Search Results (3,970)

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with limited effective therapies. In this study, a series of 2-(arylamino)thiazol-4(5H)-one derivatives was synthesized using an efficient microwave-assisted protocol, and evaluated for neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced oxidative stress (OS) in SH-SY5Y neuronal cells and an Aβ42-expressing Drosophila melanogaster model of AD. Among the synthesized compounds, 3n, 3i, and 3b exhibited low cytotoxicity and significant neuroprotection, as evidenced by increased cell viability, reduced reactive oxygen species (ROS) production, and preserved mitochondrial membrane potential. Notably, compound 3n demonstrated the highest activity and effectively ameliorated Aβ42-induced behavioral deficits in vivo. Molecular docking studies predicted favorable binding affinity within the acetylcholinesterase (AChE) active site, with the thiazol scaffold and aryl substituents stabilizing ligand binding through π–π stacking and hydrophobic interactions; compound 3n also formed additional hydrogen bonds enhancing its affinity. Consistent with the docking predictions, in vitro AChE inhibition studies demonstrated that compounds 3n, 3i, and 3b inhibited AChE in a concentration-dependent manner. Network pharmacology predicted seven potential core targets implicated in AD pathogenesis and related pathways, including OS, neuroinflammation, and synaptic dysfunction. Furthermore, in silico pharmacokinetic analysis indicated compliance with Lipinski’s and Veber’s rules, supporting favorable drug-like properties. While further experimental validation is essential, these findings highlight 2-(arylamino)thiazol-4(5H)-one derivatives, particularly compound 3n, as promising multifunctional candidates for further preclinical development against AD. Full article

The mechanisms underlying neurodegenerative diseases (NDDs) involve multiple pathological processes, such as abnormal protein aggregation, oxidative stress, neuroinflammation, mitochondrial dysfunction, and the disruption of neurovascular unit homeostasis. The blood–brain barrier (BBB) restricts drug exposure in the brain, posing a significant challenge for central nervous system delivery and for improving therapeutic efficacy. In recent years, carbon dots derived from natural products (CDs) have emerged as candidate materials for brain delivery and theranostic applications due to their small size, modifiable surfaces, fluorescence-tracking capability, and potential neuroprotective activity. This narrative review summarizes their sources, physicochemical characteristics, biological basis, interactions with the BBB, delivery strategies, neuroprotective effects, and imaging applications. Current evidence suggests that these CDs can alleviate oxidative stress and inflammatory responses, influence abnormal protein aggregation, and support drug delivery and fluorescence tracking in certain cellular and animal models. However, BBB permeability, brain fluorescence signals, brain parenchymal exposure, and therapeutic efficacy represent distinct levels of evidence and should not be considered interchangeable. Future studies should focus on strengthening material standardization, ensuring batch-to-batch consistency, characterizing absorption, distribution, metabolism, and excretion (ADME), conducting long-term safety assessments, and validating using humanized BBB models. Full article

Ferroptosis is an iron-dependent form of regulated cell death characterized by iron dyshomeostasis, glutathione depletion, glutathione peroxidase 4 dysfunction, and excessive lipid peroxidation. Exercise is a safe and accessible non-pharmacological intervention with broad neuroprotective potential, but the evidentiary basis linking exercise specifically to ferroptosis is uneven. Only a limited subset of studies directly combines an exercise intervention with ferroptosis-related outcomes in neurodegenerative models; much of the proposed pathway architecture is inferred from pharmacological, cellular, observational, or acute neurological injury studies. This review therefore separates direct exercise evidence from exercise-related supporting evidence and non-exercise mechanistic evidence. The most directly relevant findings, concentrated largely in aerobic exercise models, show exercise-associated changes in brain iron handling, the cystine/glutamate antiporter–glutathione peroxidase 4 antioxidant system, and lipoxygenase-dependent lipid peroxidation. Supporting studies suggest additional peripheral-to-central mechanisms involving muscle-derived exosomes, exercise-associated changes in systemic and cerebral iron handling, and inflammatory regulation. Bone marrow hematopoiesis, adult neurogenesis, synaptic plasticity, and astrocyte-controlled iron traffic are incorporated as biologically plausible but incompletely tested links. Evidence for resistance training, high-intensity interval training, mind–body exercise, and human disease remains insufficient. The central limitation is therefore not pathway plausibility but the scarcity of exercise-specific causal experiments demonstrating that ferroptosis suppression is required for neuroprotection. Full article

