Drug delivery system based on metal-organic framework improved 5-Fluorouracil against spring viremia of carp virus.

Spring viremia of carp virus (SVCV), as a high pathogenicity pathogen, has seriously restricts the healthy and sustainable development of cyprinid farming industry. In this study, we selected 5-Fluorouracil (5-Fu) as the drug model based on zeolitic imidazolate framework-8 (ZIF-8) to construct a drug delivery system (5-Fu@ZIF-8), and the anti-SVCV activity was detected in vitro and in vivo. The results showed 5-Fu@ZIF-8 was uniform cubic particle with truncated angle and smooth surface, and the particle size was 90 nm. The anti-SVCV activity in vitro results showed that the highest inhibition rate of 5-Fu was 77.93% at 40 mg/L and the inhibitory concentration at half-maximal activity (IC50) was 20.86 mg/L. For 5-Fu@ZIF-8, the highest inhibition rate was 91.36% at 16 mg/L, and the IC50 value was 5.85 mg/L. In addition, the cell viability was increased by 18.1% after 5-Fu treatment. Similarly, after 5-Fu@ZIF-8 treatment, the cell viability increased by 27.3%. Correspondingly, in vivo experimental results showed the viral loads reduced by 18.1% on the days 7 and the survival rate increased to 19.4% at 80 mg/L after 5-Fu treatment. For 5-Fu@ZIF-8, the viral loads reduced by 41.2% and the survival rate increased to 54.8%. Mechanistically, 5-Fu inhibits viral replication by regulating p53 expression and promoting early apoptosis in infected cells. All results indicated that 5-Fu@ZIF-8 improved the anti-SVCV activity; it may be a potential strategy to construct a drug-loaded system with ZIF-8 as a carrier for the prevention and treatment of aquatic diseases.

Functional Analysis of ß-Carotene Oxygenase 2 (BCO2) Gene in Yesso Scallop (Patinopecten yessoensis).

Carotenoids are essential nutrients for humans and animals, and carotenoid coloration represents an important meat quality parameter for many farmed animals. Increasingly, studies have demonstrated that vertebrate carotenoid cleavage oxygenases (CCOs) are essential enzymes in carotenoid metabolism and are therefore potential candidate genes for improving carotenoid deposition. However, our understanding of carotenoid bioavailability and CCOs functions in invertebrates, particularly marine species, is currently quite limited. We previously identified that a CCO homolog, PyBCO-like 1, was the causal gene for carotenoid coloration in the 'Haida golden scallop', a variety of Yesso scallop (Patinopecten yessoensis) characterized by carotenoid enrichment. Here, we found that another CCO-encoding gene named PyBCO2 (ß-carotene oxygenase 2) was widely expressed in P. yessoensis organs/tissues, with the highest expression in striated muscle. Inhibiting BCO2 expression in P. yessoensis through RNA interference led to increased carotenoid (pectenolone and pectenoxanthin) deposition in the striated muscle, and the color of the striated muscle changed from white to light orange. Our results indicate that PyBCO2 might be a candidate gene used for improving carotenoid content in normal Yesso scallops, and also in 'Haida golden scallops'.

Confined and spontaneously transformed oxidation structures due to the intrinsic heterogeneous surface morphology of C3N monolayer.

Identifying the oxidation structure of two-dimensional interfaces is crucial to improve surface chemistry and electronic properties. Beyond graphene with only phenyl rings, a novel carbon-nitrogen material, C3N, presents an intrinsic heterogeneous surface morphology where each phenyl ring is encircled by six nitrogen atoms, yet its atomistic oxidation structure remains unclear. Here, combining a series of density functional theory calculations and ab initio molecular dynamics simulations, we demonstrate that thermodynamically favorable oxidation loci are confined to the phenyl ring, and kinetic transformations of oxidation structures are feasible along the phenyl ring, whereas those toward nitrogen atoms are proven to be extremely difficult. These results are attributed to the lower barrier of oxygen atom migration along the phenyl ring, while the significantly high barriers toward nitrogen atoms are due to the heterogeneous potential energy surface for oxygen-C3N interaction. This work highlights the significance of surface morphology on the characteristics of oxidation structure, offering insights into tunable electronic properties via confined interfacial oxidation.

