Augmented Activity Research Articles

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.

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

Due to their cost-efficiency and heightened sensitivity, the rational design of artificial nanozymes has become a paramount research direction. In this investigation, we elaborate on a simplified freeze-drying methodology for fabricating Cu@MXene quantum dots-aerogel (Cu@MQDs-aerogel), which possesses augmented peroxidase-mimicking activity. Through steady-state fluorometric analysis, we delve into the catalytic mechanism of Cu@MQDs-aerogel, uncovering its proficiency in decomposing H2O2 into reactive hydroxyl radicals (OH). Density functional theory (DFT) calculations further validate that the outstanding catalytic prowess of Cu@MQDs-aerogel stems from the interfacial Cu-Ti dimer active sites, significantly activating adsorbed H2O2 and facilitating its decomposition into OH. As a result, we introduce a sensitive colorimetric sensor for pirimiphos-methyl detection, achieving a low detection limit of 0.65 nM. Additionally, it exhibits a narrow relative standard deviation (RSD) interval spanning from 1.03 % to 2.66 %. This study introduces a novel strategy for the design and synthesis of MQDs-based peroxidase-like enzymes, highlighting their significant potential in environmental pollutant 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

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

Antagonism of the muscarinic acetylcholine type 1 receptor (M1R) promotes sensory axon repair and is protective in peripheral neuropathy, however, the mechanism remains elusive. We investigated the role of the heat-sensing transient receptor potential melastatin-3 (TRPM3) cation channel in M1R antagonism-mediated nerve regeneration and explored the potential of TRPM3 activation to facilitate axonal plasticity. Dorsal root ganglion (DRG) neurons from adult control or diabetic rats were cultured and treated with TRPM3 agonists (CIM0216, pregnenolone sulfate) and M1R antagonists pirenzepine (PZ) or muscarinic toxin 7 (MT7). Ca2+ transients, mitochondrial respiration, AMP-activated protein kinase (AMPK) expression, and mitochondrial inner membrane potential were analyzed. The effect of M1R activation or blockade on TRPM3 activity mediated by phosphatidylinositol 4,5-bisphosphate (PIP2) was studied. Metabolic profiling of DRG neurons and human neuroblastoma SY-SY5Y cells was conducted. M1R antagonism induced by PZ or MT7 increased Ca2+ influx in DRG neurons and was inhibited by TRPM3 antagonists or in the absence of extracellular Ca2+. TRPM3 agonists elevated Ca2+ levels, augmented mitochondrial respiration, AMPK activation and neurite outgrowth. M1R antagonism stimulated TRPM3 channel activity through inhibition of PIP2 hydrolysis to activate Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMPK, leading to augmented mitochondrial function and neuronal metabolism. DRG neurons with AAV-mediated shRNA knockdown of TRPM3 exhibited suppressed antimuscarinic drug-induced neurite outgrowth. TRPM3 agonists increased glycolysis and TCA cycle metabolites, indicating enhanced metabolism in DRG neurons and SH-SY5Y cells. Activation of the TRPM3/CaMKKβ/AMPK pathway promoted collateral sprouting of sensory axons, positioning TRPM3 as a promising therapeutic target for peripheral neuropathy.

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

Bacterial infections considerably limit the success of scaffold transplantation. CuO2 may generate hydroxyl radicals through a self-cascade catalytic process, which is effective for sterilization. However, reducing CuO2-derived Cu+ ions to Cu° can lead to a decline in catalytic activity. To overcome these limitations, we anchored CuO2 onto MoS2 to establish stable Cu-S-Mo interfacial sites. The CuO2/MoS2 nanozyme was fabricated using a low-temperature co-precipitation technique and introduced into poly-l-lactic acid scaffolds using selective laser sintering. The Cu-S-Mo interfacial sites showed a triad of functions that synergistically enhanced catalytic performance. These sites stabilized the Cu atoms, augmented catalytic activity by facilitating efficient electron transfer through the Mo4+/Mo6+ redox couple, and improved the conduction of heat derived from the photothermal response of MoS2 to the Cu catalyst. The synergistic action of chemodynamic and photothermal therapy, mediated by the Cu-S-Mo sites, resulted in remarkable antibacterial efficacy, with 92.3 % and 93.5 % inhibition rates against Staphylococcus aureus and Escherichia coli, respectively. Experimental evidence and simulations demonstrated that Cu-S-Mo structure stabilized the Cu atoms and improved electron transfer via interatomic charge transfer. These results highlight the potential of the CuO2@MoS2/PLLA scaffold in eliminating bacterial infections.

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.

