Augmented Activity Research Articles

Viridicatol from the Deep‐Sea‐Derived Fungus Alleviates Bone Loss by Targeting the Wnt/SHN3 Pathway

AbstractAs an enticing bone anabolic target, short‐term inhibition of Schnurri‐3 (SHN3) resulted in high‐bone mass due to augmented osteoblast activity. However, no studies are conducted to identify natural products targeting SHN3 inhibition. Herein, a screening strategy for the discovery of marine compounds that facilitate osteoblast differentiation by targeting SHN3 silencing is presented. One leading quinolinone alkaloid, viridicatol (VDC), isolated from deep‐sea‐derived fungus, vigorously promotes osteogenic differentiation via the Wnt/SHN3 signaling pathway in osteoblasts, thereby preventing osteoporosis while enhancing bone‐fracture healing in a mouse model. Subsequently, the SDSSD (Ser, Asp, Ser, Ser, Asp) is further employed to engineer bone‐targeting nanovesicles (BT‐NVs) for the optimal delivery of VDC to osteoblasts, which mitigates the bone loss observed in a severe osteogenesis imperfecta model. Hence, these results initially uncover a promising marine natural product, VDC, targeting the Wnt/SHN3 pathway for the treatment of bone loss and highlighting its translational potential in clinical applications.

Green synthesis of Ag/V2O5 and Ag/V2O5-curdlan nanocomposites from Sargassum latifolium extract for enhanced antimicrobial and antioxidant activities.

Green synthesis of Ag/V2O5 and Ag/V2O5-curdlan nanocomposites from Sargassum latifolium extract for enhanced antimicrobial and antioxidant activities.

Chronic exposure to bisphenol S is associated with antagonistic neurobehavioral transformation and cleaved caspase 3 induced neurodegeneration in zebrafish brain.

Chronic exposure to bisphenol S is associated with antagonistic neurobehavioral transformation and cleaved caspase 3 induced neurodegeneration in zebrafish brain.

실과교과 에듀테크 활용을 위한 체제적 교수 설계 모형(TUEPA_ADDIE) 개발

This study explores the utilization of EduTech in the Practical Arts subject and develops a systematic instructional design model for its effective integration. Building on prior research from various institutions, EduTech was classified into four major categories-learning content, communication, creation, and management-further divided into 12 subcategories. Six EduTech utilization strategies for Practical Arts were proposed. An analysis of the 2022 revised Practical Arts curriculum, using Bloom’s Digital Taxonomy, was conducted to identify digital augmentation activities related to the curriculum’s action verbs. Building upon this, the study categorized the types of using EduTech applicable to Practical Arts education (TUEPA) into 11 types: content creation, digital learning, generative AI utilization, data analysis, experiential support, communication and collaboration, Practical Arts (cross-disciplinary) content utilization, thought expression, resource exploration, learning management, and more. To enhance the applicability of TUEPA in the field, the study developed a systematic instructional design model for integrating EduTech in Practical Arts education (TUEPA_ADDIE), by incorporating TUEPA into the five stages of the ADDIE model. This model can be applied linearly or through a cyclical and iterative process. Finally, the study validated the practical applicability of the TUEPA_ADDIE model through concrete examples of its application to teaching and learning in Practical Arts education.

Crosstalk-Assisted Augmented Activity of Polyphenolic Molecules: A Study Using Fluorescence Lifetime Imaging Microscopy.

Self-assembly of small molecules has always been an attractive topic of research in the field of physical chemistry. Fluorescence lifetime imaging microscopy (FLIM) expands our understanding by offering a molecular-level perspective to gain deeper knowledge about the microenvironments. In this work, we have unveiled the self-aggregation mechanism of two naturally occurring polyphenolic molecules named gallic acid (GA) and its derivative methyl gallate (MG), resulting in ineffectiveness as a drug molecule. GA prefers rod-like morphology, in contrast to MG, which shows a cotton-like structure. However, when both are present in an equimolar ratio, the cross-assembly manifests a fibrillar structure that loses its initial individualities. Using FLIM, we have unveiled the mechanism of structural transition and morphological information on the aggregated assemblies. Although the parental polyphenols construct significantly rigid morphologies, the cross-assembly manifests improper packing due to mismatch in their backbone, as evident from lifetime information using FLIM. Furthermore, under physiological conditions, the cross-assembly disintegrates; however, the parental molecules prevail their architectures. The co-polyphenols show prominent dose-dependent cytotoxicity and mitigate the progression of cancer cells compared to the individual polyphenols, opening up a convenient way to enhance a drug's efficacy.