Background/Objectives: 2-(2-Benzofuranyl)-2-imidazoline (2-BFI) is a selective imidazoline I₂-site ligand that has shown neuroprotective and neuromodulatory effects in preclinical central nervous system (CNS) studies. However, the primary preclinical literature remains fragmented across disease models, outcome types, mechanistic endpoints, and cellular targets, making it difficult to define where its therapeutic-development potential is strongest and how disease- or model-specific functional effects relate to molecular, cellular, tissue, and blood–brain barrier/neurovascular unit (BBB/NVU)-related findings. Methods: This systematic review integrated preclinical evidence from 36 original studies identified in the PubMed, Web of Science, Embase, and Scopus databases through searches last updated on May 19, 2026, to evaluate the strength of evidence for 2-BFI across CNS-related models and to connect functional, molecular, cellular, and neurovascular findings. The evidence categories included ischemic stroke/neurovascular outcomes (n = 13), traumatic CNS injury (n = 2), neuroinflammatory/neurodegeneration-related models (n = 9), behavioral pharmacology (n = 8), and cellular mechanisms (n = 4). Eligible studies were original CNS-related animal, cellular, or behavioral/pharmacological studies that directly evaluated 2-BFI and reported neuroprotective, neurological, cellular, molecular, vascular, inflammatory, neurotransmitter-related, or behavioral outcomes. Findings were synthesized qualitatively, and risk of bias in in vivo animal studies was assessed using SYRCLE’s risk-of-bias tool. Results: The most extensive preclinical evidence was found in ischemic stroke and neurovascular injury models, in which 2-BFI attenuated infarct size, neurological deficits, and edema, and suppressed apoptosis-related injury and blood–brain barrier/neurovascular unit (BBB/NVU) disruption. Across models, these effects are best interpreted as modulation of interconnected secondary injury processes involving N-methyl-D-aspartate receptor (NMDAR)/Ca²⁺-dependent excitotoxicity, oxidative and mitochondrial stress, inflammatory amplification, regulated cell death, and neurovascular destabilization. Evidence from traumatic CNS injury, autoimmune neuroinflammation, Alzheimer’s disease-related models, chronic epilepsy, and cellular stress models broadened the CNS relevance of 2-BFI but remained less replicated or more mechanistically indirect than the stroke/neurovascular evidence. Behavioral and pharmacological studies additionally indicated that 2-BFI modulates neurotransmitter-related systems associated with pain-, affective-, addiction-, opioid-, and compulsivity-related outcomes, although these findings should be distinguished from disease-modifying neuroprotective evidence. Conclusions: Meta-analysis was not conducted because of heterogeneity in models, dosing regimens, treatment timing, and outcomes. Overall, the current evidence does not yet support definitive dosing, treatment timing, or clinical development recommendations for 2-BFI. The strongest preclinical therapeutic rationale is currently found in ischemic stroke and neurovascular injury settings, whereas other CNS indications require further validation. Future studies should define dose–response relationships, therapeutic windows, pharmacokinetic and safety profiles, sex- and age-related effects, and efficacy in clinically relevant comorbid models before clinical translation is considered. The review was not prospectively registered. Funding was provided by a National Research Foundation of Korea grant funded by the Korean government. Full article

Background/Objectives: Sarcopenia involves a gradual decline in skeletal muscle mass that may occur during aging or in association with chronic pathological conditions. It markedly reduces muscle strength and mobility, thereby impairing quality of life. Because sarcopenia’s severity directly correlates with frailty, it represents an important predictor of prognosis and disease risk. Current preventive and therapeutic strategies rely mainly on physical activity, which is not feasible for all patients. This study investigated the biological effects of two independently prepared Tuber borchii (T. borchii) extracts in an in vitro model of sarcopenic stress. Methods: The activity of T. borchii extracts was investigated in a cell-based model of sarcopenia, following previous observations that these preparations influence proliferation-related pathways, including ERK1/2 phosphorylation. Specifically, differentiated myotubes were exposed to D-galactose to reproduce atrophy-associated cellular changes, and the impact of T. borchii extracts on protein synthesis, turnover, and cell morphology was assessed. Results: T. borchii extracts enhanced protein synthesis and turnover in myotubes. Furthermore, the treatment significantly reduced the expression of key galactose-induced sarcopenia and atrophy markers, such as MuRF1. Morphological analysis confirmed this protective effect, showing that treated myotubes maintained greater thickness and exhibited a larger cross-sectional area despite exposure to the sarcopenic stimulus. Conclusions: These results indicate that T. borchii extracts can attenuate selected cellular alterations associated with muscle aging. Future identification of the most active components may support their development as nutraceutical supplements. Full article