Harnessing the targeting potential of hyaluronic acid for augmented anticancer activity and safety of duvelisib-loaded nanoparticles in hematological malignancies

Duvelisib (DUV) is effective against numerous hematological malignancies; however, it suffers from numerous setbacks like poor aqueous solubility, low cellular uptake and adverse effects. Hyaluronic acid is an excellent ligand for CD44 receptors that are overexpressed on cancer cell surfaces. Thus, for the targeted delivery of DUV in hematological malignancies, we have fabricated hyaluronic acid-coated polylactide-co-glycolide nanoparticles (DUV-P/CH/HA-NPs) through electrostatic interactions. DUV-P/CH/HA-NPs exhibited optimum characteristics such as mean particle size of 183.63 ± 0.23 nm, polydispersity index of 0.261 ± 0.02 and drug loading capacity of 5.75 ± 0.05 %. An in-vitro release study demonstrated sustained release behavior of DUV-P/CH/HA-NPs (77.65 ± 2.89 % release in 48 h). The flow cytometry experiments revealed 1.62-fold and 1.50-fold enhanced uptake of DUV-P/CH/HA-NPs compared to non-coated nanoparticles in MOLT-4 and HH cells, respectively. The DUV-P/CH/HA-NPs showed higher cytotoxicity, arrested the cell cycle in G0/G1 phase and showed increased apoptosis compared to non-coated nanoparticles and free DUV. An in-vivo pharmacokinetic study revealed 2.9-fold and 3.6-fold enhancement in AUC0-t and MRT with the DUV-P/CH/HA-NPs compared to free DUV. Further, toxicity evaluation and hemolysis assessment of DUV-P/CH/HA-NPs indicated good safety for intravenous administration. Conclusively, DUV-P/CH/HA-NPs are an excellent option for selectively targeting hematological malignant cells.

Associative memory in alcohol-related contexts: An fMRI study with young binge drinkers.

Alcohol-related cues are known to influence craving levels, a hallmark of alcohol misuse. Binge drinking (BD), a pattern of heavy alcohol use, has been associated with cognitive and neurofunctional alterations, including alcohol attentional bias, memory impairments, as well as disrupted activity in prefrontal- and reward-related regions. However, literature is yet to explore how memories associated with alcohol-related cues are processed by BDs, and how the recall of this information may influence their reward processing. The present functional magnetic resonance imaging (fMRI) study aimed to investigate the neurofunctional signatures of BD during an associative memory task. In all, 36 university students, 20 BDs and 16 alcohol abstainers, were asked to memorize neutral objects paired with either alcohol or non-alcohol-related contexts. Subsequently, neutral stimuli were presented, and participants were asked to classify them as being previously paired with alcohol- or non-alcohol-related contexts. While behavioral performance was similar in both groups, during the recall of alcohol-related cues, BDs showed increased brain activation in two clusters including the thalamus, globus pallidus and dorsal striatum, and cerebellum and occipital fusiform gyrus, respectively. These findings suggest that BDs display augmented brain activity in areas responsible for mental imagery and reward processing when trying to recall alcohol-related cues, which might ultimately contribute to alcohol craving, even without being directly exposed to an alcohol-related context. These results highlight the importance of considering how alcohol-related contexts may influence alcohol-seeking behavior and, consequently, the maintenance or increase in alcohol use.

Doping-Engineered Piezoelectric Ultrathin Nanosheets for Synergistically Piezo-Chemocatalytic Antitumor and Antibacterial Therapies Against Cutaneous Melanoma.

The post-surgical melanoma recurrence and wound infections have persistently troubled clinical management. Piezocatalytic therapy features high efficiency in generating reactive oxygen species (ROS) for tumor therapy, but it faces limitations in piezoelectricity and redox-active site availability. Herein, Fe-doped ultrathin Bi4Ti3O12 nanosheets (designated as Fe-UBTO NSs) with synergistically piezo-chemocatalytic activity are engineered for antitumor and antibacterial treatment against cutaneous melanoma. The doping-engineered strategy induces oxygen vacancies and lattice distortions in Fe-UBTO NSs, which narrows bandgap to enhance piezocatalytic 1O2 and H2O2 generation by improving the electron-hole pairs separation, hindering their recombination, and increasing oxygen adsorption. Moreover, Fe doping establishes a piezo-chemocatalytic system, in which the piezocatalysis enables the self-supply of H2O2 and expedites electron transfer in Fenton reactions, inducing increased ·OH production. Besides, the atomic-level thickness and expanded surface area enhance the sensitivity to ultrasound stimuli and expose more redox-active sites, augmenting the piezo-chemocatalytic efficiency, and ultimately leading to abundant ROS generation. The Fe-UBTO-mediated piezo-chemocatalytic therapy causes intracellular oxidative stress, triggering apoptosis and excessive autophagy of tumor cells. Moreover, this strategy accelerates wound healing by facilitating sterilization, angiogenesis, and collagen deposition. This work provides distinct options to develop doping-engineered ultrathin nanosheets with augmented piezo-chemocatalytic activity for postoperative management of cutaneous melanoma.

