Search Results (972)

In the contemporary AI-mediated digital landscape, digital literacy has emerged as a cornerstone competency for students and is closely associated with institutional perception. This study examines the relationship between students’ digital literacy—within the context of AI-integrated learning environments—on Higher Education Online Brand Equity (HEOBE), brand trust, brand affect, and electronic word of mouth (e-WOM). Utilizing a Structural Equation Modeling (SEM) framework, data were collected from university students in Taiwan (N = 645) between January and February 2024. Statistical validation and hypothesis testing were performed using SPSS and AMOS. The results demonstrate that digital literacy in the AI era exerts a significant positive association with HEOBE, indicating that technologically proficient students within AI-integrated educational environments perceive higher value in a university’s digital brand. Furthermore, the four dimensions of HEOBE—institutional reputation, brand identification, brand loyalty, and campus perception—were found to exhibit significant positive associations with both brand trust and brand affect. Intriguingly, the study uncovers a behavioral dichotomy in word-of-mouth intentions: while brand affect is positively associated with e-WOM, brand trust shows an unexpected negative structural association with e-WOM. This suggests that while emotional attachment spurs advocacy, high cognitive trust may lead to “passive loyalty” in AI-driven digital spaces. These findings provide critical theoretical insights and practical benchmarks for higher education institutions seeking to optimize AI-augmented brand management and student engagement strategies. Full article

Background/Objective: Prediabetes is increasingly recognized as a state of chronic, low-grade inflammation that contributes to early β-cell dysfunction, insulin resistance, and progression to type 2 diabetes (T2D). This review synthesizes mechanistic and clinical evidence to characterize the inflammatory landscape of prediabetes, evaluate the consistency of candidate biomarkers, and assess potential for clinical translation. Methods: We conducted a structured narrative review and assessed 22 studies investigating inflammatory and metabolic biomarkers for prediabetes across experimental animal models, human pancreatic islets, and clinical cohorts. Biomarkers included cytokines, oxidative stress indicators, microRNAs, and immune-cell-associated factors. Studies included cross-sectional, longitudinal, and mechanistic designs. Results: Clinical studies generally reported higher CRP and hsCRP. In several cohorts, IL-6 and other inflammatory mediators were increased in individuals with prediabetes. However, inflammatory responses were not uniform across studies. One study reported elevated IL-10 and IL-4 in addition to hsCRP, while TNF-α and IL-6 were not significantly different. Overall, CRP and hsCRP demonstrated the strongest clinical translational evidence, with findings replicated across multiple cohorts and longitudinal evidence linking higher baseline hsCRP or CRP with increased risk of progression to T2D. Other candidates, including IL-6, TNF-α, adiponectin, SFRP4, oxidative stress markers, and microRNAs, remain promising but have more limited or inconsistent evidence for clinical application. Conclusions: Prediabetes is characterized by a multifaceted inflammatory response involving innate and adaptive immune pathways, altered cytokine and microRNA profiles, oxidative stress, and adipose–pancreatic interactions. Although inflammatory biomarkers may enhance conventional metabolic measures for risk stratification, current evidence does not establish any inflammatory marker as a standalone diagnostic test for prediabetes. Full article

Systemic sclerosis (SSc) is a heterogeneous autoimmune disease characterized by immune dysregulation, vasculopathy, and progressive fibrosis affecting the skin and internal organs. Although biologic therapies have expanded the therapeutic landscape of immune-mediated diseases, their impact in SSc has been uneven and remains difficult to interpret when viewed only on a drug-by-drug basis. This focused narrative review reappraises biologic therapies in SSc using a manifestation-based framework spanning cutaneous, pulmonary, vascular, gastrointestinal, musculoskeletal, and global or composite outcomes. Published evidence is most developed for selected cutaneous and pulmonary manifestations, particularly through B-cell depletion in selected cutaneous–pulmonary phenotypes and interleukin-6 blockade that attenuates pulmonary function decline in early inflammatory disease, whereas gastrointestinal and vascular manifestations have not yet shown comparable clinical evidence of benefit and remain insufficiently studied. We argue that this asymmetry not only reflects differences in trial design and endpoint selection, but also manifestation-specific pathobiology, disease stage, and the extent to which inflammatory, vascular, and fibrotic processes remain therapeutically modifiable. In particular, vasculopathy may represent an upstream pathogenic layer that constrains the disease-modifying capacity of biologics that primarily improve downstream inflammatory or fibrotic manifestations. We also highlight the relevance of Japanese contributions to the biologics literature in SSc and discuss future priorities, including manifestation-appropriate endpoint selection, early-disease enrichment, and biomarker-informed stratification. Overall, biologics have changed the treatment of SSc in a selective rather than global manner; embracing a manifestation-based view is now essential for both trial design and day-to-day therapeutic decision-making. Full article