Ischemic stroke remains a leading cause of death and long-term disability worldwide. Although acute reperfusion therapies have improved outcomes in selected patients, effective strategies that directly promote neurovascular repair during the subacute and chronic phases remain limited. Vascular network remodeling in the peri-infarct region is increasingly recognized as a key process supporting tissue repair, blood–brain barrier restoration, and functional recovery after stroke. Microglia, as resident immune cells of the central nervous system, undergo dynamic morphological, metabolic, and functional changes after ischemic injury and participate in inflammation, phagocytic clearance, blood–brain barrier regulation, and tissue repair. Among repair-associated microglial states, microglia with M2d-like features have attracted increasing attention because of their potential association with immunoregulation and pro-vascular repair. However, whether repair-associated microglia with M2d-like features represent a distinct and stable microglial subtype after stroke remains unresolved. In this review, we summarize current evidence linking repair-associated microglial responses to vascular network remodeling after ischemic stroke, with particular emphasis on the conceptual value of the M2d-like state. We discuss putative mechanisms involving paracrine signaling, perivascular localization, metabolic reprogramming, and extracellular vesicle-mediated communication. We also evaluate therapeutic implications, including traditional Chinese medicine, extracellular vesicle-based strategies, and nanodelivery systems. However, current therapeutic evidence does not establish that these interventions specifically induce M2d-like microglial states. We highlight the need for rigorous validation of cellular identity, spatial localization, and functional vascular outcomes. Overall, the M2d-like framework provides a candidate perspective for understanding immune–vascular coupling after stroke, but further studies integrating single-cell omics, spatial mapping, lineage tracing, and functional vascular assessment are required to define the identity and functional contribution of repair-associated microglia with M2d-like features. Method: This article is a narrative review. The relevant literature was searched in PubMed from database inception to June 2026 using combinations of the terms “ischemic stroke,” “microglia,” “macrophage,” “vascular remodeling,” “angiogenesis,” “M2d,” “extracellular vesicles,” “traditional Chinese medicine,” and “nanomedicine.” Priority was given to original studies directly examining microglial or myeloid responses and vascular repair after ischemic stroke. Relevant review articles were included to provide conceptual background. Because direct evidence for M2d-like microglial responses after stroke remains limited, selected studies involving peripheral macrophages, tumor-associated macrophages, traditional Chinese medicine, extracellular vesicles, and nanomedicine were included as indirect or hypothesis-generating evidence. Evidence was interpreted according to the disease model, cellular source, and vascular outcomes examined, with stroke-specific microglial studies regarded as more directly relevant than evidence extrapolated from non-stroke or non-microglial models. Full article

Cellular plasticity allows organisms to adapt dynamically to both physiological and pathological contexts. Epithelial–mesenchymal transition (EMT) is a well-known example of this plasticity and is now widely recognized as a reversible and highly dynamic spectrum of cellular states rather than a simple binary switch. In this review, we summarize current knowledge on the Hippo pathway transcriptional co-activators YAP and TAZ, focusing on their role as a central hub that integrates mechanical, biochemical and metabolic signals from the microenvironment to control cell fate reprogramming. We discuss how YAP/TAZ interact with EMT-related signaling pathways and transcriptional networks to regulate the acquisition, maintenance and dynamic remodeling of mesenchymal states, as well as hybrid epithelial/mesenchymal (E/M) phenotypes. We also highlight the presence of interconnected feed-forward and feedback regulatory loops within the YAP/TAZ–EMT axis, which contribute to the stabilization of cellular plasticity and support context-dependent transcriptional programs. These mechanisms are involved in key physiological processes, including embryonic development and tissue repair, and in pathological conditions such as organ fibrosis and cancer progression. Therefore, we propose a model where YAP/TAZ act as the central molecular hub within the networks governing cellular plasticity and EMT dynamics. Finally, we discuss how a better understanding of the mechanistic basis of YAP/TAZ-driven EMT may provide a useful framework for the development of therapeutic strategies aimed at modulating cellular plasticity in cancer, fibrotic diseases and regenerative medicine. Full article

