National University College

Pathological platelet activation is central to cardiovascular disorders. Glycoprotein VI (GPVI), a pivotal collagen receptor, is a promising antithrombotic target. While earlier studies focused on the downstream effects of peroxisome proliferator-activated receptor γ (PPARγ) ligands, we recently identified the proximal PPARγ-Src family kinase (SFK) interaction as a key regulatory node. KR-62980 is a novel non-thiazolidinedione (non-TZD) PPARγ modulator designed to minimize traditional TZD-associated adverse effects. Here, we investigated whether KR-62980 operates through this "proximal mechanism." We found that KR-62980 dose-dependently inhibited collagen-induced human platelet aggregation in both washed platelets and platelet-rich plasma. Notably, KR-62980 exhibited a predominant sensitivity toward the collagen-GPVI axis compared to thrombin-induced protease-activated receptor signaling. Mechanistically, KR-62980 targeted the top of the GPVI signaling hierarchy by disrupting the physical and functional association between PPARγ and SFKs (Lyn and Fyn). This blockade suppressed SFK autophosphorylation and dismantled the LAT signalosome, preventing the recruitment of Gads, SLP-76, Btk, and PLCγ2. These findings confirm that the "proximal interaction" paradigm is a universal feature of PPARγ-mediated antiplatelet action, regardless of the agonist's chemical structure. In vivo, oral administration of KR-62980 significantly prolonged thrombotic occlusion time in a mouse carotid artery thrombosis model. Importantly, at therapeutic doses, KR-62980 did not significantly affect tail bleeding time, demonstrating a favorable safety profile with a wide therapeutic window. These findings confirm that the "proximal interaction" paradigm is a universal feature of PPARγ-mediated antiplatelet action and suggest that KR-62980 is a promising candidate for safe antithrombotic therapy.

RNA interference (RNAi) is a major antiviral defense in fungi, yet the regulatory mechanisms governing this pathway remain incompletely characterized. In this study, we identified GzC2H056 as a host factor required for the induction of FgDICER-2 and FgAGO-1 in Fusarium graminearum during infection by the Fusarium graminearum virus 2 (FgV2). GzC2H056 expression is transcriptionally induced upon FgV2 infection and exhibits both RNA-binding and E3 ubiquitin ligase activity in vitro. Fluorescence tagging showed that GzC2H056 co-localizes with poly(A)-binding protein 1 and 5'-to-3' exoribonuclease 1, which are markers of stress granules and P-bodies, respectively. RNA-sequencing analysis further revealed that GzC2H056 regulates the expression of genes involved in RNA metabolism and transcription factors linked to RNAi induction. Together, these findings identify GzC2H056 as a regulator of antiviral RNAi in fungi, suggesting that RNA granule-associated mechanisms contribute to fungal defense against mycoviruses.

Abstract Recent observations from the James Webb Space Telescope have revealed unexpectedly luminous galaxies, exhibiting stellar masses and luminosities significantly higher than predicted by theoretical models at Cosmic Dawn. In this study, we present a suite of cosmological zoomed-in simulations targeting high-redshift ( z ≥ 10) galaxies with dark matter halo masses in the range 10 10 –10 11 M ⊙ at z = 10, using state-of-the-art galaxy formation simulation codes ( Enzo , Ramses , Changa , Gadget-3 , Gadget-4 , and Gizmo ). This study aims to evaluate the convergence of the participating codes and their reproducibility of high-redshift galaxies with the galaxy formation model calibrated at relatively low redshift, without additional physics for high-redshift environments. The subgrid physics follows the AGORA CosmoRun framework, with adjustments to resolution and initial conditions to emulate similar physical environments in the early Universe. The participating codes show consistent results for key galaxy properties (e.g., stellar mass), but also reveal notable differences (e.g., metallicity), indicating that galaxy properties at high redshifts are highly sensitive to the feedback implementation of the simulation. Massive halos ( M halo ≥5 × 10 10 M ⊙ at z = 10) succeed in reproducing observed stellar masses, metallicities, and UV luminosities at 10 ≤ z ≤ 12 without requiring additional subgrid physics, but tend to underpredict those properties at higher redshift. We also find that varying the dust-to-metal ratio modestly affects UV luminosity of simulated galaxies, whereas the absence of dust significantly enhances it. In future work, higher-resolution simulations will be conducted to better understand the formation and evolution of galaxies at Cosmic Dawn.