Augmented glycolytic activity in circulating T cells of systemic sclerosis

Augmented glycolytic activity in circulating T cells of systemic sclerosis

Muscarinic acetylcholine type 1 receptor antagonism activates TRPM3 to augment mitochondrial function and drive axonal repair in adult sensory neurons.

Muscarinic acetylcholine type 1 receptor antagonism activates TRPM3 to augment mitochondrial function and drive axonal repair in adult sensory neurons.

Directed Evolution of Silicatein Reveals Biomineralization Synergism between Protein Sequences.

Biomineralization is a green synthesis route for a variety of metal nanoparticles. Silicatein is a biomineralization protein originally found in marine sponge Tethya aurantia that converts inorganic precursors to metal oxide nanoparticles. In this work, we investigate the popular catalytic triad hypothesis and implement directed evolution with the aim to improve the solubility and kinetics of silicatein to enable increased nanoparticle synthesis. Site-directed mutagenesis with catalytic triad residues did not abolish biomineralization activity, aligning with the results seen in one previous study. Recombinant production of silicatein and mutants in Escherichia coli following library generation and a survival screen yielded several mutant proteins with augmented biomineralization activity. Sequence analysis of these mutant proteins reveals multiple sequences within a single cell that contribute to enhanced biomineralization. Combined with the sequence analysis of silicateins from different marine sponges, these results suggest the protein is permissive to wide sequence variations and that multiple protein sequences act synergistically for enhanced biomineralization.

Bimetallic doped carbon dot nanozymes for enhanced sonodynamic and nanocatalytic therapy.

Conventional inorganic semiconductors are not suitable for acting as nanozymes or sonosensitizers for in vivo therapeutic nanomedicine owing to the lack of excellent biocompatibility. Biocompatible carbon dots (CDs) exhibit a variety of biological activities due to their adjustable size and surface chemical modification; however, the simultaneous sonodynamic activity and multiple enzyme-mimicking catalytic activity of a single CD have not been reported. Herein, we report the development of bimetallic doped CDs as a high-efficiency nanozyme and sonosensitizer for enhanced sonodynamic therapy (SDT) and nanocatalytic therapy (NCT). By selecting metal-organic complexes like EDTA-FeNa as the carbon source, we ensure that the coordination environments of metal atoms are preserved throughout the low-temperature calcination process. Compared with the single metal doped CDs including Fe-CDs or Ni-CDs, the obtained Fe and Ni co-doped CDs (Fe-Ni-CDs) not only exhibit enhanced sonodynamic activity owing to the decreased bandgap, but also possess augmented dual enzyme-mimicking catalytic activities due to the synergistic effect of bimetallic ions. The Fe-Ni-CD-mediated cascade amplification of ROS generation could lead to the production of 1O2 and O2˙- through SDT, the generation of ˙OH through POD-mimicking catalytic activity, and the provision of more O2 for SDT through CAT-mimicking catalytic activity. Through the integrated multifunctionality of Fe-Ni-CDs, we successfully enhanced the effectiveness of antitumor treatment with a single drug injection and a single US irradiation for enhanced SDT and NCT. This work provides a distinct paradigm of endowing CDs with sonodynamic and multiple enzyme-mimicking catalytic activities for enhanced SDT and NCT through bimetallic ion doping.

Phenethyl isothiocyanate ameliorates liver injuries secondary to inflammatory bowel disease.

Inflammatory bowel disease (IBD) is often accompanied by secondary liver injury which further evolves into various hepatobiliary disorders. The pathogenesis of secondary liver injury involves many different mechanisms including inflammation, pyroptosis, oxidative stress, and heat shock response. Here, we tested the effect of administration of phenethyl isothiocyanate (PEITC) on secondary liver injury in DSS-induced IBD mice. PEITC supplementation reversed liver injury as determined by hepatic injury-related parameters and histopathological examinations. Severe hepatic inflammation with IBD, evidenced by ubiquitously distributed activated macrophages, increased secretion of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), enhanced expression of inflammation-related proteins (iNOS and COX-2), and augmented activation of the TLR4/NF-κB signaling pathway, was inhibited by PEITC treatment. PEITC also prevented IBD-induced increases in pyroptosis and oxidative stress in the liver. In addition, impairments of hepatic heat shock response elicited by IBD were restored by PEITC treatment. Taken together, these results suggested that PEITC may be effective as a therapeutic reagent to attenuate secondary liver injury caused by IBD.

