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BACKGROUND: High expression of ubiquitin ligase MDM2 is a primary cause of p53 inactivation in many tumors, making it a promising therapeutic target. However, MDM2 inhibitors have failed in clinical trials due to p53-induced feedback that enhances MDM2 expression. This underscores the urgent need to find an effective adaptive genotype or combination of targets. METHODS: Kinome-wide CRISPR/Cas9 knockout screen was performed to identify genes that modulate the response to MDM2 inhibitor using TP53 wild type cancer cells and found ULK1 as a candidate. The MTT cell viability assay, flow cytometry and LDH assay were conducted to evaluate the activation of pyroptosis and the synthetic lethality effects of combining ULK1 depletion with p53 activation. Dual-luciferase reporter assay and ChIP-qPCR were performed to confirm that p53 directly mediates the transcription of GSDME and to identify the binding region of p53 in the promoter of GSDME. ULK1 knockout / overexpression cells were constructed to investigate the functional role of ULK1 both in vitro and in vivo. The mechanism of ULK1 depletion to activate GSMDE was mainly investigated by qPCR, western blot and ELISA. RESULTS: By using high-throughput screening, we identified ULK1 as a synthetic lethal gene for the MDM2 inhibitor APG115. It was determined that deletion of ULK1 significantly increased the sensitivity, with cells undergoing typical pyroptosis. Mechanistically, p53 promote pyroptosis initiation by directly mediating GSDME transcription that induce basal-level pyroptosis. Moreover, ULK1 depletion reduces mitophagy, resulting in the accumulation of damaged mitochondria and subsequent increasing of reactive oxygen species (ROS). This in turn cleaves and activates GSDME via the NLRP3-Caspase inflammatory signaling axis. The molecular cascade makes ULK1 act as a crucial regulator of pyroptosis initiation mediated by p53 activation cells. Besides, mitophagy is enhanced in platinum-resistant tumors, and ULK1 depletion/p53 activation has a synergistic lethal effect on these tumors, inducing pyroptosis through GSDME directly. CONCLUSION: Our research demonstrates that ULK1 deficiency can synergize with MDM2 inhibitors to induce pyroptosis. p53 plays a direct role in activating GSDME transcription, while ULK1 deficiency triggers upregulation of the ROS-NLRP3 signaling pathway, leading to GSDME cleavage and activation. These findings underscore the pivotal role of p53 in determining pyroptosis and provide new avenues for the clinical application of p53 restoration therapies, as well as suggesting potential combination strategies.

Asunto(s)

Homólogo de la Proteína 1 Relacionada con la Autofagia , Piroptosis , Especies Reactivas de Oxígeno , Transducción de Señal , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Ratones , Especies Reactivas de Oxígeno/metabolismo , Animales , Regulación hacia Arriba , Mutaciones Letales Sintéticas , Femenino , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Línea Celular Tumoral , Proteína con Dominio Pirina 3 de la Familia NLR

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Oxaliplatin is currently used for chemotherapy in patients with hepatocellular carcinoma, but its increasing tolerance to tumours over time limits its clinical application. Studies have shown that high PD-L1 expression promotes the polarization of M2 macrophages. The increased infiltration of M2 macrophages, including those in HCC, is positively correlated with poor prognosis in various solid tumours. We found that oxaliplatin promoted the expression of PD-L1 in liver cancer cells, which might be attributed partly to the tolerance of tumours to oxaliplatin. Therefore, in this study, we explored the antitumour effect of attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin via Western blotting, immunohistochemistry, immunofluorescence, and flow cytometry. The results revealed that attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin more significantly inhibited tumour growth in tumour-bearing mice, suppressed the expression of PD-L1 in tumour tissue, increased the apoptosis of tumour cells and the expression of the tumour-related protein cleaved-caspase3, and increased the infiltration of M1 macrophages and T lymphocytes in tumour tissues. Moreover, the combination therapy increased the activation of T cells and the number of T lymphocytes and NK cells in the spleens of the mice and improved the overall antitumour immune response in the mice. Our results confirmed that attenuated Salmonella harbouring siRNA-PD-L1 combined with oxaliplatin had a significant antitumour effect and did not increase the incidence of toxic side effects, providing a theoretical reference for addressing oxaliplatin tolerance in the treatment of hepatocellular carcinoma.

