Patients with coronavirus disease 2019 (COVID‐19) with cardiovascular diseases who are at higher risk of progressing to critical illness should be treated with nirmatrelvir/ritonavir (Paxlovid). ...Ritonavir, the booster in nirmatrelvir/ritonavir, modulates multiple drug metabolizing enzymes and transporters, complicating its use in real‐world clinics. We aimed to apply physiologically‐based pharmacokinetic (PBPK) modeling to simulate the complex drug–drug interactions (DDIs) of ritonavir with two anticoagulants, rivaroxaban and racemic warfarin, to address this important clinical conundrum. Simulations were implemented within Simcyp Simulator. Compound and population models were adopted from Simcyp and our previous studies. Upon verification and validation of the PBPK model of ritonavir, prospective DDI simulations with the anticoagulants were performed in both the general population (20–65 years) and geriatric subjects (65–85 years) with or without moderate renal impairment. Elevated rivaroxaban concentrations were simulated with nirmatrelvir/ritonavir treatment, where the impact was more profound among geriatric subjects with renal impairment. The overexposure of rivaroxaban was restored to normal range on day 4 post‐discontinuation of nirmatrelvir/ritonavir, corroborating with the recovery of enzyme activity. A lower 10 mg daily dose of rivaroxaban could effectively maintain acceptable systemic exposure of rivaroxaban during nirmatrelvir/ritonavir treatment. Treatment of ritonavir marginally declined simulated S‐warfarin concentrations, but substantially elevated that of R‐warfarin, resulting in a decrease in the international normalized ratio (INR). As INR only recovered 2 weeks post‐nirmatrelvir/ritonavir treatment, a longer surveillance INR for warfarin becomes important. Our PBPK‐guided simulations evaluated clinically important yet untested DDIs and supports clinical studies to ensure proper anticoagulation management of patients with COVID‐19 with chronic coagulative abnormalities when initiating nirmatrelvir/ritonavir therapy.
The deep convolutional neural network (DeCNN) is considered one of promising techniques for classifying the high-spatial-resolution remote sensing (HSRRS) scenes, due to its powerful feature ...extraction capabilities. It is well-known that huge high-quality labeled datasets are required for achieving the better classification performances and preventing overfitting, during the training DeCNN model process. However, the lack of high-quality datasets limits the applications of DeCNN. In order to solve this problem, in this article, we propose a HSRRS image scene classification method using transfer learning and the DeCNN (TL-DeCNN) model in a few shot HSRRS scene samples. Specifically, three typical DeCNNs of VGG19, ResNet50, and InceptionV3, trained on the ImageNet2015, the weights of their convolutional layer for that of the TL-DeCNN are transferred, respectively. Then, TL-DeCNN just needs to fine-tune its classification module on the few shot HSRRS scene samples in a few epochs. Experimental results indicate that our proposed TL-DeCNN method provides absolute dominance results without overfitting, when compared with the VGG19, ResNet50, and InceptionV3, directly trained on the few shot samples.
•A constant residual noise power constraint for rank-1 MWF is proposed.•Speech covariance matrix reconstruction to fulfill the rank-1 assumption.•An extensive comparison of the multichannel linear ...filters supported by BLSTM.•A feature variance metric that correlates with the word error rate.
Multichannel linear filters, such as the Multichannel Wiener Filter (MWF) and the Generalized Eigenvalue (GEV) beamformer are popular signal processing techniques which can improve speech recognition performance. In this paper, we present an experimental study on these linear filters in a specific speech recognition task, namely the CHiME-4 challenge, which features real recordings in multiple noisy environments. Specifically, the rank-1 MWF is employed for noise reduction and a new constant residual noise power constraint is derived which enhances the recognition performance. To fulfill the underlying rank-1 assumption, the speech covariance matrix is reconstructed based on eigenvectors or generalized eigenvectors. Then the rank-1 constrained MWF is evaluated with alternative multichannel linear filters under the same framework, which involves a Bidirectional Long Short-Term Memory (BLSTM) network for mask estimation. The proposed filter outperforms alternative ones, leading to a 40% relative Word Error Rate (WER) reduction compared with the baseline Weighted Delay and Sum (WDAS) beamformer on the real test set, and a 15% relative WER reduction compared with the GEV-BAN method. The results also suggest that the speech recognition accuracy correlates more with the Mel-frequency cepstral coefficients (MFCC) feature variance than with the noise reduction or the speech distortion level.
The micro-direct methanol fuel cell (μDMFC) has the advantages of high energy density, high conversion efficiency, and simple structure, which brought vast application prospects in portable devices. ...However, some shortcomings still exist, such as low catalyst utilization and power density. This paper proposes a new cathode electrode structure for the μDMFC. The structure consists of a multi-walled carbon nanotube layer and a cathode double microporous layer (CD-MPL) prepared from carbon powder. The outer microporous layer (OMPL) is composed of multi-walled carbon nanotubes (MWCNTs), Nafion solution, and carbon powder, and the inner microporous layer (IMPL) is composed of carbon powder and polytetrafluoroethylene (PTFE). The experimental results show that the maximum power density of the μDMFC with a CD-MPL (CD-μDMFC) is 42.8 mW/cm2, which is 31.6% higher than that of the μDMFC with a cathode single microporous layer (CS-μDMFC). The pore size distribution of the OMPL of the CNT is measured by the mercury intrusion method. It can be seen that the distribution of pore size is wider and there are more pores with larger pore sizes, which are more conducive to the utilization of catalysts. The discharge experiment of the cell shows that the CD-μDMFC shows high discharge performance and fuel utilization at different concentrations. The double microporous layer (MPL) structure increases the porosity and pore range, broadens the three-phase interface for the reaction, and allows the catalyst to have more attachment sites. The existence of MWCNTs improves the conductivity and mass transfer capacity of the cathode.