Research on Fault Detection by Flow Sequence for Industrial Internet of Things in Sewage Treatment Plant Case.

Classifying the flow subsequences of sensor networks is an effective way for fault detection in the Industrial Internet of Things (IIoT). Traditional fault detection algorithms identify exceptions by a single abnormal dataset and do not pay attention to the factors such as electromagnetic interference, network delay, sensor sample delay, and so on. This paper focuses on fault detection by continuous abnormal points. We proposed a fault detection algorithm within the module of sequence state generated by unsupervised learning (SSGBUL) and the module of integrated encoding sequence classification (IESC). Firstly, we built a network module based on unsupervised learning to encode the flow sequence of the different network cards in the IIoT gateway, and then combined the multiple code sequences into one integrated sequence. Next, we classified the integrated sequence by comparing the integrated sequence with the encoding fault type. The results obtained from the three IIoT datasets of a sewage treatment plant show that the accuracy of the SSGBUL-IESC algorithm exceeds 90% with subsequence length 10, which is significantly higher than the accuracies of the dynamic time warping (DTW) algorithm and the time series forest (TSF) algorithm. The proposed algorithm reaches the classification requirements for fault detection for the IIoT.

Homologous Overexpression of Tyrosinase in Trichoderma reesei and Its Application in Glycinin Cross-Linking.

Tyrosinase is capable of oxidizing tyrosine residues in proteins, leading to intermolecular protein cross-linking, which could modify the protein network of food and improve the texture of food. To obtain the recombinant tyrosinase with microbial cell factory instead of isolation tyrosinase from the mushroom Agaricus bisporus, a TYR expression cassette was constructed in this study. The expression cassette was electroporated into Trichoderma reesei Rut-C30 and integrated into its genome, resulting in a recombinant strain C30-TYR. After induction with microcrystalline cellulose for 7 days, recombinant tyrosinase could be successfully expressed and secreted by C30-TYR, corresponding to approximately 2.16 g/L tyrosinase in shake-flask cultures. The recombinant TYR was purified by ammonium sulfate precipitation and gel filtration, and the biological activity of purified TYR was 45.6 U/mL. The purified TYR could catalyze the cross-linking of glycinin, and the emulsion stability index of TYR-treated glycinin emulsion was increased by 30.6% compared with the untreated one. The cross-linking of soy glycinin by TYR resulted in altered properties of oil-in-water emulsions compared to emulsions stabilized by native glycinin. Therefore, cross-linking with this recombinant tyrosinase is a feasible approach to improve the properties of protein-stabilized emulsions and gels.

Oxidized glutathione reverts carbapenem resistance in blaNDM-1-carrying Escherichia coli.

The emergence of drug-resistant Enterobacteriaceae carrying plasmid-mediated ß-lactamase genes has become a significant threat to public health. Organisms in the Enterobacteriaceae family containing New Delhi metallo-ß-lactamase­1 (NDM-1) and its variants, which are capable of hydrolyzing nearly all ß-lactam antibacterial agents, including carbapenems, are referred to as superbugs and distributed worldwide. Despite efforts over the past decade, the discovery of an NDM-1 inhibitor that can reach the clinic remains a challenge. Here, we identified oxidized glutathione (GSSG) as a metabolic biomarker for blaNDM-1 using a non-targeted metabolomics approach and demonstrated that GSSG supplementation could restore carbapenem susceptibility in Escherichia coli carrying blaNDM-1 in vitro and in vivo. We showed that exogenous GSSG promotes the bactericidal effects of carbapenems by interfering with intracellular redox homeostasis and inhibiting the expression of NDM-1 in drug-resistant E. coli. This study establishes a metabolomics-based strategy to potentiate metabolism-dependent antibiotic efficacy for the treatment of antibiotic-resistant bacteria.

