Glucose Oxidase Energized Osmium with Dual-Active Centers and Triple Enzyme Activities for Infected Diabetic Wound Management.

Diabetic wounds are susceptible to bacterial infections, largely linked to high blood glucose levels (hyperglycemia). To treat such wounds, enzymes like glucose oxidase (GOx) can be combined with nanozymes (nanomaterials mimic enzymes) to use glucose effectively for purposes. However, there is still room for improvement in these systems, particularly in terms of process simplification, enzyme activity regulation, and treatment effects. Herein, the approach utilizes GOx to directly facilitate the biomineralized growth of osmium (Os) nanozyme (GOx-OsNCs), leading to dual-active centers and remarkable triple enzyme activities. Initially, GOx-OsNCs use vicinal dual-active centers, enabling a self-cascaded mechanism that significantly enhances glucose sensing performance compared to step-by-step reactions, surpassing the capabilities of other metal sources such as gold and platinum. In addition, GOx-OsNCs are integrated into a glucose-sensing gel, enabling instantaneous visual feedback. In the treatment of infected diabetic wounds, GOx-OsNCs exhibit multifaceted benefits by lowering blood glucose levels and exhibiting antibacterial properties through the generation of hydroxyl free radicals, thereby expediting healing by fostering a favorable microenvironment. Furthermore, the catalase-like activity of GOx-OsNCs aids in reducing oxidative stress, inflammation, and hypoxia, culminating in improved healing outcomes. Overall, this synergistic enzyme-nanozyme blend is user-friendly and holds considerable promise for diverse applications.

High-Dose Ionizing Radiation Accelerates Atherosclerotic Plaque Progression by Regulating P38/NCOA4-Mediated Ferritinophagy/Ferroptosis of Endothelial Cells.

PURPOSE: Radiation therapy (RT) significantly increased the incidence of coronary artery diseases, especially atherosclerosis. Endothelial dysfunction has been the major side effect of RT among tumor patients who received RT. However, the involvement between endothelial dysfunction and radiation-induced atherosclerosis (RIA) remains unclear. Here, we constructed a murine model of RIA, aiming to uncover its underlying mechanisms and identify novel strategies for RIA prevention and treatment. METHODS AND MATERIALS: Eight-week-old ApoE-/- mice that were fed a Western diet were subjected to partial carotid ligation (PCL). Four weeks later, ionizing radiation (IR) of 10 Gy was performed to verify the detrimental role of IR on atherogenesis. Ultrasound imaging, RT quantitative polymerase chain reaction, histopathology and immunofluorescence, and biochemical analysis were performed 4 weeks after IR. To study the involvement of endothelial ferroptosis induced by IR in RIA, mice after IR were administrated with ferroptosis agonist (cisplatin) or antagonist (ferrostatin-1) intraperitoneally. Western blotting, autophagic flux measurement, reactive oxygen species level detection, and coimmunoprecipitation assay were carried out in vitro. Furthermore, to determine the effect of ferritinophagy inhibition on RIA, in vivo knockdown of NCOA4 was carried out by pluronic gel. RESULTS: We verified that accelerated plaque progression was concomitant with endothelial cell (EC) ferroptosis after IR induction, as suggested by a higher level of lipid peroxidation and changes in ferroptosis-associated genes in the PCL + IR group than in the PCL group within vasculature. In vitro experiments further validated the devastating effects of IR on oxidative stress and ferritinophagy in ECs. Mechanistic experiments revealed that IR induced EC ferritinophagy and subsequent ferroptosis in a P38/NCOA4-dependent manner. Both in vitro and in vivo experiments confirmed the therapeutic effect of NCOA4 knockdown in alleviating IR-induced ferritinophagy/ferroptosis of EC and RIA. CONCLUSIONS: Our findings provide novel insights into the regulatory mechanisms of RIA and first prove that IR accelerates atherosclerotic plaque progression by regulating ferritinophagy/ferroptosis of ECs in a P38/NCOA4-dependent manner.

Disulfiram protects against abdominal aortic aneurysm by ameliorating vascular smooth muscle cells pyroptosis.

