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Biomass-derived carbon for supercapacitors faces the challenge of achieving hierarchical porous carbon with graphitic structure and specific heteroatoms through a single-stage thermal process that minimises resource input. Herein, molten base carbonisation and activation is proposed. The process utilises the inherent moisture of Moso bamboo shoots, coupled with a low amount of KOH, to form potassium organic salts before drying. The resultant potassium salts promote in-situ activation during single-stage heating process, yielding hierarchical porous, large specific surface area, and partially graphitised carbon with heteroatoms (N, O). As an electrode material, this carbon exhibits a specific capacitance of 327F g-1 in 6 M KOH and 182F g-1 in 1 M TEABF4/AN, demonstrating excellent cycling stability over 10,000 cycles at 2 A/g. Overall, this study presents a straightforward process that avoids pre-drying of biomass, minimises base consumption, and employs single-stage heating to fabricate electrode carbon suitable for supercapacitors.
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Biomasa , Carbono , Capacidad Eléctrica , Electrodos , Porosidad , Carbono/química , Técnicas Electroquímicas/métodosRESUMEN
OBJECTIVE: This study explores the therapeutic effects and mechanisms of DHA-enriched phosphatidylserine (DHA-PS) on liver injury induced by cyclophosphamide (CTX) in mice, focusing on the gut-liver axis. METHODS: A mouse model was established by administering CTX (80 mg/kg) intraperitoneally for 5 days. DHA-PS (50 or 100 mg/kg) was administered for the next 7 days to assess its reparative impact on liver damage. RESULTS: The findings revealed significant improvements in liver biochemical indices, inflammatory markers, and oxidative stress levels in the mice treated with DHA-PS. Through non-targeted metabolomics analysis, DHA-PS mitigated CTX-induced metabolic disruptions by modulating lipid, amino acid, and pyrimidine metabolism. Immunofluorescence analysis further confirmed that DHA-PS reduced the expression of liver-associated inflammatory proteins by inhibiting the TLR4/NF-κB pathway. Additionally, DHA-PS restored the intestinal barrier, evidenced by adjustments in the levels of intestinal lipopolysaccharide (LPS), secretory immunoglobulin A (sIgA), and tight junction proteins (Claudin-1, Occludin, and ZO-1). It also improved gut microbiota balance by enhancing microbial diversity, increasing beneficial bacteria, and altering community structures. CONCLUSION: These results suggest that DHA-PS could be a potential therapeutic agent or functional food for CTX-induced liver injury through its regulation of the gut-liver axis.
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Eighteen compounds including eleven previously undescribed diterpenes were isolated from the leaves of Croton mangelong. The structures were determined by HRESIMS, IR, NMR, X-ray diffraction and ECD spectroscopic analysis. All isolates were assayed for their anti-hyperglycemic activities in insulin resistance (IR) 3T3-L1 adipocytes, and compound 4 was tested for its anti-diabetic activity in vivo. Results suggested compound 4 could effectively reduce blood glucose level in diabetic SD rats in a dose of 30 mg/kg.
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Células 3T3-L1 , Croton , Diterpenos , Hipoglucemiantes , Hojas de la Planta , Ratas Sprague-Dawley , Hojas de la Planta/química , Diterpenos/farmacología , Diterpenos/química , Diterpenos/aislamiento & purificación , Croton/química , Animales , Ratones , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/aislamiento & purificación , Ratas , Estructura Molecular , Diabetes Mellitus Experimental/tratamiento farmacológico , Masculino , Resistencia a la Insulina , Glucemia/efectos de los fármacos , Adipocitos/efectos de los fármacosRESUMEN
We designed a CD19-targeted CAR comprising a calibrated signaling module, termed 1XX, that differs from that of conventional CD28/CD3z and 4-1BB/CD3z CARs. Here we report the first-in-human, phase 1 clinical trial of 19(T2)28z-1XX CAR T cells in relapsed/refractory large B-cell lymphoma. We hypothesized that 1XX CAR T cells may be effective at low doses and investigated 4 doubling dose levels starting from 25×106 CAR T cells. The overall response rate (ORR) was 82% and complete response (CR) rate 71% in the entire cohort (n=28) and 88% ORR and 75% CR in 16 patients treated at 25×106. With the median follow-up of 24 months, the 1-year EFS was 61% (95% CI: 45-82%). Overall, grade ≥3 CRS and ICANS rates were low at 4% and 7%. The calibrated potency of the 1XX CAR affords excellent efficacy at low cell doses and may benefit the treatment of other hematological malignancies, solid tumors and autoimmunity.
