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Pseudomonas aeruginosa is a widespread nosocomial pathogen with a significant to cause both severe planktonic acute and biofilm-related chronic infections. Small RNAs (sRNAs) are noncoding regulatory molecules that are stabilized by the RNA chaperone Hfq to trigger various virulence-related signaling pathways. Here, we identified an Hfq-binding sRNA in P. aeruginosa PAO1, PqsS, which promotes bacterial pathogenicity and pseudomonas quinolone signal quorum sensing (pqs QS) system. Specifically, PqsS enhanced acute bacterial infections by inducing host cell death and promoting rhamnolipid-regulated swarming motility. Meanwhile, PqsS reduced chronic infection traits including biofilm formation and antibiotic resistance. Moreover, PqsS repressed pqsL transcript, increasing PQS levels for pqs QS. A PQS-rich environment promoted PqsS expression, thus forming a positive feedback loop. Furthermore, we demonstrated that the PqsS interacts and destabilizes the pqsL mRNA by recruiting RNase E to drive degradation. These findings provide insights for future research on P. aeruginosa pathogenesis and targeted treatment.
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Proteínas Bacterianas , Biopelículas , Regulación Bacteriana de la Expresión Génica , Proteína de Factor 1 del Huésped , Pseudomonas aeruginosa , Quinolonas , Percepción de Quorum , ARN Bacteriano , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/patogenicidad , Pseudomonas aeruginosa/metabolismo , Virulencia , Biopelículas/crecimiento & desarrollo , Proteína de Factor 1 del Huésped/genética , Proteína de Factor 1 del Huésped/metabolismo , ARN Bacteriano/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Quinolonas/metabolismo , Quinolonas/farmacología , Endorribonucleasas/metabolismo , Endorribonucleasas/genética , Animales , ARN Pequeño no Traducido/genética , ARN Pequeño no Traducido/metabolismo , Infecciones por Pseudomonas/microbiología , Humanos , Ratones , Glucolípidos/metabolismoRESUMEN
Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), cholesteryl ester transfer protein (CETP) and apolipoprotein C3 (APOC3) are pivotal regulators of lipid metabolism, with licensed drugs targeting these genes. The use of lipid-lowering therapy via the inhibition of these genes has demonstrated a reduction in the risk of cardiovascular disease. However, concerns persist regarding their potential long-term impact on aortic diseases and calcific aortic valve disease (CAVS). This study aims to investigate causal relationships between genetic variants resembling these genes and aortic disease, as well as calcific aortic valve disease using Mendelian randomization (MR). Methods: We conducted drug-target Mendelian randomization employing summary-level statistics of low-density lipoprotein cholesterol (LDL-C) to proxy the loss-of-function of PCSK9, HMGCR, CETP and APOC3. Subsequently, we investigated the association between drug-target genetic variants and calcific aortic valve stenosis and aortic diseases, including thoracic aortic aneurysm (TAA), abdominal aortic aneurysm (AAA), and aortic dissection (AD). Results: The genetically constructed variants mimicking lower LDL-C levels were associated with a decreased risk of coronary artery disease, validating their reliability. Notably, HMGCR inhibition exhibited a robust protective effect against TAA (odds ratio (OR): 0.556, 95% CI: 0.372-0.831, p = 0.004), AAA (OR: 0.202, 95% CI: 0.107-0.315, p = 4.84 × 10-15), and AD (OR: 0.217, 95% CI: 0.098-0.480, p = 0.0002). Similarly, PCSK9, CETP and APOC3 inhibition proxies reduced the risk of AAA (OR: 0.595, 95% CI: 0.485-0.730, p = 6.75 × 10-7, OR: 0.127, 95% CI: 0.066-0.243, p = 4.42 × 10-10, and OR: 0.387, 95% CI: 0.182-0.824, p = 0.014, respectively) while showing a neutral impact on TAA and AD. Inhibition of HMGCR, PCSK9, and APOC3 showed promising potential in preventing CAVS with odds ratios of 0.554 (OR: 0.554, 95% CI: 0.433-0.707, p = 2.27 × 10-6), 0.717 (95% CI: 0.635-0.810, p = 9.28 × 10-8), and 0.540 (95% CI: 0.351-0.829, p = 0.005), respectively. However, CETP inhibition did not demonstrate any significant benefits in preventing CAVS (95% CI: 0.704-1.544, p = 0.836). The consistency of these findings across various Mendelian randomization methods, accounting for different assumptions concerning genetic pleiotropy, enhances the causal inference. Conclusions: Our MR analysis reveals that genetic variants resembling statin administration are associated with a reduced risk of AAA, TAA, AD and CAVS. HMGCR, PCSK9 and APOC3 inhibitors but not CETP inhibitors have positive benefits of reduced CAVS. Notably, PCSK9, CETP and APOC3 inhibitors exhibit a protective impact, primarily against AAA, with no discernible benefits extending to TAA or AD.