Reversal of Endothelial Cell Anergy by T Cell-Engaging Bispecific Antibodies.

Objectives: Reduced expression of adhesion molecules in tumor vasculature can limit infiltration of effector T cells. To improve T cell adhesion to tumor endothelial cell (EC) antigens and enhance transendothelial migration, we developed bispecific, T-cell engaging antibodies (bsAb) that activate T cells after cross-linking with EC cell surface antigens. Methods: Recombinant T-cell stimulatory anti-VEGFR2-anti-CD3 and costimulatory anti-TIE2-anti-CD28 or anti-PD-L1-anti-CD28 bsAb were engineered and expressed. Primary lines of human umbilical vein endothelial cells (HUVEC) that constitutively express VEGFR2 and TIE2 growth factor receptors and PD-L1, but very low levels of adhesion molecules, served as models for anergic tumor EC. Results: In cocultures with HUVEC, anti-VEGFR2-anti-CD3 bsAb increased T cell binding and elicited rapid T cell activation. The release of proinflammatory cytokines TNF-α, IFN-γ, and IL-6 was greatly augmented by the addition of anti-TIE2-anti-CD28 or anti-PD-L1-anti-CD28 costimulatory bsAb. Concomitantly, T cell-released cytokines upregulated E-selectin, ICAM1, and VCAM1 adhesion molecules on HUVEC. HUVEC cultured in breast cancer cell-conditioned medium to mimic the influence of tumor-secreted factors were similarly activated by T cell-engaging bsAb. Migration of T cells in transwell assays was significantly increased by anti-VEGFR2-anti-CD3 bsAb. The combination with costimulatory anti-TIE2-anti-CD28 bsAb augmented activation and proliferation of migrated T cells and their cytotoxic capacity against spheroids of the MCF-7 breast cancer cell line seeded in the lower transwell chamber. Conclusions: T cells activated by anti-VEGFR2-anti-CD3 and costimulatory EC-targeting bsAb can reverse the energy of quiescent EC in vitro, resulting in improved T cell migration through an EC layer.

FAK activity exacerbates disturbed flow-mediated atherosclerosis via VEGFR2-Cbl-NF-κB signaling.

Atherosclerosis develops at predictable sites in the vasculature where branch points and curvatures create non-laminar disturbed flow. This disturbed flow causes vascular inflammation by increased endothelial cell (EC) barrier permeability and the expression of inflammatory genes such as vascular cell adhesion molecule-1 (VCAM-1). Vascular endothelial growth factor receptor 2 (VEGFR2) is important for flow-induced EC inflammation; however, there are still some gaps in the signaling pathway. Focal adhesion kinase (FAK) is a protein tyrosine kinase whose expression has been implicated in flow-mediated signaling in ECs. However, the link between FAK and VEGFR2 in flow-mediated inflammation signaling has remained unelucidated. Here we found that priming of VEGFR2 with VEGF was critical for flow-mediated activation of FAK and NF-κB. Mechanistically, FAK activation triggers tyrosine phosphorylation of Casitas B-lineage lymphoma (CBL; an E3 ubiquitin ligase) that interacts with VEGFR2 under flow conditions. Further, Apoe-/- mice fed a western diet (WD) exhibited increased FAK activity within the atheroprone disturbed flow region of the inner aortic arch compared to the outer arch. Disturbed flow-induced FAK activation is associated with elevated VEGFR2 on the surface of ECs of the inner aortic arch, but not in the outer arch. Taken together, these data suggest that suppression of augmented FAK activity under disturbed flow may prove beneficial in reducing pro-inflammatory signaling of the endothelial layer.

