Search Results (1,012)

Background/Objectives: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder traditionally characterized by the extracellular accumulation of amyloid-beta (Abeta) plaques and the formation of intracellular neurofibrillary tau tangles; however, the prevailing scientific paradigm has shifted toward an integrative model of pathogenesis that recognizes neuroinflammation as a critical, self-perpetuating driver of cognitive attrition. This multifaceted interplay is mediated by the brain–body axis, wherein chronic systemic inflammation—stemming from metabolic dysfunction, cardiovascular disease, or environmental stressors such as fine particulate matter PM_2.5—compromises the structural integrity of the blood–brain barrier. Methods: Such environmental insults serve as priming agents for the innate immune system, shifting peripheral immune populations toward a pro-inflammatory phenotype that is further exacerbated by the stabilization of hypoxia-inducible factors (HIFs) through oxidative stress-induced pseudohypoxia, even under normoxic conditions. Results: The subsequent activation of microglia and astrocytes transitions the cerebral microenvironment from a homeostatic, neurosupportive state into a neurotoxic milieu that actively promotes synaptic loss and neuronal death. Conclusions: Consequently, contemporary research has pivoted from broad-spectrum anti-inflammatory interventions toward targeted immune modulation, emphasizing that a comprehensive understanding of how systemic dysfunction perpetuates neuroinflammatory cascades is essential for developing efficacious therapies capable of attenuating AD progression and mitigating its global health burden. Full article

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neuroinflammatory disorder often leading to demyelination of the spinal cord. Progression to HAM/TSP is closely associated with the high proviral load and the presence of virally infected CD4+ T cells that release extracellular vesicles (EVs). Exosomes, an EV subtype released by many cell types, transport proteins and nucleic acids that regulate intercellular communication and have been implicated in the progression of cancer and neuroinflammatory diseases. Herein, we have studied the effect of exosomes from HTLV-1 infected cells on the Peripheral Blood Mononuclear Cells (PBMCs) of HAM/TSP patients by single-cell sequencing utilizing innovative Honeycomb technology. We observed a distinct transcriptional response in monocyte populations compared with other immune cell types. Given that monocytes remain understudied in HTLV-1 pathogenesis, these findings highlight a potential role for infection-derived exosomes in shaping monocyte-driven immune dysregulation in HAM/TSP. A total of 41 genes were identified to be differentially expressed in HAM/TSP monocytes treated with exosomes; 28 were upregulated and 13 were downregulated. The most significantly altered genes are involved in chemokine activity and signaling, macrophage differentiation, lipid metabolism, and lysosomal function. Overall, our data suggests that exosome-treated HAM/TSP monocytes undergo immune remodeling that favors cell recruitment, activation, and a shift toward a mixed M1/M2-like phenotype. Such a shift may support viral persistence and chronic inflammation. These findings highlight a potential therapeutic pathway for addressing HTLV-1-induced neuroinflammation by modulating exosome-mediated signaling. Full article

Neuroinflammation, driven by microglial activation and oxidative stress, is a key pathological feature of various neurodegenerative diseases. Dendropanax morbifera Léveille (DM) is a medicinal plant known for its diverse pharmacological activities; however, the influence of leaf developmental stage on its neuroprotective potential remains poorly understood. In this study, we compared the phytochemical profiles of young DM (YDM) and mature DM leaves and evaluated their effects on neuronal metabolism and microglia-mediated neuroinflammation. HPLC analysis revealed that YDM contained approximately 2.4-fold higher levels of chlorogenic acid than DM, while DM exhibited higher quercetin content. In differentiated N2A neuronal cells, YDM treatment significantly upregulated the expression of key metabolic and mitochondrial regulators, including PGC-1α, PPARγ, and CPT2, suggesting enhanced mitochondrial and metabolic regulatory signaling related to biogenesis and fatty acid β-oxidation. Under inflammatory conditions, YDM more potently suppressed the secretion of pro-inflammatory cytokines (IL-6 and TNF-α) in LPS-stimulated BV2 microglia compared to DM. Furthermore, in N2A cells treated with BV2-conditioned medium, both extracts effectively mitigated reactive oxygen species production and restored brain-derived neurotrophic factor expression. These findings demonstrate that leaf age is a critical determinant of the phytochemical composition and biological activity of DM. Our results suggest that chlorogenic acid-rich YDM preparations may offer superior therapeutic advantages in targeting neuroinflammatory and metabolic dysregulation in the central nervous system. Full article