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Antígeno B7-H1 , Carcinoma Hepatocelular , Neoplasias Hepáticas , Oxaliplatino , ARN Interferente Pequeño , Animales , Oxaliplatino/uso terapéutico , Oxaliplatino/farmacología , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/antagonistas & inhibidores , ARN Interferente Pequeño/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/inmunología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Ratones , Humanos , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Salmonella , Ratones Endogámicos BALB C , Masculino , Terapia Combinada , Modelos Animales de Enfermedad , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos

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BACKGROUND: Percutaneous Endoscopic Lumbar Discectomy (PELD) has emerged as routine treatment for lumbar disc herniation (LDH) due to its minimal invasiveness and quick recovery. However, PELD demands high precision from the surgeon, as the risk of intraoperative complications is substantial, including potential damage to the nerve root and dura, and a higher likelihood of recurrence post-surgery. Thus, preoperative planning utilizing CT and MRI imaging is essential. METHODS: In this study, the clinical data of 140 patients treated with PELD for LDH from January 2021 to December 2023 were retrospectively analyzed. Patients were categorized into two groups based on whether CT and MRI registration (CMR) was employed for surgical planning: a CMR group (n=68) and a control group (n=72). Data collected included surgery time, hospital stay duration, and scores from the Visual Analog Scale (VAS) for low back and leg pain, as well as the Japanese Orthopaedic Association Lumbar Spine Score (JOA). Differences between the two groups were assessed using the Student's t-test. RESULTS: No significant difference was found in hospital stay length between the groups (P=0.277). Surgery time was significantly shorter in the CMR group (P<0.001). Prior to surgery, no significant differences in VAS scores for leg and low back pain were observed between the groups (P=0.341 and P=0.131, respectively); however, at 2 months postoperatively, both scores were significantly lower in the CMR group (P<0.001 and P=0.002, respectively). Similarly, no difference in preoperative JOA scores was noted (P=0.750), but at 2 months postoperative, the CMR group exhibited significantly higher scores (P<0.001). CONCLUSION: Compared with the traditional PELD, the preoperative use of CMR has shown to reduce surgery time, alleviate leg and low back pain, and increase the lumbar JOA score at 2 months after surgery, underscoring its efficacy in enhancing surgical outcomes.

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The hydrogen (H2) evolution rates of photocatalysts suffer from weak oxidation and reduction ability and low photogenerated charge carrier separation efficiency. Herein, by combining band-gap structure optimization and vacancy modulation through a one-step hydrothermal method, In2O3 containing oxygen vacancy (Ov/In2O3) is simply introduced into In2S3 to promote photocatalytic hydrogen evolution. Specifically, the change in the sulfur source ratio can induce the coexistence of Ov/In2O3 and In2S3 in a high-temperature hydrothermal process. Under light irradiation, In2S3@Ov/In2O3-0.1 nanosheets hold a remarkable average H2 evolution rate up to 4.04 mmol g-1 h-1, which is 32.14, 11.91, and 2.25-fold better than those of pristine In2S3, In2S3@Ov/In2O3-0.02, and In2S3@Ov/In2O3-0.25 nanosheets, respectively. The ultraviolet-visible (UV-vis) diffuse reflectance and photoluminescence (PL) spectra reveal that the formation of Ov/In2O3 in In2S3 optimizes the band-gap structure and accelerates the migration of the photogenerated charge carrier of In2S3@Ov/In2O3-x nanosheets, respectively. Both the enhancement of oxidation and reduction ability and photogenerated charge carrier separation ability are responsible for the remarkable improvement in photocatalytic H2 evolution performance. This work provides a new strategy to prepare a composite of metal sulfide and metal oxide through a one-step hydrothermal method.

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Background: Previous research has suggested that dyslipidemia may be a risk factor for rotator cuff syndrome (RCS), and lipid-lowering drugs may aid in its treatment, though conclusions have not been definitive. Mendelian randomization is a statistical method that explores the causal relationships between exposure factors and diseases. It overcomes the confounding issues inherent in traditional observational studies, thereby providing more reliable causal inferences. We employed this method to investigate whether hyperlipidemia is a risk factor for rotator cuff syndrome and whether lipid-lowering drugs can effectively treat this condition. Methods: Genetic variations linked to lipid traits low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and total cholesterol (TC) were acquired from the UK Biobank and the Global Lipids Genetics Consortium (GLGC). Data on genetic variation in rotator cuff syndrome were obtained from FinnGen, including 24,061 patients and 275,212 controls. In the next step, we carried out two-sample Mendelian randomization analyses to determine whether lipid traits correlate with rotator cuff syndrome risk. Additionally, we performed drug-target Mendelian randomization (MR) analyses on 10 drug targets related to rotator cuff syndrome. For the drug targets that showed significant results, further analysis was done using Summary-data-based Mendelian Randomization (SMR) and colocalization techniques. We performed a mediation analysis to identify potential mediators between HMG-CoA reductase (HMGCR) and RCS. Results: No causative link was established between these lipid traits and rotator cuff syndrome. However, a significant association has been identified where HMGCR inhibition corresponds to a reduced risk of rotator cuff disease (OR = 0.68, [95% CI, 0.56-0.83], p = 1.510 × 10-4). Additionally, enhanced expression of HMGCR in muscle tissues is also linked to a decreased risk of rotator cuff syndrome (OR = 0.88, [95% CI, 0.76-0.99], p = 0.03). Body mass index (BMI) mediated 22.97% of the total effect of HMGCR on RCS. Conclusion: This study does not support low-density LDL-C, TG, and TC as risk factors for rotator cuff syndrome. HMGCR represents a potential pharmaceutical target for preventing and treating rotator cuff syndrome. The protective action of statins on the rotator cuff syndrome might not be associated with their lipid-lowering properties.

