Nitrogen Vacancy Modulation of Tungsten Nitride Peroxidase-Mimetic Activity for Bacterial Infection Therapy.

Bacterial infections claim millions of lives every year, with the escalating menace of microbial antibiotic resistance compounding this global crisis. Nanozymes, poised as prospective substitutes for antibiotics, present a significant frontier in antibacterial therapy, yet their precise enzymatic origins remain elusive. With the continuous development of nanozymes, the applications of elemental N-modulated nanozymes have spanned multiple fields, including sensing and detection, infection therapy, cancer treatment, and pollutant degradation. The introduction of nitrogen into nanozymes not only broadens their application range but also holds significant importance for the design of catalysts in biomedical research. The synergistic interplay between W and N induces pivotal alterations in electronic configurations, endowing tungsten nitride (WN) with a peroxidase-like functionality. Furthermore, the introduction of N vacancies augments the nanozyme activity, thus amplifying the catalytic potential of WN nanostructures. Rigorous theoretical modeling and empirical validation corroborate the genesis of the enzyme activity. The meticulously engineered WN nanoflower architecture exhibits an exceptional ability in traversing bacterial surfaces, exerting potent bactericidal effects through direct physical interactions. Additionally, the topological intricacies of these nanostructures facilitate precise targeting of generated radicals on bacterial surfaces, culminating in exceptional bactericidal efficacy against both Gram-negative and Gram-positive bacterial strains along with notable inhibition of bacterial biofilm formation. Importantly, assessments using a skin infection model underscore the proficiency of WN nanoflowers in effectively clearing bacterial infections and fostering wound healing. This pioneering research illuminates the realm of pseudoenzyme activity and bacterial capture-killing strategies, promising a fertile ground for the development of innovative, high-performance artificial peroxidases.

Risk profiling of tobacco epidemic and estimated number of smokers living in China: a cross-sectional study based on PBICR.

BACKGROUND: Evidence on the prevalence of smoking in China remains insufficient, with most previous studies focusing on a single region. However, smoking prevalence exhibits significant inequalities across the entire country. This study aimed to evaluate the risk of tobacco prevalence across the country, taking into account spatial inequalities. METHODS: The data used in this study were collected in 23 provinces, 5 autonomous regions, and 4 municipalities directly under the central government in 2022. Large population survey data were used, and a Bayesian geostatistical model was employed to investigate smoking prevalence rates across multiple spatial domains. FINDINGS: Significant spatial variations were observed in smokers and exposure to secondhand smoke across China. Higher levels of smokers and secondhand smoke exposure were observed in western and northeastern regions. Additionally, the autonomous region of Tibet, Shanghai municipality, and Yunnan province had the highest prevalence of smokers, while Tibet, Qinghai province, and Yunnan province had the highest prevalence of exposure to secondhand smoke. CONCLUSION: We have developed a model-based, high-resolution nationwide assessment of smoking risks and employed rigorous Bayesian geostatistical models to help visualize smoking prevalence predictions. These prediction maps provide estimates of the geographical distribution of smoking, which will serve as strong evidence for the formulation and implementation of smoking cessation policies. HIGHLIGHTS: Our study investigated the prevalence of smokers and exposure to secondhand smoke in different spatial areas of China and explored various factors influencing the smoking prevalence. For the first time, our study applied Bayesian geostatistical modeling to generate a risk prediction map of smoking prevalence, which provides a more intuitive and clear understanding of the spatial disparities in smoking prevalence across different geographical regions, economic levels, and development status. We found significant spatial variations in smokers and secondhand smoke exposure in China, with higher rates in the western and northeastern regions.

Lipocalin-2 induced LDHA expression promotes vascular remodelling in pulmonary hypertension.

Aerobic glycolysis is involved in the pathogenesis of pulmonary hypertension (PH). The mechanisms by which glycolysis is increased and how it contributes to pulmonary vascular remodelling are not yet fully understood. In this study, we demonstrated that elevated lipocalin-2 (LCN2) in PH significantly enhances aerobic glycolysis in human pulmonary artery smooth muscle cells (PASMCs) by up-regulating LDHA expression. Knockout of Lcn2 or having heterozygous LDHA deficiency in mice significantly inhibits the progression of hypoxic PH. Our study reveals that LCN2 stimulates LDHA expression by activating Akt-HIF-1α signalling pathway. Inhibition of Akt or HIF-1α reduces LDHA expression and proliferation of PASMCs. Both Akt and HIF-1α play critical roles in the development of PH and are suppressed in the pulmonary vessels of hypoxic PH mice lacking LCN2. These findings shed light on the LCN2-Akt-HIF1α-LDHA axis in aerobic glycolysis in PH.

miR-3202 inhibits bronchopulmonary dysplasia-mediated apoptosis and oxidative stress in bronchial epithelial cells via targeting RAG1.

