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BACKGROUND: The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. METHODS: Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. RESULTS: Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth. CONCLUSION: ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.
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Epilepsias Parciales , Proteínas de Homeodominio , Espasmos Infantiles , Animales , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Epilepsias Parciales/genética , Epilepsias Parciales/tratamiento farmacológico , Secuenciación del Exoma , Predisposición Genética a la Enfermedad , Proteínas de Homeodominio/genética , Mutación , Espasmos Infantiles/genética , DrosophilaRESUMEN
Viruses deploy multiple strategies to suppress the host innate immune response to facilitate viral replication and pathogenesis. Typical G3BP1+ stress granules (SGs) are usually formed in host cells after virus infection to restrain viral translation and to stimulate innate immunity. Thus, viruses have evolved various mechanisms to inhibit SGs or to repurpose SG components such as G3BP1. Previous studies showed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection inhibited host immunity during the early stage of COVID-19. However, the precise mechanism is not yet well understood. Here we showed that the SARS-CoV-2 nucleocapsid (SARS2-N) protein suppressed the double-stranded RNA (dsRNA)-induced innate immune response, concomitant with inhibition of SGs and the induction of atypical SARS2-N+ /G3BP1+ foci (N+ foci). The SARS2-N protein-induced formation of N+ foci was dependent on the ability of its ITFG motif to hijack G3BP1, which contributed to suppress the innate immune response. Importantly, SARS2-N protein facilitated viral replication by inducing the formation of N+ foci. Viral mutations within SARS2-N protein that impair the formation of N+ foci are associated with the inability of the SARS2-N protein to suppress the immune response. Taken together, our study has revealed a novel mechanism by which SARS-CoV-2 suppresses the innate immune response via induction of atypical N+ foci. We think that this is a critical strategy for viral pathogenesis and has potential therapeutic implications.
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COVID-19 , ADN Helicasas , Humanos , SARS-CoV-2/metabolismo , ARN Helicasas/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa , Gránulos de Estrés , Proteínas con Motivos de Reconocimiento de ARN/metabolismo , Inmunidad Innata , Replicación Viral , Proteínas de la Nucleocápside/metabolismoRESUMEN
In this study, porous polymers with nitrogen heterocyclic core structures are synthesized through the condensation of enaminonitrile and terephthalaldehyde monomers. These polymers are used as a platform to store bioactive nitric oxide (NO) and control its release. NO loading is achieved by nitrosating the polymers with acidified nitrite, a process that also imparts photoresponsivity to the polymers. Polymer composition and porosity affect NO storage and release. It is observed that under UV light at 365 nm in a PBS solution, the polymers (NO@DHP-POP) can release NO in a manner fully controlled by UV lighting. Under experimental conditions, these porous polymers release NO at a rate of ≈10.0-50.0 µmol g-1 over 60 min. These findings demonstrate the potential of these polymers for integrating NO delivery into phototherapy applications.
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Arisaema cum bile (known as Dan Nanxing in Chinese, DNX) is a herbal medicine used for treating febrile seizure (FS), which commonly prepared by using Arisaematis Rhizoma and animal bile. This study was designed to explore the optimal processing time of DNX and its potential mechanism on the anti-FS effect. A total of 17 volatile organic compounds (VOCs) were the characteristic ones to distinguish different fermentation stages of DNX by using gas chromatography-ion mobility spectrometry (GC-IMS), such as 2-heptanone monomer, and heptanal monomer. DNX with fermentation for 3 months had an obvious pattern of VOCs with others, which could be regarded as the optimal fermentation time. The Enterococcus and Staphylococcus might be the core bacteria on the production of VOCs. Additionally, DNX (2.8 g/kg, p.o.) reversed hot water bath-induced FSs of rats, as indicated by increased seizure latency and decreased seizure duration time. It also prevented hippocampal neuronal loss, increased GABAAR, and decreased GRIA1 expression. At the genus level, relative abundance of Enterococcus and Akkermansia were enriched after DNX treatment. These findings suggested that fermentation for 3 months might be the optimal process time for DNX, and DNX possess an anti-FS effect through regulating neurotransmitter disorder and gut microbiota.
