Thermally Oxidized Memristor and 1T1R Integration for Selector Function and Low-Power Memory.

Resistive switching memories have garnered significant attention due to their high-density integration and rapid in-memory computing beyond von Neumann's architecture. However, significant challenges are posed in practical applications with respect to their manufacturing process complexity, a leakage current of high resistance state (HRS), and the sneak-path current problem that limits their scalability. Here, a mild-temperature thermal oxidation technique for the fabrication of low-power and ultra-steep memristor based on Ag/TiOx/SnOx/SnSe2/Au architecture is developed. Benefiting from a self-assembled oxidation layer and the formation/rupture of oxygen vacancy conductive filaments, the device exhibits an exceptional threshold switching behavior with high switch ratio exceeding 106, low threshold voltage of ≈1 V, long-term retention of >104 s, an ultra-small subthreshold swing of 2.5 mV decade-1 and high air-stability surpassing 4 months. By decreasing temperature, the device undergoes a transition from unipolar volatile to bipolar nonvolatile characteristics, elucidating the role of oxygen vacancies migration on the resistive switching process. Further, the 1T1R structure is established between a memristor and a 2H-MoTe2 transistor by the van der Waals (vdW) stacking approach, achieving the functionality of selector and multi-value memory with lower power consumption. This work provides a mild-thermal oxidation technology for the low-cost production of high-performance memristors toward future in-memory computing applications.

Multilayer Core-Shell Fiber Device for Improved Strain Sensing and Supercapacitor Applications.

1D fiber devices, known for their exceptional flexibility and seamless integration capabilities, often face trade-offs between desired wearable application characteristics and actual performance. In this study, a multilayer device composed of carbon nanotube (CNT), transition metal carbides/nitrides (MXenes), and cotton fibers, fabricated using a dry spinning method is presented, which significantly enhances both strain sensing and supercapacitor functionality. This core-shell fiber design achieves a record-high sensitivity (GF ≈ 4500) and maintains robust durability under various environmental conditions. Furthermore, the design approach markedly influences capacitance, correlating with the percentage of active material used. Through systematic optimization, the fiber device exhibited a capacitance 26-fold greater than that of a standard neat CNT fiber, emphasizing the crucial role of innovative design and high active material loading in improving device performance.

Association between advanced lung cancer inflammation index and in-hospital mortality in ICU patients with community-acquired pneumonia: A retrospective analysis of the MIMIC-IV database.

Objective: The objective of the present study was to explore the correlation between the advanced lung cancer inflammation index (ALI) and in-hospital mortality among patients diagnosed with community-acquired pneumonia (CAP). Methods: Data from the Medical Information Mart for Intensive Care-IV database were adopted to analyze the in-hospital mortality of ICU patients with CAP. Upon admission to the ICU, fundamental data including vital signs, critical illness scores, comorbidities, and laboratory results, were collected. The in-hospital mortality of all CAP patients was documented. Multivariate logistic regression (MLR) models and restricted cubic spline (RCS) analysis together with subgroup analyses were conducted. Results: This study includes 311 CAP individuals, involving 218 survivors as well as 93 nonsurvivors. The participants had an average age of 63.57 years, and the females accounted for approximately 45.33%. The in-hospital mortality was documented to be 29.90%. MLR analysis found that ALI was identified as an independent predictor for in-hospital mortality among patients with CAP solely in the Q1 group with ALI ≤ 39.38 (HR: 2.227, 95% CI: 1.026-4.831, P = 0.043). RCS analysis showed a nonlinear relationship between the ALI and in-hospital mortality, with a turning point at 81, and on the left side of the inflection point, a negative correlation was observed between ALI and in-hospital mortality (HR: 0.984, 95% CI: 0.975-0.994, P = 0.002). The subgroup with high blood pressure showed significant interaction with the ALI. Conclusion: The present study demonstrated a nonlinear correlation of the ALI with in-hospital mortality among individuals with CAP. Additional confirmation of these findings requires conducting larger prospective investigations.

Role of hydrogen sulfide in dermatological diseases.

