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Collective cell migration is a model for nonequilibrium biological dynamics, which is important for morphogenesis, pattern formation, and cancer metastasis. The current understanding of cellular collective dynamics is based primarily on cells moving within a 2D epithelial monolayer. However, solid tumors often invade surrounding tissues in the form of a stream-like 3D structure, and how biophysical cues are integrated at the cellular level to give rise to this collective streaming remains unclear. Here, it is shown that cell cycle-mediated bioenergetics drive a forward advective flow of cells and energy to the front to support 3D collective invasion. The cell division cycle mediates a corresponding energy cycle such that cellular adenosine triphosphate (ATP) energy peaks just before division. A reaction-advection-diffusion (RAD) type model coupled with experimental measurements further indicates that most cells enter an active division cycle at rear positions during 3D streaming. Once the cells progress to a later stage toward division, the high intracellular energy allows them to preferentially stream toward the tip and become leader cells. This energy-driven cellular flow may be a fundamental characteristic of 3D collective dynamics based on thermodynamic principles important for not only cancer invasion but also tissue morphogenesis.
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Movimento Celular , Metabolismo Energético , Humanos , Movimento Celular/fisiologia , Metabolismo Energético/fisiologia , Invasividade Neoplásica , Ciclo Celular/fisiologia , Trifosfato de Adenosina/metabolismo , Modelos Biológicos , Linhagem Celular TumoralRESUMO
Metal oxides with nanoarray structures have been demonstrated to be prospective materials for the design of gas sensors with high sensitivity. In this work, the WO3 nanoneedle array structures were synthesized by a one-step hydrothermal method and subsequent calcination. It was demonstrated that the calcination of the sample at 400 °C facilitated the construction of lilac-like multiple self-supporting WO3 arrays, with appropriate c/h-WO3 heterophase junction and highly oriented nanoneedles. Sensors with this structure exhibited the highest sensitivity (2305) to 100 ppm ethylene glycol at 160 °C and outstanding selectivity. The enhanced ethylene glycol gas sensing can be attributed to the abundant transport channels and active sites provided by this unique structure. In addition, the more oxygen adsorption caused by the heterophase junction and the aggregation of reaction medium induced by tip effect are both in favor of the improvement on the gas sensing performance.
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Etilenoglicol , Nanoestruturas , Óxidos , Tungstênio , Tungstênio/química , Óxidos/química , Etilenoglicol/química , Nanoestruturas/química , Gases/análise , Gases/químicaRESUMO
INTRODUCTION: Drug resistance to echinocandins, first-line drugs used to treat Candida auris infection, is rapidly emerging. However, the accumulation of mutations in genes other than FKS1 (before an isolate develops to resistance via FKS1 mutations), remains poorly understood. Methods: Four clinical cases and 29 isolates associated with the incremental process of echinocandin resistance were collected and analyzed using antifungal drug susceptibility testing and genome sequencing to assess the evolution of echinocandin resistance. FINDINGS: Six echinocandin minimum inhibitory concentration (MIC)-elevated C. auris strains and seven resistant strains were isolated from the urinary system of patients receiving echinocandin treatment. Meanwhile, phylogenetic analyses illustrated that the echinocandin-resistant strains were closely related to other strains in the same patient. Genomic data revealed that the echinocandin-resistant strains had FKS1 mutations. Furthermore, three categories (ECN-S/E/R) of non-synonymous mutant SNP genes (such as RBR3, IFF6, MKC1, MPH1, RAD2, and MYO1) in C. auris appeared to be associated with the three-stage-evolutionary model of echinocandin resistance in C. glabrata: cell wall stress, drug adaptation, and genetic escape (FKS mutation). INTERPRETATION: Echinocandin-resistant C. auris undergoes spatial and temporal phase changes closely related to echinocandin exposure, particularly in the urinary system. These findings suggest that FKS1 mutations mediate an evolutionary accumulation of echinocandin resistance followed by modulation of chromosome remodelling and DNA repair processes that ultimately lead to FKS1 hot spot mutations and the development of drug resistance. This study provides an in-depth exploration of the molecular pathways involved in the evolution of Candida auris echinocandin resistance.