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease associated with significant olfactory dysfunction. The real-life effect of mepolizumab on smell recovery and the influence of prior surgery and peripheral eosinophilia remain unclear. Objective: Our objective was to evaluate olfactory outcomes after 12 months of mepolizumab in CRSwNP and analyze the impact of previous surgeries and baseline blood eosinophilia. Methods: This was a prospective observational study including 33 consecutive CRSwNP patients treated with mepolizumab. Olfactory function was assessed using subjective measures (VAS: Visual Analogue Scale; SNOT-22: Sino-nasal outcome test, item 21) and psychophysical testing (BOT-8: Barcelona Olfactory Test, detection and identification). Nasal Polyp Score (NPS), peripheral eosinophilia, and quality of life were recorded. Patients were stratified by number of prior sinonasal surgeries. Results: Significant improvement occurred in all subjective and objective olfactory measures at 12 months (BOT-8 detection: 100% vs. 0%; identification: 71% vs. 0%; VAS: 3 vs. 10; SNOT-22 item 21: 1 vs. 5; all p < 0.05). A lower improvement occurred in patients with ≥3 prior; however, this subgroup was small (p < 0.001). Baseline blood eosinophilia was not associated with olfactory improvement. Larger baseline polyp size correlated inversely with subjective olfactory gain (r = −0.48; p = 0.03). Conclusions: Twelve months of mepolizumab improved olfactory function in CRSwNP, especially in patients with fewer prior surgeries. Olfactory dysfunction responds to multifactorial mechanisms beyond blood eosinophilia, including tissue remodeling, nostril obstruction and possible neuroinflammatory mechanisms involving central olfactory pathways, supporting psychophysical test assessment and reinforcing olfaction as a marker of therapeutic response. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder driven by complex interactions between protein aggregation, oxidative stress, neuroinflammation, and cellular dysfunction. Among plant-derived compounds, curcumin has emerged as one of the most extensively studied polyphenols due to its broad spectrum of biological activities. This review provides a critical synthesis of the mechanistic, preclinical, and clinical evidence on curcumin in AD. Experimental studies consistently demonstrate that curcumin modulates key pathogenic processes, including neuroinflammatory signaling, oxidative stress, and amyloid-β aggregation, with more limited evidence for effects on tau pathology. While in vitro studies offer detailed mechanistic insights, in vivo models provide more integrated evidence, including improvements in cognitive performance and reductions in pathological markers. Despite this strong preclinical foundation, the clinical evidence remains limited and inconsistent. Randomized controlled trials have not demonstrated clear therapeutic efficacy, with outcomes strongly influenced by formulation, bioavailability, and study design. Poor solubility, rapid metabolism, and limited brain exposure remain key translational barriers. In response, increasing attention has been directed toward formulation strategies and structurally related compounds. Emerging curcuminoids, such as bisdemethoxycurcumin (BDMC), are discussed as potential next-generation candidates. Preliminary evidence suggests that BDMC may modulate oxidative stress, autophagy, astrocyte senescence, and amyloid-related processes, although the data remain largely preclinical. Overall, curcumin represents a mechanistically rich and preclinically promising multi-target compound but with unresolved translational limitations. Future research should prioritize pharmacokinetic optimization, formulation-dependent validation, and exploration of novel curcuminoid strategies to bridge the gap between experimental findings and clinical application in AD. Full article

