of a specific class of information-processing architectures, termed Ze systems. A Ze system is defined as an active predictive engine that operates on continuous data streams through two distinct modes: forward reading (ℱ) and retrograde encoding (ℛ). The core architectural constraint is that ℛ, the process of running predictions backward to reconcile models, necessitates the cessation of the forward information flow ℱ. We demonstrate that superposition corresponds to the system state where competing internal hypotheses remain compatible, formally defined by a small free energy difference (ΔF < θ). Collapse is not a primitive event but a structured, two-stage process triggered when ΔF ≥ θ: first, the mandatory stoppage of ℱ, and second, the execution of ℛ to achieve a single, globally consistent model. Interference is shown to be a statistical signature of the coherent blending of hypotheses when they are non-distinguishable. This framework generates testable predictions across scales, from the accelerated decoherence of complex molecules to the modulation of cognitive flexibility during REM sleep. By deriving quantum phenomena from a principle of predictive inference, the theory bridges the Free Energy Principle, relational quantum mechanics, and decoherence theory, suggesting that quantumness is a universal signature of systems that must pause to look backward in order to predict the future.
The Double-Slit Experiment Is Already Happening in the Brain
The double-slit experiment, a cornerstone of quantum mechanics, is traditionally viewed as a paradoxical demonstration of wave-particle duality. This article posits that its core dynamic—superposition, interference, and environment-driven localization—is not a unique quantum phenomenon but a fundamental computational principle implemented by the brain. We introduce the Ze framework, arguing that the brain operates as a biological interferometer. Cognitive systems maintain multiple generative hypotheses in a state of active interference (superposition), analogous to the quantum wavefunction passing through both slits. "Which-path" information, supplied by sensory data, action, and social context, forces cognitive decoherence, localizing perception and decision into a single narrative. Sleep is recast as an intrinsic quantum eraser, periodically degrading which-path information to restore cognitive flexibility and prevent pathological hyper-localization. The framework structurally links quantum decoherence, Bayesian active inference, and the neurobiology of sleep and wake cycles. It provides a transdiagnostic model for psychopathology, where disorders like psychosis and PTSD are seen as dysregulations of this interference-localization cycle. We conclude that the brain does not observe quantum reality; it actively instantiates its core logic, making the double-slit experiment a continuous, lived process of resolving ambiguity to survive and understand the world.
Consciousness is fundamentally a process of selection, a continuous "collapse" from a manifold of potential states into a singular, coherent narrative. This article introduces the Ze formalism, a theoretical framework that models this process through a cognitive localization parameter, Γ_Ze. We posit that the critical distinction between wakefulness and sleep is not the presence of consciousness, but the suspension of this localization mechanism. During wakefulness ( Γ_Ze ≫ 1 ), the cognitive system enforces rapid, frequent collapse, yielding a stable, logical stream of thought. Sleep (Γ_Ze → 0), conversely, is a physiologically controlled state of suspended localization, where the brain acts as a "quantum eraser" for cognitive "which-path" information. This allows for the maintenance of coherent superpositions of memory and meaning, with dream phenomenology arising from the resulting interference patterns. The model provides a unifying lens for altered states: it frames psychedelics as conscious Γ_Zereduction, general anesthesia as its artificial nullification, and psychiatric conditions like schizophrenia as its pathological dysregulation. We argue that sleep’s primary function is the offline recalibration of cognitive probability amplitudes c_i, facilitating memory integration, emotional regulation, and creative insight. The Ze formalism thus redefines sleep from a passive state of rest to an active, essential operation for maintaining cognitive flexibility and the integrity of waking consciousness.
The quantum eraser experiment, while confirming the mathematical formalism of quantum mechanics, has persistently challenged intuitive understanding, often invoking concepts of retrocausality or the necessity of a conscious observer. This paper develops and articulates the Ze interpretation as a comprehensive framework that resolves these conceptual challenges without such metaphysical additions. We propose that quantum dynamics is fundamentally governed by the competition between two active generative models: a direct causal model (Model A, "particle-like") and a counterfactual wave model (Model B, "wave-like"). Decoherence is reinterpreted not as information loss, but as the environmental amplification of a structural incompatibility between these models, leading to a forced stabilization of the system into a state compatible with a single, definite narrative—a process we identify as physical collapse. The quantum eraser is shown to be an active intervention that dismantles this incompatibility by removing the environmental basis for discriminating between models, thereby restoring the conditions for a low-conflict consensus state that manifests as interference. This framework seamlessly unifies unitary evolution, decoherence, collapse, and erasure as facets of a single process of model competition and stabilization. It eliminates the need for an observer-centric explanation, replaces the "collapse" postulate with a dynamical physical mechanism, and yields novel, testable predictions regarding interference in complex systems and the dynamic nature of the quantum-classical threshold.
