Search Results (62)

Power-law kinetics are observed across a wide range of physical, chemical, biological, and engineering systems, yet the thermodynamic origin of the power-law exponent remains incompletely understood. This work proposes a thermodynamic hypothesis in which power-law behavior emerges naturally from correlation-dependent contributions to the Gibbs free energy. Rather than modifying the classical Boltzmann definition of entropy, a phenomenological Correlation Constant, χ, is introduced to quantify how accumulated microstate evolution influences the accessibility of future states. The resulting correlation entropy contribution produces a free-energy term that modifies the probability of subsequent transitions and leads naturally to power-law kinetic behavior. Positive values of χ correspond to cooperative evolution in which prior evolution promotes future evolution, while negative values correspond to self-limiting behavior in which prior evolution suppresses subsequent evolution. The conventional Arrhenius-Eyring description is recovered as the special case χ = 0. The resulting framework provides a thermodynamic interpretation of the power-law exponent, establishes a connection between entropy, free energy, and kinetic evolution, and offers a unified description applicable to degradation, relaxation, diffusion, fatigue, trapping, and other evolving processes. The present work is intended as a thermodynamic hypothesis motivating further experimental and theoretical investigation of correlation-dependent kinetics. Full article

Venous thromboembolism (VTE) remains a clinically relevant complication of radical prostatectomy despite advances in surgical techniques and perioperative care. Current thromboprophylaxis strategies are largely based on fixed-duration approaches and static risk models focused on the early postoperative period. However, accumulating evidence suggests that postoperative hypercoagulability is a dynamic and prolonged process that may extend beyond this timeframe. This review summarizes the pathophysiological mechanisms and temporal dynamics of postoperative hypercoagulability after radical prostatectomy, with particular emphasis on biomarker-based evidence, including thrombin generation and von Willebrand factor. Clinical and laboratory findings suggest that haemostatic activation may persist after hospital discharge, supporting the concept of a biologically relevant post-discharge period during which insufficiently captured thrombotic risk may remain despite apparent clinical recovery. Current risk assessment models do not account for the time-dependent nature of postoperative haemostatic changes and do not incorporate biomarker data. This discrepancy highlights a gap between guideline-based thromboprophylaxis strategies and the underlying biological processes. To address this, we propose a conceptual framework in which postoperative thromboprophylaxis is considered in relation to the temporal evolution of hypercoagulability. This framework is hypothesis-generating and may help inform future studies aimed at identifying patients who could benefit from extended prophylaxis while avoiding unnecessary anticoagulation in those with more rapid haemostatic recovery. Further prospective studies are required to validate biomarker-guided strategies and to define clinically actionable thresholds for individualized thromboprophylaxis in prostate cancer patients undergoing radical prostatectomy. Full article

Selenium has played a fundamental role in the evolution of aerobic life, thanks to its unique redox properties and its incorporation into antioxidant selenoproteins such as glutathione peroxidases (GPx). This evolutionary perspective has inspired decades of research aimed at developing small organoselenium compounds as GPx-like antioxidant drugs. However, despite extensive in vitro evidence and numerous publications, no organoselenium antioxidant has been commercialized, and even Ebselen, the most extensively studied selenium-based drug candidate, has repeatedly failed in multiple clinical trials. In this opinion article, we posit the hypothesis that a conceptual bias may underlie a significant proportion of the research conducted to date in this field. The antioxidant activity of GPx is contingent on a highly regulated enzymatic environment that is extremely difficult to reproduce with small synthetic molecules. Consequently, many compounds described as GPx mimetics may behave less like true antioxidants and more like redox-active electrophiles capable of disrupting complex thiol-dependent equilibria. It is recommended that future research should adopt a more holistic approach to the study of selenium pharmacology, moving beyond a reductionist interpretation of GPx-like activity. Instead, the focus should be on the complex network of cellular redox processes and selective redox targeting. It is only through a more profound mechanistic comprehension of selenium chemistry within biological systems that it will be feasible to ascertain whether organoselenium compounds can genuinely establish a presence within the domain of medicinal chemistry, extending beyond their persistent yet predominantly laboratory-restricted achievements. In a similar vein, undertaking a thorough examination of the mechanisms may facilitate a more profound comprehension of the fate of organoselenium compounds in their intricate interaction with biological targets. This, in turn, may enable the conception of novel molecules that function as effective and selective pro-oxidants against specific targets. Full article