Objectives: Neuroinflammation is recognized as a significant characteristic of Alzheimer’s disease (AD). Currently, there is a notable absence of effective pharmacological agents to prevent or treat neuroinflammatory processes associated with AD. Heat shock protein 70 (HSP70) is pivotal in the progression of neuroinflammation. In this study, we explored the potential of maltol, a Maillard reaction product derived from red ginseng, as a therapeutic agent for neuroinflammation. Methods: In vitro, HMC3 microglial cell models were developed to examine the regulatory effects of gradient concentrations of maltol (12.5, 25, 50 μM) on the TLR4/MyD88/NF-κB p65 signaling pathway, neuroinflammation, and pyroptosis. Analyses of the GEO database and Gene Set Enrichment Analysis (GSEA) were performed to identify the core targets of maltol, followed by HSP70 gene silencing experiments to validate the targeted regulatory mechanism. Results: Maltol significantly mitigated LPS-induced neuronal damage and cognitive deficits in mice. It effectively suppressed microglia-mediated neuroinflammation and pyroptosis, reversed oxidative stress-induced neuronal ferroptosis, and inhibited neuronal apoptosis. In vitro experiments demonstrated that maltol obstructed TLR4/MyD88 binding, thereby inhibiting NF-κB p65-mediated neuroinflammation and pyroptosis, while also alleviating excessive ROS accumulation to enhance oxidative stress and ferroptosis. Bioinformatics analysis identified HSP70 as a crucial target for the anti-inflammatory and antioxidant effects of maltol. Subsequent gene silencing experiments confirmed that maltol exerted its inhibitory effects on LPS-induced neuroinflammation and pyroptosis in an HSP70-dependent manner. Conclusions: Maltol exhibits significant protective effects against Alzheimer’s disease-related neuroinflammation, oxidative stress, pyroptosis, and ferroptosis through the targeting of HSP70. This study elucidates the molecular mechanisms by which maltol improves neuroinflammatory injury and provides a novel theoretical foundation and therapeutic strategy for the intervention of Alzheimer’s disease neuroinflammation using traditional Chinese medicine. Full article

The second most prevalent neurodegenerative illness in the world, Parkinson’s disease (PD), currently has no viable treatments. Although it is yet unknown if mitochondrial dysfunction is an initial event or evolves as a result of neurodegeneration, it is thought to be a crucial component of Parkinson’s disease etiology. From the perspective of mitochondrial quality control (MQC), which includes PINK1/Parkin-mediated mitophagy, mitochondrial dynamics, and mitochondrial proteostasis, this article examines mitochondrial dysfunction. Together, these processes preserve mitochondrial homeostasis and prevent the buildup of damaged mitochondria. Dysfunctional mitochondria gradually build up and cause oxidative stress and aberrant cellular signaling when mitochondrial quality control is compromised. According to available data, mitochondrial reactive oxygen species (mtROS) primarily worsen pre-existing mitochondrial damage by encouraging α-synuclein aggregation, cardiolipin remodeling, and dopamine oxidation. In addition, innate immune pathways like cGAS–STING and TLR9 signaling can be triggered by mitochondrial damage-associated molecular patterns (mtDAMPs), especially mitochondrial DNA, which can lead to long-term neuroinflammatory reactions in PD. While new research suggests that m⁶A RNA modification may be involved in the regulation of mitochondrial stress, the PINK1/Parkin pathway is crucial for maintaining mitochondrial homeostasis. Therapeutic approaches that target mitophagy augmentation, neuroinflammatory signaling, and mitochondrial protection have garnered increasing attention. In an attempt to improve mitochondrial function and lessen persistent neuroinflammatory activation, future research will probably need to concentrate on combination treatment techniques. Full article

Zinc deficiency is increasingly recognized as a risk factor for neurodegenerative diseases, yet the underlying molecular mechanisms remain incompletely understood. In this study, we investigated the impact of intracellular zinc depletion on oxidative stress and inflammasome activation in microglial (SIM-A9) and neuronal (SH-SY5Y) cell models, and evaluated the protective effects of polyphenolic compounds. Intracellular zinc chelation with the membrane-permeable chelator TPEN markedly increased reactive oxygen species (ROS) production, reduced cell viability, and upregulated the mRNA expression of NLRP3 inflammasome-related genes and pro-inflammatory cytokines. In contrast, extracellular zinc chelation had no effect, highlighting the critical role of intracellular zinc homeostasis in maintaining redox balance. Zinc supplementation significantly attenuated these responses. Among 32 polyphenols screened by DPPH radical scavenging assay, caffeic acid derivatives—chicoric acid (ChA), rosmarinic acid (RA), and caffeic acid phenethyl ester (CAPE)—exhibited the most potent antioxidant activity, surpassing that of edaravone. These compounds suppressed ROS production and differentially protected against zinc deficiency-induced cellular damage. ChA showed the strongest ROS inhibitory activity (IC50: 1.9 µM in SIM-A9), RA provided robust cytoprotection even at low concentrations, and CAPE most effectively suppressed inflammasome-related gene expression and inhibited aggregation of both Aβ1–42 and the highly neurotoxic pyroglutamate-modified variant pEAβ3–42. These findings demonstrate that intracellular zinc deficiency drives ROS-dependent upregulation of NLRP3 inflammasome-related genes, and suggest that caffeic acid derivative polyphenols may serve as complementary agents for mitigating neuroinflammatory and amyloidogenic processes relevant to Alzheimer’s disease. Full article