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Background: Reactivate the T cell immunity by PD-1/PD-L1 checkpoint blockade is widely used in non-small cell lung cancer (NSCLC) patients, while the post-translational modification of Programmed death ligand-1 (PD-L1) is commonly existed in various cancer cells, thus increases the complexity and difficulty in therapy development. Ginsenoside Rg3 is an active component of traditional Chinese herb Ginseng with multiple pharmacological effects including immune regulation. However, the effect on the glycosylation of PD-L1 is unknown. Methods: NSCLC cell lines were tested for glycosylation of PD-L1, and the potential mechanisms were investigated. Tumor cell-T cell coculture experiment was conducted and the activation of T cells and cytotoxicity were measured by flow cytometry. In vivo xenograft mouse tumor model was used to investigate the effects of Rg3 on PD-L1-mediated immunosuppression and tumor growth. Results: Here, we identified PD-L1 is widely N-linked glycosylated in NSCLC cell lines, while Rg3 could inhibit the glycosylation of PD-L1 by downregulating the EGFR signaling and further activate GSK3b-mediated degradation, thus resulted in reduced PD-L1 expression. Moreover, the inhibition of PD-L1 glycosylation promoted the activation and cytotoxicity of T cells under coculture condition. In addition, Rg3 could decrease the tumor volume and enhance anti-tumor T cell immunity as evidence by the upregulated expression of Granzyme B and perforin in CD8+T cells, along with elevated serum IL-2, IFN-g and TNF-a level in Rg3-treated mice. Conclusions: These results suggest that Rg3 inhibits PD-L1 glycosylation and thus enhance anti-tumor immunity, which provide new therapeutic insight into drug discovery.
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Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas , Ginsenósidos , Neoplasias Pulmonares , Animales , Humanos , Ratones , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Ginsenósidos/farmacología , Ginsenósidos/uso terapéutico , Glicosilación , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The chemical behaviors of alkali and alkaline earth metal hydrides including LiH, KH, MgH2, CaH2, and BaH2 under nitrogen plasma differ significantly from one another, exhibiting an ammonia production trend that contrasts with that observed under thermal conditions. A prominent feature of KH is its ability to facilitate plasma-assisted N2 fixation without generating H2 byproduct, showing high atomic economy in utilization of hydride ions for N2 reduction.