PURPOSE: Recent studies demonstrated that pyroptosis is involved in abdominal aortic aneurysm (AAA) progression, suggesting a potential target for AAA treatment. This study aimed to identify if disulfiram could inhibit angiotensin II (Ang II)-induced vascular smooth muscle cells (VSMCs) damage, thereby exerting protective effects on AAA. METHODS: The AAA mouse model was established by continuous subcutaneous Ang II infusion for 28 days. Then aortic tissue of the mice was isolated and subjected to RNA sequencing, qRT-PCR, Western blotting, and immunofluorescence staining. To explore the therapeutic effect of disulfiram, mice were orally administered disulfiram (50 mg/kg/day) or vehicle for 28 days accompanied with Ang II infusion. Pathological changes in aortic tissues were measured using microultrasound imaging analysis and histopathological analysis. In addition, inflammatory response, pyroptosis, and oxidative stress damage were examined in mouse aortic vascular smooth muscle (MOVAS) cells stimulated with Ang II in vitro. RESULTS: The RNA sequencing and bioinformatic analysis results suggested that pyroptosis- and inflammation-related genes were significantly upregulated in AAA, consistent with the results of qRT-PCR and Western blotting. Most importantly, the therapeutic effect of disulfiram on AAA was identified in our study. First, disulfiram administration significantly attenuated Ang II-induced inflammation, pyroptosis, and oxidative stress in VSMCs, which is associated with the inhibition of the NF-κB-NLRP3 pathway. Second, in-vivo studies revealed that disulfiram treatment reduced AAA formation and significantly ameliorated collagen deposition and elastin degradation in the aortic wall. CONCLUSION: Our findings suggest that disulfiram has a novel protective effect against AAA by inhibiting Ang II-induced VSMCs pyroptosis.

Multi-Target Coordinated Search Algorithm for Swarm Robotics Considering Practical Constraints.

In order to deal with the multi-target search problems for swarm robots in unknown complex environments, a multi-target coordinated search algorithm for swarm robots considering practical constraints is proposed in this paper. Firstly, according to the target detection situation of swarm robots, an ideal search algorithm framework combining the strategy of roaming search and coordinated search is established. Secondly, based on the framework of the multi-target search algorithm, a simplified virtual force model is combined, which effectively overcomes the real-time obstacle avoidance problem in the target search of swarm robots. Finally, in order to solve the distributed communication problem in the multi-target search of swarm robots, a distributed neighborhood communication mechanism based on a time-varying characteristic swarm with a restricted random line of sight is proposed, and which is combined with the multi-target search framework. For the swarm robot kinematics, obstacle avoidance, and communication constraints of swarm robots, the proposed multi-target search strategy is more stable, efficient, and practical than the previous methods. The effectiveness of this proposed method is verified by numerical simulations.

NR1D1 Deletion Induces Rupture-Prone Vulnerable Plaques by Regulating Macrophage Pyroptosis via the NF-κB/NLRP3 Inflammasome Pathway.

Vulnerable plaque rupture is the main trigger of most acute cardiovascular events. But the underlying mechanisms responsible for the transition from stable to vulnerable plaque remain largely unknown. Nuclear receptor subfamily 1 group D member 1 (NR1D1), also known as REV-ERB α, is a nuclear receptor that has shown the protective role in cardiovascular system. However, the effect of NR1D1 on vulnerable plaque rupture and its underlying mechanisms are still unclear. By generating the rupture-prone vulnerable plaque model in hypercholesterolemic ApoE-/- mice and NR1D1-/-ApoE-/- mice, we demonstrated that NR1D1 deficiency significantly augmented plaque vulnerability/rupture, with higher incidence of intraplaque hemorrhage (78.26% vs. 47.82%, P = 0.0325) and spontaneous plaque rupture with intraluminal thrombus formation (65.21% vs. 39.13%, P = 0.1392). In vivo experiments indicated that NR1D1 exerted a protective role in the vasculature. Mechanically, NR1D1 deficiency aggravates macrophage infiltration, inflammation, and oxidative stress. Compared with the ApoE-/- mice, NR1D1-/-ApoE-/- mice exhibited a significantly higher expression level of pyroptosis-related genes in macrophages within the plaque. Further investigation based on mice bone marrow-derived macrophages (BMDMs) confirmed that NR1D1 exerted a protective effect by inhibiting macrophage pyroptosis in a NLRP3-inflammasome-dependent manner. Besides, pharmacological activation of NR1D1 by SR9009, a specific NR1D1 agonist, prevented plaque vulnerability/rupture. In general, our findings provide further evidences that NR1D1 plays a protective role in the vasculature, regulates inflammation and oxidative stress, and stabilizes rupture-prone vulnerable plaques.

Statistical Learning of Orthographic Regularities in Chinese Children With and Without Dyslexia.

