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Objective: Piperacillin/tazobactam (PIP/TAZ) is used for the treatment of lower respiratory tract bacterial infections in children. This study was performed to evaluate if the current dosing regimen results in therapeutic drug concentrations. Patients and methods: Patients suspected or proven to have lower respiratory tract bacterial infection and administrated PIP/TAZ intravenously for a duration of no less than 0.5 h, q6h-q12h daily, were enrolled. Blood samples were collected, and PIP concentrations were determined by high-performance liquid chromatography. The individual predicted concentration of PIP was evaluated using the individual empirical Bayesian estimate method. The evaluated PK/PD targets included (1) 70% time when the predicted free drug concentration exceeds the minimum inhibitory concentration (fT > MIC) and (2) 50% fT > 4× MIC. Probability of target attainment (PTA) was assessed by the proportion of patients who reached the PK/PD targets. The PIP concentrations between different groups of patients were compared. Results: A total of 57 samples were collected from 57 patients with a median age of 2.26 years (0.17-12.58). For the PK/PD targets of 70% fT > MIC and 50% fT > 4× MIC for Pseudomonas aeruginosa and Klebsiella pneumoniae, the PTA was all 0. The median Cmin of PIP was significantly higher in infants than in children, and the median Cmin after administration in q8h was significantly higher than that after administration in q12h. Conclusion: The current dose regimen of PIP/TAZ leads to extremely low plasma concentrations in most children with lower respiratory tract bacterial infections. More optimized dosing regimens or better alternative therapies need to be further explored.
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Electronically excited-state problems represent a crucial research field in quantum chemistry, closely related to numerous practical applications in photophysics and photochemistry. The emerging of quantum computing provides a promising computational paradigm to solve the Schrödinger equation for predicting potential energy surfaces (PESs). Here, we present a deep neural network model to predict parameters of the quantum circuits within the framework of variational quantum deflation and subspace search variational quantum eigensolver, which are two popular excited-state algorithms to implement on a quantum computer. The new machine learning-assisted algorithm is employed to study the excited-state PESs of small molecules, achieving highly accurate predictions. We then apply this algorithm to study the excited-state properties of the ArF system, which is essential to a gas laser. Through this study, we believe that with future advancements in hardware capabilities, quantum computing could be harnessed to solve excited-state problems for a broad range of systems.
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Goji berry (Lycium barbarum) is a plant of the Solanaceae family that is cultivated in the Chinese provinces of Xinjiang, Ningxia, Gansu, and Qinghai, and its fruit is used as a traditional Chinese medicine (Yossa Nzeuwa et al. 2019). In July 2019, fruit rot was observed at an incidence of 20 to 25% on the Goji berry at a fruit market in Yinchuan, Ningxia, China. The fruit symptoms began as slightly shriveled areas on fruit peel, with noticeable softening of the infested portion of the tissue, followed by rotting and a sour odor. To isolate the pathogen, ten symptomatic tissues were randomly collected from different boxes, surface-sterilized for 30 s with 75% ethanol, followed by 0.1% mercuric chloride, then rinsed in sterile distilled water three times and plated onto PDA. The plates were incubated at 25°C in the dark for 7 days. Five purified fungal isolates from different fruit were obtained and single-spores. Emergent fungal colonies were white with 1 to 3 mm white margins and abundant aerial hyphae, 1 to 6 mm high, that became dark gray after 4 to 5 days. Conidia were hyaline, unicellular, fusiform, and measured 19.3 to 28.2 µm× 3.8 to 6.4 µm (n=50). All the morphological characteristics were consistent with Botryosphaeria spp. (Slippers et al. 2004). Five representative isolates, BJN1-BJN5, were selected for molecular identification. Total genomic DNA of the isolates was extracted with a Plant/Fungi DNA Isolation Kit. Translation elongation factor 1-alpha (EF1) gene and internal transcribed spacer (ITS) regions were amplified with primers EF1-728F/986R (Carbone and Kohn 1999) and ITS1/ITS4, respectively. The sequencing results of the five isolates were consistent, and those of the isolate BJN1 we deposited in the NCBI GeneBank database for EF1 (MK733274) and ITS (MK359291). A BLAST search of the