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Non-union fractures pose a significant clinical challenge, often leading to prolonged pain and disability. Understanding the molecular mechanisms underlying non-union fractures is crucial for developing effective therapeutic interventions. This study integrates bioinformatics analysis and experimental validation to unravel key genes and pathways associated with non-union fractures. We identified differentially expressed genes (DEGs) between non-union and fracture healing tissues using bioinformatics techniques. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed to elucidate the biological processes and pathways involved. Common DEGs were identified, and a protein-protein interaction (PPI) network was constructed. Fibronectin-1 (FN1), Thrombospondin-1 (THBS1), and Biglycan (BGN) were pinpointed as critical target genes for non-union fracture treatment. Experimental validation involved alkaline phosphatase (ALP) and Alizarin Red staining to confirm osteogenic differentiation. Our analysis revealed significant alterations in pathways related to cell behavior, tissue regeneration, wound healing, infection, and immune responses in non-union fracture tissues. FN1, THBS1, and BGN were identified as key genes, with their upregulation indicating potential disruptions in the bone remodeling process. Experimental validation confirmed the induction of osteogenic differentiation. The study provides comprehensive insights into the molecular mechanisms of non-union fractures, emphasizing the pivotal roles of FN1, THBS1, and BGN in extracellular matrix dynamics and bone regeneration. The findings highlight potential therapeutic targets and pathways for further investigation. Future research should explore interactions between these genes, validate results using in vivo fracture models, and develop tailored treatment strategies for non-union fractures, promising significant advances in clinical management.
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To study the influence of long non-coding ribonucleic acid maternally expressed gene 3 (lncRNA MEG3) on the neuronal apoptosis in rats with ischemic cerebral infarction, and to analyze its regulatory effect on the transforming growth factor-beta 1 (TGF-ß1) pathway. A total of 36 Sprague-Dawley rats were randomly assigned into sham group, model group and low expression group. Ischemic cerebral infarction modeling was constructed in rats of the model group and low expression group. Corresponding adenoviruses were intracranially injected in rats of low expression group to knock down lncRNA MEG3 expression. At 24 h after the operation, the neurological function of rats was evaluated in each group, and the expression level of lncRNA MEG3 in cerebral tissues was determined using quantitative polymerase chain reaction (qPCR). The infarct size was measured via 2,3,5-triphenyltetrazolium chloride (TTC) staining. The apoptosis level of neurons in cerebral tissues was determined using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Besides, enzyme-linked immunosorbent assay (ELISA) was performed to determine the contents of inflammatory factors in cerebral tissues. Expression levels of apoptosis-associated proteins and vital genes in the TGF-ß1 signaling pathway in rat cerebral tissues were measured using Western blotting. Compared with the sham group, rats in the model group exhibited substantial increases in the neurological score and apoptosis level of neurons (p<0.01). Relative levels of lncRNA MEG3, interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), Caspase-3, TGF-ß1, small mothers against decapentaplegic homolog 2 (Smad2) and Smad3 (p<0.01) were higher in a model group than those in sham group. Notable declines in the content of IL-10 (p<0.01) and the ratio of B-cell lymphoma 2 (Bcl-2)/Bcl associated X protein (Bax) (p<0.01) were seen in the model group compared with the sham group. The abovementioned changes in the model group were partially abolished in the low expression group. LncRNA MEG3 is upregulated in the cerebral tissues of rats with ischemic cerebral infarction. It induces an inflammatory response, expands cerebral infarct size, and promotes neuronal apoptosis and impairment by activating the TGF-ß1 pathway.
