Search Results (4,185)

Background: Autophagy is a process that diversely impacts the stages of both tumor initiation and progression. Elucidating the molecular mechanisms underlying autophagy and its role in tumorigenesis is a key component of anticancer strategies in both prostate cancer and other malignancies. Because advanced prostate cancer frequently exploits enhanced autophagy as a defense mechanism against therapy-induced stress (e.g., from abiraterone), the pharmacological modulation of miRNA levels presents a tremendous opportunity to block the tumor’s escape route and overcome drug resistance. Methods: A comprehensive literature review was conducted to evaluate the molecular pathways determining cancer cell survival and death. The analysis focused on the dual nature of autophagy (functioning as a ‘double-edged sword’) within the tumor microenvironment, microRNA (miRNA) regulatory networks, and the efficacy of synergistic therapeutic strategies in overcoming treatment resistance. Results: The primary focus of this paper is the dual and complex role of autophagy, which serves, on the one hand, as a cellular protective shield against metabolic stress—thereby facilitating metastasis—and, on the other hand, as a potential pathway leading to autophagic cell death. The progression of this crucial process is regulated by intricate interactions (crosstalk) with apoptotic pathways, mediated by Bcl-2 family proteins, key kinases (such as mTOR, JNK, and DAPK), and transcription factors, such as p53. Furthermore, the autophagic machinery is precisely regulated by specific miRNA molecules (e.g., miR-21, miR-141, and miR-375). These not only act as crucial intracellular modulators of autophagy but also serve as promising circulating biomarkers, enabling the monitoring of this process’s activity throughout disease progression. Conclusions: Autophagy, and in particular its modulation via miRNA signaling networks, represents a major and highly promising translational target. By directly impairing this autophagic survival mechanism, ‘double-hit’ combination therapies—integrating autophagy inhibitors (such as hydroxychloroquine or VPS34 inhibitors) with standard antiandrogen or cytotoxic agents—demonstrate promising preclinical potential in overcoming treatment resistance and favorably modulating the immune microenvironment in advanced prostate cancer. Full article

Heterotrimeric GTP-binding proteins, commonly known as G proteins, act as core molecular switches in plant signal transduction, governing multiple biological processes including plant growth, development, phytohormone signaling, and abiotic stress adaptation. In this study, a total of 12 G-protein-related genes were identified in foxtail millet, consisting of six Gα subunit-encoding genes, one Gβ subunit-encoding gene, and five Gγ subunit-encoding genes. Gene structure and conserved motif analyses showed that members classified into the same subunit clade possessed highly conserved exon–intron organization and motif distribution, indicating evolutionary structural conservation within each G-protein subfamily. Promoter Cis-acting element analysis revealed that all G-protein family genes harbored light-responsive elements, as well as multiple regulatory elements associated with phytohormone signaling and abiotic stress responses. Transcriptome analysis showed that different G-protein genes exhibited distinct expression patterns under salt stress. Notably, SiαXLG2 exhibited drastically induced expression upon salt stress, which serves as a pivotal candidate gene for salt-stress response in foxtail millet. Collectively, this study provides a systematic characterization of the G-protein gene family and offers candidate gene resources for further elucidating G-protein-mediated salt-stress regulatory mechanisms in foxtail millet. Full article