Patients with early-stage myocardial infarction (MI) are at high risk of malignant ventricular arrhythmias, yet the cell-type-specific molecular landscape associated with post-infarction arrhythmogenesis has not been systematically characterized. This study integrates single-nucleus and spatial transcriptomics to define a cardiomyocyte subpopulation in early MI and dissect the NEAT1-centered regulatory network driving its ion channel remodeling. Single-nucleus transcriptomic data from post-MI human hearts were re-analyzed to identify a distinct subpopulation, termed arrhythmia-potential cardiomyocytes (aCMs), within the infarct border zone, characterized by pronounced ion channel remodeling. Gene co-expression network analysis revealed two modules highly associated with aCMs, in which NEAT1 correlated with the calcium channel gene CACNA1C and the LIM domain protein PDLIM5. All three genes were upregulated in hypoxic rat cardiomyocytes; siRNA-mediated knockdown confirmed that NEAT1 silencing downregulated CACNA1C and PDLIM5 expression, consistent with in silico knockout predictions. A ceRNA network further identified hsa-miR-204-5p/211-5p as a key mediator consistent with regulatory axis. These findings suggest that cardiomyocytes in the early MI border zone exhibit ion channel remodeling driven by elevated NEAT1, which may modulate CACNA1C and PDLIM5 through a microRNA-mediated ceRNA network, suggesting that targeting NEAT1 may warrant further investigation for preventing malignant arrhythmias in early-stage MI. Full article

Although natural biopolymers represent promising sustainable packaging alternatives, their weak mechanical and barrier properties limit industrial use. While previous reviews focus on descriptive aspects of enzymatic modification, this review fills a critical literature gap by systematically bridging molecular-level laccase-driven reactions with quantitative techno-economic and safety and regulatory frameworks. We evaluate the kinetic and topological differences between direct tyrosyl-coupled protein homopolymerisation and mediator-assisted ‘graft-then-link’ polysaccharide strategies. Crucially, we analyse how entrapment versus surface-immobilised architectures dictate mass-transfer regimes, establishing their specific functional fitness for active oxygen scavenging or intelligent time-temperature monitoring. Beyond physical performance, we critically assess the translational bottlenecks currently hindering industrial scaling. For the first time, we integrate a quantitative techno-economic analysis using the Technology Readiness Level (TRL) framework, demonstrating that active film fabrication costs (EUR 0.01–0.10/m²) are heavily offset by high-protein food waste savings (>EUR 2.00/kg). Finally, we navigate European and US regulatory landscapes for enzymatically active materials and evaluate safety risks via the Threshold of Toxicological Concern (TTC) model and deterministic migration modelling. This comprehensive analysis establishes a ‘Safe-by-Design’ paradigm, guiding the scalable development of intrinsically safe, high-performance biocatalytic packaging. Full article