Oligodendrocytes (OLs) are the myelinating cells of the central nervous system (CNS). The PLP1 gene, predominantly expressed in OLs, encodes proteolipid protein (PLP), a major structural component of CNS myelin that also regulates oligodendrocyte precursor cell (OPC) proliferation, differentiation, and maturation. Pelizaeus–Merzbacher disease (PMD) is a rare X-linked leukodystrophy caused by PLP1 mutations and characterized by defective myelination. Clinical manifestations range from severe connatal PMD to classic PMD and the milder spastic paraplegia type 2 (SPG2), reflecting substantial phenotypic heterogeneity. Beyond disrupting myelin structure, PLP1 mutations impair oligodendrocyte development and function. Increasing evidence indicates that PMD is fundamentally a proteostasis disorder, in which misfolded PLP accumulates within the endoplasmic reticulum (ER), overwhelms ER quality control mechanisms, and triggers chronic unfolded protein response (UPR) activation. Persistent ER stress and maladaptive UPR signaling ultimately promote oligodendrocyte dysfunction and degeneration. Using PMD as a representative model, this review summarizes the relationships between PLP1 mutations and disease phenotypes and discusses the cellular mechanisms by which ER stress and UPR signaling contribute to oligodendrocyte pathology. Full article

The COVID-19 pandemic underscored the need to better characterize immune and molecular responses following SARS-CoV-2 infection and vaccination. Beyond antibody and cellular immunity, COVID-19 involves oxidative stress and DNA damage, affecting repair mechanisms and metabolic adaptation linked to immune resilience. Here, we present a multidimensional analysis of 20 individuals who recovered from mild COVID-19, integrating clinical features with humoral and cellular immune responses, T cell and myeloid phenotypes, oxidative stress, DNA damage, and metabolomic and lipidomic profiles. Although most individual parameters fell within physiological ranges, network modeling revealed structured associations spanning multiple biological domains. A central finding was a coherent cluster organized around vaccine dose number, linking anti-Spike antibody titers, oxidative stress, bioenergetic signatures, and granulocyte activation. Higher vaccination was associated with stronger humoral responses, lower oxidative stress, and a more balanced myeloid–metabolic profile, suggesting a potential protective role extending beyond antibody induction. Additional associations linked symptom patterns to T cell differentiation states, anti-nucleocapsid responses to systemic inflammation, and anaerobic signatures to DNA damage markers, revealing interconnections between immunometabolism, clinical expression, and genomic stress. Despite the small sample size, these findings offer a preliminary systems-level perspective on mild COVID-19 recovery and illustrate the value of integrative exploratory frameworks in infectious disease research, laying the groundwork for validation in larger longitudinal cohorts. Full article

Background and Objectives: Acute myeloid leukemia (AML) is characterized not only by its heterogeneity but also by its high relapse rate. This results in limited treatment options, especially in elderly or therapy-refractory patients. It is known that inhibiting anti-apoptotic BCL-2 family proteins can be effective; however, cellular resistance mechanisms often limit the efficacy of this treatment. We studied the effects of the BCL-2 inhibitor ABT-737, the MCL-1 inhibitor S63845, and their combination on AML cell lines and primary AML patient cells. Materials and Methods: To analyze the effects of ABT-737 and S63845 treatment on cells, cell energy phenotype, apoptosis, and cell cycle were assessed, and gene expression by RT-qPCR and protein levels by Western blot analysis were measured. Results: Treatment with the BCL-2 inhibitor ABT-737, the MCL-1 inhibitor S63845, and their combination reduced AML cell viability and induced apoptosis. Dual treatment also altered the expression of epigenetic regulators, as the levels of DNMT1, EZH2, SUZ12, and HDAC1 were reduced, while histone acetylation was increased. An increase in pro-apoptotic markers (PARP cleavage, caspase-9) was observed, and the expression of oncogenes (MYC, WT1) was reduced in model cell lines and primary AML patient cells. Conclusions: BCL-2 and MCL-1 inhibition, alone or in combination, induced apoptosis and altered the expression of epigenetic regulators and oncogenes in AML cell lines and primary patient cells, with no consistent advantage of combined treatment over single agents. BCL-2/MCL-1 inhibition remains a promising approach for AML, and further work should clarify which patients or disease subtypes are most likely to benefit from combined versus single-agent treatment. Full article