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BACKGROUND: Existing studies have found that circular RNAs (circRNAs) act as sponges for micro RNAs (miRNAs) to control downstream genes. However, the specific functionalities and mechanisms of circRNAs in human clear cell renal cell carcinoma (ccRCC) have yet to be thoroughly investigated. METHODS: Patient cohorts from online databases were used to screen candidate circRNAs, while another cohort from our hospital was obtained for validation. CircSOD2 was identified as a potential oncogenic target, and its relevant characteristics were investigated during ccRCC progression through various assays. A positive feedback loop containing downstream miRNA and its target gene were identified using bioinformatics and validated by luciferase reporter assays, RNA pull-down, and high-throughput sequencing. RESULTS: CircSOD2 expression was elevated in tumor samples and significantly correlated with overall survival (OS) and the tumor stage of ccRCC patients, which appeared in the enhanced proliferation, invasion, and migration of tumor cells. Through competitive binding to circSOD2, miR-532-3p can promote the expression of PAX5 and the progression of ccRCC, and such regulation can be salvaged by miR-532-3p inhibitor. CONCLUSION: A novel positive feedback loop, PAX5/circSOD2/miR-532-3p/PAX5 was identified in the study, indicating that the loop may play an important role in the diagnosis and prognostic prediction in ccRCC patients.

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Carcinoma de Células Renales , Proliferación Celular , Retroalimentación Fisiológica , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales , MicroARNs , ARN Circular , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Persona de Mediana Edad , Masculino , Carcinogénesis/genética , Carcinogénesis/patología , Movimiento Celular/genética , Factor de Transcripción PAX5/metabolismo , Factor de Transcripción PAX5/genética , Oncogenes/genética , Secuencia de Bases , Progresión de la Enfermedad , Invasividad Neoplásica , Reproducibilidad de los Resultados

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OBJECTIVE: To examine the potential of galangin in a mouse model of ovalbumin (OVA)-induced allergic rhinitis (AR), as chronic AR, induced by immunoglobulin-E (IgE), leads to histamine release and nasal inflammation, and although galangin exhibits antiasthmatic and anti-inflammatory potential, its effect on AR is yet to be investigated. ANIMALS: 126 BALB/c mice. METHODS: AR induction involved sensitizing female mice with OVA (5%, 500 µL, IP) for 14 days. Post OVA challenge, the mice were divided into 7 groups (n = 18/group), including normal, AR control, montelukast (10 mg/kg), galangin (5, 10, and 20 mg/kg), and per se (galangin [20 mg/kg] treatment. Various outcomes were evaluated, including nasal symptoms, histopathology, biochemistry, and nasal lavage fluid inflammatory cytokines and signaling pathways in nasal mucosal to assess galangin potential in AR. RESULTS: In AR mice, galangin (10 and 20 mg/kg) significantly (P < .05) reduced sneezing, rubbing, and nasal discharge post-OVA challenge. Galangin treatment attenuated (P < .05) elevated serum histamine, ß-hexosaminidase, IgE, and Immunoglobulin G1 levels in AR control mice. Additionally, galangin significantly (P < .05) decreased OVA-induced alterations in IL-4, IL-6, IL-13, and interferon-γ levels in nasal lavage fluid compared to AR control mice. Western blot analysis demonstrated that galangin lowered OVA-induced AR by significantly (P < .05) downregulating the phosphorylated protein kinase B and mammalian target of rapamycin-protein expressions while markedly (P < .05) upregulating the glycogen synthase kinase-3ß protein expressions in nasal mucosal. Galangin also significantly ameliorated (P < .05) the OVA-induced histological aberrations in the nasal mucosa, reflected by reduced eosinophil infiltration, hyperplasia, and edema. CLINICAL RELEVANCE: Galangin exhibits antihistaminic and anti-inflammatory effects in AR mice by regulating IgE-mediated histamine and inflammatory release and modulating the phosphatidylinositol 3-kinase/Ak strain transforming/mammalian target of rapamycin pathways.