Artificial intelligence (AI) and machine learning (ML) are transforming the landscape of rheumatological and systemic inflammatory disease management, offering unprecedented capacity to integrate complex, multidimensional data for diagnostic support, disease monitoring, and therapeutic decision-making. This comprehensive narrative review, based on a non-systematic literature search of PubMed/MEDLINE and Google Scholar combined with the authors’ clinical expertise, provides a clinically oriented synthesis of current and emerging AI applications across the full spectrum of immune-mediated inflammatory diseases—including rheumatoid arthritis, systemic lupus erythematosus, vasculitis, inflammatory bowel disease, psoriatic arthritis, systemic sclerosis, inflammatory myopathies, and sarcoidosis—with particular attention to applications that have demonstrated or are approaching clinical utility. We discuss deep learning-based image analysis, natural language processing of electronic health records, multi-omic biomarker discovery, and the application of Fourier transform-based signal processing to biological time series as a novel approach to continuous disease monitoring. Fourier transform methods—already foundational in MRI reconstruction, cardiac electrophysiology, and clinical neurophysiology—are here systematically extended to rheumatological and inflammatory disease signals, including accelerometry, electromyography, heart rate variability, and longitudinal biomarker time series. The phenomenon of large language model hallucination—particularly critical in rare inflammatory diseases—is addressed alongside retrieval-augmented generation as a mitigation strategy. We further argue that AI-driven methods do not merely improve the interpretation of clinical data, but fundamentally expand what is observable—with profound epistemological implications for clinical knowledge transmitted through generations of medical tradition. Ethical considerations and future directions toward precision inflammatory disease medicine are outlined. Full article

Glycogen storage disease Ib (GSD Ib) is an ultra-rare metabolic disease caused by variants in the SLC37A4 gene affecting activity of the glucose-6-phosphate transporter (G6PT). G6PT mediates transport of glucose-6 phosphate from the cytoplasm into the lumen of the endoplasmic reticulum, thereby playing a key role in glucose homeostasis. To date, no approved therapies directly restore G6PT function, highlighting a major unmet need. Pharmacological chaperone (PC) therapies, including those targeting membrane transporters, are a known and clinically employed therapeutic strategy. The efficacy of PC therapy is highly dependent on the underlying pathogenic variant. While certain missense variants may respond favorably, particularly those associated with protein misfolding and residual function, null variants are generally considered unsuitable targets due to the absence of a protein that could be rescued. To the best of our knowledge, no previous review has systematically examined the global landscape of SLC37A4 variants. The aim of this review was to collect the spectrum and frequency of SLC37A4 variants reported worldwide and connect them with all available structural and functional data. In 425 GSD Ib patients, we found that approximately 10% of all variants are strong PC candidates and 14–30% are reasonable but lower-confidence candidates (other missense non-deactivating variants), while the rest are poor PC candidates (substrate-pocket variants) and null variants (nonsense, frameshift and splicing). Although functional studies are required to definitely validate PC-responsive missense variants in the SLC37A4 gene, our review suggests, for the first time, the existence of a minimal threshold at which a PC approach may become clinically relevant for GSD Ib patients. Full article

Land-use change (LUC) and salinization interact synergistically to regulate depth-dependent fractionation and biological mediation of soil organic carbon (SOC) in vulnerable agroecosystems. Unlike previous syntheses addressing these drivers separately, the present review integrates them within a depth-resolved biological framework to reveal their combined effects on fraction-specific distribution under contrasting anthropogenic and ionic regimes. In the topsoil (0–30 cm), LUC and salinity synergistically collapse fungal networks, suppress carbon use efficiency, and restructure microbial communities to accelerate particulate organic matter (POM) turnover and impair mineral-associated organic matter (MAOM) formation. In the subsoil (>30 cm), salinity-driven clay dispersion and pore occlusion restrict oxygen diffusion and carbon accessibility, while LUC-induced loss of deep-rooting vegetation reduces carbon supply to mineral-associated pools. These depth-decoupled mechanisms render subsoil MAOM relatively resilient to direct ionic stress but highly vulnerable to land-use legacy, a distinction rarely represented in existing conceptual models. The evidence highlights key management implications, including restoring biological complexity in topsoil through reduced tillage, mycorrhizal re-establishment, and osmotic stress alleviation; conserving subsoil carbon by restoring deep-rooting vegetation and maintaining favorable ionic conditions for organo-mineral stabilization; and using depth-specific biomarkers, including enzymatic stoichiometry, fungal-to-bacterial ratios to detect SOC vulnerability before measurable losses occur. Future research should prioritize depth-explicit monitoring and integrated biological–physicochemical approaches to improve predictions of SOC dynamics. The resulting framework provides a mechanistic basis for depth-differentiated carbon management in salinizing landscapes. Full article