Background: Osteosarcoma remains a biologically complex and clinically challenging malignancy, with survival gains plateauing despite decades of multimodal therapy incorporating surgery and cytotoxic chemotherapy. Unlike cancers in which mutation-centric precision oncology has yielded transformative advances, osteosarcoma is characterized by profound structural variation, copy number alteration dominance, and dynamic clonal evolution, limiting the effectiveness of single-target approaches. These realities motivate alternative strategy-level frameworks that better align treatment selection with evolving disease behavior. Methods: This narrative educational review synthesizes contemporary evidence from osteosarcoma biology, radiobiology, and translational oncology to propose a state-based framework for integrating radiotherapy—particularly stereotactic body radiotherapy (SBRT/SABR) and spatially fractionated radiotherapy (SFRT)—into osteosarcoma management and clinical trial design. Rather than relying solely on static anatomic stage, this framework emphasizes clinically actionable, time-varying state variables, including disease burden patterns (localized, oligometastatic, polymetastatic), tempo of progression, prior systemic response, and feasibility of complete local control. Results: Within this context, radiotherapy is presented not only as a local control modality but also as a hypothesis-generating biologic intervention, capable of perturbing tumor vasculature, inflammatory signaling, innate DNA-sensing pathways, and immune/myeloid programs in a dose-, fractionation-, and spatial-distribution-dependent manner. The review critically examines both the potential opportunities (e.g., local eradication, immune modulation) and limitations (e.g., rarity of abscopal responses, risk of unintended systemic signaling) of radiobiotherapy combinations, emphasizing the need for cautious interpretation and prospective validation. Conclusions: Finally, the article outlines practical implications for state-stratified, biomarker-embedded clinical trials, highlighting endpoints beyond conventional response criteria, including circulating tumor DNA dynamics, immune and myeloid signatures, and long-term patterns of disease progression. Overall, this review frames radiobiotherapy as an educational and investigational paradigm intended to support rational hypothesis generation, multidisciplinary decision-making, and learning-oriented trial designs in osteosarcoma, rather than as definitive clinical guidance. Full article

We present the results of cognitive tests on conceptual combinations, performed using specific Large Language Models (LLMs) as test subjects. In the first test, performed with ChatGPT (GPT-5.5 Thinking) and Google Gemini Advanced (Gemini 1.5 Pro), we show that Bell’s inequalities are significantly violated, which indicates the presence of a ‘non-classical probability model’ with probabilities that do not satisfy Kolmogorov’s axioms. In the second test, also performed using ChatGPT and Gemini, we identify the presence of ‘Bose–Einstein statistics’, rather than the intuitively expected ‘Maxwell–Boltzmann statistics’, in the distribution of the words contained in large-size texts. Interestingly, these findings mirror the results previously obtained in both cognitive tests with human participants and information retrieval tests on large corpora. Taken together, they point to the ‘systematic emergence of non-classical quantum-like structures in conceptual-linguistic domains’, regardless of whether the cognitive agent is human or artificial. Although LLMs are classified as neural networks for historical reasons, we believe that a more essential form of knowledge organization takes place in the distributive semantic structure of vector spaces built on top of the neural network. It is this meaning-bearing structure that lends itself to a phenomenon of evolutionary convergence between human cognition and language, slowly established through biological evolution, and LLM cognition and language, emerging much more rapidly as a result of self-learning and training. We analyze various aspects and examples that contain evidence supporting the above hypothesis. We also advance a unifying framework that explains the pervasive quantum organization of meaning that we identify. Full article