Radotinib is a second-generation tyrosine kinase inhibitor that selectively targets BCR-ABL1 and is used for the treatment of chronic myeloid leukemia (CML). This study aimed to evaluate the clinical pharmacokinetic characteristics and the food effect of radotinib. Healthy volunteers received a single oral dose of radotinib 400mg under fasted or fed conditions in a crossover manner, and CML patients received repeated oral doses of 300mg twice daily. The pharmacokinetic characteristics were evaluated by a noncompartmental method, using plasma concentration-time data following a single administration in healthy volunteers, and on Days 1 and 14 in CML patients. The food effect was assessed by comparing the pharmacokinetic parameters under fed and fasted conditions in healthy volunteers. The pharmacokinetic analyses of radotinib included data from 23 healthy male volunteers and 24 patients newly diagnosed with CML. In both populations, the plasma concentrations of radotinib peaked at approximately 3h. In healthy volunteers, the concentrations declined biexponentially with the terminal half-life (t1/2) of 17.5h under fasted conditions. In CML patients, radotinib was substantially accumulated with the accumulation ratio of 3.59 on Day 14. The effective t1/2 derived from the accumulation ratio was 25.5h. The systemic exposure to radotinib increased by 3.49-fold when administered after food intake, with time to maximum concentration delayed by 3h. The results of the study provide essential pharmacokinetic information for the clinical use of radotinib in the treatment of CML patients. ClinicalTrials.gov, Identifier NCT06461078, NCT03722420.

The presence of uninformative frames in colonoscopy videos is a major factor that reduces the accuracy and efficiency of various video analysis applications. To address this issue, research on informative frame classification has been conducted, but the lack of a publicly available dataset has made reproducibility difficult. In this study, we propose a novel dataset, InfoColon, which integrates video data collected from multiple medical institutions with major public colonoscopy datasets. All colonoscopy frames were labeled as either an informative frame or one of six types of uninformative frames. We also propose an active learning method to efficiently label large amounts of data with a small initial labeled dataset. Using the constructed InfoColon, we demonstrate the potential for its application in consecutive informative frame classification and 3D reconstruction. We expect that the proposed InfoColon will be valuable for various applications involving colonoscopy video analysis.

Sulfatases are critical enzymes regulating the dynamic sulfation states of biomolecules and have profound implications in human physiology and pathology. Abnormal sulfatase activity is strongly connected to various diseases such as hormone-dependent cancers, infectious diseases like tuberculosis, lysosomal storage disorders, and bacterial virulence, making these enzymes emerge as crucial biomarkers and therapeutic targets. This review highlights the advances in small-molecule probes for selectively detecting sulfatase activity through various imaging modalities, such as fluorescence, photoacoustic, in-gel fluorogenic assays, and bioluminescence imaging. Additionally, the enzyme-activatable probes that exploit mechanisms via self-immolative linkers, intramolecular charge transfer (ICT), photoinduced electron transfer (PET), ratiometric sensing, followed by aggregation-induced emission (AIE), to achieve high specificity and sensitivity. Along similar lines, we explored substrate-based and affinity-based designs, covering turn-on, ratiometric, and dual-modal near-infrared fluorescence, chemiluminescence, and photoacoustic (NIRF/PA) probes that enable real-time, noninvasive, and deep-tissue imaging. A special focus is given to activity-based sensing of steroid sulfatases (STS) in hormone-related cancers and on profiling bacterial sulfatases for rapid mycobacterial strain differentiation. Furthermore, emerging strategies using nanoprobes and AIEgens demonstrate potential for image-guided surgery, inhalable diagnostics, and high-throughput screening of enzyme inhibitors. Together, these innovations establish a strong framework for sulfatase activity profiling and offer powerful capabilities for disease diagnostics, inhibitor screening, and therapeutic monitoring by enabling spatiotemporal visualization of sulfatase activity both in vitro and in vivo. This review may inspire the development of novel activatable sensors suited for practical biomedical applications by consolidating recent advances in sulfatase-targeted probe design and imaging strategies.