Introduction: Neuroinflammation is a key feature of both Alzheimer’s disease (AD) and glioblastoma, although it leads to different outcomes in each disorder. In AD, chronic activation of microglia and astrocytes by amyloid-β and tau contributes to neuronal injury and cognitive decline. In glioblastoma, tumor cells exploit inflammatory pathways to create an immunosuppressive microenvironment that supports tumor growth. This review compares the shared and distinct neuroinflammatory mechanisms in AD and glioblastoma and highlights their therapeutic relevance. Materials and Methods: This study was conducted as a narrative review based on a PubMed search performed by three reviewers. English-language articles on AD, glioblastoma, and neuroinflammatory pathways were included, covering original studies, reviews, meta-analyses, and experimental and clinical reports. Keywords included neuroinflammation, microglia, astrocytes, tumor-associated macrophages, inflammasomes, NLRP3, NF-κB, HIF-1α, cytokines, blood–brain barrier, and miRNAs. Due to study heterogeneity, findings were synthesized descriptively. Results: AD and glioblastoma share major neuroinflammatory mechanisms, including microglial and astrocytic activation, cytokine signaling, inflammasome activity, blood–brain barrier dysfunction, hypoxia-related changes, and miRNA regulation. In AD, these pathways promote chronic inflammation, synaptic loss, and neurodegeneration, with NLRP3, NF-κB, and M1-like microglial polarization playing central roles. In glioblastoma, similar pathways are redirected toward tumor progression through tumor-associated macrophages, reactive astrocytes, angiogenesis, immune evasion, and therapy resistance. Key overlapping mediators include IL-1β, TNF-α, NF-κB, HIF-1α, GSK-3β, and selected miRNAs. Conclusions: AD and glioblastoma are connected by common neuroinflammatory pathways, but these processes result in neurodegeneration in AD and tumor support in glioblastoma. Understanding these shared and divergent mechanisms may guide the development of biomarkers and targeted therapies focused on microglia, inflammasomes, cytokines, and immune reprogramming in both diseases. Full article

The GGGGCC hexanucleotide repeat expansion (HRE) in C9ORF72 was recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat-associated non-AUG (RAN) translation of the expanded repeat generated dipeptide repeat proteins (DPRs), which disrupted multiple cellular processes and contributed to neurodegeneration. Emerging evidence indicated that disease pathogenesis involved both gain-of-function (GOF) and loss-of-function (LOF) mechanisms. DPR-mediated GOF toxicity induced ribosomal dysfunction, nucleolar stress, proteostatic impairment, and neuronal injury, whereas C9ORF72 LOF disrupted lysosomal and autophagic pathways in microglia, impairing the immune homeostasis. Neuronal injury further promoted the release of damage-associated signals that triggered secondary microglial activations and chronic neuroinflammations. This review summarized current knowledge of DPR biology, microglial dysfunction, and their contributions to disease progression in C9ORF72-associated ALS/FTD. Therapeutic strategies targeting repeated RNA, DPR productions, proteostasis, autophagy, and neuroinflammatory pathways were also discussed. In addition, the potentials of fluid biomarkers, including cerebrospinal fluid poly (GP) and blood neurofilament light chain (NfL), for diagnosis, disease monitoring, and therapeutic assessment were shown. Together, these findings provided important insights into disease mechanisms and potential avenues for improved clinical management. Full article