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Apoptosis , Infarto Cerebral , ARN Largo no Codificante , Animales , Ratas , Apoptosis/genética , Infarto Cerebral/genética , Infarto Cerebral/metabolismo , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , ARN Largo no Codificante/genética , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Genome-guided oncology refers to a new treatment concept that transcends histological classification and pathological ty-ping and uses drugs according to the genetic characteristics of tumors. New drug development technology and clinical trial design based on this concept provide new ideas for the clinical application of precision oncology. The multi-component and multi-target characteristics of Chinese medicine provide rich resources for the development of tumor-targeting drugs from natural products, and the design of the master protocol trial aiming at the characteristics of precision oncology supports the rapid clinical screening of effective tumor-targeting drugs. The emergence of the synthetic lethality strategy breaks through the bottleneck that the drug can only target the oncogene but cannot do anything to the tumor suppressor gene with the loss-of-function mutation in the past. With the rapid development of high-throughput sequencing technology, the cost of sequencing is also decreasing. For the development of tumor-targeting drugs, how to keep up with the update speed of target information is a difficult problem of concern. Based on the integration of innovative ideas and me-thods of precision oncology, network pharmacology, and synthetic lethality strategy on synthetic lethal interaction network of antitumor Chinese medicine compatibility formula design, and the combination of improvement of innovative clinical trial methods, such as master protocol trial, basket trial, and umbrella trial, unique advantages of Chinese medicine are expected to be exerted beyond the antibody-based drugs and small molecule-based drugs and corresponding targeted drugs are potentially developed for clinical application.
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Antineoplásicos , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Medicina Tradicional China , Medicina de Precisión/métodos , Oncología Médica , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
WHAT IS KNOWN AND OBJECTIVES: The present study aimed to predict the effect of sirolimus on disease activity in patients with systemic lupus erythematosus (SLE) using machine learning and to recommend appropriate sirolimus dosage regimen for patients with SLE. METHODS: The Emax model was selected for machine learning, where the evaluation indicator was the change rate of systemic lupus erythematosus disease activity index from baseline value. RESULTS: A total 103 patients with SLE were included for modelling, where the Emax , ET50 were -53.9%, 1.53 months in the final model respectively, and the evaluation of the final model was good. Further simulation found that the follow-up time to achieve 25%, 50%, 75% and 80% (plateau) Emax of sirolimus effecting on disease activity in patients with SLE were 0.51, 1.53, 4.59 and 6.12 months, respectively. In addition, the sirolimus dosage was flexible and adjusted according to drug concentration, where the intersection of sirolimus concentration range included in this study was about 8-10 ng/ml. WHAT IS NEW AND CONCLUSIONS: This study was the first time to predict the effect of sirolimus on disease activity in patients with SLE and in order to achieve better therapeutic effect maintaining a concentration of 8-10 ng/ml sirolimus for at least 6.12 months was necessary.
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Lupus Eritematoso Sistémico , Sirolimus , Humanos , Sirolimus/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Aprendizaje AutomáticoRESUMEN
WHAT IS KNOWN AND OBJECTIVES: Dapagliflozin was the first oral treatment approved in type 1 diabetes mellitus (T1DM) patients, simultaneously improving body weight. However, the time course and dose effect of dapagliflozin on loss of weight in T1DM patients was still unknown. The present study aimed to investigate quantitative relationship between dapagliflozin and loss of weight in T1DM patients based on Model-based Meta-analysis. METHODS: Five dapagliflozin dosage groups, two of them were 5 mg/day and three of them were 10 mg/day, 1612 T1DM patients were analysed with maximal effect (Emax ) model, and evaluation index was change rate of body weight from baseline value. RESULTS: In these T1DM patients, dosages were not incorporated into model, indicating no significant dose-response relationship between 5 and 10 mg/day affecting loss of weight. Emax and the treatment duration to reach half of the maximal effects (ET50 ) of dapagliflozin influencing loss of weight in T1DM patients were -4.9% and 10.4 weeks, and the duration to achieve 25%, 50%, 75%, and 80% (plateau) of Emax were 3.5, 10.4, 31.2, and 41.6 weeks. WHAT IS NEW AND CONCLUSIONS: It was the first time to explore quantitative relationship between dapagliflozin and loss of weight in T1DM patients. To achieve the plateau period in loss of weight, 5 mg/day dapagliflozin was required for at least 41.6 weeks.