A multi-omics study to monitor senescence-associated secretory phenotypes of Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD) is characterized by the progressive degeneration and damage of neurons in the brain. However, developing an accurate diagnostic assay using blood samples remains a challenge in clinic practice. The aim of this study was to explore senescence-associated secretory phenotypes (SASPs) in peripheral blood using mass spectrometry based multi-omics approach and to establish diagnostic assays for AD. METHODS: This retrospective study included 88 participants, consisting of 29 AD patients and 59 cognitively normal (CN) individuals. Plasma and serum samples were examined using high-resolution mass spectrometry to identify proteomic and metabolomic profiles. Receiver operating characteristic (ROC) analysis was employed to screen biomarkers with diagnostic potential. K-nearest neighbors (KNN) algorithm was utilized to construct a multi-dimensional model for distinguishing AD from CN. RESULTS: Proteomics analysis revealed upregulation of five plasma proteins in AD, including RNA helicase aquarius (AQR), zinc finger protein 587B (ZNF587B), C-reactive protein (CRP), fibronectin (FN1), and serum amyloid A-1 protein (SAA1), indicating their potential for AD classification. Interestingly, KNN-based three-dimensional model, comprising AQR, ZNF587B, and CRP, demonstrated its high accuracy in AD recognition, with evaluation possibilities of 0.941, 1.000, and 1.000 for the training, testing, and validation datasets, respectively. Besides, metabolomics analysis suggested elevated levels of serum phenylacetylglutamine (PAGIn) in AD. INTERPRETATION: The multi-omics outcomes highlighted the significance of the SASPs, specifically AQR, ZNF587B, CRP, and PAGIn, in terms of their potential for diagnosing AD and suggested neuronal aging-associated pathophysiology.

Leveraging Modeling and Simulation to Enhance the Efficiency of Bioequivalence Approaches for Generic Drugs: Highlights from the 2023 Generic Drug Science and Research Initiatives Public Workshop.

The 2023 Generic Drug Science and Research Initiative Public Workshop organized by the U.S. Food and Drug Administration (FDA) discussed the research needs to improve and enhance bioequivalence (BE) approaches for generic drug development. FDA takes such research needs and panel discussions into account to develop its Generic Drug User Fee Amendments III (GDUFA III) Science and Research Initiatives specific to generics. During the five workshop sessions, presentations and panel discussions focused on identifying and addressing scientific gaps and research needs related to nitrosamine impurity issues, BE assessment for oral products, innovative BE approaches for long-acting injectable products, alternative BE approaches for orally inhaled products, and advanced BE methods for topical products. Specifically, this report highlights the discussions on how to improve BE assessment for developing generic drug products based on research priorities for leveraging quantitative methods and modeling, as well as artificial intelligence/machine learning (AI/ML).

Anisotropic composite aerogel with thermal insulation and flame retardancy from cellulose nanofibers, calcium alginate and boric acid.

With the increasing severity of energy shortages and environmental pollution, there is an urgent need for advanced thermal insulation materials with excellent comprehensive performance, including low thermal conductivity, high flame resistance, and strong compressive strength. Herein, an anisotropic composite aerogel based on cellulose nanofibers (CNF), calcium alginate (CA), and boric acid (BA) is fabricated using a directional freeze-drying strategy. The CA and BA, as double cross-linking agents, associated with oriented porous structure provide the resultant aerogel with good mechanical strength. Additionally, self-flame retardant CA and BA act as synergistic flame retardants that endow the aerogel with excellent flame retardance properties such as a limiting oxygen index value of 44.2 %, UL-94 V-0 rating, and low heat release. Furthermore, this composite aerogel exhibits outstanding thermal insulation performance with a low thermal conductivity of approximately 30 mW m-1 K-1. Therefore, the composite aerogel is expected to have a wide potential application in areas such as construction, automotive industry, batteries, petrochemical pipelines, and high-temperature reaction devices.

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer.