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Hydrazine (N2H4) has toxic effects on the environment. Although a variety of reactive probes have been used to identify hydrazine, practical applications required continuous development of hydrazine fluorescent probes with improved performance. Here, we applied the neighboring group participation (NGP) to the design of a fluorescent probe for hydrazine. The probe exhibited a rapid response to N2H4 and strong anti-interference ability, with detection limited to 0.031 µmol/L. Theoretical calculation showed that the energy barrier could be reduced by NGP. The cyclic intermediate formed by the indole ring and the α-ester carbonyl group significantly reduced the activation energy of the reaction. Practically, the probe could detect hydrazine in actual water samples.
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Porcine deltacoronavirus (PDCoV) is an enteric pathogenic coronavirus that causes acute and severe watery diarrhea in piglets and has the ability of cross-species transmission, posing a great threat to swine production and public health. The interferon (IFN)-mediated signal transduction represents an important component of virus-host interactions and plays an essential role in regulating viral infection. Previous studies have suggested that multifunctional viral proteins encoded by coronaviruses antagonize the production of IFN via various means. However, the function of these viral proteins in regulating IFN-mediated signaling pathways is largely unknown. In this study, we demonstrated that PDCoV and its encoded nucleocapsid (N) protein antagonize type I IFN-mediated JAK-STAT signaling pathway. We identified that PDCoV infection stimulated but delayed the production of IFN-stimulated genes (ISGs). In addition, PDCoV inhibited JAK-STAT signal transduction by targeting the nuclear translocation of STAT1 and ISGF3 formation. Further evidence showed that PDCoV N is the essential protein involved in the inhibition of type I IFN signaling by targeting STAT1 nuclear translocation via its C-terminal domain. Mechanistically, PDCoV N targets STAT1 by interacting with it and subsequently inhibiting its nuclear translocation. Furthermore, PDCoV N inhibits STAT1 nuclear translocation by specifically targeting KPNA2 degradation through the lysosomal pathway, thereby inhibiting the activation of downstream sensors in the JAK-STAT signaling pathway. Taken together, our results reveal a novel mechanism by which PDCoV N interferes with the host antiviral response.IMPORTANCEPorcine deltacoronavirus (PDCoV) is a novel enteropathogenic coronavirus that receives increased attention and seriously threatens the pig industry and public health. Understanding the underlying mechanism of PDCoV evading the host defense during infection is essential for developing targeted drugs and effective vaccines against PDCoV. This study demonstrated that PDCoV and its encoded nucleocapsid (N) protein antagonize type I interferon signaling by targeting STAT1, which is a crucial signal sensor in the JAK-STAT signaling pathway. Further experiments suggested that PDCoV N-mediated inhibition of the STAT1 nuclear translocation involves the degradation of KPNA2, and the lysosome plays a role in KPNA2 degradation. This study provides new insights into the regulation of PDCoV N in the JAK-STAT signaling pathway and reveals a novel mechanism by which PDCoV evades the host antiviral response. The novel findings may guide us to discover new therapeutic targets and develop live attenuated vaccines for PDCoV infection.
