Modern biomedicine frequently contextualizes disease around isolated molecular or organ-specific mechanisms, but numerous chronic diseases, including Alzheimer’s disease, multiple sclerosis, depression, diabetes, and sepsis, share common trajectories of systemic destabilization. An increasing body of evidence indicates that health is not a property of single organs but the emergent property of interdependent feedback networks linking the microbiome, endocannabinoidome, neuroimmune system, and metabolic regulators. We propose the Endocannabinoid–Microbiota–Neuroimmune Super-System (EMN-S) as an evolutionarily conserved conceptual model that describes how these fields of influence reciprocally interact through feedback control. The microbial communities constituting the EMN-S encode environmental and dietary inputs, endocannabinoid signaling serves as an integrative regulator that synchronizes neural and immune activity, and neuroimmune circuits effectuate adaptive behaviors that alter microbiotal and lipid ecosystems. This review formalizes the EMN-S, contending that it is a unitary and cohesive model of physiological resilience, as well as offering a framework for precision feedback therapeutics. We describe how three mechanisms—encoder drift, integrator detuning, and executor overutilization—convert stabilizing negative feedback into runaway feedback cascades that underlie chronic, recurrent, and multisystemic disease. We then specify the EMN-S signature—integrated microbiome, lipidomic, and immune readouts—as an early indicator of resilience collapse and prospective preclinical state. Finally, we recapitulate the potential of AI-driven digital twins to illuminate feedback collapse, predict tipping points, and direct closed-loop intervention and treatments to restore dynamic equilibrium. By anchoring complexity in concrete and measurable feedback principles, the EMN-S shifts focus to investigate pathophysiology as opposed to reductionist lesion models of systemic derangements and embraces a systemic, empirically testable theory of stability.

Designing orthopedic implants with a long lifespan is essential for improving patients’ quality of life. It is necessary to develop new products with a high degree of personalization for the human body. Physicians and engineers analyzed the geometry and behavior of healthy joints’ motion under specific load conditions as well as the behavior over time and lifetime of orthopedic implants fitted to patients to improve their quality. The paper presents the way in which three-dimensional modeling techniques using specialized software (Catia, SolidWorks) can be combined with reverse engineering techniques (3D scanning) to optimize the design of orthopedic implants. The design of an implant consists of its three-dimensional modeling, as well as simulation of its integration into the human body, in order to analyze its behavior during motion. Therefore, it is necessary not only to 3D model the parts that make up the implant itself, but also to 3D model the bone to which the implant will be fitted. The paper highlights the complementarity of the classic modeling techniques with the reverse engineering techniques, which is necessary because the design of the parts that make up the implant itself can be achieved by specialized software modeling techniques, while the bones, having complex geometries, are better suited to 3D Modeling by scanning.

Melanoma cells in the brain may use similar mechanisms for adapting to injury and/or disease (that is, through continued reallocation of energy, matter, and information) as other cell types do to create an environment in which cancer cells can grow and sustain themselves within the confines of the brain. These adaptable mechanisms include the ability to reactivate dormant neural crest-derived migration and communication pathways. Unlike some other types of cancers that invade neural tissue as a simple invasion, melanomas are capable of achieving limited molecular, metabolic, and electrical similarity to the neural circuitry of the brain. Melanomas achieve this limited similarity through both vascular co-optation and mimicking synaptic functions, as well as through their engagement of redox-coupled metabolic pathways and feedback-regulated signal transduction pathways. The result is the creation of a metastable tumor–host system, where the relationship between tumor and host is defined by the interaction of stabilizing and destabilizing forces; forces that define the degree of coherence, vulnerability, and persistence of the tumor–host system. In this review, we integrate molecular, electrophysiological, and anatomical data to develop a single unifying hypothesis for the functional integration of melanoma cells into the neural tissue of the brain. Additionally, we describe how neural crest-based regulatory pathways are reactivated in the adult brain and how tumor–host coherence is developed as a function of the shared thermodynamic and informational constraints placed on both tumor and host. We also describe how our proposed conceptual model allows for the understanding of therapeutic interventions as selective disruptions of the neural, metabolic, and immunological couplings that support metastatic adaptation.