GenBank database indicated that the EF1 and ITS sequences had 100% and 99% similarity, respectively, to B. dothidea ex-type strain (AY236898 and KF766151). A phylogenetic tree was constructed using maximum parsimony methods in MEGA11 and BJN1 isolate clustered with the reference sequence of B. dothidea. Pathogenicity tests were performed, inoculating healthy fruit with both mycelial plugs (7 days old) and conidial suspension (1 × 106 conidia/ml), repeated three times. Mycelial plugs of five isolates (BJN1-BJN5) growing on PDA with a colony diameter of 4 mm were placed on the sterilized surface of 20 Goji berry fruit. Sterile PDA plugs were placed on 12 healthy fruit as a control. In a second test, conidial suspensions of five isolates were sprayed on the surface of 20 healthy fruit and sterilized distilled water was used as a control. The inoculated fruits were maintained in an artificial climate chamber at 25°C and 80% to 85% relative humidity with a 12-h photoperiod for 7 days. The development of soft rot, similar to that observed on the original samples, was observed on inoculated fruit while control fruits remained asymptomatic. The pathogen was reisolated from infected fruit and confirmed as B. dothidea based on morphological characteristics and molecular sequences. To our knowledge, this is the first report of B. dothidea causing postharvest fruit rot of Goji berry, and this pathogen has been reported to cause fruit rot in Kiwifruit (Li et al. 2016) and Yellowhorn (Liu et al. 2018). This study provides information on a new postharvest fruit rot of Goji berry in China that has the potential to cause economic losses.
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Mixed perovskites show immense promise for diverse applications owing to their exceptional compositional flexibility and outstanding optoelectronic performance. Nevertheless, a significant hurdle in their widespread use is their susceptibility to compositional instability. Some mixed perovskites exhibit a tendency to segregate into regions with varying halide content, negatively impacting the material's electronic properties and impeding its overall advancement. This study focuses on investigating the lattice and A-site cation dynamics in mixed-halide perovskites as well as the relationship between the stability and dynamic properties of mixed-halide perovskites. Our findings reveal an intrinsic link between the kinetics of organic molecules and halogen ion migration. The stability of halide ions is linearly positively correlated with the radius, number of H atoms, and moment of inertia of the organic molecules. Organic molecules with lower rotational kinetics effectively suppress the overall cationic kinetic activity, enhancing lattice dynamic stability in mixed perovskite systems. This inhibition further impedes the migration of halogen ions and hinders the halide segregation process. The presence of dominant I/MA vacancies in perovskites accelerates the rotation of MA and the migration of halogen ions. The coupled dynamic behavior of varying vacancy concentrations in A-site cations/X-site anions within the inorganic framework significantly impacts the photovoltaic performance of these halide perovskites.
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Spin injection stands out as a crucial method employed for initializing, manipulating, and measuring the spin states of electrons, which are fundamental to the creation of qubits in quantum computing. However, ensuring efficient spin injection while maintaining compatibility with standard semiconductor processing techniques is a significant challenge. Herein, we demonstrate the capability of inducing an ultrafast spin injection into a WSe2 layer from a magnetic CrI3 layer on a femtosecond time scale, achieved through real-time time-dependent density functional theory calculations upon a laser pulse. Following the peak of the magnetic moment in the CrI3 sublayer, the magnetic moment of the WSe2 layer reaches a maximum of 0.89 µB (per unit cell containing 4 WSe2 and 1 CrI3 units). During the spin dynamics, spin-polarized excited electrons transfer from the WSe2 layer to the CrI3 layer via type-II band alignment. The large spin splitting in conduction bands and the difference in the number of spin-polarized local unoccupied states available in the CrI3 layer lead to a net spin in the WSe2 layer. Furthermore, we confirmed that the number of available states, the spin-flip process, and the laser pulse parameters play important roles during the spin injection process. This work highlights the dynamic and rapid nature of spin manipulation in layered all-semiconductor systems, offering significant implications for the development and enhancement of quantum information processing technologies.