Hydrogen sulfide (H2S), together with carbon monoxide (CO) and nitric oxide (NO), is recognized as a vital gasotransmitter. H2S is biosynthesized by enzymatic pathways in the skin and exerts significant physiological effects on a variety of biological processes, such as apoptosis, modulation of inflammation, cellular proliferation, and regulation of vasodilation. As a major health problem, dermatological diseases affect a large proportion of the population every day. It is urgent to design and develop effective drugs to deal with dermatological diseases. Dermatological diseases can arise from a multitude of etiologies, including neoplastic growth, infectious agents, and inflammatory processes. The abnormal metabolism of H2S is associated with many dermatological diseases, such as melanoma, fibrotic diseases, and psoriasis, suggesting its therapeutic potential in the treatment of these diseases. In addition, therapies based on H2S donors that release H2S are being developed to treat some of these conditions. In the review, we discuss recent advances in the function of H2S in normal skin, the role of altering H2S metabolism in dermatological diseases, and the therapeutic potential of diverse H2S donors for the treatment of dermatological diseases.

Public health events and economic growth in a neoclassical framework.

Public health events (PHEs) have emerged as significant threats to human life, health, and economic growth. PHEs, such as COVID-19, have prompted a reevaluation for enhanced regular prevention and control (RPC). In this study, we focus on the core concept of prevention and control intensity (PCI), and establish a neoclassical economic growth model from the long-term and macro perspective to balance life protection and economic growth. The model construct the mechanism of PCI on economic growth through population dynamics and capital accumulation under the backdrop of RPC for PHEs. We find the conditions for PCI when the economy achieves steady state, and provides an algorithm establishing the optimal strategy that maximises per capita disposable income based on the optimal PCI and consumption. Simulation result quantifies an inverted U-shaped relationship between PCI and capital per capita, output per capita and consumption per capita in the steady state. The model suggests that, given the PHEs of inducing potential unemployment shock, it is worthwhile to combine the implementation of moderate PCI with coordinated policies of income distribution.

Significant Improvement in Thermoelectric Properties of Carbon-Reinforced Cementitious Composites Achieved by Regulating the Graphitization Degree of Expanded Graphite.

Building structures are exposed to direct sunlight for a long time, accumulating a large amount of low-grade thermal energy, which aggravates environmental pollution and energy consumption. Thermoelectric cement-based composites can realize the interconversion of thermal and electrical energy, showing great potential benefits in large-scale heat collection and energy conversion. Although a lot of exploration and research has been carried out on the thermoelectric properties of cement-based composites reinforced with carbon materials, the contribution of the characteristics of carbon materials, such as the graphitization degree, to the thermoelectric properties of cement-based composites is still unclear. In this article, the graphitization degree of expanded graphite (EG) was modulated by etching EG with an acid solution. The low graphitization degree improves the effective mass of carriers and aggravates the electron and phonon scattering at the interface of EG/cement-based composites. Low thermal conductivity was obtained while increasing the Seebeck coefficient of EG/cement-based composites. The power factor (17.1 µW m-1 K-2) and thermoelectric figure of merit (2.95 × 10-3) of the sample are increased by 18.6 times and 44.2 times, respectively, achieving the highest thermoelectric performance in cement-based composites reinforced with carbon materials. This study provides a direction for improving the thermoelectric properties of cement-based composites by structural regulation of carbon materials.

Synthesis and antibacterial medicinal evaluation of carbothioamido hydrazonyl thiazolylquinolone with multitargeting antimicrobial potential to combat increasingly global resistance.