Tumor-Associated Microglia Secrete Extracellular ATP to Support Glioblastoma Progression

Abstract Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis and high recurrence rates. The complex immune microenvironment of GBM is highly infiltrated by tumor-associated microglia and macrophages (TAM). TAMs are known to be heterogeneous in their functional and metabolic states and can transmit either protumoral or antitumoral signals to glioma cells. Here, we performed bulk RNA sequencing and single-cell RNA sequencing on samples from patients with GBM, which revealed increased ATP synthase expression and oxidative phosphorylation activity in TAMs located in the tumor core relative to the tumor periphery. Both in vitro and in vivo models displayed similar trends of augmented TAM mitochondrial activity, along with elevated mitochondrial fission, glucose uptake, mitochondrial membrane potential, and extracellular ATP (eATP) production by TAMs in the presence of GBM cells. Tumor-secreted factors, including GM-CSF, induced the increase in TAM eATP production. Elevated eATP in the GBM microenvironment promoted glioma growth and invasion by activating the P2X purinoceptor 7 (P2X7R) on glioma cells. Inhibition of the eATP–P2X7R axis attenuated tumor cell viability in vitro and reduced tumor size and prolonged survival in glioma-bearing mouse models. Overall, this study revealed elevated TAM-derived eATP in GBM and provided the basis for targeting the eATP–P2X7R signaling axis as a therapeutic strategy in GBM. Significance: Glioblastoma-mediated metabolic reprogramming in tumor-associated microglia increases ATP secretion that supports cancer cell proliferation and invasion by activating P2X7R, which can be inhibited to attenuate tumor growth.

Copper@MXene quantum dots-aerogel: High-performance peroxidase mimic for direct pirimiphos-methyl pesticide detection

Copper@MXene quantum dots-aerogel: High-performance peroxidase mimic for direct pirimiphos-methyl pesticide detection

Inquiry-based Augmented Reality Activities for Enhancing Reading Comprehension and Engagement of EFL Secondary School Students

Inquiry-based Augmented Reality Activities for Enhancing Reading Comprehension and Engagement of EFL Secondary School Students

Ciliopathy interacts with neonatal anesthesia to cause non-apoptotic caspase-mediated motor deficits.

Increasing evidence suggests that anesthesia may induce developmental neurotoxicity, yet the influence of genetic predispositions associated with congenital anomalies on this toxicity remains largely unknown. Children with congenital heart disease often exhibit mutations in cilia-related genes and ciliary dysfunction, requiring sedation for their catheter or surgical interventions during the neonatal period. Here we demonstrate that briefly exposing ciliopathic neonatal mice to ketamine causes motor skill impairments, which are associated with a baseline deficit in neocortical layer V neuron apical spine density and their altered dynamics during motor learning.. These neuromorphological changes were linked to augmented non-apoptotic neuronal caspase activation. Neonatal caspase suppression rescued the spine density and motor deficits, confirming the requirement for sublethal caspase signaling in appropriate spine formation and motor learning. Our findings suggest that ciliopathy interacts with ketamine to induce motor impairments, which is reversible through caspase inhibition. Furthermore, they underscore the potential for ketamine- induced sublethal caspase responses in shaping neurodevelopmental outcomes.

Protocatechuic acid relieves ferroptosis in hepatic lipotoxicity and steatosis via regulating NRF2 signaling pathway

Ferroptosis represents a newly programmed cell death, and the process is usually accompanied with iron-dependent lipid peroxidation. Importantly, ferroptosis is implicated in a myriad of diseases. Recent literature suggests a potential position of ferroptosis in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD), the most widespread liver ailment worldwide. Intriguingly, several functional genes and metabolic pathways central to ferroptosis are regulated by nuclear factor erythroid-derived 2-like 2 (NRF2). In current work, we aim to identify protocatechuic acid (PCA), a primary metabolite of antioxidant polyphenols, as a potent NRF2 activator and ferroptosis inhibitor in the hepatic lipotoxicity and steatosis models. Herein, both NRF2+/+ and NRF2−/− cell lines and mice were used to analyze the importance of NRF2 in PCA function, and hepatic lipotoxicity and steatosis models were induced by palmitic acid and high-fat diet respectively. Our results indicated that ferroptosis was mitigated by PCA intervention in hepatic cells. Furthermore, PCA exhibited therapeutic efficacy against ferroptosis, as well as hepatic lipotoxicity and steatosis. The protective role of PCA was predominantly mediated through NRF2 activation, potentially elucidating a pivotal mechanism underlying PCA's therapeutic impact on MAFLD. Additionally, the augmented mitochondrial TCA cycle activity observed in hepatic lipotoxicity and steatosis models was ameliorated by PCA, in part via NRF2-dependent pathways, further bolstering PCA's anti-ferroptosis properties. Collectively, our findings underscore PCA’s potential in alleviating hepatic ferroptosis, lipotoxicity and steatosis via inducing activation of NRF2 signaling pathway, offering a promising strategy for the therapy of MAFLD as well as related lipid metabolic disorders.