The survival of complex multicellular organisms depends on continuous inter-organ communication networks that coordinate organism-wide responses across physiological conditions and stress states, including adaptation to environmental challenges, infection, and injury. Rather than operating as isolated units, organ systems are integrated through interconnected signaling networks that transmit biological information across tissues. Building on prior work examining individual physiological pathways, this review introduces a unified systems-level framework that integrates inter-organ communication into a coherent model of organism-wide regulation. This review proposes a systems-level framework in which homeostasis is maintained through eight principal communication systems: neural, endocrine, immune-inflammatory, vascular, lymphatic, metabolic, microbiome–gut, and mechanical-structural. Epithelial barriers function as dynamic signaling interfaces within multiple systems, while extracellular vesicles act as cross-system mediators of information transfer rather than as independent communication networks. These systems operate across distinct temporal scales to coordinate host defense, metabolic adaptation, vascular regulation, and tissue repair. The framework further introduces a temporal hierarchy of signaling dynamics that links communication systems to phase-specific responses during physiological stress. Within this integrated network, glucocorticoid receptor α (GRα) is proposed to function as a systems-level regulator of inter-organ communication, supported by converging mechanistic, experimental, and clinical evidence, with variability in the strength of evidence across domains. In contrast to prior reviews, which addressed GRα function within individual systems, this work conceptualizes GRα as a central rheostat coordinating cross-system signaling and temporal transitions in homeostatic correction. Evidence was identified through hypothesis-driven searches using the Consensus AI platform and verified through manual review of primary biomedical literature. GRα, a ligand-activated transcription factor expressed in most nucleated cells, enables hormonal stress signals to coordinate gene-expression programs across tissues, modulating neuroendocrine responses, endothelial function, inflammatory signaling, metabolic regulation, microbiome–host interactions, and tissue remodeling. Systemic responses to stress progress through three phases of homeostatic correction—Priming, Modulatory, and Restorative—within which GRα supports integrated organism-wide adaptation. This integrative framework provides a mechanistic basis for understanding the emergence and temporal evolution of biological responses in health and critical illness. Full article

Background/Objectives: Sepsis is clinically dynamic, and isolated admission biomarker values may insufficiently capture early biological evolution after treatment initiation. This study evaluated whether routine biomarker reassessment at approximately 48 h provides incremental prognostic information beyond admission Sequential Organ Failure Assessment (SOFA) score for 28-day mortality in sepsis. The analysis was framed as an exploratory 48 h landmark prognostic assessment among patients who were alive and had complete biomarker reassessment data at 48 ± 6 h. Methods: We conducted a prospective single-center observational cohort study including adult patients with sepsis. Clinical and laboratory data were collected at baseline (M1) and repeated 48 ± 6 h later (M2). The primary outcome was 28-day mortality. Candidate biomarkers included C-reactive protein (CRP), procalcitonin (PCT), lactate (LAC), and neutrophil-to-lymphocyte ratio (NLR). PCT clearance and NLR change were calculated as relative changes between M1 and M2, whereas 48 h CRP and 48 h lactate were evaluated as early reassessment values. Exploratory logistic regression models were constructed using admission SOFA as the clinical reference model. Model discrimination and fit were summarized using receiver operating characteristic analysis, likelihood-ratio testing, and Nagelkerke R²; the models were not intended as validated individual-level risk calculators. Results: The 48 h landmark analytical cohort included 126 patients, of whom 44 (34.9%) died within 28 days. Admission biomarker values showed limited prognostic signal. SOFA alone showed fair discrimination (AUC 0.740). Among the primary SOFA-augmented models, SOFA plus PCT clearance showed the highest discrimination and explanatory performance (AUC 0.810; Nagelkerke R² 0.332) and significantly improved model fit compared with SOFA alone. SOFA plus NLR change and SOFA plus 48 h lactate also provided incremental prognostic information, although their gains were more modest. In exploratory combined modeling, SOFA plus PCT clearance and NLR change provided the most coherent additional signal, with all predictors retaining independent associations with 28-day mortality. Conclusions: In this exploratory single-center 48 h landmark analysis, selected routine biomarker reassessment measures were associated with 28-day mortality beyond admission SOFA. PCT clearance provided the clearest incremental prognostic signal, while NLR change offered complementary information. Persistent 48 h lactate elevation was also informative, whereas lactate clearance was not. These findings should be interpreted as hypothesis-generating and require validation in larger cohorts, ideally including serial organ dysfunction measures such as 48 h SOFA or SOFA change. Full article