The global microbial resistance is a serious threat to human health, and multitargeting compounds are considered to be promising to combat microbial resistance. In this work, a series of new thiazolylquinolones with multitargeting antimicrobial potential were developed through multi-step reactions using triethoxymethane and substituted anilines as start materials. Their structures were confirmed by 1H NMR, 13C NMR and HRMS spectra. Antimicrobial evaluation revealed that some of the target compounds could effectively inhibit microbial growth. Especially, carbothioamido hydrazonyl aminothiazolyl quinolone 8a showed strong inhibitory activity toward drug-resistant Staphylococcus aureus with MIC value of 0.0047 mM, which was 5-fold more active than that of norfloxacin. The highly active compound 8a exhibited negligible hemolysis, no significant toxicity in vitro and in vivo, low drug resistance, as well as rapidly bactericidal effects, which suggested its favorable druggability. Furthermore, compound 8a was able to effectively disrupt the integrity of the bacterial membrane, intercalate into DNA and inhibit the activity of topoisomerase IV, suggesting multitargeting mechanism of action. Compound 8a could form hydrogen bonds and hydrophobic interactions with DNA-topoisomerase IV complex, indicating the insertion of aminothiazolyl moiety was beneficial to improve antibacterial efficiency. These findings indicated that the active carbothioamido hydrazonyl aminothiazolyl quinolone 8a as a chemical therapeutic candidate demonstrated immense potential to tackle drug-resistant bacterial infections.

Mechanism of oxymatrine in the treatment of cryptosporidiosis through TNF/NF-κB signaling pathway based on network pharmacology and experimental validation.

Cryptosporidiosis is a worldwide zoonotic disease. Oxymatrine, an alkaloid extracted and isolated from the plant bitter ginseng, has been reported to have therapeutic effects on cryptosporidiosis. However, the underlying mechanism of its action remains unclear. In this study, we utilized network pharmacology and experimental validation to investigate the mechanism of oxymatrine in the treatment of cryptosporidiosis. First, the potential targets of drugs and diseases were predicted by TCMSP, Gene Cards, and other databases. Following the intersection of drug-disease targets, the DAVID database was used to implement the enrichment analysis of GO functions and KEGG pathways, and then the network diagram of "intersected target-KEGG" relationship was constructed. Autodock 4.2.6 software was used to carry out the molecular docking of core targets to drug components. Based on the establishment of a mouse model of cryptosporidiosis, the validity of the targets in the TNF/NF-κB signaling pathway was confirmed using Western blot analysis and Quantitative Rea-ltime-PCR. A total of 41 intersectional targets of oxymatrine and Cryptosporidium were generated from the results, and five core targets were screened out by network analysis, including RELA, AKT1, ESR1, TNF, and CASP3. The enrichment analysis showed that oxymatrine could regulate multiple gene targets, mediate TNF, Apoptpsis, IL-17, NF-κB and other signaling pathways. Molecular docking experiments revealed that oxymatrine was tightly bound to core targets with stable conformation. Furthermore, we found through animal experiments that oxymatrine could regulate the mRNA and protein expression of IL-6, NF-κB, and TNF-α in the intestinal tissues of post-infected mice through the TNF/NF-κB signaling pathway. Therefore, it can be concluded that oxymatrine can regulate the inflammatory factors TNF-α, NF-κB, and IL-6 through the TNF/NF-κB signaling pathway for the treatment of cryptosporidiosis. This prediction has also been validated by network pharmacology and animal experiments.

Microneedle delivery system with rapid dissolution and sustained release of bleomycin for the treatment of hemangiomas.

Hemangioma of infancy is the most common vascular tumor during infancy and childhood. Despite the proven efficacy of propranolol treatment, certain patients still encounter resistance or face recurrence. The need for frequent daily medication also poses challenges to patient adherence. Bleomycin (BLM) has demonstrated effectiveness against vascular anomalies, yet its use is limited by dose-related complications. Addressing this, this study proposes a novel approach for treating hemangiomas using BLM-loaded hyaluronic acid (HA)-based microneedle (MN) patches. BLM is encapsulated during the synthesis of polylactic acid (PLA) microspheres (MPs). The successful preparation of PLA MPs and MN patches is confirmed through scanning electron microscopy (SEM) images. The HA microneedles dissolve rapidly upon skin insertion, releasing BLM@PLA MPs. These MPs gradually degrade within 28 days, providing a sustained release of BLM. Comprehensive safety assessments, including cell viability, hemolysis ratio, and intradermal reactions in rabbits, validate the safety of MN patches. The BLM@PLA-MNs exhibit an effective inhibitory efficiency against hemangioma formation in a murine hemangioma model. Of significant importance, RNA-seq analysis reveals that BLM@PLA-MNs exert their inhibitory effect on hemangiomas by regulating the P53 pathway. In summary, BLM@PLA-MNs emerge as a promising clinical candidate for the effective treatment of hemangiomas.