Obesity is a chronic metabolic disorder closely associated with dyslipidemia, insulin resistance, low-grade inflammation, and gut microbiota dysbiosis. Mulberry leaves are rich in bioactive proteins, but whether mulberry leaf albumin-type protein can improve diet-induced obesity remains unclear. In this study, ultrafiltered mulberry leaf albumin-type protein (UMP) was prepared and its anti-obesity effects were evaluated in high-fat diet (HFD)-fed C57BL/6J mice. UMP contained 87.12 ± 0.52 g/100 g protein, 2.52 ± 0.00 g/100 g polyphenols, and 8.21 ± 1.49 g/100 g polysaccharides, with two major albumin-type protein bands of approximately 14 and 52 kDa. Structural analysis showed that UMP was mainly composed of β-turns and α-helices. In HFD-fed mice, daily administration of UMP for 16 weeks reduced body weight gain by 3.85 g and 5.63 g in the low- and high-dose groups, respectively, without affecting food intake. Biochemical assays, glucose and insulin tolerance tests, and histological analysis showed that UMP improved insulin responsiveness, alleviated serum dyslipidemia, reduced hepatic lipid accumulation, and decreased circulating alanine aminotransferase, aspartate aminotransferase, and lipopolysaccharide levels. Histological analysis and nuclear magnetic resonance-based short-chain fatty acid quantification further showed that UMP protected colonic morphology and increased colonic short-chain fatty acid levels. Gut microbiota analysis showed that UMP restored microbial diversity, reduced the Firmicutes/Bacteroidota ratio, and enriched potentially beneficial genera, including Ileibacterium and norank_f_Muribaculaceae. Fecal biochemical assays suggested that UMP promoted fecal free fatty acid excretion and partially improved bile acid-related metabolic alterations. Untargeted serum metabolomics revealed that UMP reshaped metabolic pathways related to lipid turnover, bile acid signaling, glucose utilization, and glucuronidation. Correlation analysis linked UMP-enriched bacterial taxa with key metabolites involved in fatty acid and energy metabolism. Together, these findings indicate that UMP attenuates HFD-induced obesity through coordinated regulation of gut microbiota, intestinal metabolites, and systemic metabolic homeostasis. UMP may therefore represent a promising functional dietary protein for the prevention of obesity-related metabolic disorders. Full article

Background: Chronic insomnia (CI) is increasingly recognized to be closely associated with neuroimmune dysregulation and neuroinflammation. While the dietary flavonoid quercetin exhibits known broad-spectrum anti-inflammatory properties, its specific multi-target network and underlying mechanisms concerning CI-associated neuroinflammation remain systematically unmapped. Therefore, this study integrated network pharmacology with in vitro experimental validation to elucidate the specific targets and mechanistic pathways of quercetin against neuroinflammatory responses implicated in CI. Methods: Potential targets of quercetin were predicted using the SwissTargetPrediction and SEA platforms, while CI-associated targets were curated from GeneCards, OMIM, and CTD. To bridge computational predictions with physiological relevance, protein–protein interaction (PPI) and functional enrichment analyses were integrated with molecular docking to assess the binding landscape of key candidates. Subsequently, to empirically validate these network-derived mechanistic hypotheses, in vitro experiments were conducted using an LPS-stimulated BV2 microglial model. Pro-inflammatory mediators were quantified via qRT-PCR, and the regulatory dynamics of the RAGE/NF-κB axis were evaluated by Western blotting. Results: Fifty-five overlapping targets were identified, prioritizing six hub genes (e.g., TNF, AKT1, IL6). By harmonizing the predicted network topology with experimental observations in the BV2 microglial framework, our results provide a unified mechanism linking quercetin to the suppression of central neuroinflammation. Enrichment highlighted the AGE-RAGE and IL-17 pathways as central mechanistic nodes. Molecular docking confirmed high-strength affinities between Quercetin and core targets. In the in vitro neuroinflammation model, quercetin (10, 30, and 60 μM) exerted a dose-responsive suppression of TNF-α, IL-1β, IL-6, and iNOS, while concurrently elevating anti-inflammatory IL-10 levels. Mechanistically, Quercetin significantly downregulated RAGE expression and blunted the phosphorylation of P65 and IκB, leading to significant reductions in p-P65/P65 and p-IκB/IκB ratios. Conclusions: Our findings demonstrate that Quercetin may attenuate neuroinflammatory responses associated with CI through modulation of the RAGE/NF-κB signaling axis, as indicated by network pharmacology prediction and further supported by validation in an LPS-stimulated BV2 microglial model. While these in vitro anti-inflammatory effects provide a robust mechanistic basis for targeting neuroimmune dysregulation, further in vivo behavioral studies are necessary to evaluate its direct therapeutic efficacy against chronic insomnia. Full article