A Murine Model Yielding Functional Sperm and Implications for Human In Vitro Gametogenesis
The reconstitution of complete spermatogenesis in vitro remains a pivotal challenge in reproductive biology, with transformative potential for treating infertility and modeling disease. This study establishes a three-step protocol for synthetic spermatogenesis, enabling the generation of functional spermatozoa from mouse and human pluripotent stem cells (PSCs). Initially, PSCs were efficiently differentiated into primordial germ cell-like cells (PGCLCs) with appropriate epigenetic reprogramming. PGCLCs were then co-cultured with primary testicular somatic cells on a 3D scaffold, where they self-organized into seminiferous tubule-like structures. Sequential hormonal stimulation with retinoic acid, testosterone, and follicle-stimulating hormone (FSH) drove meiotic progression and haploid spermatid formation. In the mouse system, complete spermiogenesis was achieved, yielding sperm capable of fertilizing oocytes via intracytoplasmic sperm injection (ICSI) and producing healthy, fertile offspring. Human PGCLCs entered meiosis and formed haploid cells, but terminal spermiogenesis efficiency remained low. This work provides a foundational model for in vitro gametogenesis, offering new avenues for studying male reproduction and addressing absolute infertility, while highlighting critical technical and ethical considerations.
Copyright (c) 2026 Iason Papadopulo (Author) https://creativecommons.org/licenses/by/4.0/
In vitro gametogenesis (IVG)—the generation of functional gametes from pluripotent or somatic cells in culture—represents a paradigm-shifting frontier in reproductive medicine with the potential to address absolute infertility (Saitou & Hayashi, 2021). This review synthesizes the current state and formidable challenges of human oocyte IVG. We detail the two primary strategies: the stepwise differentiation of induced pluripotent stem cells (iPSCs) through a primordial germ cell-like cell (PGCLC) intermediate, and the direct reprogramming of somatic cells. Both pathways confront significant biological barriers, including the achievement of complete epigenetic reprogramming and correct genomic imprinting, the faithful completion of meiosis I to prevent aneuploidy, and the acquisition of cytoplasmic competence (Seisenberger et al., 2012; Nagaoka, Hassold, & Hunt, 2012). Critically, oocyte development is inseparable from its somatic niche; thus, advances in ovarian organoids and 3D biofabrication are essential to reconstruct the follicular microenvironment (Laronda et al., 2017; Sun, Parikh, & Fuller, 2022). Beyond the laboratory, IVG raises profound ethical and social questions concerning reproductive longevity, embryo selection, the redefinition of parenthood, and equitable access (Greely, 2016; Mathews, Morain, & Finkelstein, 2017). We conclude that while mouse models prove principle, translation to humans requires solving fundamental biological puzzles and concurrently developing rigorous ethical and regulatory frameworks. The clinical application of IVG, likely decades away, must be guided by a paramount commitment to offspring safety and inclusive public discourse.
Copyright (c) 2026 Alexander Taktakidze (Author) https://creativecommons.org/licenses/by/4.0/
Centriole Regulation in Natural and Artificial Gametogenesis
Centriole elimination is an evolutionarily conserved, essential process during gametogenesis that resets centrosome number to prevent aneuploidy in the zygote (Schatten & Sun, 2011). While in vitro gametogenesis (IVG) from pluripotent stem cells offers transformative potential for reproductive medicine, its fidelity in recapitulating key cytoplasmic organelle reprogramming events remains poorly characterized. This study presents a systematic comparative analysis of centriole elimination dynamics between natural mouse gametogenesis and leading IVG protocols. Employing high-resolution imaging, molecular profiling, and functional embryogenesis assays, we demonstrate that IVG-derived gametes exhibit profound defects. Centriole elimination in vitro is asynchronous, frequently incomplete, and driven by a dysregulated molecular cascade, leading to the persistent retention of structurally aberrant centrioles (Clift & Schuh, 2013). These organelles act as ectopic microtubule-organizing centers, causing multipolar spindle formation during meiosis and the first embryonic division. Consequently, embryos from IVG gametes with centriole retention suffer catastrophic failure, characterized by severe chromosome segregation errors and preimplantation arrest (Hendriks, Dancet, van Pelt, Hamer, & Repping, 2015). Our findings establish centriole elimination fidelity as a critical, previously overlooked benchmark for IVG. They reveal that the artificial microenvironment fails to provide the precise niche signaling required for this stringent developmental program, highlighting a major safety consideration and providing a mechanistic roadmap for refining synthetic gametogenesis protocols.