BACKGROUND: BPD is a refractory disease affecting preterm infants with alveolar dysplasia and declined pulmonary function. However, the molecular mechanism underlying BPD is largely unknown. To explore the pathogenic mechanism of BPD and to facilitate better diagnosis and treatment of this disease. METHOD: The DEMs and DEGs in BPD vs. Control samples from the miRNA expression data in GSE108754 and mRNA expression data in the GSE108755 were screened, followed by the construction of the miRNA-mRNA regulatory network. DEGs PPI network and hub DEGs analysis were constructed by using the STRING database and Cytoscape software. Functional and pathway enrichment analyses were then performed for these DEGs and DEMs based on the ClusterProfiler package in the R and the miRWalk database. The k-mean algorithm is used to perform clustering analysis of DEGs. Cellular experiments (flow cytometry, western blot, RT-PCR, dual-luciferase reporter assay) were used to validate the results of bioinformatics. RESULTS: We obtained 20 DEMs and 262 DEGs. A 15 DEMs-11 DEGs regulatory network was constructed. miR-3202-RAG1 is a core sub-network. Hyperoxia induced a cell model of BPD. The upregulation of RAG1 and downregulation of miR-3202 were observed in BPD cells. Furthermore, siRNA targeting RAG1 was transfected into BEAS-2B cells to inhibit its expression and miR-3202 mimics was transfected into the cells to increase its expression. Inhibition of RAG1 and elevation of miR-3202 inhibit cell apoptosis and reduce ROS level caused by hyperoxia. A double-luciferase reporter assay revealed that miR-3202 directly targets RAG1. CONCLUSION: The miRNA-3202/RAG1 axis contributes into BPD-induced cell apoptosis and ROS production. The present study provides a probable target for the treatment of BPD.

Specific detection of gut pathogens for one-pot chip based on RPA-CRISPR/Cas12a.

BACKGROUND: There are billions of bacteria in the intestine, most of which are harmless and play important roles in humans. Although only a very small number of bacteria can cause diseases, once the pathogenic bacteria are ingested into the body and multiply in large quantities, it can lead to inflammatory diseases in the intestines and even other organs. Although polymerase chain reaction can specifically detect bacterial nucleic acid. However, the demand for temperature cycling limits its portability. Therefore, it is hoped to establish a high-throughput, highly specific and portable detection platform for directly detecting nucleic acid of intestinal pathogens. RESULTS: Herein, a one-pot chip based on RPA-CRCISPR/Cas12a platform was developed. The chip is the same size as a glass slide and allows detection at the same temperature. Multiple samples could be detected simultaneously on the one chip, achieved high-throughput detection and improved the integration of detection. The specific recognition of CRISPR/Cas12a avoided the influence of non-specific amplification of RPA and enhanced the specificity of the analysis. At the same time, the one-pot chip avoided secondary contamination when the lid was opened during the analysis process. And the bacterial concentration showed good linearity at 102-108 cfu mL-1. The limit of detection could be as low as 0.43 cfu mL-1. This method has been successfully used to detect pollution samples. It can provide a reliable platform for early screening of gastrointestinal and other inflammatory diseases. SIGNIFICANCE: The one-pot chip based on the RPA-CRISPR/Cas12a platform established can directly detect the nucleic acid of intestinal pathogens, with portability and specificity. It is worth noting that the platform has good programmability, can be used for other target detection by changing crRNA and RPA primers, it can achieve multi sample detection on the one chip.

Progress in mitochondrial and omics studies in Alzheimer's disease research: from molecular mechanisms to therapeutic interventions.