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Antifúngicos , Candida auris , Candidíase , Farmacorresistência Fúngica , Equinocandinas , Proteínas Fúngicas , Testes de Sensibilidade Microbiana , Mutação , Filogenia , Humanos , Equinocandinas/farmacologia , Antifúngicos/farmacologia , Farmacorresistência Fúngica/genética , Candidíase/microbiologia , Candidíase/tratamento farmacológico , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Candida auris/genética , Candida auris/efeitos dos fármacos , Evolução Molecular , Masculino , Feminino , Glucosiltransferases/genética , Candidíase InvasivaRESUMO
Reported herein is a practical, economical, and efficient construction of 3-alkylated quinoxalin-2(1H)-ones with alkyl carboxylic acids and alkyl iodides by quinoxalin-2(1H)-one excitation and cobaloxime catalysis. Primary, secondary, and tertiary alkyl iodides and carboxylic acids all could be efficiently transferred into target products with excellent functional group tolerance. Mechanism studies reveal that the quinoxalin-2(1H)-one derivatives could be directly excited and yield alkyl carbon radicals from alkyl carboxylic acids and alkyl iodides with the aid of the cobaloxime complex.
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Metal-organic gels (MOGs) are unique supramolecular gels that are convenient to synthesize. In this work, a cathodic electrochemiluminescence (ECL) system based on Ag-MOGs as a luminophore and K2S2O8 as a co-reactor was developed. The ECL spectrum of the Ag-MOGs overlapped significantly with the strong UV-Vis spectrum of the SiO2@PANI@AuNPs, which effectively quenched the ECL luminescence of the Ag-MOGs. Relying on the inner filter effect between Ag-MOGs and SiO2@PANI@AuNPs, a novel ECL-IFE immunosensor was developed for the detection of neuron-specific enolase (NSE). Under optimal conditions, the ECL signal of the immunosensor displayed excellent linearity over the NSE concentration range of 10 fg/mL-100 ng/mL. The limit of detection (LOD) was 2.6 fg/mL (S/N = 3) with a correlation coefficient R2 of 0.9975. The ECL immunosensor also exhibited excellent stability and reproducibility for the detection of NSE. The results reported provide a feasible concept for the development analytical methods for the detection of other clinically relevant biomarkers.
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Técnicas Biossensoriais , Nanopartículas Metálicas , Ouro , Dióxido de Silício , Medições Luminescentes/métodos , Imunoensaio/métodos , Técnicas Biossensoriais/métodos , Reprodutibilidade dos Testes , Técnicas Eletroquímicas/métodos , Géis , Fosfopiruvato HidrataseRESUMO
Highly oxygenated organic molecules (HOMs) are a major source of new particles that affect the Earth's climate. HOM production from the oxidation of volatile organic compounds (VOCs) occurs during both the day and night and can lead to new particle formation (NPF). However, NPF involving organic vapors has been reported much more often during the daytime than during nighttime. Here, we show that the nitrate radicals (NO3), which arise predominantly at night, inhibit NPF during the oxidation of monoterpenes based on three lines of observational evidence: NPF experiments in the CLOUD (Cosmics Leaving OUtdoor Droplets) chamber at CERN (European Organization for Nuclear Research), radical chemistry experiments using an oxidation flow reactor, and field observations in a wetland that occasionally exhibits nocturnal NPF. Nitrooxy-peroxy radicals formed from NO3 chemistry suppress the production of ultralow-volatility organic compounds (ULVOCs) responsible for biogenic NPF, which are covalently bound peroxy radical (RO2) dimer association products. The ULVOC yield of α-pinene in the presence of NO3 is one-fifth of that resulting from ozone chemistry alone. Even trace amounts of NO3 radicals, at sub-parts per trillion level, suppress the NPF rate by a factor of 4. Ambient observations further confirm that when NO3 chemistry is involved, monoterpene NPF is completely turned off. Our results explain the frequent absence of nocturnal biogenic NPF in monoterpene (α-pinene)-rich environments.