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Deltacoronavirus , Proteínas de la Nucleocápside , Factor de Transcripción STAT1 , Transducción de Señal , Animales , Porcinos , Factor de Transcripción STAT1/metabolismo , Deltacoronavirus/metabolismo , Proteínas de la Nucleocápside/metabolismo , Humanos , Quinasas Janus/metabolismo , Enfermedades de los Porcinos/virología , Enfermedades de los Porcinos/metabolismo , alfa Carioferinas/metabolismo , Interferón Tipo I/metabolismo , Infecciones por Coronavirus/virología , Infecciones por Coronavirus/metabolismo , Células HEK293 , Línea Celular , Proteolisis , Interacciones Huésped-PatógenoRESUMEN
PURPOSE: To evaluate a system for otomicrosurgery based on 4K three-dimensional (3D) exoscope technology and apply it to cochlear implantation. METHODS: An open stereoscopic vision-based surgical system, which differs from traditional surgical microscopes, was created by utilizing 4K stereo imaging technology and combining it with low-latency 4K ultra-high-definition 3D display. The system underwent evaluation based on 57 cochlear implantation operations, three designed microscopic manipulations, and a questionnaire survey. RESULTS: The surgical images displayed by the 4K-3D exoscope system (4K-3D-ES) are stereoscopic, clear, and smooth. The use of 4K-3D-ES in cochlear implantation is not inferior to traditional microscopes in terms of intraoperative bleeding and surgical complications, and the surgical duration is not slower or may even be faster than when using traditional microscopes. The results of micromanipulation experiments conducted on 16 students also confirmed this and demonstrated that 4K-3D-ES can be easily adapted. Furthermore, additional advantages of 4K-3D-ES were gathered. Significantly enlarged and high-definition stereoscopic images contribute to the visualization of finer anatomical microstructures such as chordae tympani, ensuring safer surgery. Users feel more comfortable in their necks, shoulders, waists, and backs. Real-time shared stereoscopic view for multiple people, convenient for collaboration and teaching. The ear endoscope and 4K-3D-ES enable seamless switching on the same screen. High-definition 3D images and videos can be saved with just one click, making future publication and communication convenient. CONCLUSION: The feasibility and safety of 4K-3D-ES for cochlear implantation surgery have been demonstrated. The 4K-3D-ES also offers numerous unique advantages and holds clinical application and promotional value.
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Implantación Coclear , Humanos , Implantación Coclear/métodos , Implantación Coclear/instrumentación , Masculino , Femenino , Niño , Imagenología Tridimensional/métodos , Adulto , Persona de Mediana Edad , Microcirugia/métodos , Microcirugia/instrumentación , Preescolar , Adolescente , Adulto Joven , Anciano , LactanteRESUMEN
Porcine circoviruses (PCVs) are a significant cause of concern for swine health, with four genotypes currently recognized. Two of these, PCV3 and PCV4, have been detected in pigs across all age groups, in both healthy and diseased animals. These viruses have been associated with various clinical manifestations, including porcine dermatitis and nephropathy syndrome (PDNS) and respiratory and enteric signs. In this study, we detected PCV3 and PCV4 in central China between January 2022 and February 2023. We tested fecal swabs and tissue samples from growing-finishing and suckling pigs with or without respiratory and systemic manifestations and found the prevalence of PCV3 to be 15.15% (15/99) and that of PCV3/PCV4 coinfection to be 4.04% (4/99). This relatively low prevalence might be attributed to the fact that most of the clinical samples were collected from pigs exhibiting respiratory signs, with only a few samples having been obtained from pigs with diarrhea. In some cases, PCV2 was also detected, and the coinfection rates of PCV2/3, PCV2/4, and PCV2/3/4 were 6.06% (6/99), 5.05% (5/99), and 3.03% (3/99), respectively. The complete genomic sequences of four PCV3 and two PCV4 isolates were determined. All four of the PCV3 isolates were of subtype PCV3b, and the two PCV4 isolates were of subtype PCV4b. Two mutations (A24V and R27K) were found in antibody recognition domains of PCV3, suggesting that they might be associated with immune escape. This study provides valuable insights into the molecular epidemiology and evolution of PCV3 and PCV4 that will be useful in future investigations of genotyping, immunogenicity, and immune evasion strategies.