Alzheimer's disease (Alzheimer's disease, AD) is a progressive neurological disorder characterized by memory loss and cognitive impairment. It is characterized by the formation of tau protein neurofibrillary tangles and ß-amyloid plaques. Recent studies have found that mitochondria in neuronal cells of AD patients exhibit various dysfunctions, including reduced numbers, ultrastructural changes, reduced enzyme activity, and abnormal kinetics. These abnormal mitochondria not only lead to the loss of normal neuronal cell function, but are also a major driver of AD progression. In this review, we will focus on the advances of mitochondria and their multi-omics in AD research, with particular emphasis on how mitochondrial dysfunction in AD drives disease progression. At the same time, we will focus on summarizing how mitochondrial genomics technologies have revealed specific details of these dysfunctions and how therapeutic strategies targeting mitochondria may provide new directions for future AD treatments. By delving into the key mechanisms of mitochondria in AD related to energy metabolism, altered kinetics, regulation of cell death, and dysregulation of calcium-ion homeostasis, and how mitochondrial multi-omics technologies can be utilized to provide us with a better understanding of these processes. In the future, mitochondria-centered therapeutic strategies will be a key idea in the treatment of AD.

Osteogenic Induction and Anti-Inflammatory Effects of Calcium-Chlorogenic Acid Nanoparticles Remodel the Osteoimmunology Microenvironment for Accelerating Bone Repair.

Successful bone regeneration requires close cooperation between bone marrow mesenchymal stem cells (BMSCs) and macrophages, but the low osteogenic differentiation efficiency of stem cells and the excessive inflammatory response of immune cells hinder the development of bone repair. It is necessary to develop a strategy that simultaneously regulates the osteogenic differentiation of BMSCs and the anti-inflammatory polarization of macrophages for accelerating the bone regeneration. Herein, calcium-chlorogenic acid nanoparticles (Ca-CGA NPs) are synthesized by combining the small molecules of chlorogenic acid (CGA) with Ca2+. Ca-CGA NPs internalized by cells can be dissolved to release free CGA and Ca2+ under low pH conditions in lysosomes. In vitro results demonstrate that Ca-CGA NPs can not only enhance the osteogenic differentiation of BMSCs but also promote the phenotype transformation of macrophages from M1 to M2. Furthermore, in vivo experiments confirm that Ca-CGA NPs treatment facilitates the recovery of rat skull defect model through both osteoinduction and immunomodulation. This study develops a new Ca-CGA NPs-based strategy to induce the differentiation of BMSCs into osteoblasts and the polarization of macrophages into M2 phenotype, which is promising for accelerating bone repair.

Clinical features, treatment, and follow-up of OPPG and high-bone-mass disorders: LRP5 is a key regulator of bone mass.

Osteoporosis-pseudoglioma syndrome (OPPG) and LRP5 high bone mass (LRP5-HBM) are two rare bone diseases with opposite clinical symptoms caused by loss-of-function and gain-of-function mutations in LRP5. Bisphosphonates are an effective treatment for OPPG patients. LRP5-HBM has a benign course, and age-related bone loss is found in one LRP5-HBM patient. PURPOSE: Low-density lipoprotein receptor-related protein 5 (LRP5) is involved in the canonical Wnt signaling pathway. The gain-of-function mutation leads to high bone mass (LRP5-HBM), while the loss-of-function mutation leads to osteoporosis-pseudoglioma syndrome (OPPG). In this study, the clinical manifestations, disease-causing mutations, treatment, and follow-up were summarized to improve the understanding of these two diseases. METHODS: Two OPPG patients and four LRP5-HBM patients were included in this study. The clinical characteristics, biochemical and radiological examinations, pathogenic mutations, and structural analysis were summarized. Furthermore, several patients were followed up to observe the treatment effect and disease progress. RESULTS: Congenital blindness, persistent bone pain, low bone mineral density (BMD), and multiple brittle fractures were the main clinical manifestations of OPPG. Complex heterozygous mutations were detected in two OPPG patients. The c.1455G > T mutation in exon 7 was first reported. During the follow-up, BMD of two patients was significantly improved after bisphosphonate treatment. On the contrary, typical clinical features of LRP5-HBM included extremely high BMD without fractures, torus palatinus and normal vision. X-ray showed diffuse osteosclerosis. Two heterozygous missense mutations were detected in four patients. In addition, age-related bone loss was found in one LRP5-HBM patient after 12-year of follow-up. CONCLUSION: This study deepened the understanding of the clinical characteristics, treatment, and follow-up of OPPG and LRP5-HBM; expanded the pathogenic gene spectrum of OPPG; and confirmed that bisphosphonates were effective for OPPG. Additionally, it was found that Ala242Thr mutation could not protect LRP5-HBM patients from age-related bone loss. This phenomenon deserves further study.

