Search Results (3,095)

Tuberculosis (TB) remains a leading cause of death from a single infectious agent, and its outcome is shaped not only by Mycobacterium tuberculosis (Mtb) itself, but also by the host’s metabolic state. This review synthesises current understanding of how Mtb reprograms macrophage immunometabolism and how this reprogramming propagates to a systemic level, culminating in skeletal muscle dysregulation and TB-associated cachexia. We describe the molecular mechanisms by which Mtb subverts phagosomal maturation, the glycolytic (Warburg-like) switch governed by HIF-1α and accumulation of immunomodulatory tricarboxylic acid cycle intermediates, and the M1/M2 polarisation balance that dictates bacterial containment versus persistence. We then trace the cytokine- and metabolite-mediated circuits (TNF-α, IL-6, IL-1β, lactate, ketone bodies, free fatty acids) that link infected macrophages to ubiquitin–proteasome and autophagy–lysosome-driven muscle proteolysis, mitochondrial dysfunction and oxidative stress. Building on these mechanisms, we propose an immunometabolic and muscle-derived biomarker framework that, although still requiring clinical validation, may offer value for diagnosis, host-response stratification and treatment monitoring, and we discuss host-directed therapeutic strategies that target macrophage metabolism and muscle preservation. By integrating immunity, metabolism and systemic pathology at the molecular level, this work highlights translational opportunities relevant to the host immunity, diagnosis and treatment of tuberculosis. Full article

Amphibian malformation syndromes significantly impact both conservation efforts and aquaculture, yet their underlying systemic pathophysiological mechanisms remain poorly characterized. This study comprehensively examines the multi-level pathological processes associated with the “short-leg” malformation syndrome in the black-spotted frog (Pelophylax nigromaculatus) using an integrated methodology, encompassing morphological, histopathological, gut microbiome, and hepatic transcriptomic analyses. Affected frogs demonstrated shortened limbs, impaired motor function, and a distinctive metabolic phenotype, including increased body weight despite a shorter body length, accumulation of visceral fat, and shortened intestines. Gut microbiota analysis identified significant compositional shifts, characterized by a decreased Firmicutes-to-Bacteroidota ratio, expansion of pro-inflammatory Proteobacteria, and reduction in beneficial Actinobacteriota, suggesting microbial niche restructuring that likely promotes metabolic and inflammatory disorders. Hepatic transcriptome profiling revealed 2617 differentially expressed genes, demonstrating a clear molecular dichotomy with concurrent up-regulation of immune-related pathways (e.g., neutrophil extracellular trap formation, complement cascades, and inflammatory signaling) and broad suppression of metabolic pathways (e.g., lipid oxidation, nutrient absorption, and PPAR and renin–angiotensin systems). This integrated analysis illustrates that the malformation syndrome represents a systemic pathophysiological state involving dysfunction of the gut–liver axis, characterized by the coexistence of gut microbiota alterations, hepatic metabolic suppression, and immune activation. These findings provide a framework for understanding amphibian malformations and suggest potential strategies to improve health outcomes in aquaculture. Full article

Neurogenic atrophy is the most severe type of muscle atrophy. It can be caused by injury or disease of the nerve that connects to the muscle. Damage to the sciatic nerve (nervus ischiadicus) initiates molecular processes that lead to the transformation of muscle dysfunction into an atrophic state. Oxidative stress is one of the key factors that initiates skeletal muscle atrophy. Therefore, this study evaluates the effects of oral administration of water-soluble C₆₀ fullerenes (daily dose: 1 mg/kg), as powerful antioxidants, on the contraction dynamics of the rat musculus soleus on days 15, 30, and 45 following neurogenic atrophy induced by transection of the nervus ischiadicus. Using biophysical (tensometric), biochemical, and histological analyses, we evaluated the biomechanical parameters of musculus soleus contraction (time of onset of muscle force response, integrated muscle power, maximum and minimum contraction forces), blood biochemical markers (concentrations of C-reactive protein, lactate, creatinine, and reduced glutathione, as well as superoxide dismutase and catalase activities), as well as histological and morphometric indicators of muscle damage in rats on days 15, 30, and 45 after injury induction. It was found that the use of water-soluble C₆₀ fullerenes improves the contractile activity of the musculus soleus after neurogenic atrophy and has a time-dependent nature. Specifically, by day 45 of the experiment, the maximum therapeutic effect reached 23–35 ± 2% for the biomechanical parameters of muscle contraction, and the biochemical blood parameters have nearly approached the control values. Finally, histological analysis confirmed a significant reduction in signs of destruction in muscle fibers and the level of fibrosis in the musculus soleus. These findings suggest the potential application of water-soluble C₆₀ fullerenes in the treatment of pathological conditions of the muscular system arising from peripheral nerve injury. Full article