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Infecciones por Circoviridae , Circovirus , Genotipo , Filogenia , Enfermedades de los Porcinos , Circovirus/genética , Circovirus/aislamiento & purificación , Circovirus/clasificación , Animales , Porcinos , China/epidemiología , Enfermedades de los Porcinos/virología , Enfermedades de los Porcinos/epidemiología , Infecciones por Circoviridae/veterinaria , Infecciones por Circoviridae/virología , Infecciones por Circoviridae/epidemiología , Coinfección/virología , Coinfección/veterinaria , Coinfección/epidemiología , Genoma Viral/genética , Heces/virologíaRESUMEN
Federated recommender systems (FRSs), with their improved privacy-preserving advantages to jointly train recommendation models from numerous devices while keeping user data distributed, have been widely explored in modern recommender systems (RSs). However, conventional FRSs require transmitting the entire model between the server and clients, which brings a huge carbon footprint for cost-conscious cross-device learning tasks. While several efforts have been dedicated to improving the efficiency of FRSs, it's suboptimal to treat the whole model as the objective of compact design. Besides, current research fails to handle the out-of-vocabulary (OOV) issue in real-world FRSs, where the items only occasionally appear in the testing phase but were not observed during the training process, which is another practical challenge and has not been well studied yet. To this end, we propose a privacy-enhanced federated recommendation framework with shared hash embedding, PrivFR, in cross-device settings, which is an efficient representation mechanism specialized for the embedding parameters without compromising the model capability. Specifically, it represents items in a resource-efficient way by delicately utilizing shared hash embedding and multiple hash functions. As such, it just maintains a small shared pool of hash embedding in local clients, rather than fitting all embedding vectors for each item, which can exactly achieve the dual advantages of conserving resources and handling the OOV issue. What's more, we prove that this mechanism can protect the data privacy of local clients from a theoretical perspective. Extensive experiments show that our method not only effectively reduces storage and communication overheads, but also outperforms state-of-the-art FRSs.
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BACKGROUND: Energy deficiency and oxidative stress are interconnected during ischemia/reperfusion (I/R) and serve as potential targets for the treatment of cerebral ischemic stroke. Baicalin is a neuroprotective antioxidant, but the underlying mechanisms are not fully revealed. PURPOSE: This study explored whether and how baicalin rescued neurons against ischemia/reperfusion (I/R) attack by focusing on the regulation of neuronal pyruvate dehydrogenase kinase 2 (PDK2)-pyruvate dehydrogenase (PDH) axis implicated with succinate dehydrogenase (SDH)-mediated oxidative stress. STUDY DESIGN: The effect of the tested drug was explored in vitro and in vivo with the model of oxygen-glucose deprivation/reoxygenation (OGD/R) and middle cerebral artery occlusion/reperfusion (MCAO/R), respectively. METHODS: Neuronal damage was evaluated according to cell viability, infarct area, and Nissl staining. Protein levels were measured by western blotting and immunofluorescence. Gene expression was investigated by RT-qPCR. Mitochondrial status was also estimated by fluorescence probe labeling. RESULTS: SDH activation-induced excessive production of reactive oxygen species (ROS) changed the protein expression of Lon protease 1 (LonP1) and hypoxia-inducible factor-1É (HIF-1É) in the early stage of I/R, leading to an upregulation of PDK2 and a decrease in PDH activity in neurons and cerebral cortices. Treatment with baicalin prevented these alterations and ameliorated neuronal ATP production and survival. CONCLUSION: Baicalin improves the function of the neuronal PDK2-PDH axis via suppression of SDH-mediated oxidative stress, revealing a new signaling pathway as a promising target under I/R conditions and the potential role of baicalin in the treatment of acute ischemic stroke.