The association between smoking and family health with the mediation role of personality among Chinese people: nationwide cross-sectional study.

BACKGROUND: There may be unexplored interactions between family health, personality, and smoking that could help provide new perspectives on tobacco control. OBJECTIVE: To examine the relationship between the health of one's family and their smoking habits, as well as investigate the potential influence of personality on this relationship. METHODS: For this cross-sectional investigation, a national survey conducted in China in 2022 recruited a total of 21,916 individuals. The Family Health Scale was utilized to assess the health of the family. The 10-item Big Five Inventory scale was utilized to assess the Big five personality traits. The relationship between big five personality, family health, and smoking were investigated using binary and linear logistic regression. The indirect effects mediated by Big five personality were analyzed using mediation analysis with Sobel tests, and the indirect effects were composited using the Karlson-Holm-Breen method. RESULTS: The overall prevalence of smoking in the study population was 14.87%, 26.19% for males and 3.54% for females. Urban and rural smoking prevalence was 13.81% and 16.10% respectively. Binary logistic regression analysis revealed a significant negative relationship between smoking and family health (odds ratio 0.964, 95% CI 0.959, 0.970, P < 0.001) with covariates controlled. The Karlson-Holm-Breen composition facilitated the connection between extraversion (47.81%) and nervousness (52.19%). CONCLUSIONS: Preventive interventions for smoking behavior should prioritize family health and the Big five personality as significant areas to focus on. According to this study, in addition to implementing various interventions for different personalities, family health should be strengthened to reduce smoking behavior.

Programmed cell death 4 governs NLRP3-mediated pyroptosis in septic lung disorders.

INTRODUCTION: Sepsis is a pathogenic syndrome of prolonged excessive inflammation and immunosuppression produced by invading pathogens. Programmed cell death 4 (PDCD4) may be implicated in a range of inflammatory lesions, and this study aimed to confirm the involvement of PDCD4 in septic lung injury. MATERIALS AND METHODS: Mice and bronchial epithelial 16HBE cells were separately subjected to CLP and LPS to generate in vivo and in vitro models. Following the level of PDCD4 was determined, the impacts of PDCD4 knockdown on mouse lung injury degree, inflammation, apoptosis, and pyroptosis levels were evaluated. Afterward, cells were treated with the NLRP3 agonist, and the influences of NLRP3 activation on the regulations of PDCD4 knockdown were determined. RESULTS: PDCD4 was elevated following mice developed septic lung injury, PDCD4 knockdown ameliorated septic lung injury and reduced lung inflammation and apoptosis. Moreover, PDCD4 knockdown suppressed NLRP3-mediated pyroptosis, indicating that PDCD4 also mediated pyroptosis. According to cellular models, NLRP3 activation broke the effects of PDCD4 knockdown on cells. CONCLUSIONS: The current study reveals that PDCD4 governs NLRP3-mediated pyroptosis in septic lung injury. PDCD4 is not only related to apoptosis and expands the knowledge of PDCD4 regulation of different cell death modes.

Immunogenicity Persistence of a Third-Dose Homologous BBIBP-CorV/CoronaVac Boosting Vaccination: A Prospective Open-Label Study.

The inactivated whole-virion severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine has been widely used in a two-dose schedule, but with insufficient data on the immunogenicity of homologous BBIBP-CorV/CoronaVac boosting vaccination and too little follow-up to assess the duration of the immunogenic response. We prospectively evaluated the immunogenicity of a third-dose BBIBP-CorV/CoronaVac boosting vaccination, with neutralizing titers against wild type and Omicron assessed at the baseline (immediately before the booster dose), and days 14, 28, 98, and 174 post the third-booster. Of 182 volunteers screened, 165 were assessed eligible for enrolment. No moderate/severe adverse events were observed during the term of the study. From the baseline to day 174 post the third booster, neutralizing titers against wild type and Omicron peaked by approximately sixfold increase (up to 811.83 and 33.40, respectively) at day 14 and slowly decreased over time. The geometric mean titers against Omicron were lower than against type with a 19.8-39. Sixfold reduction at all time points. The seropositivity against Omicron at the baseline, days 14, 28, 98, and 174 after the booster dose was 12.6%, 50.0%, 37.8%, 38.6%, and 22.8%, respectively. Data presented herein indicated that the BBIBP-CorV/CoronaVac booster significantly enhances the neutralizing potency against wild-type strain but elicited weaker neutralizing activity to Omicron. Our findings suggest that individuals receiving booster inactivated vaccine remain at risk for Omicron infection, which is crucial to inform ongoing and future vaccination strategies to combat coronavirus disease 2019.