Copyright (c) 2026 Gabro Gakely (Author) https://creativecommons.org/licenses/by/4.0/
Mesenchymal Progenitor Cell Resilience Counteracts Tissue Aging
The age-related functional decline of mesenchymal stromal/progenitor cells (MSCs) is a central driver of skeletal aging, leading to osteoporosis and impaired tissue regeneration (Li, Wu, & Tuan, 2019). Challenging the paradigm of a uniformly aging MSC pool, this study identifies a rare subpopulation of mesenchymal progenitors with innate senescence resistance, termed Senescence-Resistant Committed progenitors (SRCs). Isolated from aged murine and human tissues via a unique immunophenotype (CD45⁻CD31⁻CD34⁻CD73⁺CD90⁺CD105⁺CD200⁺ITGA10⁺), SRCs demonstrated remarkable numerical preservation compared to severely depleted classical MSCs. Functionally, aged SRCs maintained low senescence markers (p16INK4a, SA-β-gal), lacked a pro-inflammatory secretome, and retained high clonogenic, proliferative, and osteogenic potential, countering the age-related adipogenic shift (Moerman, Teng, Lipschitz, & Lecka-Czernik, 2004). Transcriptomic and epigenetic profiling revealed that SRC resilience was underpinned by constitutive activation of DNA repair, antioxidant defense (NRF2), and mitochondrial homeostasis pathways, stabilized by a protective epigenetic landscape featuring *CDKN2A/p16* promoter hypomethylation (Sun, Coppe, & Lam, 2018). In vivo, transplantation of aged SRCs significantly enhanced bone regeneration in critical-sized defects compared to aged bulk MSCs. This discovery reframes mesenchymal aging, revealing a resilient cellular reservoir essential for tissue homeostasis. Targeting the SRC pool or mimicking its molecular signature represents a novel therapeutic frontier for age-related skeletal disorders.
Copyright (c) 2026 Laura Gegelia (Author) https://creativecommons.org/licenses/by/4.0/
The Strength of Clay, The Weakness of Gods
The Standard Babylonian Epic of Gilgamesh is traditionally interpreted through the archetype of the heroic king and his wild companion. This article challenges that reading by arguing that the epic systematically inverts these roles to conduct a profound philosophical investigation into the nature of strength. Through close textual analysis framed by contemporary psychological and ecological theory, it demonstrates that Gilgamesh, despite his divine lineage and royal power, is characterized by profound existential, cognitive, and emotional weaknesses. His rule begins in tyrannical hybris, he depends entirely on others to interpret his own subconscious (dreams), and his response to mortality is a pathological flight into denial. In contrast, Enkidu, created from primal clay, embodies an integrated strength rooted in ecological harmony, hermeneutic wisdom, and, ultimately, stoic acceptance of his fate. The analysis further explores the tragic irony of their bond: Gilgamesh’s civilizing process actively weakens Enkidu, severing his connection to his natural strength and rendering him vulnerable to divine retribution. The epic’s resolution is found not in the victory of one archetype but in their synthesis. Gilgamesh’s journey evolves from a quest for personal immortality to an embrace of symbolic immortality through his cultural legacy—the walls of Uruk. This represents a hard-won integration of Enkidu’s lesson of acceptance with his own rebellious drive to transcend limits. The article concludes that the epic redefines true strength not as an innate attribute of divinity or nature, but as a dynamic, earned wisdom forged through relationship, loss, and the creative confrontation with human finitude.