Alzheimer’s Disease (AD) is now understood as a biologically diverse condition, with amyloid and tau pathology evolving within dynamic neuroimmune networks. This challenges the traditional view that AD-related inflammation can be broadly suppressed therapeutically. We review evidence showing that neuroinflammation in AD is stage-dependent, cell-state-specific, spatially organized, and functionally complex. Microglia and astrocytes can aid in plaque containment, debris clearance, synaptic balance, metabolic adaptation, and tissue repair, but may also exacerbate injury through type-I interferon, inflammasome, complement, tumor necrosis factor, and lipid pathways. Many failed anti-inflammatory trials likely stem from mismatches in targets, timing, spatial considerations, pathway redundancy, and biomarker selection, rather than invalidating neuroinflammation as a therapeutic target. Recent single-cell and spatial transcriptomic, proteomic, metabolomic, and network-medicine studies offer a framework for precision intervention by identifying inflammatory endotypes, anatomical niches, and pathway modules. We propose the Stage–State–Space Neuroimmune Reprogramming Model (S3-NRM), aligning AD immunotherapy with disease stage, glial/endotype state, and spatial inflammatory niche, guided by fluid, imaging, and omics biomarkers. Future therapies should selectively suppress harmful immune responses while preserving beneficial glial functions. Full article

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by memory loss and cognitive decline, reflecting widespread brain dysfunction across multiple neural systems. Early detection of pathological changes is critical for enabling timely intervention, improved management, and better therapeutic outcomes. Methods: Using non-transgenic AD rats (Samaritan) and sham rats (Long–Evans), we explored structural and functional differences with multimodal MRI and multi-unit activity (MUA). Results: Diffusion tensor imaging (DTI) revealed no significant changes in mean diffusivity of water, but AD-related microstructural alterations of fractional anisotropy were confined to subcortical regions with cortical areas and white matter tracts remaining intact. We used functional MRI (fMRI) with blood oxygenation level-dependent (BOLD) contrast in rest-state (R-fMRI) and task-based (T-fMRI) paradigms. R-fMRI revealed much stronger functional connectivity in subcortical vs. cortical areas in AD rats, implicating AD-related functional changes in subcortical areas in agreement with DTI data. T-fMRI with sensory stimulation revealed reproducible fMRI responses in both groups; however, AD rats exhibited reduced BOLD response amplitude and spatial activation extent, which was accompanied by attenuated stimulus-evoked MUA responses. These suggest that attenuated evoked BOLD response reflects diminished neuronal activity in AD, rather than impaired neurovascular and/or neurometabolic coupling. Conclusions: Together these findings suggest that AD-induced anatomical and functional changes in subcortical areas are related to altered cortical responses, highlighting multimodal MRI as a sensitive tool for early AD-related brain changes. Full article