Traditional wound therapies continue to be predominantly exogenous and address extracellular causes of the pathology without addressing the impaired function of cellular pathways that are trapped in the state of constant inflammation. The present review explores a novel putative nutriepigenetic framework, discussing how the honey matrix could act as a proposed modulator of the altered epigenetic landscape in non-healing ulcers. Honey contains a complex mixture of bioactive agents (polyphenols, flavonoids, and plant-derived xenomiRs) that are hypothesized to interact with multiple chromatin control points simultaneously. We discuss models wherein honey-induced aquaporin-mediated H₂O₂ influx and intracellular calcium transients may correlate with SIRT1/SIRT6 modulation and CRM1-mediated nuclear export of Class IIa HDACs. This review evaluates whether such multi-target signaling could foster chromatin relaxation to support gene expression required for cell migration and tissue remodeling. Full article

Background: Opioid use during pregnancy is linked to preterm birth, fetal growth restriction, and Neonatal Opioid Withdrawal Syndrome. While the placenta is the primary regulator of the uterine environment, the precise molecular mechanisms by which opioids dismantle placental function remain poorly defined. Methods: The transcriptomic landscape of opioid-exposed human placentas from a unique Hawai’i-based cohort was characterized. Results: Transcriptional signatures were defined by genes involved in translational inhibition and metabolic attenuation. Integrative network modeling predicted a prominent stress-signaling hub centered on p38 Mitogen-Activated Protein Kinase and Extracellular Signal-Related Kinase 1/2, paralleling a broad suppression of ribosomal protein transcripts (Ribosomal Protein 27S, -29, and -39). This response was further characterized by the inhibition of the Myelecytomatosis Proto-Oncogene regulatory hub, predicting a loss of mitochondrial phosphate transport through associated genes (via Solute Carrier Family 25A3) and cell-cycle progression (via S-Phase Kinase-Associated Protein 1). Additionally, the genes in this model suggested upregulation of antisense regulatory brakes, such as RAP2C Antisense RNA 1, which might further reinforce this inhibitory state. Conclusion: The findings suggest that prenatal opioid exposure is associated with the disruption of placental homeostasis. This may be coordinated by protein synthesis and bioenergetic flux, as inferred from the modeled eukaryotic Translation Initiation Factor-mediated Integrated Stress Response. These findings establish a localized, clinical baseline of human placental stress, highlighting candidate molecular regulatory nodes to guide future mechanistic studies and biomarker discovery in exposed pregnancies. Full article

The discovery of ferroptosis and cuproptosis has significantly expanded the landscape of programmed cell death. Artesunate (ART), a semisynthetic derivative of artemisinin, exhibits pleiotropic pharmacological activities beyond its canonical antimalarial role, including anticancer and neuroprotective effects. However, a comprehensive review systematically integrating ART’s roles in modulating both ferroptosis and cuproptosis remains lacking. This review bridges this gap by synthesizing recent advances. The distinct core mechanisms of ferroptosis and cuproptosis are first outlined. Extensive evidence is then summarized regarding ART-induced ferroptosis in cancers, primarily through disrupting iron homeostasis (e.g., stabilizing transferrin receptor (TFRC), promoting ferritinophagy) and impairing antioxidant defenses (e.g., suppressing the System Xc⁻/ glutathione peroxidase 4 (GPX4) axis, targeting peroxiredoxins). In contrast, the anti-cuproptotic effect of ART is currently restricted to Parkinson’s disease (PD) models, mediated by the upregulation of astrocytic metallothionein 2A (MT2A) to chelate excess copper—the only validated cuproptosis-related mechanism of ART to date. The crosstalk between ferroptosis and cuproptosis at shared metabolic nodes, including glutathione depletion, mitochondrial dysfunction, and reactive oxygen species (ROS) amplification, is further delineated as a hypothesis-generating framework. This interplay suggests a theoretical potential for ART—when combined with functional nano-materials—to synchronously engage both death pathways, though direct experimental validation of such dual-pathway synergy for ART as a single agent remains lacking. Finally, translational prospects of ART in cancer therapy, neurodegenerative diseases, and hepatic fibrosis are discussed, together with current challenges and future directions. ART acts as a context-dependent modulator: pro-ferroptotic activity is evident across multiple disease models, whereas anti-cuproptotic activity is currently limited to PD and requires further validation. Systematic characterization of ART’s context-specific effects suggests a preclinical rationale for the future design of ART-based combination strategies targeting metal-dependent cell death, pending further validation. Full article