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Compuestos de Bencidrilo/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Glucósidos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Pérdida de Peso/efectos de los fármacos , Factores de Edad , Compuestos de Bencidrilo/administración & dosificación , Peso Corporal , Relación Dosis-Respuesta a Droga , Glucósidos/administración & dosificación , Humanos , Hipoglucemiantes/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios RetrospectivosRESUMEN
WHAT IS KNOWN AND OBJECTIVES: The initial tacrolimus dose regimen in paediatric lung transplant recipients is unknown. The present study optimized the initial tacrolimus dose regimen for paediatric lung transplant recipients. METHODS: This study was based on a published population pharmacokinetic model of tacrolimus in lung transplant recipients and used Monte Carlo simulations to recommend an initial dose regimen of tacrolimus in paediatric lung transplant recipients. RESULTS: Without voriconazole, the tacrolimus doses recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers were 0.02, 0.03, and 0.04 mg/kg/day, split into two doses, for weights of 10-16, 16-30, and 30-40 kg, respectively. For paediatric lung transplant recipients who were CYP3A5*1 carriers, the tacrolimus doses of 0.03, 0.04, 0.05, and 0.06 mg/kg/day, split into two doses, were recommended for weights of 10-16, 16-25, 25-30, and 30-40 kg, respectively. With voriconazole, the tacrolimus dose recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers was 0.02 mg/kg/day, split into two doses, for weights of 10-40 kg. For paediatric lung transplant recipients who were CYP3A5*1 carriers, tacrolimus doses of 0.02 and 0.03 mg/kg/day, split and two doses, were recommended for weights of 10-24 and 24-40 kg, respectively. WHAT IS NEW AND CONCLUSIONS: This study developed tacrolimus dose regimens for the first time for paediatric lung transplant recipients using Monte Carlo simulation and optimized initial dosage in paediatric lung transplant recipients.
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Trasplante de Riñón , Tacrolimus , Niño , Citocromo P-450 CYP3A/genética , Genotipo , Humanos , Inmunosupresores , Pulmón , Método de Montecarlo , Receptores de Trasplantes , VoriconazolRESUMEN
AIMS: Our previous study demonstrated that Ca2+ influx through the Orai1 store-operated Ca2+ channel in macrophages contributes to foam cell formation and atherosclerosis via the calcineurin-ASK1 pathway, not the classical calcineurin-nuclear factor of activated T-cell (NFAT) pathway. Moreover, up-regulation of NFATc3 in macrophages inhibits foam cell formation, suggesting that macrophage NFATc3 is a negative regulator of atherogenesis. Hence, this study investigated the precise role of macrophage NFATc3 in atherogenesis. METHODS AND RESULTS: Macrophage-specific NFATc3 knockout mice were generated to determine the effect of NFATc3 on atherosclerosis in a mouse model of adeno-associated virus-mutant PCSK9-induced atherosclerosis. NFATc3 expression was decreased in macrophages within human and mouse atherosclerotic lesions. Moreover, NFATc3 levels in peripheral blood mononuclear cells from atherosclerotic patients were negatively associated with plaque instability. Furthermore, macrophage-specific ablation of NFATc3 in mice led to the atherosclerotic plaque formation, whereas macrophage-specific NFATc3 transgenic mice exhibited the opposite phenotype. NFATc3 deficiency in macrophages promoted foam cell formation by potentiating SR-A- and CD36-meditated lipid uptake. NFATc3 directly targeted and transcriptionally up-regulated miR-204 levels. Mature miR-204-5p suppressed SR-A expression via canonical regulation. Unexpectedly, miR-204-3p localized in the nucleus and inhibited CD36 transcription. Restoration of miR-204 abolished the proatherogenic phenotype observed in the macrophage-specific NFATc3 knockout mice, and blockade of miR-204 function reversed the beneficial effects of NFATc3 in macrophages. CONCLUSION: Macrophage NFATc3 up-regulates miR-204 to reduce SR-A and CD36 levels, thereby preventing foam cell formation and atherosclerosis, indicating that the NFATc3/miR-204 axis may be a potential therapeutic target against atherosclerosis.