Ferroptosis is an iron-dependent, non-apoptotic form of cell death resulting from the accumulation of lipid peroxides. Colorectal cancer (CRC) accumulates high levels of intracellular iron and reactive oxygen species (ROS), thereby sensitizing cells to ferroptosis. The selenoprotein glutathione peroxidase (GPx4) is a key enzyme in the detoxification of lipid peroxides and can be inhibited by the compound (S)-RSL3 ([1S,3R]-RSL3). However, the stereoisomer (R)-RSL3 ([1R,3R]-RSL3), which does not inhibit GPx4, exhibits equipotent activity to (S)-RSL3 across a panel of CRC cell lines. Utilizing CRC cell lines with an inducible knockdown of GPx4, we demonstrate that (S)-RSL3 sensitivity does not align with GPx4 dependency. Subsequently, a biotinylated (S)-RSL3 was then synthesized to perform affinity purification-mass spectrometry (AP-MS), revealing that (S)-RSL3 acts as a pan-inhibitor of the selenoproteome, targeting both the glutathione and thioredoxin peroxidase systems as well as multiple additional selenoproteins. To investigate the therapeutic potential of broadly disrupting the selenoproteome as a therapeutic strategy in CRC, we employed further chemical and genetic approaches to disrupt selenoprotein function. The findings demonstrate that the selenoprotein inhibitor Auranofin can induce ferroptosis and/or oxidative cell death both in-vitro and in-vivo. Consistent with this data we observe that AlkBH8, a tRNA-selenocysteine methyltransferase required for the translational incorporation of selenocysteine, is essential for CRC growth. In summary, our research elucidates the complex mechanisms underlying ferroptosis in CRC and reveals that modulation of the selenoproteome provides multiple new therapeutic targets and opportunities in CRC.

Accumulated LPS induced by colitis altered the activities of vitamin D-metabolizing hydroxylases and decreased the generation of 25-hydroxyvitamin D.

It is generally accepted that low vitamin D (VD) levels are associated with a high prevalence factor for Inflammatory bowel disease (IBD). IBD patients have observed higher levels of lipopolysaccharide (LPS), ALT, and AST than healthy people. Gut-derived LPS causes inflammatory injury in the liver and kidney. The VD-metabolizing mechanism is involved in the liver and kidney, which means IBD might impact VD metabolism. However, whether IBD affects VD metabolism has not been studied. In vitro LPS resulted in decreased CYP2R1 in liver cells as well as decreased CYP27B1 and increased CYP24A1 in kidney cells, revealing that LPS changed the activities of several hydroxylases. Mice with acute colitis had an increased LPS in serum and liver with mild hepatic injuries, while mice with chronic colitis had a significant elevation of LPS in serum, liver, and kidney with hepatorenal injuries. Thus, the liver hydroxylase for VD metabolism would be the first to be affected in IBD. Consequently, serum 25-hydroxyvitamin D declined dramatically with a significant elevation of 24,25-dihydroxyvitamin D and 1,24,25-trihydroxyvitamin D. Unchanged serum levels of 1,25-dihydroxyvitamin D might be the result of other factors in vivo. In acute colitis, a small dosage (4 IU/day) of cholecalciferol could protect the colon, decrease the serum level of LPS, and finally increase serum 25-hydroxyvitamin D. However, this improvement of cholecalciferol was fading in chronic colitis. These results suggested that VD supplementations for preventing and curing IBD in the clinic should consider hepatorenal hydroxylases and be employed as soon as possible for a better outcome.

Black rice anthocyanins nanoparticles based on bovine serum albumin and hyaluronic acid: Preparation, characterization, absorption and intestinal barrier function protection in Caco-2 monolayers.