Tay-Sachs disease is a rare genetic disorder characterized by the accumulation of GM2 ganglioside in neuronal lysosomes due to deficient β-hexosaminidase A (HexA) activity. Progressive GM2 storage leads to severe neurodegeneration, including developmental delay, motor weakness, seizures, ataxia, and early death, typically by five years of age. Previous studies have elucidated several neuronal mechanisms, including apoptosis, endoplasmic reticulum stress, neuroinflammation, and demyelination, these investigations have focused almost exclusively on neurons. However, other components of the central nervous system, particularly astroglia, may play a critical role in disease pathophysiology as suggested by studies in related lysosomal storage disorders. To address this gap, we generated an astrocyte-like model deficient in HexA by targeted knockdown of the HEXA gene in U87MG astrocytoma cells. The resulting cell line recapitulates key pathological features, including lysosomal accumulation, increased neutral lipid content, reduced mitochondrial mass, and elevated reactive oxygen species production. Transcriptomic analysis revealed significant alterations in pathways associated with neuronal degeneration, synaptic organization, mitochondrial dysfunction, and ganglioside metabolism. In summary, this model reproduces some classical cellular alterations reported in Tay-Sachs disease and could potentially provide novel insight into astrocyte involvement in its pathophysiology. These findings support the relevance of non-neuronal cells in disease pathophysiology and establish this system as a valuable platform for screening potential novel mechanisms and therapeutic approaches. Furthermore, this approach highlights the importance of integrating cell type specific models to better understand disease heterogeneity and providing insights into the progressive neurodegeneration of Tay-Sachs disease, positioning this model as a valuable tool for studying its underlying pathophysiology. Full article

Major depressive disorder (MDD) has been linked to oxidative stress, mitochondrial dysfunction, and impaired neuronal plasticity, but the reproducibility of related transcriptomic alterations across postmortem brain cohorts remains uncertain. We performed a targeted cross-platform analysis of a prespecified 14-gene panel spanning antioxidant defense, mitochondrial-redox regulation, cellular stress responses, neurotrophic signaling, synaptic plasticity, and polyamine metabolism across seven postmortem dorsolateral prefrontal cortex cohorts comprising 146 MDD cases and 179 controls. Primary support required Fisher-combined evidence, Benjamini–Hochberg correction across the panel, and concordant MDD-minus-control direction across all available cohorts. NPTX2, EGR1, VGF, BDNF, and SAT1 met these criteria, with lower expression in MDD. The same five-gene pattern was supported by weighted signed Stouffer analysis, one-stage generalized least-squares models, random-effects meta-analysis, and 200,000 disease-label permutations; none produced at least five genes meeting the complete primary-support criterion (empirical p = 5.0 × 10⁻⁶). The most robust cross-cohort finding was a convergent lower-expression pattern across genes supporting redox-linked stress adaptation, polyamine homeostasis, neurotrophic signaling, activity-dependent transcription, and synaptic plasticity. This pattern suggests impaired molecular capacity for neuronal stress resilience and adaptive plasticity in MDD. Full article

In precision oncology, the combination of the strengths of both histopathology and medical imaging provides a fertile ground for tumor characterization. Although histopathology offers a definitive cellular diagnosis, this approach is invasive and only provides a small-scale characterization of the tumor, while medical imaging modalities, such as X-ray, CT, MRI, ultrasound, and PET scans, provide a complete characterization of the tumor but, until recently, relied on the subjective ability of a human observer. The application of machine learning to radiomics aims at filling this gap, as images are mined to reveal patterns of disease not visible to the naked eye. In this perspective paper, the trajectory of machine learning in radiomics for oncology applications is critically discussed. By exploring studies using different imaging modalities, we seek to look beyond the achievements of innovative algorithms and identify the systemic weaknesses in the field, which are holding it back from translating to the clinic. In this regard, we identify two major challenges in the field: the significant effects of inter-modality and inter-scanner variability in model generalizability, and the ‘interpretability gaps’ in understanding the rationale for the decision-making process in ML algorithms. In this paper, we assert that these challenges are holding back even the best of algorithms and thus set the direction for the field in the future, advocating for the development of ML systems with emphasis on their performance in real-world settings as opposed to the lab. Full article