This study examined distributional statistical learning of positional, phonetic, and semantic regularities of an artificial orthography in Chinese children aged 8-10 years: 29 with dyslexia, 29 age-matched controls, and 30 reading-level matched controls. Despite having positional regularity learning performance comparable to the controls, the children with dyslexia were poorer at learning left-right structured characters than top-bottom structured characters in high- and low-consistency conditions. Moreover, they showed difficulties in mapping a given sound or meaning to a specific character compared with the typically developing controls. These findings suggest that children with dyslexia have deficits in some, though not all, aspects of statistical learning of character orthography, which may reflect their difficulties in coping with distractors and inconsistency of orthographic input.

Quantity Matters: Children With Dyslexia Are Impaired in a Small, but Not Large, Number of Exposures During Implicit Repeated Sequence Learning.

PURPOSE: The present study investigated the onset of statistical learning and examined whether the number of exposures to a repeated sequence influences the learning performance of children with dyslexia on a serial reaction time task. METHOD: Three groups of children (29 with dyslexia, 29 age-matched controls, and 30 reading level-matched controls) were administered a serial reaction time task, and their statistical learning performances after a small and a large number of exposures (40 vs. 180 exposures) were recorded and compared. RESULTS: Children with dyslexia showed impaired statistical learning after a small number of exposures to a sequence, but intact statistical learning after a large number of exposures. In contrast, the age-matched and reading level-matched control groups showed intact statistical learning after both small and large numbers of exposures. Children with dyslexia also exhibited a slower learning rate than either control group. CONCLUSION: These results suggest that the amount of exposure to statistical patterns influences statistical learning performance in children with dyslexia.

Tone matters for Cantonese-English bilingual children's English word reading development: A unified model of phonological transfer.

Languages differ considerably in how they use prosodic features, or variations in pitch, duration, and intensity, to distinguish one word from another. Prosodic features include lexical tone in Chinese and lexical stress in English. Recent cross-sectional studies show a surprising result that Mandarin Chinese tone sensitivity is related to Mandarin-English bilingual children's English word reading. This study explores the mechanism underlying this relation by testing two explanations of these effects: the prosodic hypothesis and segmental phonological awareness transfer. We administered multiple measures of Cantonese tone sensitivity, English stress sensitivity, segmental phonological awareness in Cantonese and English, nonverbal ability, and English word reading to 123 Cantonese-English bilingual children ages 7 and 8 years. Structural equation modeling revealed a longitudinal prediction of Cantonese tone sensitivity to English word reading between 8 and 9 years of age. This relation was realized through two parallel routes. In one, Cantonese tone sensitivity predicted English stress sensitivity, and English stress sensitivity, in turn, significantly predicted English word reading, as postulated by the prosodic hypothesis. In the second, Cantonese tone sensitivity predicted English word reading through the transfer of segmental phonological awareness between Cantonese and English, as predicted by segmental phonological transfer. These results support a unified model of phonological transfer, emphasizing the role of tone in English word reading for Cantonese-English bilingual children.

Coronary-Heart-Disease-Associated Genetic Variant at the COL4A1/COL4A2 Locus Affects COL4A1/COL4A2 Expression, Vascular Cell Survival, Atherosclerotic Plaque Stability and Risk of Myocardial Infarction.

Genome-wide association studies have revealed an association between coronary heart disease (CHD) and genetic variation on chromosome 13q34, with the lead single nucleotide polymorphism rs4773144 residing in the COL4A2 gene in this genomic region. We investigated the functional effects of this genetic variant. Analyses of primary cultures of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) from different individuals showed a difference between rs4773144 genotypes in COL4A2 and COL4A1 expression levels, being lowest in the G/G genotype, intermediate in A/G and highest in A/A. Chromatin immunoprecipitation followed by allelic imbalance assays of primary cultures of SMCs and ECs that were of the A/G genotype revealed that the G allele had lower transcriptional activity than the A allele. Electrophoretic mobility shift assays and luciferase reporter gene assays showed that a short DNA sequence encompassing the rs4773144 site interacted with a nuclear protein, with lower efficiency for the G allele, and that the G allele sequence had lower activity in driving reporter gene expression. Analyses of cultured SMCs from different individuals demonstrated that cells of the G/G genotype had higher apoptosis rates. Immunohistochemical and histological examinations of ex vivo atherosclerotic coronary arteries from different individuals disclosed that atherosclerotic plaques with the G/G genotype had lower collagen IV abundance and thinner fibrous cap, a hallmark of unstable, rupture-prone plaques. A study of a cohort of patients with angiographically documented coronary artery disease showed that patients of the G/G genotype had higher rates of myocardial infarction, a phenotype often caused by plaque rupture. These results indicate that the CHD-related genetic variant at the COL4A2 locus affects COL4A2/COL4A1 expression, SMC survival, and atherosclerotic plaque stability, providing a mechanistic explanation for the association between the genetic variant and CHD risk.