Background: Mitochondria are the primary organelles that regulate cellular bioenergetic metabolism and maintain homeostasis, providing essential structural support for optimal cell survival. Nonetheless, advancing age leads to cumulative damage to mitochondrial structure and functional integrity, which is a defining characteristic of biological aging and is closely linked to the emergence and progression of numerous age-related diseases, including neurodegenerative disorders, cardiovascular diseases, and metabolic disorders. Scope of review: This article offers a thorough summary and review of mitochondrial quality control (MQC), emphasizing numerous critical processes, including mitochondrial biosynthesis, dynamic remodeling (fusion and fission), and mitophagy. We thoroughly elucidate the molecular pathways that regulate MQC and demonstrate how age-related dysregulation precipitates cellular senescence, highlighting the transition from physiological maintenance to pathological malfunction, which ultimately culminates in cellular aging. Conclusions and implications: This study systematically elaborates the pathophysiological mechanisms in the field, comprehensively evaluates the clinical translational potential of targeting the MQC pathway, highlights the key objectives of “restoring mitochondrial plasticity and removing dysfunctional mitochondria”, and explores novel intervention strategies. The restoration of normal mitochondrial function in cells throughout aging is a very promising path for precision medicine therapeutics with great translational potential, according to recent state-of-the-art research. The development of novel therapeutic approaches to improve functional healthy mitochondria can effectively delay aging and reduce the rising global burden of age-related diseases. Full article

The etiology of inflammatory bowel disease (IBD) is not precisely defined. However, it involves environmental factors, genetic predisposition, the involvement of gut microbiota, and abnormal immune response. Angiogenesis seems to be an integral part of IBD. Impairment of the intestinal barrier may represent an initiating or early feature of the disease. Disruption of the epithelial barrier leads to the translocation of microbiota and other antigens into the mucosa, resulting in an enhanced immune response, whereas damage to the vascular barrier is related to endothelial activation and pathologic angiogenesis, both of which promote inflammation. Angiogenesis during IBD is a very complex phenomenon that includes endothelial and immune cells, growth factors, cytokines, adhesion molecules, intestinal microbiota, and signal transduction. It seems that intestinal microvascular hemostasis shifts toward a prothrombotic state, and microthrombi formation exacerbates ischemia. The angiogenic process in IBD is regulated, at least in part, by the intestinal microbiota. Antiangiogenic therapy represents a novel and significant approach to the treatment of IBD. Biologic anti-inflammatory therapy for IBD simultaneously attenuates angiogenesis to a similar degree. However, the expression of VEGF and other growth factors may have dual and opposing effects, probably depending on the stage of the disease. Thus, anti-angiogenic treatment in patients with IBD remains controversial, and clinical trials of anti-angiogenic agents are warranted. Full article

Background: Alzheimer’s disease (AD) is a complex neurodegenerative disorder and a major global health challenge. The traditional “one drug–one target” paradigm has shown limitations in addressing its multifactorial nature. Multitarget-directed ligands (MTDLs), designed to modulate multiple pathological pathways, have emerged as a promising therapeutic strategy. Objectives: To examine the structural, thematic, and temporal evolution of multitarget strategies for AD treatment between 2006 and 2025. Methods: A total of 1184 Web of Science-indexed articles were analyzed. Publication growth, h-index, author productivity, institutional and national contributions, and keyword co-occurrence networks were evaluated using VOSviewer. Bibliometric laws (Price, Bradford, Zipf, and Lotka) were applied to characterize productivity patterns and thematic organization. Results: Multitarget research shows exponential growth, suggesting a consolidation of the MTDL paradigm. China, India, the United States, Italy, and Spain were the most productive countries. Early studies focused on cholinesterase inhibition, particularly acetylcholinesterase-based hybrids. The field expanded to include β-amyloid aggregation, oxidative stress, metal chelation, and blood–brain barrier permeability. Recent trends emphasize integration of computational approaches, including molecular docking, molecular dynamics, virtual screening, and network pharmacology, alongside targets such as BACE1 and GSK-3β. Conclusions: Multitarget strategies have evolved toward a systems-oriented framework. Despite advances, challenges remain in reducing cholinesterase dependency and improving translational validation. This study provides a framework to interpret therapeutic evolution and guide future network-based drug design. Full article