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Chloroplast (cp) genome sequences have been extensively used for phylogenetic and evolutionary analyses, as many have been sequenced in recent years. Identification of Quercus is challenging because many species overlap phenotypically owing to interspecific hybridization, introgression, and incomplete lineage sorting. Therefore, we wanted to gain a better understanding of this genus at the level of the maternally inherited chloroplast genome. Here, we sequenced, assembled, and annotated the cp genomes of the threatened Quercus marlipoensis (160,995 bp) and Q. kingiana (161,167 bp), and mined these genomes for repeat sequences and codon usage bias. Comparative genomic analyses, phylogenomics, and selection pressure analysis were also performed in these two threatened species along with other species of Quercus. We found that the guanine and cytosine content of the two cp genomes were similar. All 131 annotated genes, including 86 protein-coding genes, 37 transfer RNA genes, and 8 ribosomal RNA genes, had the same order in the two species. A strong A/T bias was detected in the base composition of simple sequence repeats. Among the 59 synonymous codons, the codon usage pattern of the cp genomes in these two species was more inclined toward the A/U ending. Comparative genomic analyses indicated that the cp genomes of Quercus section Ilex are highly conserved. We detected eight highly variable regions that could be used as molecular markers for species identification. The cp genome structure was consistent and different within and among the sections of Quercus. The phylogenetic analysis showed that section Ilex was not monophyletic and was divided into two groups, which were respectively nested with section Cerris and section Cyclobalanopsis. The two threatened species sequenced in this study were grouped into the section Cyclobalanopsis. In conclusion, the analyses of cp genomes of Q. marlipoensis and Q. kingiana promote further study of the taxonomy, phylogeny and evolution of these two threatened species and Quercus.
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Especies en Peligro de Extinción , Evolución Molecular , Genoma del Cloroplasto , Filogenia , Quercus , Quercus/genética , Genoma del Cloroplasto/genética , Uso de Codones , Cloroplastos/genéticaRESUMEN
BACKGROUND: Gastrectomy is one of the main treatment modalities for gastric cancer (GC) and induces pathophysiological changes that significantly affect patients' postoperative recovery. In this study, we investigated the relationships between altered insulin resistance (IR), inflammation, and gut microbiota associated with gastrectomy. PATIENTS AND METHODS: This study was a single-center prospective cohort investigation involving 60 patients with GC who underwent gastrectomy between May 2023 and April 2024. Monitoring encompassed IR, inflammation, and nutrition-related markers via blood assays, while gut microbiota analysis employed high-throughput sequencing, and short-chain fatty acids (SCFAs) were examined through targeted metabolomics. The study is registered under the number ChiCTR2300075653. RESULTS: The patients exhibited a significant increase in post-gastrectomy IR markers (P < 0.001), accompanied by elevated inflammation markers (P < 0.001), and also showed decreased nutrition-related indicators (P < 0.001). Notable alterations were observed in the gut microbiota, including reductions in Bifidobacterium and Faecalibacterium, an increase in Streptococcus, and a noteworthy decrease in fecal butyrate. Patients with postoperative IR exhibited poorer inflammation markers (P < 0.05), nutritional indicators (P < 0.05), and postoperative recovery parameters (P < 0.05). Furthermore, significant negative correlations were observed between IR and Bifidobacterium, Faecalibacterium, as well as butyrate. CONCLUSIONS: Patients with GC post-gastrectomy displayed heightened IR, exacerbated inflammation, and compromised nutritional status. Disturbed gut microbiota and reduced fecal butyrate were observed. Gut microbiota and metabolite butyrate production may be predictors of postoperative IR and short-term outcomes in patients with GC.
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The advent of cancer immunotherapy has imparted a transformative impact on cancer treatment paradigms by harnessing the power of the immune system. However, the challenge of practical and precise targeting of malignant cells persists. To address this, engineered nanoparticles (NPs) have emerged as a promising solution for enhancing targeted drug delivery in immunotherapeutic interventions, owing to their small size, low immunogenicity, and ease of surface modification. This comprehensive review delves into contemporary research at the nexus of NP engineering and immunotherapy, encompassing an extensive spectrum of NP morphologies and strategies tailored toward optimizing tumor targeting and augmenting therapeutic effectiveness. Moreover, it underscores the mechanisms that NPs leverage to bypass the numerous obstacles encountered in immunotherapeutic regimens and probes into the combined potential of NPs when co-administered with both established and novel immunotherapeutic modalities. Finally, the review evaluates the existing limitations of NPs as drug delivery platforms in immunotherapy, which could shape the path for future advancements in this promising field.