Lawsonia intracellularis, the etiological agent for proliferative enteropathy, remains a major cause of productivity loss and economic burden in the global swine industry. Currently available vaccines provide suboptimal protection and raise safety concerns, highlighting the need for improved immunization strategies. In this study, we developed Salmonella Typhimurium-based vaccine candidates against L. intracellularis in a murine model, incorporating immunoprotective epitopes from the surface autotransporter protein LatA, the flagellar protein FliC, and the heat shock protein 60 (HSP60). These antigens were expressed using dual bacterial-host plasmids, pJHL270 and pJHL305, containing prokaryotic (Ptrc) and eukaryotic (CMV) promoters to ensure both extracellular and intracellular antigen presentation. The attenuated Salmonella delivery strain JOL3086 (Δlon ΔpagL) exhibited a high safety profile with markedly reduced endotoxicity. Western blot analysis confirmed antigen expression in both bacterial and mammalian systems in vitro. Immunization with the recombinant Salmonella strains elicited significant humoral (systemic IgG and mucosal IgA) and cell-mediated (CD4+, CD8+ T cells) immune responses, accompanied by significantly increased levels of Ifng, Il6, Il4, and Il10 cytokines. Among the three vaccine strains, JOL3149 (pJHL305 expressing FliC-HSP60) induced the most pronounced immunological responses and conferred superior protection in C57BL/6 mice challenged with L. intracellularis, as evidenced by decreased fecal bacterial shedding, reduced intestinal bacterial load, and alleviated intestinal lesions postchallenge. Collectively, these findings demonstrate the potential of the Salmonella-mediated dual expression platform as a safe and effective delivery system forL. intracellularisantigens, offering a promising foundation for next-generation vaccines against L. intracellularis.

With the rapid advancements in genome sequencing technologies, microbial genome data has exponentially increased, making it essential to continuously update dataset for accurate microbial identification and classification. We present the development of Microbial Identification using rRNA Operon Region (MIrROR) release 02, an expanded dataset based on 1,690,470 genomes (1,674,514 bacterial and 15,956 archaeal) sourced from NCBI. The final curated dataset covers 476,579 sequences, 249,907 genomes, and 29,051 species, representing increases of 387.39%, 472.49%, and 206.28% over the previous release. Key updates include the addition of archaeal genomes and taxonomy reclassification based on GTDB R220. Extensive curation was performed, including filtering operon lengths (3,500-7,000 bp), removing duplicate sequences, eliminating sequences with ambiguous nucleotides, and clustering of sequences at 99% identity to remove redundancies. The updated dataset showed improved performance in microbial mock community analyses, supporting its accuracy and reliability. These improvements make MIrROR release 02 a valuable resource for microbial profiling and various microbiological research applications.

Spontaneous intracranial hypotension (SIH) is an underrecognized condition with rapidly evolving diagnostic and therapeutic strategies. This study investigated temporal and regional trends in diagnostic and therapeutic modalities for SIH in the published literature. We systematically reviewed SIH-related clinical studies in PubMed from inception through December 2024. Data on study site (continent/country/institute) and diagnostic and treatment modalities used in clinical settings were extracted. To assess temporal and regional trends, the reported use of each modality was analyzed over 5-year intervals and across regions, separately for case reports and original articles, which respectively reflect real-world and research settings. A total of 789 articles (529 case reports and 260 original articles) were included. In case reports, brain MRI (84.4%), lumbar puncture (84.4%), and RI cisternography (50%) were the most frequently used diagnostics in 1990–1999, while brain MRI (91.1%) and spine MRI (74.8%) became predominant in 2020–2024. The use of lumbar puncture and RI cisternography declined to 24.4% and 5.9%, respectively, while dynamic CT myelography (18.5%) and digital subtraction myelography (23.7%) became more common in 2020–2024. Conservative management (81.3%) was the most common treatment in 1990–1999, while surgical repair increased to 39.8% in 2020–2024. Similar trends were observed in original articles. These temporal trends were similar across regions; however, in 2020–2024, dynamic CT myelography, DSM, and surgical repair were reported more frequently in publications from North America and Europe than in those from Asia (dynamic CT myelography: 35.4% and 22.0% vs. 4.7%; DSM: 40.8% and 33.0% vs. 6.7%; surgical repair: 59.3% and 42.5% vs. 13.6%). Diagnostic and therapeutic modalities for SIH have markedly shifted over time, reflecting the actual changes both in real-world practice and academic settings. Standardized diagnostic and treatment guidelines and broader global awareness of evolving practice are warranted.