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Poluentes Atmosféricos , Monoterpenos Bicíclicos , Ozônio , Compostos Orgânicos Voláteis , Monoterpenos/química , Nitratos/química , Aerossóis/análise , Compostos Orgânicos Voláteis/químicaRESUMO
Sensitive detection of pro-gastrin-releasing peptide (Pro-GRP) is crucial because it is a highly sensitive and specific tumor marker for small cell lung cancer. Herein, we synthesized an efficient luminescent europium metal-organic framework and developed a sandwich ECL immunosensor for the sensitive detection of Pro-GRP, which used Eu3+ as the central ion and 2,4,6-tri (4-carboxyphenyl)-1,3,5-triazine (H3TATB) as the organic ligand. H3TATB acted as a strong absorbing reagent and transferred its energy to Eu3+ via the antenna effect to enhance the ECL response signal of Eu3+. As per calculations, the ECL efficiency of Eu-TATB, which was a promising ECL luminophore, was up to 130 %. The Cu2O cube worked as a substrate to assist the electron transfer and was used as a co-reaction accelerator to catalyze S2O82- to produce more SO4â¢- and then enhance the ECL intensity of Eu-TATB. Under optimal experimental conditions, the ECL immunosensor had a linear range of 5 fg mL-1-50 ng mL-1 for detecting Pro-GRP with a detection limit of 1.6 fg mL-1; moreover, it demonstrated excellent stability and specificity and has been successfully applied for detecting Pro-GRP in the human serum.
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Técnicas Biossensoriais , Nanopartículas Metálicas , Estruturas Metalorgânicas , Humanos , Peptídeo Liberador de Gastrina , Európio , Medições Luminescentes , Técnicas Eletroquímicas , Imunoensaio , Limite de DetecçãoRESUMO
This study aimed to investigate the effects of replacing fishmeal (FM) with African giant snail (Achatina fulica) meal (SM) on the growth performance of giant river prawn (Macrobrachium rosenbergii), as well as to analyze the associated metabolomic changes. Six diets were formulated, replacing FM with SM at different inclusion levels ranging from 0 % to 100 %. Growth performance and feed conversion ratio of prawns fed diets with FM replaced by SM up to 80 % were not significantly different from control. In contrast, significantly decreased growth performance and higher feed conversion ratio (FCR) occurred with diets containing 100 % SM. To gain insights into the metabolic regulation of prawns fed different diets, a 1H NMR metabolomics approach was used to assess the metabolic changes in prawns fed diets containing 0 % and 80 % SM. The results revealed up-regulated metabolites significantly involved in several metabolic pathways, including alanine, aspartate, and glutamate metabolism; citrate cycle (TCA cycle); aminoacyl-tRNA biosynthesis; and valine, leucine, and isoleucine biosynthesis. These findings imply that including SM in the diet might modulate the regulation of muscle amino acids and tRNA synthesis, suggesting a potential impact on protein biosynthesis mechanisms. Additionally, alterations in the TCA cycle may reflect changes in carbon utilization, potentially contributing to the growth performance of giant river prawns when fishmeal is replaced with SM without adversely affecting their growth. In conclusion, this study demonstrated that SM could be a promising alternative protein source in aquafeed. The metabolomic approach provides valuable insights into the metabolic changes in prawns fed different diets, aiding in the development of more effective aquafeeds in the future. The study's limitations, such as the simplified diet formulation and the limited scope of the metabolomic analysis, were acknowledged and discussed, highlighting the need for further research to build upon these findings.