A Novel SiC Trench MOSFET with Self-Aligned N-Type Ion Implantation Technique.

We propose a novel silicon carbide (SiC) self-aligned N-type ion implanted trench MOSFET (NITMOS) device. The maximum electric field in the gate oxide could be effectively reduced to below 3 MV/cm with the introduction of the P-epi layer below the trench. The P-epi layer is partially counter-doped by a self-aligned N-type ion implantation process, resulting in a relatively low specific on-resistance (Ron,sp). The lateral spacing between the trench sidewall and N-implanted region (Wsp) plays a crucial role in determining the performance of the SiC NITMOS device, which is comprehensively studied through the numerical simulation. With the Wsp increasing, the SiC NITMOS device demonstrates a better short-circuit capability owing to the reduced saturation current. The gate-to-drain capacitance (Cgd) and gate-to-drain charge (Qgd) are also investigated. It is observed that both Cgd and Qgd decrease as the Wsp increases, owing to the enhanced screen effect. Compared to the SiC double-trench MOSFET device, the optimal SiC NITMOS device exhibits a 79% reduction in Cgd, a 38% decrease in Qgd, and a 41% reduction in Qgd × Ron,sp. A higher switching speed and a lower switching loss can be achieved using the proposed structure.

Glucagon-like peptide-1 receptor agonists for the management of diabetic peripheral neuropathy.

Diabetes mellitus is a prevalent chronic disease characterized by hyperglycemia. Diabetic peripheral neuropathy (DPN) is one of the complications of diabetes mellitus and is caused by neuron injury induced by hyperglycemic circumstances. The incidence of DPN varies among different countries and regions, ranging from nearly 20% to over 70%. Patients with DPN may encounter symmetric pain or discomfort of the extremes, leading to reduced quality of life and even amputation. The pharmacological management for painful DPN mainly includes antidepressants due to their analgesic effects. Nevertheless, effective therapies to impact the pathogenesis and progression of DPN are lacking. Glucagon-like peptide-1 receptor (GLP-1R) agonists show efficacy in controlling blood glucose and serve as a treatment modality for diabetes mellitus. In recent years, evidence has been proposed that GLP-1R agonists exert neuroprotective effects through modulating inflammation, oxidative stress, and mitochondrial dysfunction. On the other hand, clinical evidence on the potential of GLP-1R agonists for treating DPN is still controversial and limited. This narrative review summarizes the preclinical and clinical studies investigating the capacity of GLP-1R agonists as therapeutic agents for DPN.

The nuclear factor kappa B signaling pathway is a master regulator of renal fibrosis.

Renal fibrosis is increasingly recognized as a global public health problem. Acute kidney injury (AKI) and chronic kidney disease (CKD) both result in renal fibrosis. Oxidative stress and inflammation play central roles in progressive renal fibrosis. Oxidative stress and inflammation are closely linked and form a vicious cycle in which oxidative stress induces inflammation through various molecular mechanisms. Ample evidence has indicated that a hyperactive nuclear factor kappa B (NF-ƙB) signaling pathway plays a pivotal role in renal fibrosis. Hyperactive NF-ƙB causes the activation and recruitment of immune cells. Inflammation, in turn, triggers oxidative stress through the production of reactive oxygen species and nitrogen species by activating leukocytes and resident cells. These events mediate organ injury through apoptosis, necrosis, and fibrosis. Therefore, developing a strategy to target the NF-ƙB signaling pathway is important for the effective treatment of renal fibrosis. This Review summarizes the effect of the NF-ƙB signaling pathway on renal fibrosis in the context of AKI and CKD (immunoglobulin A nephropathy, membranous nephropathy, diabetic nephropathy, hypertensive nephropathy, and kidney transplantation). Therapies targeting the NF-ƙB signaling pathway, including natural products, are also discussed. In addition, NF-ƙB-dependent non-coding RNAs are involved in renal inflammation and fibrosis and are crucial targets in the development of effective treatments for kidney disease. This Review provides a clear pathophysiological rationale and specific concept-driven therapeutic strategy for the treatment of renal fibrosis by targeting the NF-ƙB signaling pathway.