Black rice anthocyanins (BRA) nanoparticles (NPs) were prepared using hyaluronic acid (HA), oxidized hyaluronic acid (OHA) and bovine serum albumin (BSA) to enhance the absorption and bioactivity of anthocyanins (ACNs). Results showed that HA/OHA-BSA-BRA NPs had a spherical morphology and excellent dispensability, with hydrated radius ~ 500 nm, zeta potential ~ - 30 mV, and encapsulation efficiency ~21 %. Moreover, using in vitro gastrointestinal release assay, we demonstrated that both BRA-loaded NPs exhibited effective controlled release properties of ACNs, significantly enhancing the accessibility of ACNs to the intestine. Cellular experiments showed that both two NPs had good biocompatibility and increased uptake of BRA. Furthermore, in comparison to the free BRA group, both BRA NPs groups significantly decreased the TEER value and increased the expression of tight junction proteins (Claudin 1, Occludin and ZO-1) in Caco-2 cell monolayers with LPS-induced damage. Therefore, our study demonstrated that HA/OHA-BSA-BRA NPs are promising carriers of ACNs and can effectively prevent the LPS-induced intestinal barrier injury in vitro.

Cellular functions, molecular signalings and therapeutic applications: Translational potential of deubiquitylating enzyme USP9X as a drug target in cancer treatment.

Protein ubiquitination, one of the most significant post-translational modifications, plays an important role in controlling the proteins activity in diverse cellular processes. The reversible process of protein ubiquitination, known as deubiquitination, has emerged as a critical mechanism for maintaining cellular homeostasis. The deubiquitinases (DUBs), which participate in deubiquitination process are increasingly recognized as potential candidates for drug discovery. Among these DUBs, ubiquitin-specific protease 9× (USP9X), a highly conserved member of the USP family, exhibits versatile functions in various cellular processes, including the regulation of cell cycle, protein endocytosis, apoptosis, cell polarity, immunological microenvironment, and stem cell characteristics. The dysregulation and abnormal activities of USP9X are influenced by intricate cellular signaling pathway crosstalk and upstream non-coding RNAs. The complex expression patterns and controversial clinical significance of USP9X in cancers suggest its potential as a prognostic biomarker. Furthermore, USP9X inhibitors has shown promising antitumor activity and holds the potential to overcome therapeutic resistance in preclinical models. However, a comprehensive summary of the role and molecular functions of USP9X in cancer progression is currently lacking. In this review, we provide a comprehensive delineation of USP9X participation in numerous critical cellular processes, complicated signaling pathways within the tumor microenvironment, and its potential translational applications to combat therapeutic resistance. By systematically summarizing the updated molecular mechanisms of USP9X in cancer biology, this review aims to contribute to the advancement of cancer therapeutics and provide essential insights for specialists and clinicians in the development of improved cancer treatment strategies.

Naphthalene-based donor-acceptor covalent organic frameworks as an electron distribution regulator for boosting photocatalysis.

By incorporating the electron-rich naphthalene and electron-deficient triazine as an electron donor and an electron acceptor, a new donor-acceptor covalent organic framework as an electron distribution regulator was obtained for boosting photocatalytically oxidative coupling of benzylamines and selective oxidation of thioethers under the irradiation of green light (520 nm).

Reversible light-induced spin state switching in a dinuclear Fe(II) spin crossover complex.

A dinuclear Fe(II) spin crossover (SCO) complex with the formula [Fe2L5(NCS)4]·2DMF·2H2O (1) was synthesised from 1-naphthylimino-1,2,4-triazole (L). Complex 1 exhibits an incomplete thermally induced spin transition with a transition temperature T1/2 of 95 K and a thermally trapped metastable high-spin state at low temperatures. Furthermore, it undergoes a reversible light-induced spin crossover by alternate irradiation with 532 and 808 nm lasers.

Reinforcing oxygen reduction reaction and accelerating charge migration kinetics on In4SnS8 by polypyrrole for photocatalytic hydrogen peroxide production.