Bispecific antibodies (bsAbs) and bispecific antibody–drug conjugates (bsADCs) represent promising classes of emerging targeted therapeutics with the potential to overcome tumor heterogeneity and resistance in colorectal cancer (CRC). BsAbs can simultaneously engage multiple tumor antigens or immune cells or bind two distinct epitopes within a single target, enabling mechanisms of action beyond the capabilities of monoclonal antibodies. Bispecific T cell engagers facilitate targeted destruction of tumors through immune cell recruitment, while dual immune checkpoint inhibitors enhance immune activation by blocking T cell inhibitory signals. Furthermore, bsAbs can mediate dual signaling pathway inhibition through binding multiple receptor tyrosine kinase receptors or other tumor cell surface proteins. BsADCs integrate the dual-antigen recognition of bsAbs with targeted payload delivery, utilizing receptor-mediated endocytosis to deliver potent cytotoxic payloads selectively to CRC cells, while minimizing systemic toxicity. Recent advances in bsAb engineering, linker chemistry, site-specific conjugation, and payload design have accelerated the development of bsADCs for solid tumors, including CRC. BsAbs and bsADCs provide opportunities to improve tumor selectivity, enhance internalization, overcome antigen escape, and expand the population of CRC patients eligible for targeted therapy. Emerging preclinical studies demonstrate encouraging anti-tumor activity for bispecific modalities in CRC, while early clinical trials are beginning to establish their translational potential. This review summarizes the current landscape of bsAbs and bsADCs in therapeutic development for CRC, highlighting key biological targets, engineering strategies, mechanisms of action, and clinical status. We also discuss the major challenges facing clinical translation and provide perspectives on future directions for bispecific therapies in CRC. Full article

(1) Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with gut microbiota dysbiosis and metabolic perturbations. Although Liubao tea (LBT) has gastroprotective benefits, the precise mechanisms by which LBT extract (LBTE) alleviates UC by orchestrating microbial and metabolic homeostasis remain poorly understood. (2) Methods: A DSS-induced UC mouse model was used to evaluate LBTE efficacy. Serum pharmacochemistry, untargeted metabolomics, 16S rRNA sequencing, and targeted SCFA metabolomics were integrated to characterize absorbable active constituents, metabolic shifts, and gut microbiota landscapes. SCFA- and arachidonic acid metabolism-related targets were validated by RT-qPCR and Western blotting. PGF models and FMT were used to assess the causal role of gut microbiota in LBTE-mediated efficacy. (3) Results: LBTE preserved colon length and mucosal integrity while reducing IL-6, TNF-α, IL-1β, and oxidative stress. It enriched SCFA-producing genera and increased colonic butyric and valeric acids, activating GPR41/GPR109A signaling, upregulating ZO-1 and occludin, and strengthening the intestinal barrier. LBTE also downregulated PTGS2 and ALOX5, restored PTGS1 and CYP3A11, and inhibited NF-κB signaling. These effects were weakened in PGF mice but reproduced by FMT from LBTE-treated donors, confirming microbiota-dependent protection. (4) Conclusions: LBTE may serve as a complementary strategy for UC prevention and management. Full article