Cu-S-Mo interfacial sites in CuO2@MoS2/PLLA scaffolds for robust synergistic antibacterial efficacy via CDT and PTT

Cu-S-Mo interfacial sites in CuO2@MoS2/PLLA scaffolds for robust synergistic antibacterial efficacy via CDT and PTT

CTNI-46. WINDOW-OF-OPPORTUNITY TRIAL OF ULIXERTINIB FOR MAPK-ACTIVATED LOWER GRADE GLIOMAS IN ADULTS

Abstract Overexpression of MAPK (Ras-Raf-MEK-ERK) signaling is well known in NF1-associated tumors. MEK inhibition has shown promising results in pediatrics NF1-associated tumors. In addition, we have observed augmented MAPK signaling and anti-tumor activity with MAPK inhibition in preclinical models of CIC-mutated vs. wild-type oligodendroglioma. Ulixertinib is a small molecule inhibitor of ERK that is being developed as a novel anti-cancer drug. A phase I study of ulixertinib in advanced solid malignancies had shown two central nervous system responses. We hypothesized that ulixertinib crosses the blood-brain barrier (BBB) and it will result in improved responses in MAPK-activated lower-grade gliomas in adults (recurrent NF1-mutated gliomas grade 1,2,3 and oligodendrogliomas grade 2,3 which are enriched in CIC-mutation). This is a window-of-opportunity study of ulixertinib in patients ≥18 yo. Twenty patients who are candidates for non-emergent surgical resection will be enrolled (10 in each cohort). Patients will receive neoadjuvant ulixertinib at 600mg BID. Selected patients will undergo CSF collection 1-week after and all will undergo surgical intervention 2-weeks after initiation of ulixertinib. Patients will then continue treatment until disease progression or unacceptable toxicity. Primary endpoints are ulixertinib tumor concentration and tumor/plasma ratio in enhancing and non-enhancing disease. Secondary endpoints include median PFS, overall response rate (ORR) and disease control rate at 12mo, duration of response, time-to-next intervention and time-to-response, safety profile, and ulixertinib CSF and tumor/CSF ratio. Exploratory endpoint includes ORR of plexiform neurofibromas in NF1 patients. To date, 4 patients have been dosed; 3 CIC-mutated oligodendroglioma and 1 NF1-mutated glioma. A fifth patient with NF1-mutated glioma has been consented. Upon collection of tumor tissue on all 5 patients, initial assessment of tumor and CSF drug concentration will be conducted and presented at the conference. Ulixertinib’s ability to cross the BBB could influence what tumor types may be explored for further patient benefit.

Remote ischemic periconditioning suppresses cardiac sympathetic activation in acute myocardial infarction: a randomized controlled trial.

Remote ischemic periconditioning (RIPC) has demonstrated cardioprotective effects and improved clinical outcomes as an adjunct to emergent percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI). However, whether RIPC affects the cardiac sympathetic nerve activity in patients with STEMI remains unclear. This study investigated the effects of RIPC on cardiac sympathetic nerve activity in patients with STEMI. We prospectively assigned patients with STEMI who underwent emergent PCI to receive RIPC or no procedure (control group) upon arrival at the cardiac catheterization laboratory. The primary endpoint was cardiac sympathetic nerve activity assessed through the washout rate (WR) in cardiac 123I-metaiodobenzylguanidine (123I-MIBG) imaging. Patients in the RIPC (n = 62) and control (n = 60) groups had similar demographic and clinical characteristics at baseline. Multivariable linear regression models revealed that the culprit lesion of the left anterior descending artery and hemoglobin level were significantly and independently associated with WR at discharge. WRs of the groups differed insignificantly at discharge. However, the RIPC group (n = 49) showed significantly lower WR than the control group (n = 47) at 1year after discharge (p = 0.027). In the single-photon emission computed tomography analysis at 1year after discharge, the RIPC group demonstrated significantly higher late uptake (p = 0.021) and lower WR (p = 0.013) in the nonculprit lesion, with a non-significant decrease in WR for the culprit lesion. RIPC can suppress augmented cardiac sympathetic nerve activity in patients with STEMI, particularly in nonculprit lesions.