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Palaemonidae , Animais , Palaemonidae/fisiologia , Dieta , Caramujos , RNA de TransferênciaRESUMO
Agriculture provides people with food, but poses environmental challenges. Via comprehensive observations on an agricultural land at Qvidja in Southern Finland, we were able to show that soil-emitted compounds (mainly ammonia and amines), together with available sulfuric acid, form new aerosol particles which then grow to climate-relevant sizes by the condensation of extremely low volatile organic compounds originating from a side production of photosynthesis (compounds emitted by ground and surrounding vegetation). We found that intensive local clustering events, with particle formation rates at 3 nm about 5-10 times higher than typical rates in boreal forest environments, occur on around 30% of all days. The requirements for these clustering events to occur were found to be clear sky, a low wind speed to accumulate the emissions from local agricultural land, particularly ammonia, the presence of low volatile organic compounds, and sufficient gaseous sulfuric acid. The local clustering will then contribute to regional new particle formation. Since the agricultural land is much more effective per surface area than the boreal forest in producing aerosol particles, these findings provide insight into the participation of agricultural lands in climatic cooling, counteracting the climatic warming effects of farming.
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Copper phosphate hybrid nanoflowers (Cu3(PO4)2HNFs) were demonstrated to produce cathodic ECL emission in the presence of potassium persulfate (K2S2O8) and then used as a carrier due to their large specific surface area. AgNPs modified on Cu3(PO4)2HNFs provided more binding sites for immobilizing secondary antibodies and accelerating the electron transfer rate to enhance the ECL signal. In addition, FONDs-Au was used to capture primary antibodies due to its good biocompatibility and large specific surface area. A sandwich electrochemiluminescence (ECL) immunosensor based on copper phosphate hybrid nanoflower/Ag nanoparticle (Cu3(PO4)2HNFs@Ag) composite and Au NPs-functionalized Fe2O3 nanodendrites (FONDs-Au) was constructed to detect prostate-specific antigen (PSA) in real samples. Under optimal conditions, the constructed sandwich ECL immunosensor was sensitive to PSA with a detection limit of 0.037 pg/mL (S/N = 3), a linear detection concentration range of 0.0001-50 ng/mL, and a recovery range of 97.33-102.5%. This immunosensor is expected to provide a method to detect PSA or other biomarkers.
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Técnicas Biossensoriais , Nanopartículas Metálicas , Masculino , Humanos , Antígeno Prostático Específico , Cobre , Imunoensaio , Prata , Anticorpos , FosfatosRESUMO
Introduction: Candida palmioleophila is a rare human pathogenic fungus, which has been poorly characterized at the genome level. In this study, we reported the first fatal case of C. palmioleophila infection in China and investigate the microevolution of C. palmioleophila in the human host environment. Methods: A series of C. palmioleophila stains were collected from the patient at different time points for routine microbial and drug sensitivity testing. The first C. palmioleophila isolate 07202534 was identified by de novo whole genome sequencing. The in vitro and in vivo genetic evolutionary characteristics of C. palmioleophila were discussed based on the analysis of bioinformatics data. Results: The six C. palmioleophila isolates displayed dose-dependent sensitivity to fluconazole. The C. palmioleophila genome contained homologous genes such as CDR1 and MDR1, which were recognized to be related to azole resistance. In addition, amino acid variation was detected at F105L and other important sites of ERG11. In addition, the mean divergence time between C. palmioleophila and Scheffersomyces stipites CBS 6054 was 406.04 million years, indicating that C. palmioleophila originated earlier than its closest relative. In addition, the six strains of C. palmioleophila isolated form the patient had higher homology and fewer mutation sites, which indicated the stability in C. palmioleophila genome. We also found that C. palmioleophila had a wide natural niche and may evolve slowly. Discussion: We believe that this study will contribute to improve our understanding of the genetic evolution, pathogenicity, and drug resistance of C. palmioleophila and will aid in the prevention and control of its spread.
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The construction of advanced systems capable of accurately detecting neuron-specific enolase (NSE) is essential for rapidly diagnosing small-cell lung cancer. In this study, an electrochemiluminescence (ECL) resonance energy transfer immunosensor was proposed for the ultra-sensitive detection of NSE. The co-reactants C2O42- and Ru(bpy)32+ were integrated to form a self-enhanced ECL luminophore (Ru-ZnMOF) as the ECL donor. The abundant carboxyl functional groups of Ru-ZnMOF supported antibody 1 via an amidation reaction. Polydopamine-modified zinc dioxide nanoflowers, as ECL acceptors, inhibited Ru-ZnMOF ECL signaling. The linear range of NSE was 10 fg mL-1 to 100 ng mL-1 with a detection limit of 3.3 fg mL-1 (S/N = 3), which is suitably low for determining NSE in real samples.