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Flavonoides , Ratones Endogámicos BALB C , Ovalbúmina , Rinitis Alérgica , Animales , Flavonoides/farmacología , Flavonoides/uso terapéutico , Ratones , Femenino , Rinitis Alérgica/tratamiento farmacológico , Rinitis Alérgica/inducido químicamente , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Modelos Animales de Enfermedad , Quinolinas/farmacología , Quinolinas/uso terapéutico , Citocinas/metabolismo , Mucosa Nasal/efectos de los fármacos , Inmunoglobulina E/sangre , Acetatos , Ciclopropanos , Sulfuros

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Delicately manipulating nanomorphology is recognized as a vital and effective approach to enhancing the performance and stability of organic solar cells (OSCs). However, the complete removal of solvent additives with high boiling points is typically necessary to maintain the operational stability of the device. In this study, two commercially available organic intermediates, namely thieno[3,2-b]thiophene (TT) and 3,6-dibromothieno[3,2-b]thiophene (TTB) are introduced, as solid additives in OSCs. The theoretical simulations and experimental results indicate that TT and TTB may exhibit stronger intermolecular interactions with the acceptor Y6 and donor PM6, respectively. This suggests that the solid additives (SAs) can selectively intercalate between Y6 and PM6 molecules, thereby improving the packing order and crystallinity. As a result, the TT-treated PM6:Y6 system exhibits a favorable morphology, improved charge carrier mobility, and minimal charge recombination loss. These characteristics contribute to an impressive efficiency of 17.75%. Furthermore, the system demonstrates exceptional thermal stability (T80 > 2800 h at 65 °C) and outstanding photostability. The universal applicability of TT treatment is confirmed in OSCs employing D18:L8-BO, achieving a significantly higher PCE of 18.3%. These findings underscore the importance of using appropriate solid additives to optimize the blend morphology of OSCs, thereby improving photovoltaic performance and thermal stability.

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Bovine viral diarrhea virus (BVDV) has caused massive economic losses in the cattle business worldwide. Fatty acid synthase (FASN), a key enzyme of the fatty acid synthesis (FAS) pathway, has been shown to support virus replication. To investigate the role of fatty acids (FAs) in BVDV infection, we infected CD8+T lymphocytes obtained from healthy cattle with BVDV in vitro. During early cytopathic (CP) and noncytopathic (NCP) BVDV infection in CD8+ T cells, there is an increase in de novo lipid biosynthesis, resulting in elevated levels of free fatty acids (FFAs) and triglycerides (TG). BVDV infection promotes de novo lipid biosynthesis in a dose-dependent manner. Treatment with the FASN inhibitor C75 significantly reduces the phosphorylation of PI3K and AKT in BVDV-infected CD8+ T cells, while inhibition of PI3K with LY294002 decreases FASN expression. Both CP and NCP BVDV strains promote de novo fatty acid synthesis by activating the PI3K/AKT pathway. Further investigation shows that pharmacological inhibitors targeting FASN and PI3K concurrently reduce FFAs, TG levels, and ATP production, effectively inhibiting BVDV replication. Conversely, the in vitro supplementation of oleic acid (OA) to replace fatty acids successfully restored BVDV replication, underscoring the impact of abnormal de novo fatty acid metabolism on BVDV replication. Intriguingly, during BVDV infection of CD8+T cells, the use of FASN inhibitors prompted the production of IFN-α and IFN-ß, as well as the expression of interferon-stimulated genes (ISGs). Moreover, FASN inhibitors induce TBK-1 phosphorylation through the activation of RIG-1 and MDA-5, subsequently activating IRF-3 and ultimately enhancing the IFN-1 response. In conclusion, our study demonstrates that BVDV infection activates the PI3K/AKT pathway to boost de novo fatty acid synthesis, and inhibition of FASN suppresses BVDV replication by activating the RIG-1/MDA-5-dependent IFN response.