Screening Transition-Metal-Incorporated β-AgVO3 for Augmented Oxygen Reduction Activity.

Exploring cost-effective alternatives to Pt-based catalysts for the oxygen reduction reaction (ORR) in fuel cells is crucial for their large-scale deployment in green energy applications. Silver vanadate (AgVO3) is a well-studied material for photocatalytic applications. Here, we investigate the electrocatalytic ORR activity of the thermodynamically stable β phase of AgVO3 through computational modeling based on DFT. It is found that β-AgVO3 exhibits weak catalytic activity for the ORR, with vanadium being the preferable active site. Incorporating single atoms of transition metals at surface-level vacancies in β-AgVO3 significantly modifies the ORR activity. We study the scaling of free energy changes for the ORR intermediates *OOH, *OH, and *O for various transition metals incorporated, which leads to an optimal overpotential for the system. The optimal overpotential thus obtained is remarkably lower than that of pristine β-AgVO3. For the transition metal atoms we consider here, Co-incorporated β-AgVO3 exhibits the best ORR catalytic activity due to its optimal binding of ORR species to the vanadium site. It is also observed that some of the transition metals considered like Re, Rh, Os, or Mn show weak activity, either due to strong or weak binding. Analysis of the electronic structure of the adsorbate-catalyst interface shows a strong correlation between optimal activity and evolution of midgap states in β-AgVO3, due to transition metal incorporation. Our study concludes that the ORR activity of a stable mixed transition metal oxide like β-AgVO3 can be enhanced with a minimal loading of transition metals, which could help in developing a novel series of ORR catalysts.

An innovative approach in middle school science courses: effects of collaborative augmented reality activities on motivation, cognitive load, and satisfaction

ABSTRACT This study examines the effects of collaborative augmented reality activities supported by the 5E teaching model on students’ motivation, cognitive load, and satisfaction levels in a science course. In this context, explanatory design, one of the mixed research methods, was used in this study. The research process was conducted with 18 sixth-grade (5 girls and 13 boys) students studying in a private school for four hours a week for four weeks in a science course. In the quantitative dimension of the study, the effects of collaborative augmented reality activities were examined using one group pretest-posttest design through questionnaires and scales, and student views were evaluated through semi-structured interviews as a result. The quantitative data analysis used the Wilcoxon signed-rank test and descriptive statistics methods. Qualitative data were analyzed through the content analysis method. As a result of the study, it was observed that collaborative augmented reality activities positively affected students’ motivation and satisfaction levels in the science learning process. In addition, collaborative augmented reality activities contributed to balancing the cognitive load. In this regard, it can be asserted that students’ learning processes can be made more effective using collaborative augmented reality activities, especially in teaching complex science subjects.

“We are an active family”: a randomized trial protocol to evaluate a family-system social identity intervention to promote child physical activity

BackgroundRegular engagement in moderate-to-vigorous physical activity (MVPA) during childhood yields a myriad of health benefits, and contributes to sustained MVPA behaviors into adulthood. Given the influence of parents on shaping their child’s MVPA behaviour, the family system represents a viable target for intervention. The purpose of this study is to compare the effects of two intervention conditions designed to increase child MVPA: (1) A standard education + planning intervention providing information about benefits, action planning, and coping planning; and (2) An augmented physical activity education + planning intervention that includes the components of the standard intervention, as well as a focus on family identity promotion and developing as an active member of the family.MethodsA two-arm parallel single-blinded randomized trial will compare the two conditions over 6 months. Eligible families have at least one child aged 6–12 years who is not meeting the physical activity recommendations within the Canadian 24-Hour Movement Guidelines (i.e.,<60 min/day of MVPA). Intervention materials targeting family identity promotion will be delivered online via zoom following baseline assessment, with booster sessions at 6-weeks and 3-months. Child MVPA will be measured by wGT3X-BT Actigraph accelerometry at baseline, 6-weeks, 3-months, and 6-months as the primary outcome. At these same time points, parent cognition (e.g., attitudes, perceived control, behavioral regulation, habit, identity) and support behaviours, and parent-child co-activity will be assessed via questionnaire as secondary outcomes. Child-health fitness measures will be also administered through fitness testing at baseline and 6-months as secondary outcomes. Finally, upon completion of the trial’s 6-month measures, a follow-up end-of-trial interview will be conducted with parents to examine parents’ experiences with the intervention.ResultsSo far, 30 families have been enrolled from the Southern Vancouver Island and Vancouver Lower Mainland area. Recruitment will be continuing through 2026 with a target of 148 families.DiscussionThis study will contribute to the understanding of effective strategies to increase child physical activity by comparing two intervention approaches. Both provide parents with education on physical activity benefits, action planning, and coping planning supports. However, one intervention also incorporates components focused on promoting an active family identity and involving all family members in physical activity together. The findings from this study have the potential to inform the design and implementation of public health initiatives aimed at improving physical activity participation in children and guide the development of more effective interventions that leverage the crucial role of parents and the family system in shaping children’s physical activity behaviors.Trial RegistrationThe clinical trial registration ID is NCT05794789. This trial was registered with clinicaltrials.gov on March 2nd, 2023, with the last updated release on September 28th, 2023.