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Técnicas Biossensoriais , Nanopartículas Metálicas , Técnicas Eletroquímicas , Imunoensaio , Medições Luminescentes , Fosfopiruvato Hidratase , Transferência de Energia , Limite de DetecçãoRESUMO
A new electrochemiluminescence (ECL) cytosensor is proposed for the simultaneous determination of phosphatidylserine (PS) and epidermal growth factor receptor (EGFR) based on the ECL signals of metal-organic framework-5 (MOF-5) loaded CdS quantum dots and N-(aminobutyl)-N-(ethylisoluminol)-polyethylenimine capped Au and Ag nanoparticles. Apoptosis promotes the exposure of PS and reduces the expression of EGFR in cell membranes. Two spatially resolved areas on dual-disk glassy carbon electrodes were designed to eliminate the interference from different ECL probes. Using HepG2 cells treated with resveratrol to induce apoptosis, the cytosensor exhibited high sensitivity, simplicity, and high reproducibility, demonstrating its potential in drug screening and rapid apoptotic cell detection. The strategy reported provides a promising platform for the highly sensitive cytosensing and convenient screening of clinically relevant anticancer drugs.
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Técnicas Biossensoriais , Nanopartículas Metálicas , Estruturas Metalorgânicas , Fosfatidilserinas , Reprodutibilidade dos Testes , Medições Luminescentes , Prata , Receptores ErbB , Membrana Celular , Apoptose , Família de Proteínas EGFRESUMO
In order to understand the occurrence characteristics and ecological risks of pharmaceuticals and personal care products (PPCPs) in surface water and sediments of Hongze Lake and Gaoyou Lake in the lower reaches of the Huaihe River, 43 surface water and sediment samples from 23 sampling sites were collected, and 61 PPCPs were detected in the samples. The concentration level and spatial distribution of target PPCPs in Hongze Lake and Gaoyou Lake were analyzed, the distribution coefficient of typical PPCPs in the water/sediment system in the study area was calculated, and the ecological risk of target PPCPs was evaluated using the entropy method. The results showed that the PPCPs in surface water of Hongze Lake and Gaoyou Lake were 1.56-2534.44 ng·L-1 and 3.32-1027.47 ng·L-1, respectively, and those in sediment were 1.7-926.7 ng·g-1 and 1.02-289.37 ng·g-1, respectively. The concentrations of lincomycin (LIN) in surface water and doxycycline (DOX) in sediment were the highest, and antibiotics were the main components. The spatial distribution of PPCPs was higher in Hongze Lake and lower in Gaoyou Lake. The distribution characteristics of typical PPCPs in the study area showed that typical PPCPs tended to stay in the water phase, and there was a significant correlation between lg Koc and lg Kd, indicating that total organic carbon (TOC) played an important role in the distribution of typical PPCPs in the water/sediment system. The ecological risk assessment results showed that the ecological risk of PPCPs to algae in surface water and sediment was significantly higher than that of fleas and fish, the ecological risk value of PPCPs in surface water was higher than that in sediment, and the ecological risk of Hongze Lake was higher than that of Gaoyou Lake.
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Lagos , Rios , Animais , Medição de Risco , Antibacterianos , ÁguaRESUMO
In this study, an electrochemiluminescence resonance energy transfer (ECL-RET) immunosensor was constructed to detect beta-2-microglobulin (B2M). As a donor-acceptor pair, a carbon nitride nanosheet modified with gold nanoparticles (Au@g-C3N4NSs) and a nickel- and iron-based organic framework modified with gold nanoparticles (Au@NiFeMOFs) were prepared. The sandwich immunosensor was successfully constructed so that ECL-RET occurred between Au@NiFeMOFs and Au@g-C3N4NSs. The ECL intensity of the immunosensor decreased with the increase the B2M concentration due to the low conductivity of B2M. The linear range of the ECL-RET immunosensor was from 10 fg/mL to 10 ng/mL, and the limit of detection was 2.3 fg/mL (S/N = 3). The developed immunosensor had high sensitivity, high specificity, and excellent stability. It could realize the sensitivity test of B2M and provide a novel idea for the detection of biomarkers.