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Aterosclerosis , MicroARNs , Animales , Aterosclerosis/genética , Células Espumosas , Humanos , Leucocitos Mononucleares , Ratones , MicroARNs/genética , Factores de Transcripción NFATC/genética , Proproteína Convertasa 9RESUMEN
CELSR1 gene, encoding cadherin EGF LAG seven-pass G-type receptor 1, is mainly expressed in neural stem cells during the embryonic period. It plays an important role in neurodevelopment. However, the relationship between CELSR1 and disease of the central nervous system has not been defined. In this study, we performed trios-based whole-exome sequencing in a cohort of 356 unrelated cases with partial epilepsy without acquired causes and identified CELSR1 variants in six unrelated cases. The variants included one de novo heterozygous nonsense variant, one de novo heterozygous missense variant, and four compound heterozygous missense variants that had one variant was located in the extracellular region and the other in the cytoplasm. The patients with biallelic variants presented severe epileptic phenotypes, whereas those with heterozygous variants were associated with a mild epileptic phenotype of benign epilepsy with centrotemporal spikes (BECTS). These variants had no or low allele frequency in the gnomAD database. The frequencies of the CELSR1 variants in this cohort were significantly higher than those in the control populations. The evidence from ClinGen Clinical-Validity Framework suggested a strong association between CELSR1 variants and epilepsy. These findings provide evidence that CELSR1 is potentially a candidate pathogenic gene of partial epilepsy of childhood.
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Epilepsias Parciales , Humanos , Epilepsias Parciales/genética , Cadherinas/genética , Alelos , Heterocigoto , Mutación Missense/genéticaRESUMEN
As antimicrobial resistance has been increasing, new antimicrobial agents are desperately needed. Azalomycin F, a natural polyhydroxy macrolide, presents remarkable antimicrobial activities. To investigate its pharmacokinetic characteristics in rats, the concentrations of azalomycin F contained in biological samples, in vitro, were determined using a validated high-performance liquid chromatography-ultraviolet (HPLC-UV) method, and, in vivo, samples were assayed by an ultra-high performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method. Based on these methods, the pharmacokinetics of azalomycin F were first investigated. Its plasma concentration-time courses and pharmacokinetic parameters in rats were obtained by a non-compartment model for oral (26.4 mg/kg) and intravenous (2.2 mg/kg) administrations. The results indicate that the oral absolute bioavailability of azalomycin F is very low (2.39 ± 1.28%). From combinational analyses of these pharmacokinetic parameters, and of the results of the in-vitro absorption and metabolism experiments, we conclude that azalomycin F is absorbed relatively slowly and with difficulty by the intestinal tract, and subsequently can be rapidly distributed into the tissues and/or intracellular f of rats. Azalomycin F is stable in plasma, whole blood, and the liver, and presents plasma protein binding ratios of more than 90%. Moreover, one of the major elimination routes of azalomycin F is its excretion through bile and feces. Together, the above indicate that azalomycin F is suitable for administration by intravenous injection when used for systemic diseases, while, by oral administration, it can be used in the treatment of diseases of the gastrointestinal tract.