Exploring the evolving roles and clinical significance of circRNAs in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) represents the predominant malignancies in the head and neck region, and has limited therapeutic alternatives. Circular RNAs (circRNAs), a substantial category of non-coding RNA molecules, exert influential roles in human disease development and progression, employing various mechanisms such as microRNA sponging, interaction with RNA-binding proteins, and translational capabilities. Accumulating evidence highlights the differential expression of numerous circRNAs in HNSCC, and numerous dysregulated circRNAs underscore their crucial involvement in malignant advancement and resistance to treatment. This review aims to comprehensively outline the characteristics, biogenesis, and mechanisms of circRNAs, elucidating their functional significance in HNSCC. In addition, we delve into the clinical implications of circRNAs, considering their potential as biomarkers or targets for diagnosis, prognosis, and therapeutic applications in HNSCC. The discussion extends to exploring future challenges in the clinical translation of circRNAs, emphasizing the need for further research.

Two-Dimensional GeS/SnSe2 Tunneling Photodiode with Bidirectional Photoresponse and High Polarization Sensitivity.

A two-dimensional (2D) broken-gap (type-III) p-n heterojunction has a unique charge transport mechanism because of nonoverlapping energy bands. In light of this, type-III band alignment can be used in tunneling field-effect transistors (TFETs) and Esaki diodes with tunable operation and low consumption by highlighting the advantages of tunneling mechanisms. In recent years, 2D tunneling photodiodes have gradually attracted attention for novel optoelectronic performance with a combination of strong light-matter interaction and tunable band alignment. However, an in-depth understanding of the tunneling mechanisms should be further investigated, especially for developing electronic and optoelectronic applications. Here, we report a type-III tunneling photodiode based on a 2D multilayered p-GeS/n+-SnSe2 heterostructure, which is first fabricated by the mechanical exfoliation and dry transfer method. Through the Simmons approximation, its various tunneling transport mechanisms dependent on bias and light are demonstrated as the origin of excellent bidirectional photoresponse performance. Moreover, compared to the traditional p-n photodiode, the device enables bidirectional photoresponse capability, including maximum responsivity values of 43 and 8.7 A/W at Vds = 1 and -1 V, respectively, with distinctive photoactive regions from the scanning photocurrent mapping. Noticeably, benefiting from the in-plane anisotropic structure of GeS, the device exhibits an enhanced photocurrent anisotropic ratio of 9, driven by the broader depletion region at Vds = -3 V under 635 nm irradiation. Above all, the results suggest that our designed architecture can be potentially applied to CMOS imaging sensors and polarization-sensitive photodetectors.

Single-cell RNA sequencing analysis provides novel insights into the role of apoptosis-related genes in muscle aging.

OBJECTIVE: This study employed a comprehensive single-cell analysis approach to explore the role of cell apoptosis-related genes in muscle aging. METHODS: The single-cell RNA sequencing data from the GSE143704 dataset were used to identify distinct cell clusters and assess gene expression patterns related to apoptosis activation. The "limma" package was used to identify hub genes, after which we performed Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to identify relevant pathways. Additionally, Gene Set Enrichment Analysis(GSEA) and Gene Set Variation Analysis (GSVA) were used to uncover relevant biological pathways. The Receiver Operating Characteristic Curve (ROC) was used to evaluate the diagnostic value of the hub genes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to analyze the immune cell infiltration levels. RESULTS: Single-cell sequencing data from muscle aging patients allowed the identification of various cell types, including epithelial cells, adipocytes, and tissue-resident macrophages. By conducting a differential expression analysis that intersected active and nonactive apoptosis, as well as comparing elderly and young samples, a total of 22 hub genes were identified (p < 0.05). The 22 hub genes have discriminative ability as potential biomarkers for diagnosing muscle aging. The enrichment analysis indicated that these genes were closely associated with diverse pathways, including "response to UV-B" and "extracellular matrix organization" (p < 0.05). Furthermore, GSEA and GSVA indicated that multiple pathways emerged-for example, the "complement and coagulation cascades", "proteasome", "insulin signaling pathway", and "MAPK signaling pathway". Additionally, the analysis of immune cell infiltration revealed positive correlations between most of the hub genes and immune cells. CONCLUSION: Our study identified 22 apoptosis-related genes involved in muscle aging and indicated their potential diagnostic value. These findings offer a novel perspective on the pathogenesis of muscle aging and present potential targets for therapeutic interventions.