For decades, visual perception was treated as a linear, feature-extracting mechanism driven almost exclusively by bottom-up sensory inputs. Emerging insights from affective neuroscience and cognitive psychology have systematically dismantled this view, revealing that vision operates within a continuous, bidirectional dialog with emotional systems. This review synthesizes the multi-layered neurobiological architectures underpinning this relationship. The pathways through which top–down emotional states recalibrate sensory processing are analyzed. Mechanisms including amygdalocortical feedback, frontoparietal attentional networks, and insular interoceptive monitoring are examined. These systems prioritize survival-driven motivational salience over objective accuracy. In the opposite direction, the text charts how ambient environmental features, such as lighting dynamics, spatial geometry, and structural ambiguity, immediately register along rapid subcortical and detailed cortical streams to instantiate emotional states. By situating these reciprocal dynamics within predictive coding and active inference frameworks, this paper illustrates how affective states function as precision weights that dynamically adjust internal perceptual priors. Finally, the clinical utility of these interconnected systems is evaluated, demonstrating how subtle visual aberrations like disrupted contrast suppression serve as diagnostic signatures for mood disorders, while structural retinal decay offers an accessible window into neurodegenerative pathology. Ultimately, the evidence indicates that conscious vision is fundamentally an affective construction, carrying transformative implications for early biomathematical and ocular screening in psychopathology. Full article

The surgical pathology report remains one of the richest yet least computable artefacts in the clinical record. Diagnostic, prognostic, and treatment-relevant information is recorded predominantly as a free-text narrative that resists aggregation for research, quality monitoring, and cancer registration, while manual abstraction is slow, costly, and difficult to scale. Large language models (LLMs) have rapidly emerged as a means of converting unstructured pathology narrative into structured, analysis-ready data. This perspective examines the current state of the evidence, with particular reference to breast pathology, and foregrounds the distinction between proprietary cloud-hosted models and locally deployed open-weight models. Recent comparative studies indicate that open-weight models can approach the accuracy of proprietary systems for structured extraction, offering a privacy-preserving and cost-controlled alternative that keeps protected health information inside the institutional firewall—a decisive advantage under data-protection regimes such as Singapore’s Personal Data Protection Act (PDPA) and Human Biomedical Research Act (HBRA). We argue that hybrid architectures—pairing deterministic rule-based extraction for unambiguous fields with local LLMs for narrative reasoning—currently offer the most defensible route to laboratory deployment. We also highlight the “reality gap” between synthetic benchmark performance and real-world clinical accuracy, and the need to align studies with emerging reporting and appraisal frameworks (TRIPOD-LLM, PROBAST + AI). Structured extraction is compatible with the quality and traceability expectations of accredited laboratories only when it is verified before use, monitored over time, and kept under human oversight. Full article

Background/Objectives: Circadian disruption resulting from factors such as jet lag, shift work, or aging leads to exaggerated inflammatory responses and increased disease susceptibility. However, the core dynamical mechanism by which circadian disruption exacerbates innate immune responses remains poorly understood. Methods: We develop an integrated mathematical model coupling the mammalian circadian clock with antigen-induced innate immune responses, incorporating key regulatory interactions including glucocorticoid modulation and pro-inflammatory positive feedback loops. Results: The model successfully recapitulates experimental data regarding homeostatic immune circadian oscillations and time-dependent gating of acute inflammatory responses. Dynamic analyses reveal that the circadian clock exerts its gating function by modulating the bistable characteristics within pro-inflammatory positive feedback loops. Circadian disruption, simulated as jet lag or age-related reduction in clock gene amplitude, reshapes this bistable landscape and prolongs residence duration in the pathological hyperinflammatory state. Conclusions: This shift not only amplifies acute cytokine bursts but also sustains exaggerated inflammatory activity, providing a mechanistic explanation for acute tissue injury and chronic low-grade inflammation (inflammaging) under these circadian disruption scenarios. Full article