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Malignant tumors remain a primary cause of human mortality. Among the various treatment modalities for neoplasms, tumor vaccines have consistently shown efficacy and promising potential. These vaccines offer advantages such as specificity, safety, and tolerability, with mRNA vaccines representing promising platforms. By introducing exogenous mRNAs encoding antigens into somatic cells and subsequently synthesizing antigens through gene expression systems, mRNA vaccines can effectively induce immune responses. Katalin Karikó and Drew Weissman were awarded the 2023 Nobel Prize in Physiology or Medicine for their great contributions to mRNA vaccine research. Compared with traditional tumor vaccines, mRNA vaccines have several advantages, including rapid preparation, reduced contamination, nonintegrability, and high biodegradability. Tumor-targeted therapy is an innovative treatment modality that enables precise targeting of tumor cells, minimizes damage to normal tissues, is safe at high doses, and demonstrates great efficacy. Currently, targeted therapy has become an important treatment option for malignant tumors. The application of mRNA vaccines in tumor-targeted therapy is expanding, with numerous clinical trials underway. We systematically outline the targeted delivery mechanism of mRNA vaccines and the mechanism by which mRNA vaccines induce anti-tumor immune responses, describe the current research and clinical applications of mRNA vaccines in tumor-targeted therapy, and forecast the future development trends of mRNA vaccine application in tumor-targeted therapy.
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BACKGROUND: Previous studies have identified the hemoglobin (Hb) to red blood cell distribution width (RDW) ratio (HRR) is associated with the prognosis of a variety of malignant tumors. However, the relationship between HRR and pancreatic ductal adenocarcinoma (PDAC) prognosis remains unexplored. This study aims to ascertain the prognostic significance of HRR in PDAC patients. METHODS: In a retrospective analysis, 128 PDAC patients undergoing initial surgical resection at Ningbo Medical Center Lihuili Hospital between January 2016 and September 2021 were included. Based on receiver operating characteristic curve-derived cut-off values, participants were categorized into low and high HRR groups. The correlation between HRR and patient prognosis was subsequently examined. RESULTS: Significant disparities in age, Hb levels, RDW, tumor locality, surgical intervention, and postoperative chemotherapy were observed between the two groups (P < 0.05). Notably, the low HRR cohort exhibited inferior disease-free survival (DFS) and overall survival (OS) rates (P = 0.002 for both). Univariate analysis indicated that male gender, adjacent tissue invasion, TNM stages III/IV, non-O blood types, low HRR, and lack of postoperative chemotherapy were linked to adverse DFS and OS outcomes (P < 0.05). Multivariate analysis further delineated low HRR as an independent predictor of poor DFS and OS outcomes (HR: 1.520, 95% CI: 1.028-2.247, P = 0.036; HR: 1.537, 95% CI: 1.034-2.284, P = 0.034, respectively). CONCLUSION: Our findings suggest that a lower HRR is indicative of poorer DFS and OS in PDAC patients, underscoring its potential utility as a prognostic biomarker for this population.