Thought processes in the brain occur as it continually modifies its use of energy. This review integrates research findings from molecular neurology, vascular physiology and non-equilibrium thermodynamics to create a comprehensive perspective on thinking as a coordinated energy process. Data shows that there is a relationship between the processing of information and metabolism throughout all scales, from the mitochondria’s electron transport chain to the rhythmic changes in the microvasculature. Through the cellular level of organization, mitochondrial networks, calcium (Ca²⁺) signals from astrocytes and the adaptive control of capillaries work together to maintain a state of balance between order and dissipation that maintains function while also maintaining the ability to be flexible. The longer-term regulatory mechanisms including redox plasticity, epigenetic programs and organelle remodeling may convert short-lived states of metabolism into long-lasting physiological “memory”. As well, data indicates that the cortical networks of the brain appear to be operating close to their critical regimes, which will allow them to respond to stimuli but prevent the brain from reaching an unstable energetic state. It is suggested that cognition occurs as the result of the brain’s ability to coordinate energy supply with neural activity over both time and space. Providing a perspective of the functional aspects of neurons as a continuous thermodynamic process creates a framework for making predictive statements that will guide future studies to measure coherence as a key link between energy flow, perception, memory and cognition.

Although there have been advancements in stroke treatment (reperfusion) therapy, and it has been shown that many individuals continue to suffer from partial recoveries and continuing decline in their neurological status as a result of suffering a stroke, a primary barrier to providing precise care to patients with stroke continues to be the inability to capture changes in molecular and cellular programs over time and in biological compartments. This review synthesizes evidence that represents the entire continuum of ischemia, beginning with acute metabolic failure and excitotoxicity, and ending with immune response in the nervous system, reprogramming of glial cells, remodeling of vessels, and plasticity at the level of networks, and organizes this evidence in a temporal framework that includes three biological compartments:central nervous system tissue, cerebrospinal fluid, and peripheral blood. Additionally, this review discusses new technologies which enable researchers to discover biomarkers at an extremely high resolution, including single-cell and spatial multi-omics, profiling of extracellular vesicles, proteoform-resolved proteomics, and glymphatic imaging, as well as new computational methods and machine-learning algorithms to integrate data from multiple modalities and predict trajectories of disease progression. The final section of this review will provide an overview of translationally relevant and ethically relevant issues regarding the deployment of predictive biomarkers, such as privacy, access, equity, and fairness, and emphasize the importance of global coordination of research efforts in order to ensure the clinical applicability and global equity of biomarker-based diagnostics and treatments.

Background: First described by Carl Toldt in the late 19th century, the mesorectum has since been a topic of anatomical and surgical debate. Its clinical importance was redefined by Heald’s introduction of Total Mesorectal Excision (TME), nowadays the golden standard in oncologic rectal surgery. This study aims to elucidate the embryological development and adult anatomy of the mesorectum and the mesorectal fascia, with a focus on clinically significant relations, particularly the peritoneum, and components of the hypogastric plexuses. Methods: We performed anatomical dissections on four 12–15-week-old human fetuses and eight formalin-fixed adult cadavers. In addition, a transverse pelvic section was examined to assess the spatial organization of mesorectal and fascial structures. Results: Our findings confirm the presence of a dorsal mesentery at the rectal level during fetal development, illustrating its transformation into the adult mesorectum. We identified the mesorectal contents in the fetus and examined the course and relations of the superior rectal vessels, hypogastric nerves, and pelvic splanchnic nerves, in both fetal and adult specimens. Conclusions: The observed fetal and adult configurations provide a continuous morphological description of the mesorectum and its compartmental organization within the pelvis. This study enhances the understanding of the mesorectum’s embryology, structure, and vital surgical landmarks. By delineating the so-called ‘Holy plane’ of Heald (the natural avascular plane between the mesorectal and presacral fasciae used during total mesorectal excision) and the delicate connective fibers known surgically as ‘angel’s hair’, which become visible when this plane is correctly entered, rectal and presacral fasciae, and neurovascular elements, provides a comprehensive anatomical framework that may inform surgical plane identification and support future clinical investigations into nerve-sparing rectal surgery.