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Flavonoides , Neuronas , Fármacos Neuroprotectores , Estrés Oxidativo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Daño por Reperfusión , Flavonoides/farmacología , Animales , Daño por Reperfusión/tratamiento farmacológico , Neuronas/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Fármacos Neuroprotectores/farmacología , Succinato Deshidrogenasa/metabolismo , Masculino , Especies Reactivas de Oxígeno/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Ratas Sprague-Dawley , Supervivencia Celular/efectos de los fármacos , Ratas , Antioxidantes/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismoRESUMEN
BACKGROUND: Phospholipase A2 (PLA2) enzymes are pivotal in various biological processes, such as lipid mediator production, membrane remodeling, bioenergetics, and maintaining the body surface barrier. Notably, these enzymes play a significant role in the development of diverse tumors. AIM: To systematically and comprehensively explore the expression of the PLA2 family genes and their potential implications in cholangiocarcinoma (CCA). METHODS: We conducted an analysis of five CCA datasets from The Cancer Genome Atlas and the Gene Expression Omnibus. The study identified differentially expressed genes between tumor tissues and adjacent normal tissues, with a focus on PLA2G2A and PLA2G12B. Gene Set Enrichment Analysis was utilized to pinpoint associated pathways. Moreover, relevant hub genes and microRNAs for PLA2G2A and PLA2G12B were predicted, and their correlation with the prognosis of CCA was evaluated. RESULTS: PLA2G2A and PLA2G12B were discerned as differentially expressed in CCA, manifesting significant variations in expression levels in urine and serum between CCA patients and healthy individuals. Elevated expression of PLA2G2A was correlated with poorer overall survival in CCA patients. Additionally, the study delineated pathways and miRNAs associated with these genes. CONCLUSION: Our findings suggest that PLA2G2A and PLA2G12B may serve as novel potential diagnostic and prognostic markers for CCA. The increased levels of these genes in biological fluids could be employed as non-invasive markers for CCA, and their expression levels are indicative of prognosis, underscoring their potential utility in clinical settings.
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BACKGROUND: Traditional nanodrug delivery systems have some limitations, such as eliciting immune responses and inaccuracy in targeting tumor microenvironments. MATERIALS AND METHODS: Targeted drugs (Sorafenib, Sora) nanometers (hollow mesoporous silicon, HMSN) were designed, and then coated with platelet membranes to form aPD-1-PLTM-HMSNs@Sora to enhance the precision of drug delivery systems to the tumor microenvironment, so that more effective immunotherapy was achieved. RESULTS: These biomimetic nanoparticles were validated to have the same abilities as platelet membranes (PLTM), including evading the immune system. The successful coating of HMSNs@Sora with PLTM was corroborated by transmission electron microscopy (TEM), western blot and confocal laser microscopy. The affinity of aPD-1-PLTM-HMSNs@Sora to tumor cells was stronger than that of HMSNs@Sora. After drug-loaded particles were intravenously injected into hepatocellular carcinoma model mice, they were demonstrated to not only directly activate toxic T cells, but also increase the triggering release of Sora. The combination of targeted therapy and immunotherapy was found to be of gratifying antineoplastic function on inhibiting primary tumor growth. CONCLUSIONS: The aPD-1-PLTM-HMSNs@Sora nanocarriers that co-delivery of aPD-1 and Sorafenib integrates unique biomimetic properties and excellent targeting performance, and provides a neoteric idea for drug delivery of personalized therapy for primary hepatocellular carcinoma (HCC).
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Animales , Ratones , Sorafenib/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Biomimética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Microambiente TumoralRESUMEN
Traditional Chinese medicine residue (TCMR) was utilized as an inexpensive carbon source for the production of poly(3-hydroxybutyrate) (PHB) using the newly isolated Bacillus altitudinis HBU-SI7. The results showed that Yu Ping Feng TCMR could be directly hydrolysed by cellulase to obtain a high proportion of glucose (99 % of total sugar) without pretreatment, achieving an enzymatic hydrolysis rate of up to 89.2 %. B. altitudinis could grow and produce PHB when using enzymatically hydrolysed TCMR in a 5-L fermenter. After 20 h of fermentation, the maximum concentration of PHB was 11.2 g/L, and the highest cell dry weight (CDW) was 15.4 g/L, with 72.7 % of the PHB fraction in CDW. Moreover, this strain could utilize enzymatic hydrolysates from various herbal formulas to produce high levels of PHB. This novel approach aims to accumulate PHB from TCMR hydrolysates, offering an effective and environmentally friendly method to reduce production costs and achieve mass production.