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Carcinoma Ductal Pancreático , Índices de Eritrocitos , Hemoglobinas , Neoplasias Pancreáticas , Humanos , Masculino , Femenino , Estudios Retrospectivos , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/cirugía , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Persona de Mediana Edad , Hemoglobinas/análisis , Pronóstico , Anciano , Supervivencia sin Enfermedad , AdultoRESUMEN
INTRODUCTION: Currently, there is a lack of large-scale prospective cohort data to explore the response of neck pain to anterior cervical decompression and fusion (ACDF). The aim of this study was to investigate whether patients with neck pain can achieve consistent neck pain relief following ACDF regardless of preoperative neurological symptoms and number of surgical segments. MATERIALS AND METHODS: The study was a pooled analysis of 3 multicenter prospective cohort studies. Patients with cervical radiculopathy and/or myelopathy with significant neck pain (visual analog scale [VAS] ≥ 4) who underwent ACDF were included. Neck pain VAS scores (VAS-neck) were collected at preoperative and postoperative follow-up time points (3 months, 6 months, and 1 year). Subgroup analyses were conducted for patients with radiculopathy, myelopathy, or myeloradiculopathy, as well as for single- versus multi-segment ACDF. RESULTS: A total of 237 patients were confirmed. Patients showed significant improvement in VAS-neck at all follow-up time points compared with baseline (P < 0.001 for each). In the first year after surgery, VAS-neck were reduced by 3.3 points (57.0%) on average, and the rates of achieving minimum clinically important difference and patient acceptable symptom state were 72.2% and 73.8%, respectively. Meanwhile, one year after surgery, there was no significant difference in ΔVAS-neck, recovery rate, minimum clinically important difference, and patient acceptable symptom state attainment rate between the radiculopathy, myelopathy and myeloradiculopathy groups, and the same trend was observed between the single-segment and multi-segment groups. CONCLUSIONS: This study found that ACDF significantly improved neck pain in patients with cervical spondylosis, regardless of preoperative neurological symptoms and number of surgical segments.
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In this paper, the innovative design of a robotic hand with soft jointed structure is carried out and a tendon-driven mechanism, a master-slave motor coordinated drive mechanism, a thumb coupling transmission mechanism and a thumb steering mechanism are proposed. These innovative designs allow for more effective actuation in each finger, enhancing the load capacity of the robotic hand while maintaining key performance indicators such as dexterity and adaptability. A mechanical model of the robotic finger was made to determine the application limitations and load capacity. The robotic hand was then prototyped for a set of experiments. The experimental results showed that the proposed theoretical model were reliable. Also, the fingertip force of the robotic finger could reach up to 10.3 N, and the load force could reach up to 72.8 N. When grasping target objects of different sizes and shapes, the robotic hand was able to perform the various power grasping and precision grasping in the Cutkosky taxonomy. Moreover, the robotic hand had good flexibility and adaptability by means of adjusting the envelope state autonomously.
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Diseño de Equipo , Fuerza de la Mano , Mano , Robótica , Robótica/instrumentación , Mano/fisiología , Humanos , Fuerza de la Mano/fisiología , Dedos/fisiología , Biomimética/métodos , Tendones/fisiología , Modelos BiológicosRESUMEN
Functionalized thermosensitive hydrogel materials exhibit excellent properties for the fabrication of sensing devices that enable real-time visual detection of food safety duo to their good plasticity and powerful loading capacity. Here, a ratiometric fluorescent device based on an interpenetrating network (IPN) thermosensitive hydrogel was designed to embed functionalized Au nanoclusters (Au NCs) and Blue Carbon dots (BCDs) composites in a multi-network structure to build a sensitive hazardous material nitrite (NO2-) chemsensor. The hydrogel was utilized poloxamer 407 (P407), lignin and cellulose to form stable IPN structure, which resulted in complementation and synergy, thereby strengthening its porous network structure. The combination of fluorescent nanoprobes with the porous network structure has the potential to enhance stable fluorescence signals and improve sensing sensitivity. Moreover, the thermosensitive liquid-solid transition characteristics of the hydrogel facilitate its preparation into diverse sensing devices following curing at room temperature. The hydrogel device, when combined with a smartphone system, converted image information into data information, thereby enabling the accurate quantification of NO2- with a detection limit of 9.38 nM in 2 s. The designed multi-functional hydrogel device is capable of real-time differentiation of NO2- dosage with the naked eye, offering a high-contrast, rapid-response sensing methodology for visual assessment of food freshness. This research contributes to the expansion of hydrogel materials applications and the detection of hazardous materials in food safety.