Water-dispersible macromolecular antioxidants for toughening and strengthening cellulose membranes.

Biodegradable packaging materials from cellulose are eco-friendly alternatives to traditional petroleum-based plastics. Balancing its mechanical properties as well as protective values (antioxidation, oxygen barrier, etc.) is critical. However, most studies to improve its antioxidation performance were accompanied by sacrificed mechanical properties. In the current work, a series of linear -COOH functionalized phenolic polymers were prepared from phenolic compounds (vanillin, 3,4-dihydroxy benzaldehyde) through a facile tri-component thiol-aldehyde polycondensation. While circumventing the cumbersome protection-deprotection of phenol groups, the one-pot strategy also affords water dispersible polymers for fabricating composites with cellulose nanofibers in an aqueous medium. After introducing 5-10 wt% of the copolymers, a minor soft phase was formed inside the composites, contributing to enhanced mechanical strength, toughness, antioxidation capability, and ultra-violet blocking performance, while its oxygen barrier property was well maintained.

Harnessing External Irradiation for Precise Activation of Metal-Based Agents in Cancer Therapy.

Cancer is a significant global health issue. Platinum-based chemotherapy drugs, including cisplatin, are crucial in clinical anti-cancer treatment. However, these drugs have limitations such as drug resistance, non-specific distribution, and irreversible toxic and side effects. In recent years, the development of metal-based agents has led to the discovery of other anti-cancer effects beyond chemotherapy. Precise spatiotemporal controlled external irradiation can activate metal-based agents at specific sites and play a different role from traditional chemotherapy. These strategies can not only enhance the anti-cancer efficiency, but also show fewer side effects and non-cross-drug resistance, which are ideal approaches to solve the problems caused by traditional platinum-based chemotherapy drugs. In this review, we focus onvarious metal-based agent-mediated cancer therapies that are activated by three types of external irradiation: near-infrared (NIR) light, ultrasound (US), and X-ray, and give some prospects. We hope that this review will promote the generation of new kinds of metal-based anti-cancer agents.

Aesthetic Reconstruction of the Sequelae of Large Facial Involuted Infantile Hemangioma with Tissue Expanders.

BACKGROUND: Large involuted infantile hemangioma remains a challenge in facial reconstruction. The characteristic fibrofatty residuum and multiple subunits/tissues involvement contribute significantly to the difficulty of surgical management. Tissue expander plays an important role in facial reconstruction, allowing plastic surgeons to repair skin damaged by both congenital and acquired defects. METHODS: Between 2009 and 2021, 30 patients who underwent tissue expansion surgery were reviewed in a single hospital. The demographic data, lesion characteristics, surgical approaches, complication rate, and aesthetic outcomes were analyzed. RESULTS: Thirty patients (5 men and 25 women) with a mean age of 14.03 ± 7.25 years (range, 4-33 years) were included. The mean follow-up is 35.92 months, ranging from 9 to 75 months. Tissue expansion-related complications include closed infection, 2/30 (6.67%); skin ischemia, 2/30 (6.67%); hematoma, 1/30 (3.33%); flap necrosis, 1/30 (3.33%). CONCLUSION: Large facial involuted infantile hemangiomas have variable patterns of presentation and necessitate tailored therapy. Tissue expansion is a reproducible approach to achieving aesthetic reconstruction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Multilevel Regulation of NF-κB Signaling by NSD2 Suppresses Kras-Driven Pancreatic Tumorigenesis.