Multiple sclerosis (MS) is a neuro-inflammatory disease characterized by demyelination in the central nervous system (CNS). Although a substantial endogenous capacity for remyelination has been demonstrated, this process is frequently incomplete and exhibits marked intra- and inter-individual heterogeneity. Several factors influence the extent of spontaneous myelin regeneration, including age, sex, disease course, and lesion localization. Oligodendrocytes (OL), derived from oligodendrocyte progenitor cells (OPCs), are the principal myelinating cells of the CNS. The regenerative cascade involves several key stages, including OPC activation, recruitment, differentiation into oligodendrocytes (OL), and myelin deposition. This process is orchestrated in a spatiotemporal manner by a complex interplay of intracellular signaling pathways, genetic determinants, and dynamic microenvironmental cues, which together balance inhibitory and pro-remyelinating influences. Several lines of evidence indicate that chronically demyelinated axons are vulnerable to degeneration, whereas successful remyelination may confer neuroprotection. These observations underscore remyelination as a promising neuroprotective therapeutic target for preventing or slowing disability progression in MS, a condition in which gradual neuroaxonal degeneration is believed to underlie irreversible disability progression. In this review, we aim to bridge the gap between fundamental biological mechanisms of remyelination and their clinical relevance. We examine recent advances in in vivo techniques for assessing remyelination and discuss how these measures correlate with clinical and disability outcomes. In addition, we review recent clinical trials of remyelination-promoting therapies and analyze the challenges that have limited their advancement beyond phase II. Overall, we seek to provide a comprehensive overview of the remyelination process from bench to bedside, highlighting both the obstacles and the therapeutic potential of remyelination strategies in MS. Full article

Basonuclin 2 (BNC2) is a highly conserved cysteine–histidine (C2H2)-type zinc-finger nuclear regulatory protein characterized by three pairs of zinc-finger domains, a putative nuclear localization signal, a serine-rich region, broad tissue distribution, and remarkable transcript diversity generated through alternative promoter usage, alternative splicing, and polyadenylation. Increasing evidence from human genetics, animal models, functional genomics, and transcriptomic studies indicates that BNC2 links nuclear regulatory mechanisms to tissue-specific developmental and disease phenotypes. In the nervous system, BNC2-positive neuronal populations and BNC2-derived circular RNAs have been implicated in energy-balance circuits and neuroinflammatory regulation. In the skeletal system, BNC2 contributes to osteochondral development, periosteal stem-cell activation, chromatin remodeling, fracture repair, and genetic susceptibility to adolescent idiopathic scoliosis. BNC2 variants have also been associated with congenital lower urinary tract obstruction, whereas its expression and regulatory landscape are closely related to germ-cell development, epithelial ovarian cancer susceptibility, pigmentation traits, fibrosis, and several tumor contexts. Mechanistically, BNC2-associated phenotypes appear to involve cysteine–histidine zinc-finger-mediated transcriptional regulation, non-coding enhancer activity, epigenetic alterations, RNA-processing-associated nuclear functions, and chromatin-remodeling-dependent control of cell proliferation, differentiation, and stromal activation. This review integrates current evidence on the molecular architecture and regulatory functions of BNC2, critically discusses its context-dependent roles across development and disease, and highlights unresolved questions regarding isoform-specific activity, cell-type-specific regulation, downstream target networks, and clinical translation. A clearer understanding of these mechanisms may support the future evaluation of BNC2 as a biomarker, genetic susceptibility locus, molecular stratification factor, and potential therapeutic regulatory node. Full article

Neuroinflammation plays a central role in the onset and progression of neurodegenerative disorders. Several disease-modifying therapies have been developed to target neuroinflammatory pathways in specific disorders. However, their ability to stop disease progression or restore neuronal and mitochondrial homeostasis remains limited. This is still a major unmet clinical need. In this context, mesenchymal stromal cell (MSC)-derived Extracellular Vesicles (EVs) have emerged as a promising cell-free therapeutic strategy due to their ability to modulate immune responses and promote neuroprotection through the delivery of bioactive cargo. Recent evidence has identified a distinct subset of EVs, known as mitochondrial EVs (mito-EVs), which carry mitochondrial DNA, proteins, and functional components. These vesicles may uniquely influence cellular bioenergetics, redox balance, and neuroinflammatory signaling, offering additional therapeutic potential compared to conventional MSC-EVs. This review summarizes the role of MSC-derived EVs in neuroinflammatory disorders, with a particular focus on mito-EVs. It also discusses preconditioning strategies to enhance EV efficacy, including hypoxic, inflammatory, pharmacological priming and genetic engineering approaches. Finally, we critically evaluate current preclinical evidence regarding the treatment of major neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis, as well as Traumatic Injury, highlighting the key challenges for clinical translation. Full article