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Oro , Hidrogeles , Nitritos , Hidrogeles/química , Nitritos/análisis , Nitritos/química , Oro/química , Temperatura , Nanopartículas del Metal/química , Colorantes Fluorescentes/química , Puntos Cuánticos/química , Límite de Detección , Carbono/química , Teléfono InteligenteRESUMEN
Highly sensitive detection of low-frequency EGFR-L858R mutation is particularly important in guiding targeted therapy of nonsmall-cell lung carcinoma (NSCLC). To this end, a ligase chain reaction (LCR)-based electrochemical biosensor (e-LCR) with an inverted sandwich-type architecture was provided by combining a cooperation of lambda exonuclease-RecJf exonuclease (λ-RecJf exo). In this work, by designing a knife-like DNA substrate (an overhang ssDNA part referred to the "knife arm") and introducing the λ-RecJf exo, the unreacted DNA probes in the LCR were specially degraded while only the ligated products were preserved, after which the ligated knife-like DNA products were hybridized with capture probes on the gold electrode surface through the "knife arms", forming the inverted sandwich-type DNA structure and bringing the methylene blue-label close to the electrode surface to engender the electrical signal. Finally, the sensitivity of the e-LCR could be improved by 3 orders of magnitude with the help of the λ-RecJf exo, and due to the mutation recognizing in the ligation site of the employed ligase, this method could detect EGFR-L858R mutation down to 0.01%, along with a linear range of 1 fM-10 pM and a limit detection of 0.8 fM. Further, the developed method could distinguish between L858R positive and negative mutations in cultured cell samples, tumor tissue samples, and plasma samples, whose accuracy was verified by the droplet digital PCR, holding a huge potential in liquid biopsy for precisely guiding individualized-treatment of NSCLC patients with advantages of high sensitivity, low cost, and adaptability to point-of-care testing.
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Carcinoma de Pulmón de Células no Pequeñas , Técnicas Electroquímicas , Receptores ErbB , Exodesoxirribonucleasas , Neoplasias Pulmonares , Mutación , Receptores ErbB/genética , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Exodesoxirribonucleasas/química , Exodesoxirribonucleasas/metabolismo , Exodesoxirribonucleasas/genética , Técnicas Biosensibles , Reacción en Cadena de la Ligasa , Límite de Detección , Proteínas ViralesRESUMEN
Carbon quantum dots (CQDs), an emerging nanomaterial, are gaining attention in ophthalmological applications due to their distinctive physical, chemical, and biological characteristics. For example, their inherent fluorescent capabilities offer a novel and promising alternative to conventional fluorescent dyes for ocular disease diagnostics. Furthermore, because of the excellent biocompatibility and minimal cytotoxicity, CQDs are well-suited for therapeutic applications. In addition, functionalized CQDs can effectively deliver drugs to the posterior part of the eyeball to inhibit neovascularization. This review details the use of CQDs in the management of ophthalmic diseases, including various retinal diseases, and ocular infections. While still in its initial phases within ophthalmology, the significant potential of CQDs for diagnosing and treating eye conditions is evident.
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Carbono , Oftalmopatías , Puntos Cuánticos , Humanos , Oftalmopatías/diagnóstico , Oftalmopatías/terapia , Sistemas de Liberación de MedicamentosRESUMEN
Food safety is a serious issue worldwide and practical detection method is vital for the supervision of food safety. It is necessary to establish efficient and economical methods to detect antibiotics, especially antibiotics in complex systems. This study employs citric acid and m-phenylenediamine to synthesize N, P-codoped carbon dots (N, P-CDs) by a microwave-assisted method. Anhydrous ethanol and phosphoric acid are essential to the properties of N, P-CDs. A "turn-on" fluorescent probe based on N, P-CDs was established for detecting ciprofloxacin (CIP) with detection limit down to 24.2 nm. Semiquantitative test stripe and a PS color detection system for CIP were developed to achieve visual and smart detection. The test stripe is applied to the visual detection of CIP residues in milk and a popular Chinese cuisine, Malatang, for the first time. N, P-CDs can also be used to detect pH in the range of pH 7.5-12.