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Productos Biológicos/farmacocinética , Macrólidos/farmacocinética , Streptomyces/química , Animales , Biopelículas , Productos Biológicos/sangre , Productos Biológicos/química , Hígado/química , Hígado/metabolismo , Macrólidos/sangre , Macrólidos/química , Masculino , Ratas , Ratas Sprague-Dawley , Streptomyces/metabolismoRESUMEN
OBJECTIVE: To explore the significance of the resistance to polymyxin resistance of the extensively drug resistant Acinetobacter baumannii (XDRAB) lipopolysaccharide (LPS) lpx A, lpx C, lpx D and to screen appropriate combination therapy. METHODS: In the past two years, 72 XDRAB in the secretions of our patients were selected as the research object. According to the minimum inhibitory concentration (MIC) of the XDRAB strain on polymyxin, they were included in the drug resistance group and the sensitive group. The gene sequences of strains lpx A, lpx C, lpx D were compared with the standard strains to analyze gene mutations and compared the mutation rates in the drug resistant group and the sensitive group. The efficacy of the combination drugs was evaluated by microcheckerboard dilution method, including polymyxin+imipenem group, polymyxin+meropenem group, polymyxin+cefoperazone/sulbactam group, polymyxin+levofloxacin group, and polymyxin+fosfomycin group. Calculated the fractional inhibitory concentration (FIC) index of the combined medication regimen and compared the percentage of strains that exhibited synergistic, additive, irrelevant, and antagonistic effects. RESULTS: Tentyone were in the drug resistant group, accounting for 21 (29.17%,) and 51 were in the sensitive group, accounting for 70.83%. Some strains had mutations in lpx A, lpx C, lpx D genes. The mutation rate in the drug resistant group was 90.48%, which was significantly higher than 11.76% in the sensitive group, the difference was statistically significant ( P<0.05). The combined drug sensitivity test showed, compared with the polymyxin+fosfomycin group, the mycotin+fosfomycin group had a higher percentage of strains with synergistic FIC index in the polymyxin+imipenem group, the difference was statistically significant ( P<0.01). CONCLUSION: XDRAB is resistant to polymyxin, which is related to mutations in LPS lipid A biosynthesis genes lpx A, lpx C, lpx D. Clinical treatment should adopt a combination of polymyxin+imipenem/meropenem and other drug combination to reduce the secondary infection of drug resistant bacteria.
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Infecciones por Acinetobacter , Acinetobacter baumannii , Infecciones por Acinetobacter/tratamiento farmacológico , Acinetobacter baumannii/genética , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana Múltiple/genética , Sinergismo Farmacológico , Humanos , Lípido A , Lipopolisacáridos , Pruebas de Sensibilidad Microbiana , Mutación , Polimixinas/farmacologíaRESUMEN
A novel soluble molecularly imprinted polymer (SMIP) without chemical cross-linker was successfully synthesized. The quinine (QN), which the structure was similar to the template, was chosen as the immobile template to improve the affinity of MIP. 4-Methyl phenyl dicyclohexyl ethylene (MPDE) was used as the liquid crystal (LC) monomer to increase the rigid of the composite. The cooperative effect of QN and MPDE was demonstrated by comparing with the conventional MIP, which synthesized without QN and MPDE. The polymerization conditions of SMIP including the ratio of MAA to MPDE, template to functional monomer, and HQN to QN were also optimized. Moreover, the characterizations of the SMIP were investigated by the transmission electron microscopy (TEM), field emission scanning electron microscopy (SEM), thermogravimetric analysis (TGA), X-ray diffraction (XRD), and nitrogen adsorption. In binding behavior, the SMIP presented the maximum adsorption capacity (0.37 ± 0.06 mmol/g) and imprinting factor (3.44 ± 0.25). And above all, the obtained polymer exhibited the solubility in the organic solution. In addition, the proposed SMIP as the electrochemical sensor exhibited a significant conductivity and sensitivity with the detection limit of 0.33 µM for HQN, the recoveries for the sample analysis varied from 97.4 to 100.8%, and the intra-day precision and inter-day precision were within 5.5% and 12.5%, respectively. It turned out that the SMIP had demonstrated more excellent potential than the traditional insoluble MIP in the development of the membrane-based electrochemical sensors.Graphical abstract.
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Antimicrobial resistance has emerged as a serious threat to public health. Bacterial biofilm, as a natural lifestyle, is a major contributor to resistance to antimicrobials. Azalomycin F5a, a natural guanidine-containing polyhydroxy macrolide, has remarkable activities against Gram-positive bacteria, including Staphylococcus aureus, a major causative agent of hospital-acquired infections. To further evaluate its potential to be developed as a new antimicrobial agent, its influence on S. aureus biofilm formation was evaluated using the crystal violet method, and then its eradication effect against mature biofilms was determined by confocal laser scanning microscopy, the drop plate method, and regrowth experiments. The results showed that azalomycin F5a could significantly inhibit S. aureus biofilm formation, and such effects were concentration dependent. In addition, it can also eradicate S. aureus mature biofilms with the minimum biofilm eradication concentration of 32.0 µg/mL. As extracellular deoxyribonucleic acid (eDNA) plays important roles in the structural integrity of bacterial biofilm, its influence on the eDNA release in S. aureus biofilm was further analyzed using gel electrophoresis. Combined with our previous works, these results indicate that azalomycin F5a could rapidly penetrate biofilm and causes damages to the cell membrane, leading to an increase in DNase release and eventually eradicating S. aureus biofilm.