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(-)-Epigallocatechin-3-gallate (EGCG) has been shown antibacterial activity against Campylobacter jejuni; however, the relevant antibacterial mechanism is unknown. In this study, phenotypic experiments and RNA sequencing were used to explore the antibacterial mechanism. The minimum inhibitory concentration of EGCG on C. jejuni was 32 µg/mL. EGCG-treated was able to increase intracellular reactive oxygen species levels and decline bacterial motility. The morphology and cell membrane of C. jejuni after EGCG treatment were observed collapsed, broken, and agglomerated by field emission scanning electron microscopy and fluorescent microscopy. The RNA-seq analysis presents that there are 36 and 72 differential expressed genes after C. jejuni was treated by EGCG with the concentration of 16 and 32 µg/mL, respectively. EGCG-treated increased the thioredoxin expression, which was a critical protein to resist oxidative stress. Moreover, downregulation of the flgH and flgM gene in flagellin biosynthesis of C. jejuni was able to impair the flagella, reducing cell motility and virulence. The primary antibacterial mechanism revealed by RNA-seq is that EGCG with iron-chelating activity competes with C. jejuni for iron, causing iron deficiency in C. jejuni, which potentially impacts the survival and virulence of C. jejuni. The results suggested a new direction for exploring the activity of EGCG against C. jejuni in the food industry. PRACTICAL APPLICATION: A deeper understanding of the antibacterial mechanism of EGCG against C. jejuni was more beneficial in improving the food safety, eliminating concerns about human health caused by C. jejuni in future food, and promoting the natural antibacterial agent EGCG application in the food industry.
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Campylobacter jejuni , Catequina , Catequina/análogos & derivados , Humanos , Campylobacter jejuni/genética , Antibacterianos/farmacología , Perfilación de la Expresión Génica , Estrés Oxidativo , Catequina/farmacologíaRESUMEN
Improving the selectivity of electrochemical CO2 reduction to multi-carbon products (C2+ ) is an important and highly challenging topic. In this work, we propose and validate an effective strategy to improve C2+ selectivity on Cu electrodes, by introducing a synergistic effect between cation (Na+ ) and aprotic solvent (DMSO) to the electrolyte. Based on constant potential ab initio molecular dynamics simulations, we first revealed that Na+ facilitates C-C coupling while inhibits CH3 OH/CH4 products via reducing the water network connectivity near the electrode. Furthermore, the water network connectivity was further decreased by introducing an aprotic solvent DMSO, leading to suppression of both C1 production and hydrogen evolution reaction with minimal effect on *OCCO* hydrogenation. The synergistic effect enhancing C2 selectivity was also experimentally verified through electrochemical measurements. The results showed that the Faradaic efficiency of C2 increases from 9.3 % to 57 % at 50â mA/cm2 under a mixed electrolyte of NaHCO3 and DMSO compared to a pure NaHCO3 , which can significantly enhance the selectivity of the C2 product. Therefore, our discovery provides an effective electrolyte-based strategy for tuning CO2 RR selectivity through modulating the microenvironment at the electrode-electrolyte interface.