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Bacillus , Polihidroxialcanoatos , Hidroxibutiratos/química , Medicina Tradicional China , Bacillus/metabolismo , Fermentación , Poliésteres/metabolismoRESUMEN
PURPOSE: To develop a nomogram model for the predicted overall survival (OS) in patients aged 18 to 59 years with nasopharyngeal carcinoma (NPC) and assess the value of the clinical application. METHODS: In total, 1334 registers of NPC patients from 2010 to 2015 were retrieved from the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox analysis were used to screen out independent risk factors affecting patients. Cox analysis predicted OS for patients with NPC at 3, 5, and 8 years. Nomogram performance was validated using the concordance index (C-index), receiver operating characteristic, calibration curve, and decision curve analysis (DCA). RESULTS: Age, sex, race, marital, histological type, tumor size, AJCC stage, and radiotherapy were independent risk factors. The C-index of the nomogram was 0.69 [95% confidence interval (CI): 0.68-0.71] for the training set, and the C-index of the AJCC stage was 0.63 (95% CI: 0.62-0.65), both statistically significant (P < .01). The area under the curve for the nomogram at these intervals (0.755, 0.729, and 0.729, respectively) was higher than that of the AJCC stage (0.667, 0.646, and 0.646, respectively), indicating better predictive accuracy. The calibration curves revealed a high degree of agreement between the observation and the prediction. Compared to the American Joint Committee on Cancer (AJCC) stage, DCA showed better clinical utility. CONCLUSION: The nomogram as novel predictor for nasopharyngeal carcinoma patients' survival.
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INTRODUCTION: Pancreaticobiliary reflux (PBR) can induce gallstone formation; however, its pathogenic mechanism remains unclear. In this study, we explored the mechanism of PBR by the non-targeted metabolomic analysis of bile in patients with PBR. OBJECTIVE: The aim of this study was to investigate the pathogenic mechanism in PBR by the non-targeted metabolomic analysis of bile collected during surgery. METHODS: Sixty patients who underwent gallstone surgery at our center from December 2020 to May 2021 were enrolled in the study. According to the level of bile amylase, 30 patients with increased bile amylase ( > 110 U/L) were classified into the PBR group, and the remaining 30 patients were classified into the control group (≤ 110 U/L). The metabolomic analysis of bile was performed. RESULTS: The orthogonal projections to latent structure-discriminant analysis of liquid chromatography mass spectrometry showed significant differences in bile components between the PBR and control groups, and 40 metabolites were screened by variable importance for the projection value (VIP > 1). The levels of phosphatidylcholine (PC) and PC (20:3(8Z,11Z,14Z)/14:0) decreased significantly, whereas the levels of lysoPC (16:1(9z)/0:0), lysoPC (15:0), lysoPC (16:0), palmitic acid, arachidonic acid, leucine, methionine, L-tyrosine, and phenylalanine increased. CONCLUSIONS: Significant differences in bile metabolites were observed between the PBR and control groups. Changes in amino acids and lipid metabolites may be related to stone formation and mucosal inflammation.
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Bilis , Cálculos Biliares , Humanos , Cálculos Biliares/cirugía , Cálculos Biliares/metabolismo , Metabolómica/métodos , Cromatografía Líquida con Espectrometría de Masas , AmilasasRESUMEN
Porcine deltacoronavirus (PDCoV) is an emerging enteropathogenic coronavirus that mainly causes diarrhea and death in suckling piglets and also has the potential for cross-species transmission, threatening public health. However, there is still no effective vaccine or drug to prevent PDCoV infection. In order to accelerate the development of antiviral drugs, we established a high-throughput screening platform using a novel genome editing technology called transformation-associated recombination cloning in yeast. The recombinant PDCoV and PDCoV reporter virus expressing enhanced green fluorescent protein were both rapidly rescued with stable genealogical characteristics during passage. Further study demonstrated that the reporter virus can be used for high-throughput screening of antiviral drugs with a Z-factor of 0.821-0.826. Then, a medicine food homology compound library was applied, and we found that three compounds were potential antiviral reagents. In summary, we have established a fast and efficient reverse genetic system of PDCoV, providing a powerful platform for the research of antiviral drugs.