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer with a dismal overall prognosis. NSD2 is an H3K36-specific di-methyltransferase that has been reported to play a crucial role in promoting tumorigenesis. Here, the study demonstrates that NSD2 acts as a putative tumor suppressor in Kras-driven pancreatic tumorigenesis. NSD2 restrains the mice from inflammation and Kras-induced ductal metaplasia, while NSD2 loss facilitates pancreatic tumorigenesis. Mechanistically, NSD2-mediated H3K36me2 promotes the expression of IκBα, which inhibits the phosphorylation of p65 and NF-κB nuclear translocation. More importantly, NSD2 interacts with the DNA binding domain of p65, attenuating NF-κB transcriptional activity. Furthermore, inhibition of NF-κB signaling relieves the symptoms of Nsd2-deficient mice and sensitizes Nsd2-null PDAC to gemcitabine. Clinically, NSD2 expression decreased in PDAC patients and negatively correlated to nuclear p65 expression. Together, the study reveals the important tumor suppressor role of NSD2 and multiple mechanisms by which NSD2 suppresses both p65 phosphorylation and downstream transcriptional activity during pancreatic tumorigenesis. This study opens therapeutic opportunities for PDAC patients with NSD2 low/loss by combined treatment with gemcitabine and NF-κBi.

The effectiveness of booster vaccination of inactivated COVID-19 vaccines against susceptibility, infectiousness, and transmission of omicron BA.2 variant: a retrospective cohort study in Shenzhen, China.

Little studies evaluated the effectiveness of booster vaccination of inactivated COVID-19 vaccines against being infected (susceptibility), infecting others (infectiousness), and spreading the disease from one to another (transmission). Therefore, we conducted a retrospective cohort study to evaluate the effectiveness of booster vaccination of inactivated COVID-19 vaccines against susceptibility, infectiousness, and transmission in Shenzhen during an Omicron BA.2 outbreak period from 1 February to 21 April 2022. The eligible individuals were classified as four sub-cohorts according to the inactivated COVID-19 vaccination status of both the close contacts and their index cases: group 2-2, fully vaccinated close contacts seeded by fully vaccinated index cases (reference group); group 2-3, booster-vaccinated close contacts seeded by fully vaccinated index cases; group 3-2, fully vaccinated close contacts seeded by booster-vaccinated index cases; and group 3-3, booster-vaccinated close contacts seeded by booster-vaccinated index cases. Univariate and multivariate logistic regression analyses were applied to estimate the effectiveness of booster vaccination. The sample sizes of groups 2-2, 2-3, 3-2, and 3-3 were 846, 1,115, 1,210, and 2,417, respectively. We found that booster vaccination had an effectiveness against infectiousness of 44.9% (95% CI: 19.7%, 62.2%) for the adults ≥ 18 years, 62.2% (95% CI: 32.0%, 78.9%) for the female close contacts, and 60.8% (95% CI: 38.5%, 75.1%) for the non-household close contacts. Moreover, booster vaccination had an effectiveness against transmission of 29.0% (95% CI: 3.2%, 47.9%) for the adults ≥ 18 years, 38.9% (95% CI: 3.3%, 61.3%) for the female close contacts, and 45.8% (95% CI: 22.1%, 62.3%) for the non-household close contacts. However, booster vaccination against susceptibility did not provide any protective effect. In summary, this study confirm that booster vaccination of the inactivated COVID-19 vaccines provides low level of protection and moderate level of protection against Omicron BA.2 transmission and infectiousness, respectively. However, booster vaccination does not provide any protection against Omicron BA.2 susceptibility.

Oyster Peptides Ameliorate Dextran Sulfate Sodium-Induced Ulcerative Colitis via Modulating the Gut Microbiota and Inhibiting the TLR4/NF-κB Pathway.