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Virus de la Diarrea Viral Bovina Tipo 1 , Virus de la Diarrea Viral Bovina , Bovinos , Animales , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Virus de la Diarrea Viral Bovina/fisiología , Linfocitos T CD8-positivos , Ácidos Grasos , Lípidos

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The treatment of hepatocellular carcinoma (HCC) remains a major challenge in the medical field. Lenvatinib, a multi-target tyrosine kinase inhibitor, has demonstrated anti-HCC effects by targeting and inhibiting pathways such as vascular endothelial growth factor receptor 1-3 (VEGFR1-3). However, the therapeutic efficacy of Lenvatinib is subject to various influences, with the hypoxic microenvironment of the tumor being a pivotal factor. Consequently, altering the hypoxic milieu of the tumor emerges as a viable strategy to augment the efficacy of Lenvatinib. Hypoxia-inducible factor-1α (HIF-1α), synthesized by tumor cells in response to oxygen-deprived conditions, regulates the expression of resistance genes, promotes tumor angiogenesis and cell proliferation, enhances tumor cell invasion, and confers resistance to radiotherapy and chemotherapy. Thus, we constructed a self-designed siRNA targeting HIF-1α to suppress its expression and improve the efficacy of Lenvatinib in treating HCC. The therapeutic efficacy of siRNA-HIF-1α in combination with Lenvatinib on HCC were evaluated through in vivo and in vitro experiments. The results showed that the recombinant Salmonella delivering siRNA-HIF-1α in combination with Lenvatinib effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice. This treatment approach reduced cell proliferation and angiogenesis in HCC tissues while promoting tumor cell apoptosis. Additionally, this combined therapy significantly increased the infiltration of T lymphocytes and M1 macrophages within the tumor microenvironment, as well as elevated the proportion of immune cells in the spleen, thereby potentiating the host's immune response against the tumor.

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Carcinoma Hepatocelular , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neoplasias Hepáticas , Compuestos de Fenilurea , Quinolinas , ARN Interferente Pequeño , Tratamiento con ARN de Interferencia , Salmonella , Animales , Ratones , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/terapia , Línea Celular Tumoral , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/terapia , Compuestos de Fenilurea/uso terapéutico , Quinolinas/uso terapéutico , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/uso terapéutico , Microambiente Tumoral , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Terapia Combinada , Tratamiento con ARN de Interferencia/métodos

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Introduction: Resveratrol, a polyphenol extracted from many plant species, has emerged as a promising pro-apoptotic agent in various cancer cells. However, the role of resveratrol in cell proliferation and apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis (RA-FLS) is not fully understood. The study was aimed at elucidating the role of resveratrol in cell proliferation and apoptosis of RA-FLS and the underlying molecular mechanism. Material and methods: Cultured RA-FLSs were subjected to tumour necrosis factor α (TNF-α). The cell proliferation was measured by Cell Counting Kit-8 assay. Cell apoptosis and cell cycle of RA-FLSs were determined by flow cytometry. The levels of apoptosis or autophagy or cell cycle-related protein were detected by immunoblot analysis. Results: In our study, we confirmed that resveratrol reversed TNF-α mediated cell proliferation in RA-FLS. Meanwhile, resveratrol blocked cells at the G2/M stage and reduced the ratio of S phase cells through upregulation of p53 and consequently led to apoptotic cell death. Quite interestingly, we found that resveratrol reversed TNF-α-induced autophagy. Inhibition of autophagy by resveratrol or autophagy inhibitor or Beclin-1 siRNA suppressed TNF-α mediated cell survival and promoted cell apoptosis. However, the autophagy inducer rapamycin (RAPA) reversed the effect of resveratrol on autophagy and cell proliferation. Mechanistic studies revealed that resveratrol inhibited the activation of the phosphoinositide 3-kinases/serine-threonine kinase (PI3K/AKT) pathway. Inhibition of PI3K/AKT pathway by inhibitor LY294002 or resveratrol increased the expression of p53 and decreased the expression of cycle protein (cyclin B1), which further led to block cells in the G2/M arrest. Conclusions: Our preliminary study indicated that resveratrol may suppress RA-FLS cell survival and promote apoptosis at least partly through regulation of autophagy and the AKT-p53 axis.