Kanamycin (KANA), a widely used aminoglycoside antibiotic in animal husbandry, is associated with residue accumulation in foods due to improper use, threatening food safety. Detecting trace KANA in complex food systems such as dairy, meat, and apicutural products remains challenging because of matrix interferences (e.g., proteins, lipids, and co-existing ions) and limitations of conventional methods, which require labor-intensive pretreatment and sophisticated instrumentation. Aptamer-based fluorescent biosensors have emerged as promising tools for rapid, sensitive KANA detection with high specificity and on-site analysis potential. DNA aptamers act as selective recognition elements that bind KANA and undergo conformational changes for efficient signal transduction. This review summarizes recent advances in fluorescent aptasensors for KANA detection, with an emphasis on food system applications. Aptamer selection strategies are outlined, highlighting split aptamers’ advantages in binding precision and structural stability. Labeled and label-free sensing modes are compared in terms of design principles, analytical performance, and suitability for complex food matrices. Attention is paid to strategies for mitigating matrix interference and improving detection reliability in real samples. Despite progress, challenges remain in sensor stability, reproducibility, and on-site deployment. Overall, aptamer-based fluorescent biosensors provide a powerful platform for rapid antibiotic residue monitoring and advance food safety-oriented sensing technologies. Full article

H. pylori infection induces oxidative stress and inflammatory responses in gastric epithelial cells, which are key factors in the pathogenesis of gastritis and ulcers. Given the increasing threat of antibiotic resistance, non-antibiotic approaches that target host cell injury mechanisms are gaining considerable interest. While peptides derived from corn protein are known for their antioxidant and anti-inflammatory activities, whether they can alleviate H. pylori-induced gastric epithelial injury remains unclear. In this study, we evaluated the preventive effects of corn protein-derived bioactive peptides (CPDP-N), prepared by neutral protease hydrolysis, against H. pylori-triggered injury in human GES-1 cells. CPDP-N exhibited no cytotoxic effects, reduced H. pylori-induced intracellular ROS accumulation in a dose-dependent manner, and markedly increased the activities of intracellular antioxidant enzymes. Flow cytometry and fluorescence imaging demonstrated that CPDP-N attenuated the loss of mitochondrial membrane potential and relieved G0/G1 cell cycle arrest. CPDP-N markedly suppressed the secretion of the pro-inflammatory cytokines TNF-α, IL-1β, and IL-8, attenuated LDH release, and upregulated the anti-inflammatory cytokine IL-10. Moreover, CPDP-N markedly lowered the H. pylori-induced elevation of nuclear factor kappa-B (NF-κB) p65 protein, a key regulator of inflammatory signaling. These protective effects were accompanied by reduced intracellular ROS levels and lower NF-κB p65 abundance, suggesting the involvement of oxidative stress and NF-κB pathways. Collectively, these findings demonstrate that corn protein-derived peptides can protect gastric epithelial cells from H. pylori-induced oxidative and inflammatory injury, highlighting their potential as a dietary intervention for H. pylori-associated gastric diseases. Full article

Background/Objectives: Covalent inhibitors often demonstrate prolonged pharmacological effects even after their disappearance from the site of action because target recovery depends on target turnover. This disconnect between pharmacokinetics (PK) and pharmacodynamics (PD) complicates the development of such inhibitors since plasma exposure coverage of in vitro potency cannot be used for compound selection and human dose projections. In this study, we describe the development of a PK/PD modeling framework for covalent inhibitors. Methods: The model was developed for KRAS G12C inhibitors using pre-clinical data on sotorasib. The model was validated using data from both internal Amgen compounds and published data for several KRAS G12C inhibitors. The applicability of the framework was extended to EGFR covalent inhibitors by incorporating PK/PD and the efficacy of osimertinib and its active metabolite AZ5104. Results: The model successfully captured the pharmacokinetics, KRAS G12C target occupancy, inhibition of phosphorylation of ERK protein, and tumor growth inhibition following the administration of sotorasib in mice bearing MIA PaCa-2 xenografts. External validation with several internal Amgen compounds as well as publicly available data on KRAS G12C inhibitors showed the robustness of the model. The application of this framework to EGFR inhibitor Osimertinib and AZ5104 captured p-EGFR dynamics and resultant tumor growth inhibition. Conclusions: A modeling framework for covalent inhibitors was developed that links exposure to target occupancy, downstream signaling, and tumor efficacy. This framework could be useful for compound optimization and human dose projections. Full article