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Carbono , Ciprofloxacina , Puntos Cuánticos , Ciprofloxacina/análisis , Carbono/química , Concentración de Iones de Hidrógeno , Puntos Cuánticos/química , Animales , Contaminación de Alimentos/análisis , Leche/química , Antibacterianos/análisis , Límite de Detección , Colorantes Fluorescentes/químicaRESUMEN
In this study, a formulation of NaGdF4:Tm/Er@NaGdF4 (core@shell) UCNPs loaded with melatonin drug was synthesized. The novel melatonin-loaded UCNPs were then encapsulated within NIR-responsive biopolymeric chitosan (CS) based polymersome and investigated against gastric cancer (HGC27 & AGS) cells. The photolysis of the ONB moiety and disruption of the disulfide linkage in the polymersome induced by NIR light facilitated by the NaGdF4:Tm/Er@NaGdF4 UCNPs and GSH results in an increased release of melatonin drug. The DLS and zeta potential measurements exhibit a reduced particle size (21.9 ± 3.56 nm) and a low zeta potential (17.91 mV). Furthermore, drug release profiles demonstrated superior melatonin drug release (79.78 %) at pH 5.0 for CS-polymersome-coated melatonin-UCNPs resembling the Hixson-Crowell model. Remarkably, CS-polymersome-coated melatonin-UCNPs exhibit excellent anti-proliferative properties for HGC27 (IC50 = 0.096 µM) and AGS (IC50 = 0.16 µM) cancer cells. The flow cytometry data demonstrate a significant elevation in ROS levels which promoted cell death in both HGC-27 and AGS cells. The observed cell mortality in HGC-27 and AGS cells is primarily caused by the destruction of the nucleus, mtDNA, rupture of disulfide (R-S-S-R) bonds, and nuclear DNA. Contrarily, L929 and HUVECs cells incubated with CS-polymersome coated melatonin-UCNPs (100 µg/mL) reveal a notable cell viability of 88.7 % and 93 % indicating superior biocompatibility. The western blotting analysis revealed the induction of autophagy by CS-polymersome-coated melatonin-UCNPs which subsequently led to apoptosis by regulating the ROS/PI3K/Akt/mTOR molecular signaling pathway.
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Quitosano , Melatonina , Nanopartículas , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Especies Reactivas de Oxígeno , Transducción de Señal , Neoplasias Gástricas , Serina-Treonina Quinasas TOR , Melatonina/farmacología , Melatonina/química , Quitosano/química , Quitosano/farmacología , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Nanopartículas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Línea Celular Tumoral , Rayos Infrarrojos , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Liberación de Fármacos , Supervivencia Celular/efectos de los fármacosRESUMEN
A photoreductive halogen-atom transfer (XAT) strategy for 1,4-dicarbofunctionalization of 1,3-enynes with organoiodides and cyanoarenes is disclosed, enabling access to functionalized allenes in a highly regio-, chemo-, and stereoselective manner. Upon the photoredox catalysis and the activation of Et3N XAT agents, the mild conditions and high functional group tolerance of this protocol enable the formation of two C-C bonds, including a C(sp3)-C(sp3) bond and a C(sp2)-C(sp2) bond, in a single reaction step, and provides a general avenue to polysubstituted allenes and late-stage modification of bioactive compounds.