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Elaeocarpus decipiens is widely cultivated as an ornamental tree of commercial importance in southern China. During March 2018 to March 2021, leaf spot disease was observed in about 40% of E. decipiens on the campus of Jiangnan University in Wuxi, Jiangsu, China (31.48°N, 120.46°E). Leaf symptoms began as small, light brown lesions that enlarged, turned olive brown in color and then became necrotic. Ten symptomatic leaves were collected from five different trees on the Jiangnan University campus and surface sterilized with 75% ethanol for 30 seconds, followed by 1% sodium hypochlorite for 1 minute, and rinsed three times with sterile distilled water before being cultured onto potato dextrose agar and incubated in the dark at 25°C for 5 days. Five purified fungal isolates were obtained by the single spore isolation method. Emergent fungal colonies were olive-green in color with 1 to 3 mm white margins and abundant aerial hyphae. Conidia were borne in chains or singly and were obclavate or obpyriform and measured 6.5 to 17.4 × 21.3 to 32.8 µm (n=50) with one to seven transverse septa and zero to three longitudinal septa. Based on morphological characteristics, the pathogen was identified as Alternaria spp.(Simmons 2007). Three representative isolates, At1, At2 and At3, were selected for molecular identification, total genomic DNA of the fungus isolates were extracted with Plant/Fungi DNA Isolation Kit (Sigma-Aldrich, Ontario, Canada). Plasma membrane ATPase (ATP) gene, chitin synthase (CHS) gene and translation elongation factor 1-alpha (EF1) gene were amplified with primers ATPDF1/ATPDR1, CHS-79F/CHS-345R (Lawrence et al. 2013) and EF1-728F/EF1-986R (Carbone and Kohn 1999). The amplification results of the three isolate genes were consistent, and we deposited the results of the ATP (MN046377), CHS (MN046378) and EF1 (MN046379) sequences of At1 in the NCBI GeneBank. The ATPase gene from the representative isolate At1 shared 99.83% similarity to A. alternata causing leaf Spot of Codonopsis pilosula in China (OM362504, Shi et al. 2022), the CHS gene shared 100% similarity to A. alternata causing brown leaf spot on Paris polyphylla var. chinensis in China (MK391053, Fu et al. 2019), and the EF1 gene shared 100% similarity to A. alternata CBS 916.96 ex-type on Arachis hypogaea in India (KC584634). A phylogenetic tree constructed with the EF1 gene using the neighbor-joining algorithm in MEGA 11 software with 1,000 bootstrap replicates revealed that the examined isolate, At1, belongs to the fungus A. alternata. For pathogenicity tests, 10 leaves of five healthy plants were sprayed with spore suspensions (1 × 107 conidia/ml) of the 10-day-old isolates (At1, At2 and At3, respectively). As a control, five plants were sprayed with sterile distilled water. After inoculation, use the bags to moisturize for 48 hours. Pathogenicity tests were conducted three times. Fourteen days after inoculation, olive brown necrotic lesions developed on inoculated leaves while control leaves remained symptomless. The pathogen was reisolated from infected leaves and confirmed as A. alternata based on morphological characteristics and molecular markers. To date, A. alternata has been reported to cause leaf spot disease on many plants inculuding Ficus religiosa (Du et al. 2022), Tilia miqueliana (Yue et al. 2023), Ligustrum japonicum (Fang et al. 2023) and so on. To our knowledge, this is the first report of the occurrence of A. alternata causing leaf spot on E. decipiens in China. The increasing area of E. decipiens cultivation and global climate change have led to an increase in the incidence of E. decipiens diseases, which should be taken into account by forest conservationists.
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Mulberry leaves (MLs) are reported to have beneficial effects in modulating obesity in male models. However, the impact of different types of mulberry leaf extracts (MLEs) on female models, specifically their influence on adipocytes, gut microbiota, and related metabolic markers, remains poorly understood. In this study, we observed a strong correlation between the total phenolic content (TPC), antioxidant and adipocyte modulation effects of water extracted MLEs. HB-W (water-extracted baiyuwang) and HY-W (water-extracted Yueshen) demonstrated remarkable inhibition effects on adipocytes in 3 T3-L1 adipocytes model. Moreover, MLEs effectively reduced the levels of triglycerides (TG), non-esterified fatty acids (NEFA), and total cholesterol (T-CHO) in adipocytes in vitro. In vivo experiments conducted on female mice with high fat diet (HFD)-induced obesity revealed the anti-obesity effects of HB-W and HY-W, leading to a significant decrease in weight gain rates and notable influence on the ratios of adipose tissue, particularly white adipose tissue (WAT). Gene expression analysis demonstrated the up-regulation of WAT-related genes (Pla2g2a and Plac8) by HB-W, while HY-W supplementation showed beneficial effects on the regulation of blood sugar-related genes. Furthermore, both HB-W and HY-W exhibited modulatory effects on obesity-related gut microbiota (Firmicutes-to-Bacteroidetes ratio) and short chain fatty acid (SCFA) contents. Importantly, they also mitigated abnormalities in liver function and uncoupling protein 1 (UPC1) expression. Overall, our findings underscore the anti-obesity effects of MLEs in female rats with high-fat diet-induced obesity.