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Técnicas Biossensoriais , Nanopartículas Metálicas , Ouro , Medições Luminescentes , Imunoensaio , Técnicas Eletroquímicas , Limite de DetecçãoRESUMO
This study aimed to design a sandwich electrochemiluminescence (ECL) immunosensor with double co-reaction accelerators for sensitively detecting squamous cell carcinoma antigen (SCCA). First, silver orthophosphate (Ag3PO4) nanoparticles were modified on the surface of EuPO4 nanowires to improve their poor dispersibility/solubility. At the same time, EuPO4 was used as a co-reaction accelerator to catalyze S2O82- to produce more intermediates (SO4â¢-), significantly enhancing the ECL signal of Ag3PO4. Ag nanoparticles (AgNP) modified on Ag3PO4@EuPO4 composite nanomaterials were used not only as linkers of luminescence groups and biomarkers but also as a co-reaction accelerator to effectively enhance ECL signal. The designed ECL immunosensor displayed several advantages, including good stability and reproducibility. Under the optimal conditions, its linear range in detecting SCCA was 0.0001-50 ng·mL-1, the detection limit was 25 fg·mL-1 (S/N = 3), the recovery was 96.6-100.4%, and the relative standard deviation was less than 4.8%. It was successfully applied to detect SCCA in human serum.
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Antígenos de Neoplasias , Técnicas Biossensoriais , Nanopartículas Metálicas , Serpinas , Humanos , Técnicas Eletroquímicas , Imunoensaio , Medições Luminescentes , Reprodutibilidade dos Testes , Prata , Antígenos de Neoplasias/análise , Serpinas/análiseRESUMO
A novel sandwich electrochemiluminescence (ECL) biosensor based on aggregation-induced electrochemiluminescence resonance energy transfer (AIECL-RET) was designed for the sensitive detection of amyloid ß42 (Aß42). The synthesized silver nanoparticle-functionalized zinc metal-organic framework (Ag@ZnPTC) and gold nanoparticle-functionalized zirconium organic framework (Au@UiO-66-NH2) were used as the ECL donor and acceptor, respectively. AgNPs were generated in situ on the surface of ZnPTC, which further improved the ECL intensity and the loading of antibody 1 (Ab1). Under the optimized experimental conditions, the linear detection range of Aß42 concentration was 10 fg/mL to 100 ng/mL, and the detection limit was 2.4 fg/mL (S/N = 3). The recoveries of Aß42 were 99.5-104%. The method has good stability, repeatability, and specificity. Ag@ZnPTC/Au@UiO-66-NH2 provides an assay for the sensitive detection of disease biomarkers.
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Técnicas Biossensoriais , Nanopartículas Metálicas , Estruturas Metalorgânicas , Compostos Organometálicos , Peptídeos beta-Amiloides , Ouro , Zinco , Medições Luminescentes/métodos , Prata , Técnicas Biossensoriais/métodos , Transferência de Energia , Técnicas Eletroquímicas/métodos , Limite de DetecçãoRESUMO
A dual-emitting electrochemiluminescence (ECL) immunosensor based on manganese dioxide nanoflowers (MnO2NFs) and zinc sulfide quantum dots (ZnSQDs) was constructed for the first time to sensitively detect procalcitonin (PCT) in human serum. rGO@Ag functioned not only to adsorb primary antibodies (Ab1) but also to improve the electrical conductivity of the immunosensor. The MnO2NFs and ZnSQDs in the nanocomposite, synergistically with silver nanoparticles, simultaneously functioned as cathodic ECL emitters to enhance the detection sensitivity of PCT by shortening the electron-transfer path, thereby reducing energy loss. Under the optimized experimental conditions, the ECL immunosensor was capable of quantitatively detecting PCT in the linear range of 0.1 pg mL-1 to 100 ng mL-1 and over the scanning potential range of -2.0-0 V, with a detection limit of 0.033 pg mL-1. Furthermore, the ECL immunosensor demonstrated high specificity for PCT in the presence of other competing antigens, excellent stability over 10 cycles, and excellent reproducibility, corroborating its potential for measuring PCT concentrations in clinical samples.