Ulcerative colitis (UC) is an inflammatory bowel disease with an increasing prevalence year over year, and the medications used to treat patients with UC clinically have severe side effects. Oyster peptides (OPs) have anti-inflammatory and antioxidant properties as functional foods that can alleviate a wide range of inflammatory conditions. However, the application of oyster peptides in ulcerative colitis is not well studied. In this work, an animal model of acute colitis was established using 3% dextran sulfate sodium (DSS), and the impact of OP therapy on colitis in mice was examined. Supplementing with OPs prevented DSS-induced colitis from worsening, reduced the expression of oxidative stress and inflammatory markers, and restored the intestinal barrier damage caused by DSS-induced colitis in mice. The 16S rDNA results showed that the OP treatment improved the gut microbiota structure of the UC mice, including increasing microbial diversity, increasing beneficial bacteria, and decreasing harmful bacteria. In the UC mice, the OP therapy decreased the relative abundance of Family_XIII_AD3011_group and Prevotella_9 and increased the relative abundance of Alistipes. In conclusion, OP treatment can inhibit the TLR4/NF-κB pathway and improve the intestinal microbiota in UC mice, which in turn alleviates DSS-induced colitis, providing a reference for the treatment of clinical UC patients.

TRIM25-mediated XRCC1 ubiquitination accelerates atherosclerosis by inducing macrophage M1 polarization and programmed death.

BACKGROUND: Macrophage-mediated cleaning up of dead cells is a crucial determinant in reducing coronary artery inflammation and maintaining vascular homeostasis. However, this process also leads to programmed death of macrophages. So far, the role of macrophage death in the progression of atherosclerosis remains controversial. Also, the underlying mechanism by which transcriptional regulation and reprogramming triggered by macrophage death pathways lead to changes in vascular inflammation and remodeling are still largely unknown. TRIM25-mediated RIG-I signaling plays a key role in regulation of macrophages fate, however the role of TRIM25 in macrophage death-mediated atherosclerotic progression remains unclear. This study aims to investigate the relationship between TRIM25 and macrophage death in atherosclerosis. METHODS: A total of 34 blood samples of patients with coronary stent implantation, including chronic total occlusion (CTO) leisions (n = 14) or with more than 50% stenosis of a coronary artery but without CTO leisions (n = 20), were collected, and the serum level of TRIM25 was detected by ELISA. Apoe-/- mice with or without TRIM25 gene deletion were fed with the high-fat diet (HFD) for 12 weeks and the plaque areas, necrotic core size, aortic fibrosis and inflammation were investigated. TRIM25 wild-type and deficient macrophages were isolated, cultured and stimulated with ox-LDL, RNA-seq, real-time PCR, western blot and FACS experiments were used to screen and validate signaling pathways caused by TRIM25 deletion. RESULTS: Downregulation of TRIM25 was observed in circulating blood of CTO patients and also in HFD-induced mouse aortas. After HFD for 12 weeks, TRIM25-/-ApoeE-/- mice developed smaller atherosclerotic plaques, less inflammation, lower collagen content and aortic fibrosis compared with TRIM25+/+ApoeE-/- mice. By RNA-seq and KEGG enrichment analysis, we revealed that deletion of TRIM25 mainly affected pyroptosis and necroptosis pathways in ox-LDL-induced macrophages, and the expressions of PARP1 and RIPK3, were significantly decreased in TRIM25 deficient macrophages. Overexpression of TRIM25 promoted M1 polarization and necroptosis of macrophages, while inhibition of PARP1 reversed this process. Further, we observed that XRCC1, a repairer of DNA damage, was significantly upregulated in TRIM25 deficient macrophages, inhibiting PARP1 activity and PARP1-mediated pro-inflammatory change, M1 polarization and necroptosis of macrophages. By contrast, TRIM25 overexpression mediated ubiquitination of XRCC1, and the inhibition of XRCC1 released PARP1, and activated macrophage M1 polarization and necroptosis, which accelerated aortic inflammation and atherosclerotic plaque progression. CONCLUSIONS: Our study has uncovered a crucial role of the TRIM25-XRCC1Ub-PARP1-RIPK3 axis in regulating macrophage death during atherosclerosis, and we highlight the potential therapeutic significance of macrophage reprogramming regulation in preventing the development of atherosclerosis.