This review explores the hypothesis that schizophrenic symptoms may be understood not as isolated deficits, but as interconnected manifestations of a structural reorganization of consciousness. The premises of this work are grounded in a comparative matrix that suggests an underlying “consanguinity” between the philosopher’s voluntary epoché—the suspension of the natural attitude performed to study the inner workings of consciousness—and the involuntary “unworlding” passively experienced in schizophrenia. By exploring this shared ontological ground, the text suggests how specific phenomenological shifts, such as the collapse of the “vital drive,” may manifest as clinical markers; this process may eventually lead to an involuntary “transcendental reduction” where the mind’s internal machinery becomes an object of forced awareness. Building on these premises, the review tentatively outlines several key achievements. It addresses the substrate-subjectivity gap by linking biological sensory-binding failures to the onset of involuntary hyper-reflexivity. Regarding structural loss and gain of function, it suggests that the psychotic transition involves a simultaneous erosion of common-sense coherence and an intensified receptivity to unfiltered perceptual fragments, which may trigger a search for metaphysical meanings. In terms of a therapeutic synthesis, it proposes exploring the conversion of “artless decentering” into a manageable, strategic distance through mindfulness and person-centered position-taking. Finally, it discusses a potential nosographic evolution, advocating for future diagnostic classifications that prioritize the experiencing self and qualitative insights to support a more translational and empathetic approach to psychiatry. Full article

Humans, and most other late Homo species, are characterized by large brains and bodies. However, the discovery of two small-brained Homo species—H. floresiensis and Homo naledi—has cast doubts on large brain size as a defining feature of our genus. We reevaluated brain and body size scaling using data for 225 extant primates and 16 fossil hominid taxa, including one of the most diminutive species in genus Homo, H. floresiensis. Brain and body size are tightly correlated in genus Homo, varying along a positively allometric slope (R² = 0.84, F(1,5) = 33, p < 0.01) that is significantly different from the slope characterizing extant primates (R² = 0.94, F(1,222) = 3294, p < 0.001). Both small-bodied Homo floresiensis and Homo naledi have endocranial volumes (ECVs) that are consistent with their body size given the scaling relationship that characterizes genus Homo. Paired ECV and body mass estimates demonstrate considerable overlap of brain:body size proportions across fossil hominid taxa. Earlier hominids, Ardipithecus ramidus and Australopithecus anamensis, are characterized by ancestral brain:body size scaling; we discuss the hypothesis that a fundamental biological shift ca. 3 Ma altered the trajectory of encephalization—potentially linked to changes in fetal growth and gestation in Pleistocene fossil hominids—and may be directly implicated in the evolution of complex symbolic behavior in our lineage. Full article