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Proteínas Fluorescentes Verdes , Saccharomyces cerevisiae , Enfermedades de los Porcinos , Porcinos , Animales , Saccharomyces cerevisiae/genética , Antivirales/farmacología , Recombinación Genética , Clonación MolecularRESUMEN
Amphiphilic protein has lipophilic and hydrophilic domains, displaying the potential for development as a biosurfactant. The polyhydroxyalkanoate (PHA) surface binding protein derived from Bacillus is a type of protein that has not been studied for its emulsifying properties. In this study, PHA granule-associated protein (PhaP), PHA regulatory protein (PhaQ), and PHA synthase subunit (PhaR) derived from an alkali-tolerant PHA-producing Bacillus cereus HBL-AI were found and heterologously expressed in E. coli and purified to investigate their application as biosurfactants. It showed that the emulsification ability and stability of three amphiphilic proteins were higher than those of widely used chemical surfactants in diesel oil, vegetable oil, and lubricating oil. In particular, the PhaQ protein studied for the first time can form a stable emulsion layer in vegetable oil at a lower concentration (50 µg/mL), which greatly reduced the amount of protein used in emulsification. This clearly demonstrated that the PHA-binding protein of HBL-AI can be well applied as an environmentally friendly biosurfactants.
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Bacillus , Polihidroxialcanoatos , Polihidroxialcanoatos/metabolismo , Bacillus/genética , Bacillus/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Proteínas de la Membrana , Tensoactivos/metabolismo , Escherichia coli/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismoRESUMEN
6-Diazo-5-oxo-L-norleucine (DON) is a potent glutamine antagonist with toxic side effects; in order to reduce these effects, multiple prodrugs have been designed. However, there are currently no reports of a DON prodrug with a defined mechanism to achieve high tumor selectivity. To improve the selective toxicity of DON to tumor cells while reducing systemic toxicity, a hypoxia-activated prodrug, termed HDON, was designed. HDON achieved remarkable tumor suppression of 76.4 ± 5.2% without leading to weight loss in an H22 murine liver cancer model with high hypoxia. Moreover, to augment the therapeutic efficacy of HDON, combretastatin A4 nanoparticles were used to aggravate tumor hypoxia of MC38 murine colon cancer and 4T1 murine breast cancer, activate HDON to DON, and stimulate a robust anti-tumor immune response while selectively killing in tumor cells in vivo, achieving significantly elevated tumor suppression rates of 98.3 ± 3.4% and 98.1 ± 3.1%, with cure rates of 80.0% and 20.0%, respectively.