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Microbioma Gastrointestinal , Morus , Masculino , Femenino , Ratas , Ratones , Animales , Dieta Alta en Grasa/efectos adversos , Obesidad/metabolismo , Tejido Adiposo Blanco , AguaRESUMEN
Phenyllactic acid (PLA) generally recognized as a natural organic acid shows against Vibrio parahaemolyticus activity. In this study, V. parahaemolyticus ATCC17802 (Vp17802) was cultured under the stress of 1/2MIC PLA, and then the antibacterial mechanisms were explored via transcriptomics. The minimum inhibitory concentration (MIC) of PLA against Vp17802 was 3.2 mg/mL, and the time-kill analysis resulted that Vp17802 was inhibited. PLA was able to destroy the bacterial membrane, leading to the leakage of intracellular substances and decline of ATP levels. The RNA-sequencing analysis results indicated that 1616 significantly differentially expressed genes were identified, among which 190 were up-regulated and 1426 were down-regulated. Down-regulation of the icd2 gene in the TCA cycle mediates blockage of tyrosine metabolic, arginine biosynthesis, and oxidative phosphorylation, causing insufficient energy supply of Vp17802. Moreover, PLA could cause amino acids, metal ions, and phosphate transporters to be blocked, affecting the acquisition of nutrients. The treatment by PLA altered the expression of genes encoding functions involved in quorum sensing, flagellar assembly, and cell chemotaxis pathway, which may be interfering with the biofilm formation in Vp17802, reducing cell motility. Overall, 1.6 mg/mL PLA inhibited the growth of Vp17802 by disrupting to uptake of nutrients, cell metabolism, and the formation of biofilms. The results suggested a new direction for exploring the activity of PLA against Vp17802 and provided a theoretical basis for bacterial pathogen control in the food industry. KEY POINTS: â¢RNA sequencing was carried out to indicate the antibacterial mechanism of Vp17802. â¢The icd2 gene in the TCA cycle mediates blockage of metabolic of Vp17802. â¢The biofilm formation has interfered with 1.6 mg/mL PLA, which could reduce cell motility and virulence.
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Lactatos , Vibrio parahaemolyticus , Vibrio parahaemolyticus/genética , Perfilación de la Expresión Génica , Antibacterianos/farmacología , PoliésteresRESUMEN
Compared with Zn2+ storage, non-metallic charge carrier with small hydrated size and light weight shows fast dehydration and diffusion kinetics for Zn-organic batteries. Here we first report NH4 + /H+ co-storage in self-assembled organic superstructures (OSs) by intermolecular interactions of p-benzoquinone (BQ) and 2, 6-diaminoanthraquinone (DQ) polymer through H-bonding and π-π stacking. BQ-DQ OSs exhibit exposed quadruple-active carbonyl motifs and super electron delocalization routes, which are redox-exclusively coupled with high-kinetics NH4 + /H+ but exclude sluggish and rigid Zn2+ ions. A unique 4e- NH4 + /H+ co-coordination mechanism is unravelled, giving BQ-DQ cathode high capacity (299â mAh g-1 at 1â A g-1 ), large-current tolerance (100â A g-1 ) and ultralong life (50,000 cycles). This strategy further boosts the capacity to 358â mAh g-1 by modulating redox-active building units, giving new insights into ultra-fast and stable NH4 + /H+ storage in organic materials for better Zn batteries.
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Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135-369 L/h with simnotrelvir alone, and decreased significantly to 19.5-29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.