Background/Objectives: Most patients with metastatic renal cell carcinoma (mRCC) progress on first-line immune checkpoint inhibitor (ICI). Subsequent vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) is standard. Due to the rapid evolution in treatment landscape, data directly comparing outcomes of VEGF-TKI following ICI versus VEGF-TKI alone are limited. This scoping review aimed to explore whether VEGF-TKI following prior ICI is associated with improved outcome, potentially reflecting a treatment sequence effect. Methods: PubMed/MEDLINE and ClinicalTrials.gov were searched systematically to identify phase 2/3 prospective clinical trials that investigated VEGF-TKI in patients who had progressed after ≥1 therapy published from 2004. Included studies were summarised by prior therapy and reported outcomes. Data from subgroups/arms were extracted and weighted overall response rate (ORR), progression free survival (PFS) and overall survival (OS) calculated for patients pretreated with VEGF-TKI versus ICI. An exploratory, hypothesis generating analysis was performed comparing outcomes between patients who received prior VEGF-TKI only or ICI-based therapy. Results: In total, 17 clinical trials were included: 2538 patients had prior VEGF-TKI (15 subgroups/arms) and 724 prior ICI-based therapy (11 subgroups/arms). In prior VEGF-TKI, weighted mORR was 8% (IQR 6–16%) versus 28% (IQR 20–41%) post-ICI. Weighted mPFS was 3.9 m (IQR 3.6–5.4) with prior VEGF-TKI versus 8.3 m (IQR 7.4–10.3) in prior ICI group. Weighted mOS was 15.2 m (IQR 11.1–16.6) versus 22.1 m (IQR 10.9–22.1) with prior ICI. Conclusions: Improved outcomes in ICI pretreated population in this exploratory analysis suggests ongoing biological benefit of ICI therapy. As prospective 2L randomised studies are not feasible, we conclude that VEGF therapy in pretreated mRCC is at least as good, if not better, since the introduction of 1st line ICI. Full article

We propose a novel mathematical framework for understanding consciousness as a dynamical phenomenon governed by nonlinear integrable equations. The central hypothesis identifies conscious state dynamics with the Painlevé VI equation and its confluence limits, providing a unified description of stability, bifurcation, and collapse across cognitive regimes. In this approach, consciousness is modeled as an emergent phase sustained near criticality, where coherent quantum-like structures and classical decoherence coexist in a regulated balance. The theory is formulated in terms of isomonodromic deformations on $\mathrm{SL}(2,\mathbb{C})$ character varieties, allowing conscious states to be characterized by monodromy data and their controlled evolution. This geometric setting naturally encodes memory, attention, and transitions between conscious and unconscious phases, while confluence processes account for irreversible loss of coherence. A two-stage quantum-to-classical transition is identified, separating microscopic coherence from macroscopic stabilization. The framework yields universal signatures such as critical slowing down, scaling laws near transition points, and robustness under perturbations, linking consciousness dynamics to broader classes of critical phenomena observed in physics and complex systems. By replacing heuristic assumptions with a mathematically constrained dynamical structure, this work extends existing quantum consciousness models and provides a tractable platform for comparison with neural, biological, and informational data. Full article

Emerging from millions of years of evolutionary optimization, Natural products (NPs) remain unique, unparalleled sources of bioactive scaffolds. Unlike synthetic molecules engineered around single therapeutic targets, NPs often exhibit multi-target, system-level bioactivity, aligned with the principles of network pharmacology, which modulates pathways in a coordinated, non-disruptive manner. This approach reduces resistance, buffers compensatory feedback loops, and enhances therapeutic resilience. Fungal endophytes represent one of the most chemically diverse and biologically sophisticated NP reservoirs known, producing polyketides, alkaloids, terpenoids, and peptides with intricate three-dimensional architectures and emergent bioactivity patterns that remain exceptionally difficult to design de novo. Advances in artificial intelligence (AI), machine learning, deep learning, and multi-omics integration have redefined the discovery landscape, transforming previously intractable fungal metabolomes and cryptic biosynthetic gene clusters (BGCs) into tractable, predictable, and engineerable systems. AI accelerates genome mining, metabolomic annotation, BGC-metabolite linking, structure prediction, and activation of silent pathways. Generative AI and diffusion models now enable de novo design of NP-inspired scaffolds while preserving biosynthetic feasibility, opening new opportunities for direct evolution, pathway refactoring, and precision biomanufacturing. This review synthesizes the chemical and biosynthetic diversity of major NP classes from fungal endophytes and maps them onto the rapidly expanding ecosystem of AI-driven tools. We outline how AI transforms NP discovery from empirical screening into a predictive, hypothesis-driven discipline with direct industrial implications for drug discovery and synthetic biology. By coupling evolutionarily refined chemistry with modern computational intelligence, the field is poised for a new era in which natural-product leads are not only rediscovered but systematically expanded, engineered, and industrialized to address urgent biomedical and sustainability challenges. Full article