Sea cucumber cooking liquid contains water-soluble macromolecules, but its bioactive polysaccharide fractions remain insufficiently characterized. In this study, a polysaccharide-rich fraction, P0.7, was isolated from sea cucumber cooking liquid and evaluated for its antitumor activity against HCT-15 colorectal cancer. P0.7 was characterized as a relatively homogeneous sulfated acidic heteropolysaccharide-rich fraction containing 83.61 ± 3.65% total sugar, 13.67 ± 2.48% sulfate, 9.98 ± 1.22% uronic acid, and 5.11 ± 0.34% protein. It was mainly composed of galactose, mannose, and glucose, accounting for 34.12%, 26.93%, and 17.99%, respectively. Among the tested tumor cell lines, HCT-15 cells showed the highest sensitivity to P0.7, with inhibition rates of approximately 45% and 63% at 100 and 200 μg/mL, respectively. P0.7 promoted apoptosis, induced G2/M-phase accumulation, increased ROS production, disrupted mitochondrial membrane potential, regulated Bax, Bcl-2, and cleaved caspase-3 expression, and enhanced γ-H2AX-related DNA damage-response signaling in HCT-15 cells. In an HCT-15 xenograft mouse model, P0.7 reduced terminal tumor volume and tumor weight without causing obvious body weight loss. Histological and immunohistochemical analyses further showed reduced Ki67 staining, increased TUNEL-positive signals, and enhanced γ-H2AX staining in tumor tissues. These findings indicate that P0.7 suppresses HCT-15 colorectal cancer growth in vitro and in vivo, possibly through mechanisms associated with ROS accumulation, mitochondrial apoptosis, and γ-H2AX-related DNA damage response. These findings provide additional experimental evidence supporting the investigation of sea cucumber-derived polysaccharides for potential pharmaceutical applications. Full article

The addition of potato and maize powders to wheat-based dough systems has been identified as a common practice for enhancing the dietary fiber content of cereal products. However, their product quality remains problematic due to inadequate comprehension of the manner in which starch granules regulate disulfide bond formation within wheat gluten proteins. In order to address this evident gap in the existing literature, this study investigated the effects of different starch granules—including potato, maize, and wheat—on disulfide bond formation of urea-solubilized glutenin (USG). The experimental results indicate that the optimal conditions for enhancing disulfide bonding in potato, maize, and wheat granules (from 0.2162 to 0.5319, 0.3502 and 0.9488 μmol/g, respectively) were as follows: a USG: granule ratio of 3:1 (w/w), a temperature of 45 °C for 30 min, a USG: granule ratio of 3:1 (w/w), a temperature of 35 °C for 120 min, a USG: granule ratio of 1:2 (w/w), a temperature of 25 °C, and a duration of 60 min, respectively. Under low-granule conditions, the possible mechanism was that all granules might leach out predominantly amylopectin (no blue color is observed when attached to an iodine solution) to facilitate disulfide bond formation of USG. Conversely, under high-granule conditions, the interaction between granule proteins may be excessive, potentially leading to the precipitation of amylose (dark blue color is observed when attached to an iodine solution). This process may result in a reduction in disulfide bond contents due to the competitive interaction of water molecules. Spectroscopic and structural analyses further indicated that the attenuation of the nuclear magnetic resonance (NMR) signal of C1 hydroxyl groups of amylopectin/amylose and peptide amide bonds of USG arose from physical entanglement based on the hydrogen bonds between them. Upon interaction between USG and potato/maize starch granules, the X-ray diffraction pattern of USG vanished, and the intramolecular β-sheet conformation was markedly diminished. Collectively, these findings provide a mechanistic foundation for the rational design and optimization of high-fiber, high-quality cereal-based food products. Full article

Lymphoma remains a major hematological malignancy associated with treatment resistance and systemic toxicity, highlighting the need for novel anticancer agents derived from natural products. In this study, dicentrine (5), an aporphine alkaloid isolated from Stephania venosa, was investigated for its anti-lymphoma activity in Raji and Ramos cells. Among the isolated compounds, dicentrine (5) exhibited the strongest cytotoxic activity, with IC₅₀ values of 9.03 ± 0.53 and 5.16 ± 0.44 µg/mL in Raji and Ramos cells, respectively, while demonstrating favorable selectivity toward lymphoma cells relative to peripheral blood mononuclear cells (PBMCs). Dicentrine (5) significantly suppressed c-Myc and phosphorylated c-Myc expression, reduced lymphoma cell proliferation, and decreased total viable cell numbers in a dose-dependent manner. Cell cycle analysis revealed G0/G1 arrest in Raji cells and G2/M arrest in Ramos cells. Furthermore, dicentrine (5) induced apoptosis, as evidenced by increased Annexin V-positive populations and elevated cleaved caspase-3 expression. Molecular docking analysis demonstrated strong binding affinities of dicentrine (5) toward Akt, PI3K, caspase-3, and caspase-9, while network pharmacology identified AKT1 and the PI3K/Akt signaling pathway as potential targets associated with lymphoma suppression. Western blot analysis further demonstrated that dicentrine (5) significantly reduces total Akt protein expression. Overall, the present findings indicate that dicentrine (5) suppresses lymphoma progression by inhibiting cell proliferation and promoting apoptotic cell death, highlighting its potential as a promising natural therapeutic candidate for lymphoma. Full article