The influence of Quercetin on behavior, performance and splenic immunity in broiler chickens

Quercetin (QRT), a potent flavonoid, holds immense mechanistic potential in enhancing various aspects of broiler chicken physiological status. This comprehensive study explores the profound еffеcts of QRT on behavior, productive performance, and immune functions, unraveling the underlying mechanisms behind its efficacy. Four hundred, one-day-old Cobb 500 chicks were placed randomly into 4 supplementation groups (100 birds /group and five replicates) and provided diets enriched with varying concentrations of QRT (0, 200, 400, and 600 ppm) for six weeks. Visual scanning revealed significant (P > 0.05) improvements in feeding and body care behaviors, accompanied by reduced instances of idleness and walking in the QRT-supplemented groups. Moreover, QRT supplementation exerted a substantial (P > 0.05) positive influence on weight gain, feed intake and the final body weight of the broilers. In-depth evaluation of immune parameters, QRT supplementation elicited significant (P > 0.05) enhancements in immune functions, including improved spleen, thymus, and bursa indices, enhanced secretion of immunoglobulin M (IgM) and immunoglobulin A (IgA), and stimulated humoral immunity against sheep red blood cells (SRBCs). Furthermore, QRT displays potent antioxidant properties, as showed by diminished splenic malondialdehyde levels and augmented activity of antioxidative stress enzymes. Remarkably, QRT supplementation elicited dose-dependent upregulation (P < 0.001) of key immune-related genes, such as intеrlеukin-4 (IL-4), interferon-γ (INF-γ), Toll-like receptor 2 (TLR2), and tumor necrosis factor-α (TNF-α) in the splenic tissue. Collectively, these mechanistic insights underscore the profound impact of QRT as a functional feed additive, fostering enhanced behavior, performance, and immune function in broiler chickens, while delivering robust antioxidant fortification.

Targeted inhibition of glycogen synthase kinase-3 using 9-ING-41 (elraglusib) enhances CD8 T-cell-reactivity against neuroblastoma cells

The prognosis of patients with high-risk neuroblastoma remains poor, partly due to inadequate immune recognition of the tumor. Neuroblastomas display extremely low surface MHC-I, preventing recognition by cytotoxic T lymphocytes (CTLs) and contributing to an immunosuppressive tumor microenvironment. Glycogen synthase kinase-3 beta (GSK-3β) is involved in pathways that may affect the MHC-I antigen processing and presentation pathway. We proposed that therapeutic inhibition of GSK-3β might improve the surface display of MHC-I molecules on neuroblastoma cells, and therefore tested if targeting of GSK-3β using the inhibitor 9-ING-41 (Elraglusib) improves MHC-I-mediated CTL recognition. We analyzed mRNA expression data of neuroblastoma tumor datasets and found that non-MYCN-amplified neuroblastomas express higher GSK-3β levels than MYCN-amplified tumors. In non-MYCN-amplified cells SH-SY5Y, SK-N-AS and SK-N-SH 9-ING-41 treatment enhanced MHC-I surface display and the expression levels of a subset of genes involved in MHC-I antigen processing and presentation. Further, 9-ING-41 treatment triggered increased STAT1 pathway activation, upstream of antigen presentation pathways in two of the three non-MYCN-amplified cell lines. Finally, in co-culture experiments with CD8 + T cells, 9-ING-41 improved immune recognition of the neuroblastoma cells, as evidenced by augmented T-cell activation marker levels and T-cell proliferation, which was further enhanced by PD-1 immune checkpoint inhibition. Our preclinical study provides experimental support to further explore the GSK-3β inhibitor 9-ING-41 as an immunomodulatory agent to increase tumor immune recognition in neuroblastoma.