Objectives: Endocrine neoplasms, as a general rule, show systemic, neuro-inflammatory and metabolic consequences, known as paraneoplastic syndrome. The comorbidity of thyroid tumors with neurological and autoimmune diseases prompt looking for common neuro-immuno-endocrine mechanisms of these disorders. While most TCs are well described, there is a gap in the literature after the isolation of oncocytic/Hürthle cell carcinoma (HCC), as a unique type due to immunoendocrine and metabolic features (low TSH-receptor expression and radioiodine avidity). The aim of this study was to collect clearly defined reports of HCC (as a separate entity) and to attempt determining common clinical symptoms and the usefulness of various diagnostic techniques (comprehensive critical review). This may be an introduction to modern treatment (patient-centered care) since the main cause of mortality is not local progression or metastases. Results: Until now, due to misnomenclature and data misinterpretation, HCC has been treated according to general standards (with overuse of TSH-ST and RIA). High thyroglobulin level, decreased total thyroxin (with normal FT3 and spontaneous decrease in TSH), hypercalcemia, as well as the “reverse flip-flop” phenomenon, as common symptoms, indicate the neuroendocrine origin of HCC. Sparse, well-documented lymph node metastases are another feature, although from few studies. Most studies omit the N stage. Whole-body ¹³¹iodine and ¹⁸F-fluorodeoxyglucose scintigraphy may be useful before FNAB. Fine-needle aspiration biopsy (FNAB), as a “gold standard” in early diagnosis of thyroid nodules, delays HCC diagnosis because of the inability to determine a benign/malignant nature. Conclusions: Final HCC outcome may be affected by various overlapping immunoendocrine factors (paraneoplastic effects). Due to very few thyroid function tests performed in HCC, we have proposed a set of basic laboratory analyses, core biopsy in HCC differentiation, and diagnostic chain for standardization. According to the review, adaptation and treatment of HCC based on existing standards for other thyroid cancers seem to be insufficient, and the risks outweigh the benefits. The key recommendations resulting from the 5th edition of the WHO Classification of Endocrine Neoplasms are only the beginning of refuting many myths and biases. Full article

Major depressive disorder (MDD) is a complex and heterogeneous psychiatric disorder with a high prevalence. Neuroinflammation may define biologically distinct patient subgroups with different mechanisms, clinical phenotypes, and treatment responses. This narrative review integrates current evidence around three linked questions: how neuroinflammatory processes contribute to depression, how biomarkers can identify clinically relevant inflammatory phenotypes, and how these findings can inform anti-inflammatory treatment strategies. The major mechanisms discussed include microglial activation and neuroimmune signaling, hypothalamic–pituitary–adrenal axis dysregulation and glucocorticoid receptor resistance, kynurenine pathway alterations, and cytokine-driven impairment of neurogenesis and synaptic plasticity. These pathways interact with stress responses, neurotransmitter systems, and neuronal function, while their expression may vary according to sex, age, hormonal status, disease stage, and treatment exposure. These interconnected pathways may contribute to depressive symptoms by disrupting neurotransmitter systems and impairing neural plasticity. In addition, this review discusses several candidate biomarkers, including C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF) and transforming growth factor-β1 (TGF-β), which may support patient stratification, treatment prediction, and assessment of target engagement. Clinical trials of anti-inflammatory agents have shown inconsistent and generally modest effects in unselected MDD populations. By integrating mechanistic evidence with biomarker-guided therapeutic implications, this review aims to clarify how neuroinflammatory research may inform more precise and individualized treatment strategies for depression. Full article