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Técnicas Biossensoriais , Grafite , Nanopartículas Metálicas , Pontos Quânticos , Humanos , Pró-Calcitonina , Reprodutibilidade dos Testes , Técnicas Eletroquímicas , Limite de Detecção , Medições Luminescentes , Imunoensaio , PrataRESUMO
In this study, we evaluated the intestinal microbiota, intestinal and fecal metabolites production and the intestinal RNA-seq analysis of the Nile tilapia intestine after feeding with 105and 107 of the inactive Bacillus subtilis var. natto. First, we assessed the influence of heat inactive Bacillus subtilis var. natto on the growth performance, biochemical blood analysis, and evaluated the liver/body, spleen/body and intestine/body ratio. This evidence was known feeding with inactive Bacillus subtilis var. natto was able to improve the growth performance after 4 weeks, but not to affect the inflammatory biochemical blood parametres total protein (T-pro), albumin (Alb), Alb/T-pro ratio, creatine-phospho-kinase (CPK) and lactate dehydrogenase (LDH). Further, in the intestine microbiota, the Lactobacillaceae, Firmicutes, Chromatiales, and Rhodobacteria, was significantly higher than the control and the Firmicutes/Bacteroidetes ratio (F/B), which was indicated with a significantly increased. The intestine tissue metabolites OPLS-DA analysis indicated that the prominent bioactive metabolites changed. The peonidin-3-glucoside, l-Tyrosine, 1-Deoxy-1-(N6-lysino)-d-fructose was significantly increased. The feces metabolite OPLS-DA analysis indicated that the palmitelaidic acid, 5-KETE, tangeritin was significantly increased. In the transcriptome, the Gene Ontology (GO) analysis was found to enhance the intestine intestinal immune network. Combine of these evidence, feeding of the heat inactive Bacillus subtilis var. natto exactly improved the O. niloticus growth performance and regulation of the microbiota to promote the metabolites. In the transcriptome analysis, it was found to involve in the intestine immune phagosome response. Summarized of this study, the heat inactive Bacillus subtilis var. natto was reported to affect Nile tilapia intestine microbiota, and could positively regulate the intestine and fecal metabolites production to improve the intestine immune network.
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Ciclídeos , Microbioma Gastrointestinal , Probióticos , Animais , Bacillus subtilis , Temperatura Alta , Intestinos/microbiologia , FagossomosRESUMO
Osimertinib is a highly selective third-generation irreversible inhibitor of epidermal growth factor receptor mutant, which can be utilized to treat non-small cell lung cancer. As the substrate of cytochrome P450 enzyme, it is mainly metabolized by the CYP3A enzyme in humans. Among the metabolites produced by osimertinib, AZ5104, and AZ7550, which are demethylated that is most vital. Nowadays, deuteration is a new design approach for several drugs. This popular strategy is deemed to improve the pharmacokinetic characteristics of the original drugs. Therefore, in this study the metabolism profiles of osimertinib and its deuterated compound (osimertinib-d3) in liver microsomes and human recombinant cytochrome P450 isoenzymes and the pharmacokinetics in rats and humans were compared. After deuteration, its kinetic isotope effect greatly inhibited the metabolic pathway that produces AZ5104. The plasma concentration of the key metabolite AZ5104 of osimertinib-d3 in rats and humans decreased significantly compared with that of the osimertinib. This phenomenon was consistent with the results of the metabolism studies in vitro. In addition, the in vivo results indicated that osimertinib-d3 had higher systemic exposure (AUC) and peak concentration (Cmax ) compared with the osimertinib in rats and human body.