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Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Macrólidos/farmacología , Staphylococcus aureus/fisiología , Antibacterianos/química , Antibacterianos/metabolismo , ADN/química , ADN/metabolismo , Desoxirribonucleasa I/metabolismo , Macrólidos/química , Macrólidos/metabolismo , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: Despite recent advances in the treatments of hepatocellular carcinoma (HCC), the prognosis of HCC patients remains controversial. The purpose of this study was to investigate the prognostic performance of pretreatment albumin to C-reactive protein ratio (ACR) in patients with HCC. METHODS: This study included 409 initially diagnosed HCC patients retrospectively. The optimal cut-off points for distinguishing high and low ACR value was determined by the X-tile software. The chi-squared test was used for comparing the baseline clinicopathologic parameters in different groups and subgroups. The Cox regression with log-rank tests was used to analyze OS and DFS, and Kaplan-Meier curves was used to estimate the prognosis of HCC patients. RESULTS: Patients with lower ACR were significantly correlated with advanced clinical parameters, using a cut-off points of 5.4 (high ACR, n = 236 vs. low ACR, n = 173). Multivariate analysis demonstrated that ACR was associated with OS (HR = 0.544, 95% CI: 0.385-0.769, p = 0.001), with DFS (HR = 0.550, 95% CI: 0.392-0.772, p = 0.001). Treatment exposure (HR = 2.191; 95% CI: 1.533-3.132; p < 0.001), tumor size (HR = 1.973; 95% CI: 1.230-3.164; p = 0.005), serum AFP level (HR = 1.752; 95% CI: 1.277-2.403; p = 0.001), and TNM stage (HR = 0.470; 95% CI: 0.319-2.504; p < 0.001), were independent factors for OS in HCC patients. Treatment exposure (HR = 2.244; 95% CI: 1.590-3.166; p < 0.001), TNM stage (HR = 2.075; 95% CI: 1.436-3.000; p < 0.001), serum AFP level (HR = 1.819; 95% CI: 1.340-2.469; p = 0.001), tumor size (HR = 1.730; 95% CI: 1.113-2.689; p = 0.015), and ACR (HR = 0.550; 95% CI: 0.392-0.772; p = 0.001) were independent factors for DFS in HCC patients. CONCLUSIONS: Pretreatment ACR is a convenient and useful parameter for HCC patients predicting OS and DFS. Lower ACR was associated with advanced TNM stage, larger tumor size, and a high concentration of AFP. These results may help to design strategies to personalize management approaches among HCC patients.
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Proteína C-Reactiva/análisis , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidad , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidad , Albúmina Sérica Humana/análisis , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Distribución de Chi-Cuadrado , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Carga Tumoral , Adulto Joven , alfa-Fetoproteínas/análisisRESUMEN
Polymer dots (Pdots) represent newly developed semiconductor polymer nanoparticles and exhibit excellent characteristics as fluorescent probes. To improve the sensitivity and biocompatibility of Pdots ratiometric pH biosensors, we synthesized 3 types of water-soluble Pdots: Pdots-PF, Pdots-PP, and Pdots-PPF by different combinations of fluorescent dyes poly(9,9-dioctylfluorenyl-2,7-diyl) (PFO), poly[(9,9-dioctyl-fluorenyl-2,7-diyl)-co-(1,4-benzo-{2,1',3}-thiadazole)] (PFBT), and fluorescein isothiocyanate (FITC). We found that Pdots-PPF exhibits optimal performance on pH sensing. PFO and FITC in Pdots-PPF produce pH-insensitive (λ = 439 nm) and pH-sensitive (λ = 517 nm) fluorescence respectively upon a single excitation at 380 nm wavelength, which enables Pdots-PPF ratiometric pH sensing ability. Förster resonance energy transfer (FRET) together with the use of PFBT amplify the FITC signal, which enables Pdots-PPF robust sensitivity to pH. The emission intensity ratio (I517/I439) of Pdots-PPF changes linearly as a function of pH within the range of pH 3.0 to 8.0. Pdots-PPF also possesses desirable reversibility and stability in pH measurement. More importantly, Pdots-PPF was successfully used for cell imaging in Hela cells, exhibiting effective cellular uptake and low cytotoxicity. Our study suggests the promising potential of Pdots-PPF as an in vivo biomarker.