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INTRODUCTION: China initialised the expanded hepatitis A vaccination programme (EHAP) in 2008. However, the effectiveness of the programme remains unclear. We aimed to comprehensively evaluate the effectiveness of EHAP in the country. METHODS: Based on the provincial data on the incidence of hepatitis A (HepA), the population and meteorological variables in China, we developed interrupted time series (ITS) models to estimate the effectiveness of EHAP with the autocorrelation, seasonality and the meteorological confounders being controlled. Results were also stratified by economic zones, age groups and provinces. RESULTS: We found a 0.9% reduction (RR=0.991, 95% CI: 0.990 to 0.991) in monthly HepA incidence after EHAP, which was 0.3% greater than the reduction rate before EHAP in China. Across the three economic regions, we found a 1.1% reduction in HepA incidence in both central and western regions after EHAP, which were 0.3% and 1.2% greater than the reduction rates before EHAP, respectively. We found a decreased reduction rate for the eastern region. In addition, we found generally increased reduction rate after EHAP for age groups of 0-4, 5-14 and 15-24 years. However, we found decreased reduction rate among the 25-64 and ≥65 years groups. We found a slight increased rate after EHAP in Shanxi Province but not elsewhere. CONCLUSION: Our finding provides comprehensive evidence on the effectiveness of EHAP in China, particularly in the central and western regions, and among the population aged 0-24 years old. This study has important implications for the adjustment of vaccination strategies for other regions and populations.

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Hepatitis A , Humanos , Recién Nacido , Lactante , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Hepatitis A/epidemiología , Hepatitis A/prevención & control , Análisis de Series de Tiempo Interrumpido , Vacunación , China/epidemiología , Incidencia

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Non-noble metal catalysts are known for their efficient catalytic performance for oxygen reduction reaction (ORR), oxygen evolution reaction (OER), and hydrogen evolution reaction (HER). Metal organic gels (MOGs) can be considered as a promising electrocatalyst owing to the diverse physicochemical properties but usually suffer from its poor electrical conductivity and catalytic stability. Here, a FeCo-MOG is constructed with considerable trifunctional activity. The optimal P-CoFe-H3 prepared by using phytic acid (PA) and 2,4,6-Tris[(p-carboxyphenyl)amino]-1,3,5-triazine benzoic acid (H3TATAB) as dual ligands), exhibits outstanding ORR, OER, and HER activities as well as stability, exceeding most of state-of-the-art catalysts. As expected, the flexible Zn-air battery applied with P-CoFe-H3 as air cathode displays considerable power density, discharge voltage plateau, and cycling stability. Impressively, it is also capable of driving the overall water-splitting device by applying the P-CoFe-H3 as anode and cathode. Furthermore, theoretical calculations reveal that dual ligands can optimize the coordination environment and charge density of active sites, thereby reducing the absorption energy of intermediate species and boosting the catalytic performance. This work endows the dual-ligands coordination strategy with great potentiality for MOGs-based electrocatalysts in energy conversion devices.

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Titanium dioxide (TiO2)-based photodynamic antibacterial (PDA) agents present a novel approach for addressing drug-resistant bacterial infections and the associated tissue damage. However, the suboptimal dispersibility, negative charge, and weak photocatalytic activity under visible light of TiO2 hinder its practical applications. This study aimed to address these limitations by developing a highly hydrophilic and dispersed Zn-TiO2/reduced graphene oxide (rGO) (HTGZ) nano-system with exceptional visible light catalytic activity and tissue repair ability. HTGZ produced an antibacterial ratio over 98% within a short time, likely due to the enhanced production of reactive oxygen species under visible light. After being co-cultured for 4 days, L929 cells and BMSCs maintained over 90% activity, indicating that HTGZ had no significant cytotoxicity. Furthermore, the transcriptomic and metabolic analyses revealed that the antibacterial mechanism mainly came from the destruction of cell membranes and the disruption of various metabolic processes, such as purine metabolism and fatty acid biosynthesis. Critically, results of in vivo experiments had authenticated that HTGZ significantly promoted infected tissue regeneration by slaughtering bacteria and release Zn2+. After 14 days, the wound area was only one-third that of the control group. Overall, the enhanced antibacterial efficacy and wound-healing potential position HTGZ as a promising nano-antibacterial medication for the clinical treatment of infectious bacterial diseases.

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Antibacterianos , Luz , Antibacterianos/farmacología , Titanio/farmacología