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Neoplasias de la Mama , Nanopartículas , Profármacos , Estilbenos , Humanos , Animales , Ratones , Femenino , Glutamina/metabolismo , Profármacos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológicoRESUMEN
Interleukin-2 (IL-2) used in multiple sclerosis (MS) therapy modulates the balance between regulatory T (Treg) cells and effector T (Teff) cells. However, the off-target activation of Teff cells by IL-2 limits its clinical application. Therefore, a rapidly prepared immunoswitch nanomodulator termed aT-IL2C NPs was developed, which specifically recognized Treg cells with high TIGIT expression thanks to the presence of an anti-TIGIT and an IL-2/JES6-1 complex (IL2C) being delivered to Treg cells but not to Teff cells with low TIGIT expression. Then, IL2C released IL-2 due to the specific expression of the high-affinity IL-2 receptor on Treg cells, thus enabling the active targeting and selective proliferation of Treg cells. Moreover, the anti-TIGIT of aT-IL2C NPs selectively inhibited the proliferation of Teff cells while leaving the proliferation of Treg cells unaffected. In addition, since the IL-2 receptor on Teff cells had medium-affinity, the IL2C hardly released IL-2 to Teff cells, thus enabling the inhibition of Teff cell proliferation. The treatment of experimental autoimmune encephalomyelitis (EAE) mice with aT-IL2C NPs ameliorated the severity of the EAE and restored white matter integrity. Collectively, this work described a potential promising agent for effective MS therapy.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Ratones , Animales , Linfocitos T Reguladores , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/metabolismo , Interleucina-2/farmacología , Interleucina-2/uso terapéutico , Interleucina-2/metabolismo , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Proliferación Celular , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: The rising global cancer burden has led to an increasing demand for imaging tests such as [18F]fluorodeoxyglucose ([18F]FDG)-PET-CT. To aid imaging specialists in dealing with high scan volumes, we aimed to train a deep learning artificial intelligence algorithm to classify [18F]FDG-PET-CT scans of patients with lymphoma with or without hypermetabolic tumour sites. METHODS: In this retrospective analysis we collected 16 583 [18F]FDG-PET-CTs of 5072 patients with lymphoma who had undergone PET-CT before or after treatment at the Memorial Sloa Kettering Cancer Center, New York, NY, USA. Using maximum intensity projection (MIP), three dimensional (3D) PET, and 3D CT data, our ResNet34-based deep learning model (Lymphoma Artificial Reader System [LARS]) for [18F]FDG-PET-CT binary classification (Deauville 1-3 vs 4-5), was trained on 80% of the dataset, and tested on 20% of this dataset. For external testing, 1000 [18F]FDG-PET-CTs were obtained from a second centre (Medical University of Vienna, Vienna, Austria). Seven model variants were evaluated, including MIP-based LARS-avg (optimised for accuracy) and LARS-max (optimised for sensitivity), and 3D PET-CT-based LARS-ptct. Following expert curation, areas under the curve (AUCs), accuracies, sensitivities, and specificities were calculated. FINDINGS: In the internal test cohort (3325 PET-CTs, 1012 patients), LARS-avg achieved an AUC of 0·949 (95% CI 0·942-0·956), accuracy of 0·890 (0·879-0·901), sensitivity of 0·868 (0·851-0·885), and specificity of 0·913 (0·899-0·925); LARS-max achieved an AUC of 0·949 (0·942-0·956), accuracy of 0·868 (0·858-0·879), sensitivity of 0·909 (0·896-0·924), and specificity of 0·826 (0·808-0·843); and LARS-ptct achieved an AUC of 0·939 (0·930-0·948), accuracy of 0·875 (0·864-0·887), sensitivity of 0·836 (0·817-0·855), and specificity of 0·915 (0·901-0·927). In the external test cohort (1000 PET-CTs, 503 patients), LARS-avg achieved an AUC of 0·953 (0·938-0·966), accuracy of 0·907 (0·888-0·925), sensitivity of 0·874 (0·843-0·904), and specificity of 0·949 (0·921-0·960); LARS-max achieved an AUC of 0·952 (0·937-0·965), accuracy of 0·898 (0·878-0·916), sensitivity of 0·899 (0·871-0·926), and specificity of 0·897 (0·871-0·922); and LARS-ptct achieved an AUC of 0·932 (0·915-0·948), accuracy of 0·870 (0·850-0·891), sensitivity of 0·827 (0·793-0·863), and specificity of 0·913 (0·889-0·937). INTERPRETATION: Deep learning accurately distinguishes between [18F]FDG-PET-CT scans of lymphoma patients with and without hypermetabolic tumour sites. Deep learning might therefore be potentially useful to rule out the presence of metabolically active disease in such patients, or serve as a second reader or decision support tool. FUNDING: National Institutes of Health-National Cancer Institute Cancer Center Support Grant.