Background: Breast cancer remains a leading cause of cancer-related mortality, and reliable computational decision support is increasingly viewed as a complement to expert pathological assessment rather than a replacement for it. Variational quantum classifiers (VQCs) and Quantum Support Vector Machines (QSVMs) have recently been promoted as candidate models for medical classification, yet most published comparisons rely on internal hold-out validation alone and report only a single point estimate of discrimination, omitting calibration, decision-analytic value, and explainability—three ingredients that any clinically credible model must furnish. Methods: We assembled a complete quantum–classical machine learning pipeline and evaluated it under a deliberately stringent protocol designed to expose, rather than conceal, the limitations of current Noisy Intermediate-Scale Quantum (NISQ)-era models. The analytical hypothesis was conservative and stated in advance; in light of saturated classical baselines on this benchmark, we did not anticipate a quantum advantage in raw discrimination, and we framed the study as a methodological probe rather than as a competition. Using the Wisconsin Diagnostic Breast Cancer (WDBC) dataset (n = 569) for development and an independent Wisconsin Original (WBC) cohort (n = 683) for external validation, we benchmarked five classical learners (XGBoost, LightGBM, CatBoost, RandomForest, RBF-SVM), two quantum models (an eight-qubit VQC implemented in PennyLane and a ZZ-feature-map QSVM implemented in Qiskit), and a stacked hybrid ensemble. The evaluation framework combined Optuna-driven hyperparameter optimisation, internal–external cross-validation, and external validation on the independent WBC cohort. Robustness and interpretability were then probed through circuit depth and embedding rotation ablation, depolarising noise stress tests, learning curve and feature stability analysis, decision curve analysis, and dual SHAP-based explanations covering both a direct tree-based explanation and a quantum surrogate. Reporting followed the TRIPOD + AI guideline. Results: On the internal test partition, RBF-SVM achieved the highest discrimination (AUC = 0.998), with XGBoost, LightGBM, CatBoost, the hybrid ensemble, and the VQC clustering between 0.992 and 0.996; the QSVM with a ZZ-fidelity kernel underperformed substantially (AUC = 0.727). Pairwise tests for correlated ROC curves indicated that most differences among top models were not statistically significant. On the external WBC cohort, model rankings reorganised, as RBF-SVM (AUC = 0.986, 95% CI 0.946–0.997), RandomForest (0.985, 95% CI 0.945–0.996), VQC (0.983, 95% CI 0.942–0.995), and the hybrid ensemble (0.982, 95% CI 0.941–0.995) all retained near-ceiling discrimination with extensively overlapping confidence intervals. Ablation analysis demonstrated that the choice of embedding rotation is decisive—Z-rotation embeddings collapsed VQC performance to chance levels (AUC ≈ 0.50), whereas X- and Y-rotations preserved it. Depolarising noise up to p = 0.10 had a negligible effect on the VQC, and SHAP analyses converged on worst concave points, mean concave points, and worst area as the dominant predictors across both classical and quantum models. Decision curve analysis showed positive net benefit for both classical and hybrid models across the clinically meaningful threshold range, exceeding both the treat-all and treat-none reference strategies throughout. Conclusions: In the present regime, the principal contribution of QML is not raw discrimination—modern classical learners are already at the data ceiling—but the construction of a rigorous, reproducible, externally validated, and interpretable benchmarking framework in which quantum models can be fairly compared with their classical counterparts. Because evaluation was confined to curated benchmark datasets rather than real-world clinical populations, the interpretability and net benefit findings reported here should be read as benchmark-level evidence and not as a demonstration of readiness for clinical deployment. Full article