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COVID-19 , Inhibidores de Proteasas , Adulto , Humanos , Antivirales/efectos adversos , Inhibidores Enzimáticos , Voluntarios Sanos , Inhibidores de Proteasas/efectos adversos , Ritonavir/uso terapéutico , SARS-CoV-2RESUMEN
New therapeutic targets and drugs are urgently needed to halt the fibrosing process in idiopathic pulmonary fibrosis (IPF). SHR-1906 is a novel fully humanized monoclonal antibody against the connective tissue growth factor, which plays an essential role in the genesis of IPF. We assessed the safety, tolerability, pharmacokinetics (PKs), and immunogenicity of single dose SHR-1906 in healthy participants. This was a randomized, double-blind, placebo-controlled, dose-escalation, phase I study. Twelve healthy participants for each dose level were enrolled to receive single ascending doses of SHR-1906 intravenously (1.5, 6, 12, 20, 30, and 45 mg/kg) or placebo and followed for 71 days. The primary end points were safety and tolerability. Treatment-related treatment-emergent adverse events occurred in 25 participants (46.3%) in the SHR-1906 group and 11 (61.1%) in the placebo group. No serious adverse events occurred. Over the dose range investigated, the geometric mean clearance was 0.14-0.63 mL/h/kg, the geometric mean volume of distribution at steady-state was 47.4-75.5 mL/kg, and the terminal elimination half-life was 51.9-349 h. SHR-1906 showed nonlinear PKs. The peak concentration increased in a dose-proportional manner, whereas the area under the concentration-time curve showed a greater than dose-proportional increase. Anti-drug antibodies of SHR-1906 were detected in nine of 54 participants (16.7%). A single dose of SHR-1906 up to 45 mg/kg demonstrated a favorable tolerability profile in healthy participants. The PKs and immunogenicity of SHR-1906 were evaluated, supporting further clinical development.
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Anticuerpos Monoclonales Humanizados , Factor de Crecimiento del Tejido Conjuntivo , Humanos , Voluntarios Sanos , Anticuerpos Monoclonales Humanizados/farmacocinética , Método Doble CiegoRESUMEN
Designing zincophilic and stable carbon nanostructures is critical for Zn-ion storage with superior capacitive activity and durability. Here, we report solvent-guided Lewis acid-base self-assembly to customize heterodiatomic carbon nanotubes, triggered by the reaction between iron chloride and α,α'-dichloro-p-xylene. In this strategy, modulating the solvent-precursor interaction through the optimization of solvent formula stimulates differential thermodynamic solubilization, growth kinetics, and self-assembly behaviors of Lewis polymeric chains, thereby accurately tailoring carbon nanoarchitectures to evoke superior Zn-ion storage. Featured with open hollow interiors and porous tubular topologies, the solvent-optimized carbon nanotubes allow low ion-migration barriers to deeply access the built-in zincophilic sites by high-kinetics physical Zn2+/CF3SO3- adsorption and robust chemical Zn2+ redox with pyridine/carbonyl motifs, which maximizes the spatial capacitive charge storage density. Thus, as-designed heterodiatomic carbon nanotube cathodes provide all-round improvement in Zn-ion storage, including a high energy density (140 W h kg-1), a large current activity (100 A g-1), and an exceptional long-term cyclability (100,000 cycles at 50 A g-1). This study provides appealing insights into the solvent-mediated Lewis pair self-assembly design of nanostructured carbons toward advanced Zn-ion energy storage.