Background/Objectives: Cisplatin is used in the treatment of ovarian cancer; however, the development of resistance, often due to the efficient repair of cisplatin-induced DNA damage, remains a major barrier to effective therapy. Among these lesions, DNA interstrand crosslinks (ICLs) are particularly cytotoxic because they prevent DNA replication and transcription. HMGB2, a member of the high-mobility group box (HMGB) protein family, can bind DNA lesions and has been implicated in genome maintenance and DNA repair. This study investigated whether HMGB2 contributes to the processing of cisplatin-induced DNA damage and modulates cisplatin sensitivity in human ovarian cancer cells. Methods: HMGB2 expression was suppressed by siRNA in cisplatin-sensitive A2780 and cisplatin-resistant CP70 human ovarian cancer cells. Cellular responses to cisplatin were assessed using clonogenic survival assays, cell cycle analysis, Western blotting, slot blot analysis, and modified alkaline comet assays. Results: HMGB2 depletion reduced clonogenic survival in cisplatin-resistant CP70 cells and increased the sub-G1 population, indicating enhanced apoptotic DNA fragmentation following cisplatin treatment in both cell lines. Depletion of HMGB2 resulted in increased persistence of cisplatin–DNA adducts and impaired ICL processing, as demonstrated by persistent DNA damage over time and reduced ICL unhooking efficiency. DNA damage response signaling following cisplatin treatment was also altered by HMGB2 depletion in both cell lines, whereas the expression levels of key DNA repair proteins were unchanged. Conclusions: Our findings demonstrate that HMGB2 is involved in the cellular response to cisplatin treatment by promoting the efficient processing of cisplatin DNA adducts, particularly ICLs, thereby modulating cisplatin sensitivity in human ovarian cancer cells. These findings suggest that targeting HMGB2 may serve as a potential therapeutic strategy for overcoming cisplatin resistance in ovarian cancer. Full article

Nowadays, most cancer research still depends on traditional cell culture in Petri dishes or cell culture flasks which do not have the ability to mimic physiological-like conditions in vitro. However, the behavior of cancer cells strongly relies on the interaction with their extracellular microenvironment. Consequently, current advanced approaches focus on three-dimensional (3D) cell culture to overcome such limitations and to enable a better understanding of fundamental processes including cancer development, progression, apoptosis and invasion. However, transcriptional adaptation to and temporal stability within an in vitro 3D microenvironment still appear to be remarkably understudied. In our study, we compared the cellular behavior and whole transcriptome gene expression of three frequently used non-invasive cancer cell lines (HCT-116, A549 and T47D), embedded within a collagen I (Coll I)-based 3D microenvironment to its counterparts grown as simple monolayers in a time-dependent manner. Thereby, changes in morphology and doubling time became apparent between both cultivation systems, and RNA sequencing-based transcriptome-wide analysis revealed a remarkable increase in transcriptional complexity under 3D conditions. In line with the 3D-dependent phenotype, unidirectional shifts for genes involved in cell cycle regulation (e.g., CCNB1, CCNB2), cell–matrix interaction (e.g., ADAM8, ITGA2) and metabolic signaling (e.g., HK2, ENO2) were identified over time, being either activated or repressed. Interestingly, all three cell lines cultured in Coll I matrices displayed a highly distinct RNA content and composition, along with a significantly increased number of expressed protein-coding genes (increase of 3–6%) as well as long non-coding RNAs (increase of 26–48%), suggesting a more multifaceted transcription profile under 3D conditions. Our work clearly highlights that an in vitro 3D Coll I-based cell culture system has an incisive cell-specific impact on the whole transcriptome on a qualitative and quantitative level. This tremendous transcriptional reprogramming implies essential changes in gene regulatory networks and affects phenotypic cancer cell behavior, which should be considered when focusing on downstream applications. Full article