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The evolution of hypervirulent and carbapenem-resistant Klebsiella pneumoniae can be categorized into three main patterns: the evolution of KL1/KL2-hvKp strains into CR-hvKp, the evolution of carbapenem-resistant K. pneumoniae (CRKp) strains into hv-CRKp, and the acquisition of hybrid plasmids carrying carbapenem resistance and virulence genes by classical K. pneumoniae (cKp). These strains are characterized by multi-drug resistance, high virulence, and high infectivity. Currently, there are no effective methods for treating and surveillance this pathogen. In addition, the continuous horizontal transfer and clonal spread of these bacteria under the pressure of hospital antibiotics have led to the emergence of more drug-resistant strains. This review discusses the evolution and distribution characteristics of hypervirulent and carbapenem-resistant K. pneumoniae, the mechanisms of carbapenem resistance and hypervirulence, risk factors for susceptibility, infection syndromes, treatment regimens, real-time surveillance and preventive control measures. It also outlines the resistance mechanisms of antimicrobial drugs used to treat this pathogen, providing insights for developing new drugs, combination therapies, and a "One Health" approach. Narrowing the scope of surveillance but intensifying implementation efforts is a viable solution. Monitoring of strains can be focused primarily on hospitals and urban wastewater treatment plants.
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Antibacterianos , Carbapenémicos , Infecciones por Klebsiella , Klebsiella pneumoniae , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/patogenicidad , Humanos , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/epidemiología , Infecciones por Klebsiella/tratamiento farmacológico , Virulencia , Carbapenémicos/farmacología , Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/genética , Enterobacteriaceae Resistentes a los Carbapenémicos/genética , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Enterobacteriaceae Resistentes a los Carbapenémicos/patogenicidad , Enterobacteriaceae Resistentes a los Carbapenémicos/aislamiento & purificación , Plásmidos/genética , Salud Pública , Salud Global , Factores de Virulencia/genética , Factores de RiesgoRESUMEN
Early-onset epilepsy following ischemic stroke is a severe neurological condition, the pathogenesis of which remains incompletely understood. Recent studies suggest that Neural stem/progenitor cells (NSPCs) play a crucial role in the disease process, yet the precise molecular mechanisms regulating NSPCs have not been thoroughly investigated. This study utilized single-cell transcriptome sequencing and bioinformatics analysis to identify disease-related genes, which were subsequently validated in both in vitro and in vivo experiments. The findings revealed that Hsp90aa1 (heat shock protein 90 kDa alpha, class A member 1), Jun proto-oncogene (JUN), and CC Motif Ligation 2 (Ccl2) constitute an important regulatory axis influencing the migration and differentiation of NSPCs, potentially impacting the onset and progression of early-onset epilepsy post-ischemic stroke. Additionally, the expression of Hsp90aa1 was found to influence the likelihood of seizure occurrence and the severity of brain ischemia.
Asunto(s)
Diferenciación Celular , Movimiento Celular , Epilepsia , Proteínas HSP90 de Choque Térmico , Accidente Cerebrovascular Isquémico , Células-Madre Neurales , Proteínas HSP90 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/genética , Animales , Células-Madre Neurales/metabolismo , Movimiento Celular/fisiología , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Diferenciación Celular/fisiología , Epilepsia/metabolismo , Epilepsia/genética , Ratones , Proto-Oncogenes Mas , Masculino , Humanos , Ratones Endogámicos C57BL , Progresión de la EnfermedadRESUMEN
Metal-based chemoimmunotherapy has recently garnered significant attention for its capacity to stimulate tumor-specific immunity beyond direct cytotoxic effects. Such effects are usually caused by ICD via the activation of DAMP signals. However, metal complexes that can elicit antitumor immune responses other than ICD have not yet been described. Herein, we report that a rhodium complex (Rh-1) triggers potent antitumor immune responses by downregulating Wnt/ß-catenin signaling with subsequent activation of T lymphocyte infiltration to the tumor site. The results of mechanistic experiments suggest that ROS accumulation following Rh-1 treatment is a critical trigger of a decrease in ß-catenin and enhanced secretion of CCL4, a key mediator of T cell infiltration. Through these properties, Rh-1 exerts a synergistic effect in combination with PD-1 inhibitors against tumor growth in vivo. Taken together, our work describes a promising metal-based antitumor agent with a noncanonical mode of action to sensitize tumor tissues to ICB therapy.