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Esophageal squamous cell carcinoma (ESCC) is one of the most lethal solid tumors in China, with the 5-year overall survival rate less than 20%. Although the carcinogenic process of ESCC is still not clear, recent studies using whole genomic profiling revealed that dysregulation of Hippo signaling pathway might play important roles in ESCC progression. The ubiquitin-like with PHD and RING finger domain 1 (RNF106) was a modifier of DNA methylation and histone ubiquitination. In this study, we evaluate the oncogenic function of RNF106 in ESCC both in vitro and in vivo. Wound healing and transwell data showed that RNF106 was required for ESCC cell migration and invasion. RNF106 depletion dramatically restrained Hippo signaling targeted gene expression. The bioinformatics analysis displayed that RNF106 was increased in ESCC tumor tissues and related with poor survival in ESCC patients. Mechanistic studies demonstrated that RNF106 was associated with LATS2 and facilitate LATS2 K48-linked ubiquitination and degradation, which subsequently inhibited YAP phosphorylation and promoted YAP oncogenic function in ESCC. Taken together, our study revealed a novel link between RNF106 and Hippo signaling in ESCC, suggesting that RNF106 could be a promising target for ESCC therapy.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Regulación Neoplásica de la Expresión Génica , Vía de Señalización Hippo , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Renal interstitial fibrosis (RIF) is the crucial pathway in chronic kidney disease (CKD) leading to the end-stage renal failure. However, the underlying mechanism of Shen Qi Wan (SQW) on RIF is not fully understood. In the current study, we investigated the role of Aquaporin 1 (AQP1) in SQW on tubular epithelial-to-mesenchymal transition (EMT). A RIF mouse model induced by adenine and a TGF-ß1-stimulated HK-2 cell model were etablished to explore the involvement of AQP 1 in the protective effect of SQW on EMT in vitro and in vivo. Subsequently, the molecular mechanism of SQW on EMT was explored in HK-2 cells with AQP1 knockdown. The results indicated that SQW alleviated kidney injury and renal collagen deposition in the kidneys of mice induced by adenine, increased the protein expression of E-cadherin and AQP1 expression, and decreased the expression of vimentin and α-smooth muscle actin (α-SMA). Similarly, treatmement with SQW-containing serum significantly halted EMT process in TGF-ß1 stimulated HK-2 cells. The expression of snail and slug was significantly upregulated in HK-2 cells after knockdown of AQP1. AQP1 knockdown also increased the mRNA expression of vimentin and α-SMA, and decreased the expression of E-cadherin. The protein expression of vimentin increased, while the expression of E-cadherin and CK-18 significantly decreased after AQP1 knockdown in HK-2 cells. These results revealed that AQP1 knockdown promoted EMT. Furthermore, AQP1 knockdown abolished the protective effect of SQW-containing serum on EMT in HK-2 cells. In sum, SQW attentuates EMT process in RIF through upregulation of the expression of AQP1.
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Acuaporina 1 , Medicamentos Herbarios Chinos , Insuficiencia Renal Crónica , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacología , Humanos , Animales , Ratones , Masculino , Línea Celular , Ratas , Riñón/patología , Riñón/fisiología , Fibrosis/tratamiento farmacológico , Insuficiencia Renal Crónica/tratamiento farmacológico , Adenina , Transición Epitelial-Mesenquimal , Acuaporina 1/metabolismoRESUMEN
Tin organic-inorganic halide perovskites (tin OIHPs) possess a desirable band gap and their power conversion efficiency (PCE) has reached 14 %. A commonly held view is that the organic cations in tin OIHPs would have little impact on the optoelectronic properties. Herein, we show that the defective organic cations with randomly dynamic characteristics can have marked effect on optoelectronic properties of the tin OIHPs. Hydrogen vacancies originated from the proton dissociation from FA [HC(NH2 )2 ] in FASnI3 can induce deep transition levels in the band gap but yield relatively small nonradiative recombination coefficients of 10-15 â cm3 s-1 , whereas those from MA (CH3 NH3 ) in MASnI3 can yield much larger nonradiative recombination coefficients of 10-11 â cm3 s-1 . Additional insight into the "defect tolerance" is gained by disentangling the correlations between dynamic rotation of organic cations and charge-carrier dynamics.