Cardiovascular disease (CVD) is the leading cause of mortality worldwide. The healthy adult heart depends on flexible energy use, but a diseased or injured heart is associated with a loss of flexibility and metabolic remodeling. Since metabolism plays a central role in cardiac health and disease, there is a growing need to understand how metabolic reprogramming contributes to cardiac dysfunction and impaired CM maturation. Human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) are widely used as a platform to study human cardiac development and disease mechanisms. However, current models are limited by metabolic and structural immaturity. This review provides an overview of the dynamic shifts in cardiac metabolic states from fetal development to senescence, while delineating the metabolic signatures of healthy versus disease states. These metabolic switches are orchestrated by a complex interplay of upstream signals driven by variations in substrate availability, post-translational modifications and key transcriptional regulatory networks, which ultimately regulate downstream cardiac remodeling and pathological cascades. As cardiac metabolic function is affected by a coordinated multicellular network, this review also includes the metabolic crosstalk between CMs and non-CMs, including fibroblasts, endothelial cells and immune cells. In addition, various strategies to further mature hiPSC-CMs are summarized to enhance their metabolic profiles. Investigating cardiac metabolic shifts bridges developmental biology, stem cell biology, and regenerative cardiology by revealing how energy metabolism governs cellular identity, maturation, and regenerative potential. These insights are essential for improving stem-cell-derived CMs for disease modeling, drug discovery, and heart repair. Full article

Renal cell carcinoma (RCC) accounts for the majority of kidney cancers, with approximately 80,000 new diagnoses and over 14,000 deaths annually in the United States. Risk stratification is essential for prognostication, treatment selection, and clinical trial design across all disease stages. In localized and locally advanced RCC, pathological stage, histology, and grade remain the primary prognostic factors, while the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria serve as the standard risk stratification tool in the metastatic setting. However, current models rely predominantly on clinical and pathologic variables that act as indirect surrogates of tumor biology and do not account for the molecular heterogeneity inherent to RCC. This narrative review synthesizes and compares established and emerging risk stratification and prognostic models across all stages of RCC. Established models such as the IMDC criteria and the stage, size, grade, and necrosis (SSIGN) score demonstrate robust prognostic performance but are limited by their reliance on clinical and pathologic variables alone. Emerging biomarkers—including circulating tumor DNA, methylated DNA, artificial intelligence-based radiomics, and tissue-based molecular signatures—show promise for improving risk discrimination. The molecular heterogeneity of RCC underscores an urgent need for integrated molecular–clinical–pathologic prognostic tools tailored to specific histologic subtypes to enable more precise, individualized care. Full article

Osteoporosis (OP) and osteoarthritis (OA) are two common degenerative musculoskeletal disorders associated with aging and are traditionally classified and managed as distinct disease entities. Emerging evidence suggests that OP and OA may share bidirectional associations and common biological mechanisms, and that under specific pathological conditions they may develop into a mutually reinforcing comorbid state. The comorbidity of osteoporosis and osteoarthritis (OP–OA) is not a simple superimposition of bone loss and cartilage degeneration; rather, it represents a disorder of the osteochondral unit centered on disruption of the subchondral bone microenvironment. Alterations in the structural strength, remodeling dynamics, vascular and neural status, and bone marrow lesions of subchondral bone collectively reshape the local microenvironment, thereby directly affecting mechanical signal transmission and cellular behavior within the joint. Focusing on the subchondral bone microenvironment as the central pathological nexus, this review systematically summarizes how mechanical imbalance, aberrant bone remodeling, inflammatory activation, metabolic dysregulation, and cellular senescence jointly remodel the local niche in OP–OA comorbidity. These microenvironmental changes further induce phenotypic remodeling and fate deviation of bone marrow mesenchymal stem cells, bone remodeling-related cells, osteoimmune cells, and chondrocytes. On this basis, we integrate the regulatory roles of developmental signaling, mechanotransduction pathways, and inflammatory–immune signaling networks, and propose that microenvironment-driven cell fate plasticity may serve as a key mechanistic hub promoting the initiation and progression of OP–OA comorbidity as well as the persistent destabilization of the osteochondral unit. This perspective may help overcome the limitations of current studies that address OP and OA separately, and may provide a theoretical framework for early identification and stratification, biomarker discovery, and combined precision-targeted interventions for this comorbid condition. Full article