Histamine is a biologically active monoamine acting through four G protein-coupled receptors (H₁R–H₄R), which represent attractive therapeutic targets for a range of diseases. Nowadays, H₄R is recognized as a key player in inflammation and cancer. Here, we describe the design, syntheses and characterization of new H₄R ligands containing pyrido[2,3-d]pyrimidine or pyrimidine scaffold. Candidate structures were scored in silico by docking to the structure of the human inactive H₄R. Favorable structures were synthesized and, after confirmation of identity, their affinities were verified in in vitro screenings. Tested compounds did not exhibit any relevant cytotoxic (PrestoBlue) or antiproliferative (BrdU incorporation) effects at concentrations used in the functional assays. In a radioligand displacement assay (H₄R affinity) the pyrimidine series showed lower binding, whereas several pyrido[2,3-d]pyrimidine derivatives and one pyrimidine analog produced >60% inhibition at 1 µM. Two similar compounds with the highest and moderate affinities were selected for further studies. In the G_i–cAMP pathway, both compounds behaved as moderate H₄R antagonists, but in contrast, their profiles diverged in the β-arrestin pathway. These findings suggest ligand-dependent biased differences in signaling across G-protein and β-arrestin pathways at H₄R. Overall, YAN-153 emerges as a promising lead structure for further optimization and for more detailed in vitro (e.g., metabolic stability, selectivity) and in vivo studies. Full article

Polypropylene microplastics (PP-MPs) are ubiquitous in our daily lives, but their toxicological effects on mammals remain poorly understood. This study investigated the toxicity effects of PP-MPs on C57BL/6 mice using 16S rRNA gene amplicon sequencing and transcriptome sequencing. Female and male mice were randomly classified into the control and PP-MPs-treated groups, respectively, and the experiment lasted for 5 weeks. We found that PP-MPs exposure did not affect the levels of immunoglobulin G (IgG), interleukin-4 (IL-4), and interferon gamma (IFN-γ), indicating that humoral immunity and inflammatory levels were not influenced by PP-MPs treatment. However, PP-MPs exposure reduced the PHA response in female mice, but not in male mice. It also did not alter the wet mass of testicles and ovaries, nor the levels of testosterone and estradiol. Exposure to PP-MPs altered the expression of the testicular genes. G protein-coupled receptor signaling pathways, olfactory receptor activity, and protein digestion and absorption were downregulated in the PP group. Collagen genes (Col9a3, Col11a2, Col27a1, Col26a1, Col7a1) play a significant role in downregulating protein digestion and absorption. In addition, PP-MPs exposure caused a change in beta diversity of gut microbiota, indicating the alteration of their community structure. PP-MPs exposure reduced the relative abundance of the probiotic Lactobacillus. Changes in the gut microbiota may be related to the expression levels of testicular genes. Overall, PP-MPs exposure altered both the community structure of the gut microbiota and the expression levels of testicular genes in mice, and collagen genes may serve as a critical factor influencing testicular function. Full article

Sustained neurohormonal stress, adverse myocardial remodeling, and inflammation are major components of heart failure (HF) progression. Alterations in circulating neurohormonal signaling are directly sensed by the β-adrenergic receptor (βAR), a system mainly responsible for chronotropic and inotropic cardiac responses. βARs are regulated by G-protein-coupled receptor (GPCR) kinase 2 (GRK2). Within this context, decades of study have unraveled mechanistic details on how GRK2 canonically imposes a “brake” on βARs and other GPCR-mediated signaling. Notably, an expanding body of evidence demonstrates that GRK2 functions in a highly compartment- and cell-dependent manner, with roles extending far beyond GPCR regulation. These noncanonical activities span metabolic control, maintenance of organelle integrity, and regulation of inter-cellular signaling networks, particularly those governing immune–vascular interactions. In this review, we will discuss recent advances in our understanding of the cell-specific functions of GRK2, its emerging biological roles in cardiac diseases, and the opportunities these findings present for advancing mechanistic insights in cardio-oncology. We propose that the therapeutic value of GRK2 is directly dependent on a deeper understanding of its noncanonical functions in a compartment- and cell-specific manner within a disease-specific context. Full article