Airway remodelling plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Epithelial-mesenchymal transition (EMT) is a significant process during the occurrence ...of airway remodelling. Increasing evidence suggests that glucose transporter 3 (GLUT3) is involved in the epithelial mesenchymal transition (EMT) process of various diseases. However, the role of GLUT3 in EMT in the airway epithelial cells of COPD patients remains unclear.
We detected the levels of GLUT3 in the peripheral lung tissue of COPD patients and cigarette smoke (CS)-exposed mice. Two Gene Expression Omnibus GEO datasets were utilised to analyse GLUT3 gene expression profiles in COPD. Western blot and immunofluorescence were used to detect GLUT3 expression. In addition, we used the AAV9-GLUT3 inhibitor to reduce GLUT3 expression in the mice model. Masson's staining and lung function measurement were used detect the collagen deposition and penh in the mice. A cell study was performed to confirm the regulatory effect of GLUT3. Inhibition of GLUT3 expression with siRNA, Western blot, and immunofluorescence were used to detect the expression of E-cadherin, N-cadherin, vimentin, p65, and ZEB1.
Based on the GEO data set analysis, GLUT3 expression in COPD patients was higher than in non-smokers. Moreover, GLUT3 was highly expressed in COPD patients, CS exposed mice, and BEAS-2B cells treated with CS extract (CSE). Further research revealed that down-regulation of GLUT3 significantly alleviated airway remodelling in vivo and in vitro. Lung function measurement showed that GLUT3 reduction reduced airway resistance in experimental COPD mice. Mechanistically, our study showed that reduction of GLUT3 inhibited CSE-induced EMT by down-regulating the NF-κB/ZEB1 pathway.
We demonstrate that CS enhances the expression of GLUT3 in COPD and further confirm that GLUT3 may regulate airway remodelling in COPD through the NF-κB/ZEB1 pathway; these findings have potential value in the diagnosis and treatment of COPD. The down-regulation of GLUT3 significantly alleviated airway remodelling and reduced airway resistance in vivo. Our observations uncover a key role of GLUT3 in modulating airway remodelling and shed light on the development of GLUT3-targeted therapeutics for COPD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The covalently closed circular DNA (cccDNA) of HBV plays a crucial role in viral persistence and is also a risk factor for developing HBV-induced diseases, including liver fibrosis. Stimulator of ...interferon genes (STING), a master regulator of DNA-mediated innate immune activation, is a potential therapeutic target for viral infection and virus-related diseases. In this study, agonist-induced STING signaling activation in macrophages was revealed to inhibit cccDNA-mediated transcription and HBV replication via epigenetic modification in hepatocytes. Notably, STING activation could efficiently attenuate the severity of liver injury and fibrosis in a chronic recombinant cccDNA (rcccDNA) mouse model, which is a proven suitable research platform for HBV-induced fibrosis. Mechanistically, STING-activated autophagic flux could suppress macrophage inflammasome activation, leading to the amelioration of liver injury and HBV-induced fibrosis. Overall, the activation of STING signaling could inhibit HBV replication through epigenetic suppression of cccDNA and alleviate HBV-induced liver fibrosis through the suppression of macrophage inflammasome activation by activating autophagic flux in a chronic HBV mouse model. This study suggests that targeting the STING signaling pathway may be an important therapeutic strategy to protect against persistent HBV replication and HBV-induced fibrosis.
Spectral pretreatments, such as background removal from Raman big data, are crucial to have a smooth link to advanced spectral analysis. Recently, we developed an automated background removal method, ...where we considered the shortest length of a spectrum by changing the scaling factor of the background spectrum. Here, we propose a practical way to correct the systematic error caused by noise from measurements. This correction has been realized to be more effective and accurate for automatic background removal.
The continuous introduction of new synthetic cannabinoid (SC) subtypes and analogues remains a major problem worldwide. Recently, a new "OXIZID" generation of SCs surfaced in seized materials across ...various countries. Hence, there is an impetus to identify urinary biomarkers of the OXIZIDs to detect their abuse.
We adapted our previously reported two-pronged approach to investigate the metabolite profiles and disposition kinetics of 4 OXIZID analogues, namely, BZO-HEXOXIZID (MDA-19), BZO-POXIZID (5C-MDA-19), 5F-BZO-POXIZID (5F-MDA-19), and BZO-CHMOXIZID (CHM-MDA-19). First, bottom-up in vitro incubation experiments comprising metabolite identification, metabolic stability, and reaction phenotyping were performed using human liver microsomes and recombinant human cytochrome P450 enzymes. Second, top-down analysis of authentic urine samples from drug abusers was performed to corroborate the in vitro findings and establish a panel of urinary biomarkers.
A total of 42 to 51 metabolites were detected for each OXIZID, and their major metabolic pathways included N-alkyl and phenyl hydroxylation, oxidative defluorination (for 5F-BZO-POXIZID), oxidation to ketone and carboxylate, amide hydrolysis, and N-dealkylation. The OXIZIDs were metabolically unstable, mainly metabolized by cytochromes P3A4, P3A5, and P2C9, and demonstrated mechanism-based inactivation of cytochrome P3A4. Integrating with the results of 4 authentic urine samples, the parent drug and both N-alkyl and phenyl mono-hydroxylated metabolites of each OXIZID were determined as suitable urinary biomarkers.
Drug enforcement agencies worldwide may apply these biomarkers in routine monitoring procedures to identify abusers and counter the escalation of OXIZID abuse.
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