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The electrochemical interface, where the adsorption of reactants and electrocatalytic reactions take place, has long been a focus of attention. Some of the important processes on it tend to possess relatively slow kinetic characteristics, which are usually beyond the scope of ab initio molecular dynamics. The newly emerging technique, machine learning methods, provides an alternative approach to achieve thousands of atoms and nanosecond time scale while ensuring precision and efficiency. In this Perspective, we summarize in detail the recent progress and achievements made by the introduction of machine learning to simulate electrochemical interfaces, and focus on the limitations of current machine learning models, such as accurate descriptions of long-range electrostatic interactions and the kinetics of the electrochemical reactions occurring at the interface. Finally, we further point out the future directions for machine learning to expand in the field of electrochemical interfaces.
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AIMS: Apatinib is widely used in Chinese cancer patients. As the in vivo drug disposition of apatinib has large individual differences, adverse events are prone to occur. Cytochrome P450 (CYP)3A5 and cancer types maybe the main factors affecting this individual differences. The objective of our study was to establish a population pharmacokinetics (PK) model of apatinib in adult cancer patients, and to explore optimal dosage regimens for individualized treatment. METHODS: Adult patients with various types of cancer treated with apatinib were enrolled. The concentration of apatinib in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. CYP3A5 genotype was determined using TaqMan allelic discrimination technique. The population PK model was developed by NONMEM V7.4. The dosing regimen was optimized based on Monte Carlo simulations. RESULTS: A population PK model of apatinib in adult cancer patient was established. CYP3A5 genotype and systemic cancer type (digestive system cancers, nondigestive system cancers) were the most significant covariates for PK parameters. Patients with CYP3A5*1 expressers (CYP3A5*1/*1 and CYP3A5*1/*3) had lower apparent clearance and apparent volume of distribution than patients who do not express CYP3A5*1 (CYP3A5*3/*3). Patients with nondigestive system cancer had higher apparent volume of distribution and absorption rate constant than digestive system cancer. The results of dose simulation suggest that the apatinib dose in patients who do not express CYP3A5*1 should be 33.33-50.00% higher than that in CYP3A5*1 expressers. CONCLUSIONS: A population PK model of apatinib in adult cancer patients was established. CYP3A5 genotype and systemic cancer type had concurrent effects on PK parameters. CYP3A5 patients who do not express CYP3A5*1 required higher doses.
Asunto(s)
Citocromo P-450 CYP3A , Neoplasias , Humanos , Adulto , Citocromo P-450 CYP3A/genética , Farmacogenética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Piridinas/efectos adversos , Genotipo , Inmunosupresores , TacrolimusRESUMEN
Objectives: INS068 is a novel, soluble, and long-acting insulin analog. In this study, we evaluated the pharmacokinetics and relative bioavailability of two formulations of INS068 in healthy Chinese subjects: a reference formulation packaged in vials and administered via syringe (R), and a test formulation packaged and administered via pen injector (T). Methods: A randomized, open-label, two-period, two-sequence crossover study was conducted with 24 healthy Chinese subjects. Subjects were randomized and administered subcutaneously in the abdomen at 0.4 U/kg of test or reference INS068 injection according to an open crossover design. INS068 concentrations in the serum were measured using LC-MS/MS, and the pharmacokinetic parameters of maximum concentration (Cmax) and area under the concentration-time curve (AUC0-t and AUC0-∞) were used to evaluate relative bioavailability. Results: After a single dose at 0.4 U/kg, the median Tmax of INS068 was 12 h for both formulations, and the mean t1/2 for T and R was 13.0 h and 12.6 h, respectively. The geometric means of Cmax and AUC0-∞ were 3.99 nmol/L and 120 h·nmol/L for the T, and 4.05 nmol/L and 117 h·nmol/L for the R, respectively. The geometric mean ratios of Cmax, AUC0-t and AUC0-∞ of T over R were 98.7% (90% CI: 92.7%-105.2%), 102.6% (90% CI: 100.0%-105.3%) and 102.8% (90% CI: 100.1%-105.5%). Conclusion: The overall PK profile of the two formulations of INS068 injection was comparable in healthy subjects, and the pen injector of INS068 had adequate safety and tolerability, supporting it as a new formulation in a phase III study and bridging PK data from early phase clinical trials. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT05336071.