Background/Objectives: Autism spectrum disorder (ASD) is traditionally classified as a neurodevelopmental condition, whereas neurodegenerative diseases are defined by progressive neuronal decline in later life. This separation has shaped research and clinical practice, yet emerging evidence suggests potential biological overlap. This review aims to evaluate whether ASD and neurodegenerative disorders represent distinct entities or are linked through shared mechanisms operating across the lifespan. Methods: This narrative review synthesizes findings from genetic, molecular, cellular, circuit-level, and epidemiological studies examining ASD and major neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, and Amyotrophic lateral sclerosis. Emphasis is placed on identifying convergent pathways and evaluating evidence within a lifespan-oriented framework. Results: Across multiple levels of analysis, ASD and neurodegenerative diseases share partially overlapping biological mechanisms, including mitochondrial dysfunction, impaired proteostasis, neuroimmune alterations, and network-level instability. Genetic and molecular data reveal pleiotropic pathways influencing both early neurodevelopment and later neuronal resilience. Circuit-level studies highlight shared principles of network vulnerability, including cerebellar involvement and excitation–inhibition imbalance. Epidemiological data further indicate increased risk of dementia and parkinsonian features in autistic adults. These convergences suggest that early neurodevelopmental alterations may establish latent vulnerabilities that, under specific conditions, intersect with neurodegenerative processes later in life. Conclusions: ASD and neurodegenerative diseases are best understood as distinct clinical conditions that share partially overlapping biological substrates. Rather than implying a deterministic progression, the evidence supports a model of lifespan convergence in which timing, context, and individual susceptibility shape outcomes. This framework highlights the need for integrated research and clinical approaches that consider brain health as a continuous process from development through aging. Full article

Background/Objectives: Obesity and related metabolic diseases arise from an interplay of lipid overload, insulin resistance and oxidative stress. Acetyl-CoA carboxylase 2 (ACC2) controls malonyl-CoA production and thereby gates mitochondrial fatty-acid oxidation, placing it at the intersection of lipid handling and redox-sensitive metabolic dysfunction. Dietary antioxidants such as polyphenols, flavonoids and terpenoids are increasingly studied as modulators of these pathways, yet systematic prioritization of food-derived antioxidant compounds against defined metabolic targets remains challenging. We developed an integrated deep learning and structure-based workflow to prioritize FooDB compounds with predicted ACC2-binding potential. Methods: A curated set of 3983 ACC2 bioactivity records from ChEMBL 36 was used to train scaffold-split models, including graph neural-network and graph–Morgan fingerprint-fusion architectures. The calibrated ensemble screened 139,988 FooDB compounds; 200 candidates with predicted activity probability above 0.70 were docked against the ACC2 carboxyltransferase domain (PDB ID: 3FF6), and six prioritized complexes underwent 500 ns molecular dynamics and MM/GBSA analysis. Results: Redocking of the co-crystallized ligand reproduced the experimental pose (RMSD 1.2 Å). Although the highest-ranked screening hits were antioxidant terpenoids and alkaloids, docking-based prioritization from the top candidates selected six larger, more polar food-derived compounds, including glycosides and two nucleotide/cofactor-like conjugates, which showed docking scores from −7.47 to −6.65 kcal/mol versus −6.21 kcal/mol for the reference ligand. Glu539 emerged as a recurrent interaction hotspot. All candidates gave more favourable MM/GBSA binding free energies than the reference (ΔG = −22.52 kcal/mol), led by FDB029596 (−35.65), FDB021568 (−34.14) and FDB017807 (−33.87 kcal/mol). Conclusions: This workflow provides a reproducible framework for prioritizing food-derived compounds as candidate ACC2 binders relevant to obesity and metabolic disease, generating structurally supported hypotheses for biochemical and nutritional validation. The prioritized compounds are computational candidates only and require biochemical and cellular (experimental) validation before any ACC2-related biological relevance can be established. Full article