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Técnicas Biosensibles , Fluorenos/química , Fluoresceína-5-Isotiocianato/química , Colorantes Fluorescentes/química , Imagen Óptica/métodos , Polímeros/química , Puntos Cuánticos/química , Transferencia Resonante de Energía de Fluorescencia , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Semiconductores , Solubilidad , AguaRESUMEN
Biofilm processes have a better nitrogen removal ability than traditional activated sludge at low temperatures (< 15 °C). Many biofilm processes, as well as integrated biofilm and activated sludge processes, are potential and realizable nitrogen removal upgrading methods for domestic wastewater treatment plants (WWTPs). Therefore, biofilm packing material is attractive for domestic WWTP upgrading and reconstruction in winter. For a half decade, researchers have successfully applied activated carbon to biochar as biofilm carrier in the wastewater treatment field. Biochar, as a biostable soil amendment with pores and crevices on its surface, has been applied in the soil-plant system, which promoted the adsorption of NH4+ and NO3-, decreased N2O emission, transcriptional level of narG, nxrA, and nirS, and changed the microbial community composition for better nitrogen removal. However, in the field of wastewater treatment, the study of biochar-packed process is merely in the laboratory stage of simulated wastewater, which deserves further research in the future. In this mini review, we will discuss the performances of different processes at low temperatures, the related mechanism of the biochar-packed process for nitrogen removal, and other potential applications of biochar carriers.
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Carbón Orgánico , Frío , Desnitrificación , Nitrógeno/metabolismo , Estaciones del Año , Purificación del Agua/métodos , Bacterias/metabolismo , Biopelículas , Aguas del Alcantarillado , Aguas Residuales/químicaRESUMEN
This study explored the relationship between the fractional exhaled nitric oxide (FeNO) level and the efficacy of inhaled corticosteroid (ICS) in asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) patients with different disease severity. A total of 127 ACOS patients with ACOS (case group) and 131 healthy people (control group) were enrolled in this study. Based on the severity of COPD, the ACOS patients were divided into: mild ACOS; moderate ACOS; severe ACOS; and extremely severe ACOS groups. We compared FeNO levels, pulmonary function parameters including percentage of forced expiratory volume in 1 second (FEV1) to predicted value (FEV1%pred), ratio of FEV1 to forced vital capacity (FEV1/FVC), inspiratory capacity to total lung capacity (IC/TLC) and residual volume to total lung capacity (RV/TLC), arterial blood gas parameters, including PH, arterial partial pressure of oxygen (PaO2) and arterial partial pressure of carbon dioxide (PaCO2), total serum immunoglobulin E (IgE), induced sputum eosinophil (EOS), plasma surfactant protein A (SP-A), plasma soluble receptor for advanced glycation end products (sRAGE), sputum myeloperoxidase (MPO), sputum neutrophil gelatinase-associated lipocalin (NGAL) and Asthma Control Test (ACT) scores, and COPD Assessment Test (CAT) scores. Compared with pre-treatment parameters, the FeNO levels, RV/TLC, PaCO2, total serum IgE, induced sputum EOS, plasma SP-A, sputum MPO, sputum NGAL, and CAT scores were significantly decreased after 6 months of ICS treatment, while FEV1%pred, FEV1/FVC, IC/TLC, PH, PaO2, plasma sRAGE, and ACT scores were significantly increased in ACOS patients with different disease severity after 6 months of ICS treatment. This finding suggests that the FeNO level may accurately predict the efficacy of ICS in the treatment of ACOS patients.