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) increasingly combines high-risk clonal expansion, mobile resistance platforms and limited treatment options. We investigated the genomic epidemiology, resistance and virulence architecture, plasmid backbones, and therapeutic vulnerabilities of CRKP circulating in Oman. Methods: Between 2021 and 2024, 135 non-duplicate CRKP isolates were recovered from diverse clinical specimens. New antimicrobial agents were evaluated phenotypically, while 38 representative extensively drug-resistant (XDR)/pan-drug resistant (PDR) isolates underwent whole-genome sequencing (WGS) for multilocus sequence typing (MLST), capsular typing, resistome, virulome, plasmid and mobile genetic elements (MGEs) analysis. In vitro synergy of ceftazidime–avibactam/aztreonam, meropenem/fosfomycin and amikacin/fosfomycin was assessed using gradient diffusion-based FICI. Results: WGS revealed a striking shift towards OXA-232-producing ST-2096, which dominated the sequenced collection and carried KL64 with a conserved multidrug-resistant backbone. NDM-5/ST147 and NDM-1 + KPC-2/ST11 formed distinct high-risk lineages with broader extended-spectrum β-lactamase (ESBL) repertoires, greater plasmid heterogeneity and, in co-producers, the highest MGE burden. Across isolates, resistance was reinforced by widespread blaCTX-M variants, armA, aac(6′)-Ib-cr, fosA, porin alterations and fluoroquinolone-resistance mutations, while core virulence and fitness loci including fimH, mrkA, iutA, fyuA and irp2 were widely retained. Cefiderocol showed the most consistent in vitro activity across carbapenemase groups, and eravacycline remained active, whereas plazomicin and fosfomycin activity was compromised by methyltransferase and fos genes. Ceftazidime–avibactam/aztreonam demonstrated universal synergy, while meropenem/fosfomycin and amikacin/fosfomycin showed limited, carbapenemase-dependent activity. Conclusions: CRKP in Oman is characterised by convergent clonal expansion, plasmid-mediated resistance, retained virulence potential and narrowing therapeutic options. Integrated genomic surveillance with carbapenemase-directed susceptibility and synergy testing is essential to guide precision antimicrobial stewardship in high-risk healthcare settings and inform early infection prevention responses to emerging regional CRKP lineages. Full article

Despite major advances in lipid-lowering therapies, a significant unmet need remains, particularly for patients with homozygous familial hypercholesterolemia (HoFH), severe heterozygous familial hypercholesterolemia (HeFH), and those who fail to achieve guideline-recommended LDL-C targets. Nucleic acid-based therapeutics have emerged as a transformative approach for treating hypercholesterolemia. Antisense oligonucleotides and small interfering RNAs (siRNAs) have demonstrated durable hepatic gene silencing and have led to approved therapies, while gene replacement and in vivo genome-editing strategies offer the potential for long-lasting, and possibly one-time, interventions. In parallel, microRNAs (miRNAs) have attracted increasing interest because of their ability to coordinately regulate multiple genes involved in lipoprotein metabolism, cholesterol transport, and lipid homeostasis. Human genetic studies further support the importance of miRNA-mediated regulation, exemplified by a rare ~2.5 kb deletion in the distal LDLR 3′UTR (“del2.5”) that disrupts miRNA-binding sites and is associated with lifelong low LDL-C levels. This review summarizes recent advances, mechanisms of action, clinical progress, and remaining challenges across antisense oligonucleotides, siRNAs, gene therapy, genome editing, and emerging miRNA-based therapeutics for hypercholesterolemia. As an example of the latter approach, the liver-directed miR-30c analog C2 has demonstrated preclinical activity by coordinately reducing hepatic lipoprotein secretion and lipogenesis while enhancing cholesterol elimination, resulting in reduced LDL-C and atherosclerosis. However, it must be noted that these findings remain preclinical, and further optimization of delivery, pharmacokinetics, safety, and long-term efficacy will be required before clinical evaluation. Continued advances in RNA chemistry, targeted delivery, and genome engineering are expected to further expand the therapeutic landscape for dyslipidemia and cardiovascular disease. Full article