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To clarify the risk of tuberculosis (TB) infection in patients with Takayasu arteritis (TAK). In this study, we conducted a comprehensive search across multiple databases, including PubMed, Web of Science, Embase, Cochrane, and Medline, from the inception of the Literature Library to May 16, 2023. Using a specific set of keywords, including "Takayasu Arteritis", "Tuberculosis", and "Mycobacterium tuberculosis", the main objective of this search was to identify all relevant observational studies, including case-control studies, cohort studies, and cross-sectional studies, that report the prevalence of TB in individuals diagnosed with TAK. Two independent evaluators rigorously screened the studies, extracted data, and assessed the study quality using the Joanna Briggs Institute (JBI) critical appraisal tools. Statistical analyses were conducted using R software version 4.3.0, which allowed for the synthesis of prevalence and subgroup analyses. Subgroup analyses were stratified based on quality scores, World Health Organization regional categorizations, and TB categories. Assessment of publication bias was performed using a funnel plot. The study included a total of 30 studies with 5548 participants. The findings showed that individuals with TAK exhibited an average prevalence of TB infection at 31.27% (95% CI 20.48-43.11%). Significantly, the prevalence of TB infection demonstrated notable regional disparities, ranging from 16.93% (95% CI 7.71-28.76%) in the Western Pacific Region to 63.58% (95% CI 35.70-87.66%) in the African Region. Moreover, the study revealed that patients with TAK displayed a high prevalence of latent TB infection (LTBI) at 50.01% (95% CI 31.25-68.77%) and active TB at 14.40% (95% CI 9.03-20.68%). The high heterogeneity observed in the data highlights significant variability in TB infection rates among the populations studied, with the African Region exhibiting the highest rates. The study concludes that there is a high prevalence of TB infection in the TAK population, with regional variations. Consideration should be given to  implementing rigorous TB screening measures and preventive interventions specifically tailored for the TAK population.

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Tuberculosis Latente , Arteritis de Takayasu , Tuberculosis , Humanos , Estudios Transversales , Tuberculosis Latente/diagnóstico , Prevalencia , Arteritis de Takayasu/complicaciones , Arteritis de Takayasu/epidemiología , Tuberculosis/epidemiología , Tuberculosis/diagnóstico , Estudios Observacionales como Asunto

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Bismuth telluride and its alloys are widely utilized in thermoelectric refrigeration and power generation devices. Waste bismuth telluride-based cooling chips contain valuable elements; however, recycling processes for these materials remain underdeveloped due to their complexity. In this study, we developed a concise and efficient chemical method that does not require expensive reagents or equipment, enabling the separation and purification of tellurium, bismuth, selenium, and antimony from waste bismuth telluride-based cooling chips. Initially, the waste was leached with HCl and NaClO3 to dissolve primary elements and recover 99.9% of selenium using hydroxylamine hydrochloride. Subsequently, Na2S and NaOH were employed for precipitation and leaching, resulting in a solution containing tellurium. The precipitated residue was treated with HNO3 to oxidize antimony into insoluble SbOHN and dissolve bismuth completely. 99.8% of the bismuth telluride waste was dissolved via oxidative leaching through hydrolysis. A small amount of sodium sulfide reduced the precipitation percentage of tellurium from 11.9% to 7.5% in an alkaline solution, and the direct recovery percentage of tellurium in the form of TeO2 exceeded 90%, while the purity of TeO2 reached 99.9%. By adjusting the pH of the bismuth solution to 0.15, 98.9% of the bismuth was able to precipitate and be recovered as BiOCl, with the purity also reaching 99.9%. In summary, this study presents an efficient hydrometallurgical method for treating bismuth telluride waste and provides theoretical guidance for reagent dosage, demonstrating the significant potential for industrial applications.

RESUMEN

A general method for the direct synthesis of highly homogeneous and dense polymerized carbon nitride (PCN) nanosheet films on F: SnO2 (FTO) is developed. Detailed photoelectrochemical (PEC) water-splitting studies reveal that the as-synthesized PCN films exhibit outstanding performance as photoanode for PEC water-splitting. The optimal PCN photoanode exhibits excellent photocurrent density of 650 µA cm-2 , and monochromatic incident photon-to-electron conversion efficiency (IPCE) value up to 30.55% (λ = 400 nm) and 25.97% (λ = 420 nm) at 1.23 VRHE in 0.1 m KOH electrolyte. More importantly, the PCN photoanode has an excellent hole extraction efficiency of up to 70 ± 3% due to the abundance of active sites provided by the PCN photoanode nanosheet, which promotes the transport rates of OER-relevant species. These PCN films provide a new benchmark for PCN photoanode materials.