Solar light-driven hydrogen peroxide (H2O2) production through the two-electron oxygen reduction reaction (ORR) from the earth-abundant O2 and water is a potential alternative to the energy-consuming anthraquinone oxidation process, although the activity of the common photocatalysts is still insufficient to satisfy the industrial demands. Poor accessibility of O2 to surface/interface and fast carrier recombination is the limiting-factor for catalytic systems. Herein, we develop a nanohybrid photocatalysts by introducing 1D conducting polymer of polypyrrole (PPy) nanotube on In4SnS8 to promote H2O2 evolution under visible light, obtaining up to 254.8 µM in 2 h, which is 2.4- and 13-fold larger than that of individual In4SnS8 and PPy. The detailed characterizations of hybrid structure, O2 adsorption behaviors, charge carrier dynamics over PPy/In4SnS8 in conjunction with computational calculations corroborate that the modification of PPy could enlarge the amount of O2 adsorption amount, expedite the cycle of O2 adsorption/desorption and accelerate the transportation of electrons from In4SnS8 to the interface, eventually speeding up H2O2 photoproduction via indirect 2e- ORR pathway. This work establishes a paradigm of regulating the interfacial microenvironment by polymer for boosting H2O2 photogeneration through high selectivity of ORR.

Valvar bypass surgery to ameliorate persistent lower limb edema caused by post-thrombotic syndrome: a case report and literature review.

Obstruction and/or reflux compromise during venous emptying can facilitate different pathophysiologies in chronic venous insufficiency (CVI). We present a patient with persistent lower limb CVI edema caused by post-thrombotic syndrome (PTS), who responded well to femoral vein valve therapy via axillary vein bypass after unsuccessful valvuloplasty, and led a normal life. During a 12 month observation period, bridging vessels completely restored original anatomical structures. In a literature study, no similar surgeries were reported, but we show that this operation may be feasible in selected patients.

Characterization of cellular responses and cell lysis to elevated hydrodynamic stress from benchtop perfusion bioreactors.

The effective design of perfusion cell culture is currently challenging regarding balancing the operating parameters associated with the hydrodynamic conditions due to increased system complexity. To address this issue, cellular responses of an industrial CHO cell line to different types of hydrodynamic stress in benchtop perfusion bioreactors originating from agitation, sparging, and hollow fibers (HF) in the cell retention devices were systematically investigated here with the analysis of cell lysis. It was found that cell lysis was very common and most associated with the sparging stress, followed by the HF and lastly the agitation, consequently heavily impacting the estimation of process descriptors related to biomass. The results indicated that the agitation stress led to a reduced cell growth with a shift toward a more productive phenotype, suggesting an energy redirection from biomass formation to product synthesis, whereas the sparging stress had a small impact on the intracellular metabolic flux distribution but increased the cell death rate drastically. For HF stress, a similar cell maintenance profile was found as the sparging while the activity of glycolysis and the TCA cycle was significantly impeded, potentially leading to the lack of energy and thus a substantial decrease in cell-specific productivity. Moreover, a novel concept of volume average shear stress was developed to further understand the relations of different types of stress and the observed responses for an improved insight for the perfusion cell culture.

Spatial continuous modeling of early Cenozoic carbon cycle and climate.

A real spatial continuous modeling of climate and carbon cycle is developed, and tested for early Cenozoic from 60 Ma to 40 Ma.

QSAR analysis of VEGFR-2 inhibitors based on machine learning, Topomer CoMFA and molecule docking.

VEGFR-2 kinase inhibitors are clinically approved drugs that can effectively target cancer angiogenesis. However, such inhibitors have adverse effects such as skin toxicity, gastrointestinal reactions and hepatic impairment. In this study, machine learning and Topomer CoMFA, which is an alignment-dependent, descriptor-based method, were employed to build structural activity relationship models of potentially new VEGFR-2 inhibitors. The prediction ac-curacy of the training and test sets of the 2D-SAR model were 82.4 and 80.1%, respectively, with KNN. Topomer CoMFA approach was then used for 3D-QSAR modeling of VEGFR-2 inhibitors. The coefficient of q2 for cross-validation of the model 1 was greater than 0.5, suggesting that a stable drug activity-prediction model was obtained. Molecular docking was further performed to simulate the interactions between the five most promising compounds and VEGFR-2 target protein and the Total Scores were all greater than 6, indicating that they had a strong hydrogen bond interactions were present. This study successfully used machine learning to obtain five potentially novel VEGFR-2 inhibitors to increase our arsenal of drugs to combat cancer.