The interface between synthetic materials and biological systems is a critical determinant of performance in medical devices and biosensors. This review examines the evolution of biointerface science through the lens of self-assembled monolayers (SAMs) of thiols on gold, a model system that offers atomic-level control over surface chemistry. We trace the field from the foundational structural characterization to the establishment of empirical design rules for bio-inertness. While early theoretical models attributed protein resistance to steric repulsion forces in polymer brushes, contemporary understanding has shifted toward the “water barrier” hypothesis, which posits that tightly bound interfacial water prevents direct biomolecular contact. We highlight recent studies that extend these concepts into “realistic” crowded biological environments. Their work reveals that fouling surfaces in crowded media generate a “viscous interphase layer” (VIL) that extends tens of nanometers into solution, whereas zwitterionic surfaces maintain a robust hydration shell that prevents this accumulation. Furthermore, this hydration barrier is shown to fundamentally alter bacterial mechanics, forcing microorganisms into a reversible, tethered “hovering” state at a significant biological interaction distance (>100 nm) from the surface, effectively precluding biofilm nucleation. These insights underscore that the future of antifouling material design lies in the precise engineering of interfacial hydration structures. Full article

The highly pathogenic avian influenza (HPAI) H5N1 virus poses a growing global health threat, particularly following its unprecedented spillover into dairy cattle and subsequent transmission to more than 1000 dairy farms in 18 states. This study investigates the host cell responses to distinct H5N1 strains (bovine- and mink-derived H5N1) in the presence and absence of raw milk across diverse mammalian cell lines (MDCK, MDBK, A549, Vero, MV1). Our findings reveal that the bovine-derived H5N1 strain exhibits more robust replication than the mink-derived H5N1 and demonstrates intra-host viral evolution with emerging amino acid substitutions detectable by deep sequencing. Although raw milk supplementation did not directly enhance viral replication in vitro, it significantly modulated host gene expression, often dampening key antiviral interferon-stimulated gene (ISG) responses and disrupting essential host cellular processes like intracellular trafficking and sialic acid biosynthesis. These host gene modulations are cell-type- and strain-specific, suggesting a complex interplay that may theoretically influence virus–host dynamics, though the biological significance of these in vitro observations requires validation through infectious virus assays and in vivo studies. This hypothesis-generating work provides preliminary insights into H5N1-milk interactions, highlighting the need for further mechanistic investigation to assess potential implications for viral transmission in dairy environments. Full article

There is much confusion about the apparent opposition between Darwinian evolution and the second law of thermodynamics. Both entropy and entropy production play more fundamental roles in the origin of life and Darwinian evolution than is generally recognized. I argue that Darwinian evolution can be understood as a tendency for entropy production to increase. Since the second law is about the increase in entropy, this hypothesis goes beyond the second law because it is about the increase in entropy production. This hypothesis can explain some aspects of biology that Darwinism struggles with, such as the origin of life, the origin of Darwinism, ecological successions, and an apparent general trend towards biological complexity. Gould proposed a wall of minimal complexity to explain this apparent increase in biological complexity. I argue that the apparent increase in biological complexity can be understood as a tendency for biological entropy production to increase through a broader range of free energy transduction mechanisms. In the context of a simple universe-in-a-cup-of-coffee model, entropy production is proposed as a more quantifiable replacement for the notion of complexity. Finally, I sketch the cosmic history of entropy production, which suggests that increases and decreases of free energy availability constrain the tendency for entropy production to increase. Full article