RESUMEN

BACKGROUND AND AIMS: Leisure sedentary behavior (LSB) is associated with the risk of cancer, but the causal relationship between them has not been clarified. The aim of this study was to assess the potential causal association between LSB and risk of 15 site-specific cancers. METHODS: The causal association between LSB and cancer were assessed with univariate Mendelian randomization (UVMR) and multivariate Mendelian randomization (MVMR). 194 SNPs associated with LSB (from the UK Biobank 408,815 individuals) were adopted as the instrument variables. Sensitivity analyses were performed to ensure the robustness of the results. RESULTS: UVMR analysis revealed that television watching significantly increased the risk of endometrial cancer (OR = 1.29, 95% CI = 1.02-1.64, p = 0.04) (mainly the endometrioid histology [OR = 1.28, 95% CI = 1.02-1.60, p = 0.031])，breast cancer (OR = 1.16, 95% CI = 1.04-1.30, p = 0.007) (both ER+ breast cancer [OR = 1.17, 95% CI = 1.03-1.33, p = 0.015], and ER- breast cancer [OR = 1.55, 95% CI = 1.26-1.89, p = 2.23 × 10-5 ]). Although causal association was not found between television watching and ovarian cancer, it was seen in low grade and low malignant potential serous ovarian cancer (OR = 1.49, 95% CI = 1.07-2.08, p = 0.018). However, significant results were not obtained in the UVMR analysis between driving, computer use and the 15 types of cancer. Further MVMR analysis indicated that the above results are independent from most metabolic factors and dietary habits, but mediated by educational attainment. CONCLUSION: LSB in form of television watching has independent causal association with the risk of endometrial cancer, breast cancer, and ovarian cancer.

Asunto(s)

Neoplasias de la Mama , Neoplasias Endometriales , Neoplasias Ováricas , Femenino , Humanos , Factores de Riesgo , Conducta Sedentaria , Análisis de la Aleatorización Mendeliana/métodos , Neoplasias Ováricas/genética , Neoplasias de la Mama/etiología , Neoplasias de la Mama/genética , Neoplasias Endometriales/etiología , Neoplasias Endometriales/genética , Polimorfismo de Nucleótido Simple , Actividades Recreativas , Estudio de Asociación del Genoma Completo

RESUMEN

Natural products have emerged as "rising stars" for treating viral diseases and useful chemical scaffolds for developing effective therapeutic agents. The nonstructural protein NS5B (RNA-dependent RNA polymerase) of NADL strain BVDV was used as the action target based on a molecular docking technique to screen herbal monomers for anti-BVDV viral activity. The in vivo and in vitro anti-BVDV virus activity studies screened the Chinese herbal monomers with significant anti-BVDV virus effects, and their antiviral mechanisms were initially explored. The molecular docking screening showed that daidzein, curcumin, artemisinine, and apigenin could interact with BVDV-NADL-NS5B with the best binding energy fraction. In vitro and in vivo tests demonstrated that none of the four herbal monomers significantly affected MDBK cell activity. Daidzein and apigenin affected BVDV virus replication mainly in the attachment and internalization phases, artemisinine mainly in the replication phase, and curcumin was active in the attachment, internalization, replication, and release phases. In vivo tests demonstrated that daidzein was the most effective in preventing and protecting BALB/C mice from BVDV infection, and artemisinine was the most effective in treating BVDV infection. This study lays the foundation for developing targeted Chinese pharmaceutical formulations against the BVDV virus.

Asunto(s)

Curcumina , Virus de la Diarrea Viral Bovina , Animales , Ratones , ARN Polimerasa Dependiente del ARN/metabolismo , Línea Celular , Simulación del Acoplamiento Molecular , Curcumina/farmacología , Curcumina/metabolismo , Apigenina/farmacología , Apigenina/metabolismo , Medicina Tradicional China , Ratones Endogámicos BALB C , Replicación Viral , Proteínas no Estructurales Virales/metabolismo , ARN Viral/metabolismo

RESUMEN

Catalysts for the electrolysis of water are critical in the production of hydrogen for the energy industry. The use of strong metal-support interactions (SMSI) to modulate the dispersion, electron distribution, and geometry of active metals is an effective strategy for improving catalytic performance. However, in currently used catalysts, the supporting effect does not significantly contribute directly to catalytic activity. Consequently, the continued investigation of SMSI, using active metals to stimulate the supporting effect for catalytic activity, remains very challenging. Herein, the atomic layer deposition technique was employed to prepare an efficient catalyst composed of platinum nanoparticles (Pt NPs) deposited on nickel-molybdate (NiMoO4) nanorods. Nickel-molybdate's oxygen vacancies (Vo) not only help anchor highly-dispersed Pt NPs with low loading but also strengthen the SMSI. The valuable electronic structure modulation between Pt NPs and Vo resulted in a low overpotential of the hydrogen and oxygen evolution reactions, returning results of 190 mV and 296 mV, respectively, at a current density of 100 mA cm-2 in 1 M KOH. Ultimately, an ultralow potential (1.515 V) for the overall decomposition of water was achieved at 10 mA cm-2, outperforming state-of-art catalysts based on the Pt/C || IrO2 couple (1.668 V). This work aims to provide reference and a concept for the design of bifunctional catalysts that apply the SMSI effect to achieve a simultaneous catalytic effect from the metal and its support.