Measurement properties of the EQ-5D-Y-3L, PedsQL 4.0, and PROMIS-25 Profile v2.0 in pediatric patients with spinal muscular atrophy.

OBJECTIVE: The objective of this study was to examine the psychometric properties of the EQ-5D-Y-3 L, Patient Reported Outcomes Measurement System 25-item version profile v2.0 (PROMIS-25), and Pediatric Quality of Life Inventory™ version 4.0 Generic Core Scale (PedsQL 4.0) in Chinese pediatric patients with spinal muscular atrophy (SMA). METHODS: The data used in this study were obtained via a web-based cross-sectional survey. Parents of pediatric patients with SMA completed the proxy-reported EQ-5D-Y-3 L, PedsQL 4.0, and PROMIS-25 measures. Information about socioeconomic and health status was also obtained. The ceiling and floor effects, factorial structure, convergent validity, and known-group validity of the three measures were assessed. RESULTS: Three hundred and sixty-three parents of children aged from 5 to 12 completed the questionnaires. Strong floor effects were observed for the physical function components of the PROMIS-25 (41.3%) and PedsQL 4.0 (67.8%). For EQ-5D-Y-3 L, 84.6% of the respondents reported having "a lot of" problems with the dimensions "walking" and "looking after myself." Minimal ceiling or floor effects were observed for the EQ-5D-Y-3 L index value. The confirmatory factor analysis supported a six-factor structure for the PROMIS-25, but did not support a four-factor structure for the PedsQL 4.0. All hypothesized correlations of the dimensions among the three measures were confirmed, with coefficients ranging from 0.28 to 0.68. Analysis of variance showed that EQ-5D-Y-3 L demonstrated better known-group validity than the other two measures in 14 out of 16 comparisons. CONCLUSIONS: The EQ-5D-Y-3 L showed better discriminant power than the other two measures. The physical health dimensions of all three measures showed the significant floor effects. These findings provide valuable insights into the effectiveness of these measures at capturing and quantifying the impact of SMA on patients' health-related quality of life.

APPA-3D: an autonomous 3D path planning algorithm for UAVs in unknown complex environments.

Due to their high flexibility, low cost, and ease of handling, Unmanned Aerial Vehicles (UAVs) are often used to perform difficult tasks in complex environments. Stable and reliable path planning capability is the fundamental demand for UAVs to accomplish their flight tasks. Most researches on UAV path planning are carried out under the premise of known environmental information, and it is difficult to safely reach the target position in the face of unknown environment. Thus, an autonomous collision-free path planning algorithm for UAVs in unknown complex environments (APPA-3D) is proposed. An anti-collision control strategy is designed using the UAV collision safety envelope, which relies on the UAV's environmental awareness capability to continuously interact with external environmental information. A dynamic reward function of reinforcement learning combined with the actual flight environment is designed and an optimized reinforcement learning action exploration strategy based on the action selection probability is proposed. Then, an improved RL algorithm is used to simulate the UAV flight process in unknown environment, and the algorithm is trained by interacting with the environment, which finally realizes autonomous collision-free path planning for UAVs. The comparative experimental results in the same environment show that APPA-3D can effectively guide the UAV to plan a safe and collision-free path from the starting point to the target point in an unknown complex 3D environment.

MALAT1 DEREPRESSES MIR-433-3P-MEDIATED RPTOR SUPPRESSION TO IMPAIR AUTOPHAGY AND DRIVE PYROPTOSIS IN ENDOTOXEMIA.

ABSTRACT: Objective: Autophagy elevation in endotoxemia plays a protective role by negatively regulating the pyroptosis of vascular endothelial cells, but the molecular mechanisms are still poorly understood. The present study aimed to identify the mechanism underlying autophagy and pyroptosis in endotoxemia. Methods: Bioinformatics analysis and whole-gene transcriptome sequencing prediction were used to identify the endotoxemia-related lncRNA-miRNA-mRNA axis of interest. Human umbilical vein endothelial cells (HUVECs) were activated by lipopolysaccharide (LPS) to mimic the inflammatory environment encountered in endotoxemia. Autophagy and pyroptosis of LPS-treated HUVECs were assessed in response to the knockdown of MALAT1 (metastasis-associated lung adenocarcinoma transcript 1)/miR-433-3p (miRNA-433-3p)/RPTOR (regulatory-associated protein of mTOR). The binding affinity of MALAT1, miR-433-3p, and RPTOR was detected by RNA pull-down and luciferase activity assays. The endothelial cell-specific RPTOR knockout mice were developed and rendered septic using LPS induction to verify the role of RPTOR in autophagy, pyroptosis, and inflammatory response in vivo . Results: The in vitro experiments indicated that LPS could stimulate HUVECs to highly express RPTOR, and its knockdown enhanced cellular autophagy and restricted pyroptosis to curb inflammatory responses. Mechanically, MALAT1 is competitively bound to miR-433-3p to release RPTOR expression, thereby promoting pyroptosis and aggravating endotoxemia. In vivo experiments further confirmed that the knockdown of RPTOR activated autophagy and curtailed pyroptosis in septic mice. Conclusion: MALAT1 is highly expressed in endotoxemia. MALAT1 promotes RPTOR expression by competitively absorbing miR-433-3p, inhibits LPS-activated HUVEC cell autophagy, promotes cell death, enhances LPS-induced inflammatory activation of vascular endothelial cells, and ultimately promotes the progression of endotoxemia.

Acid/reduction dual-sensitive amphiphilic graft polyurethane with folic acid and detachable poly(ethylene glycol) as anticancer drug delivery carrier.

In order to not only improve the stability of nanomicelles in blood circulation but also promote the cellular uptake in tumors and rapidly release the encapsulated drugs in tumor cells, a kind of acid/reduction dual-sensitive amphiphilic graft polyurethane with folic acid and detachable poly(ethylene glycol) (FA-PUSS-gimi-mPEG) was synthesized by grafting folic acid and monomethoxy poly(ethylene glycol) to the polyurethane side chain. FA-PUSS-gimi-mPEG could self-assemble in aqueous solution to form negatively charged nanomicelles, which endowed them good stability under normal physiological condition. Using ultraviolet-visible spectrometer (UV-vis) and dynamic light scattering (DLS), it was found that the hydrophilic poly(ethylene glycol) layer of FA-PUSS-gimi-mPEG micelles could be detached due to the cleavage of benzoic-imine bond under slightly acidic condition, which resulted in reversing the charge of the micellar surface and exposing folic acid to the micellar surface. FA-PUSS-gimi-mPEG micelles could load doxorubicin (DOX), moreover the drug release rate was faster at pH 5.0 and 10 mM glutathione (GSH) than that under normal physiological condition. The results of cell experiments further demonstrated that FA-PUSS-gimi-mPEG micelles had acid/reduction dual-sensitive property. The changes in the structure of FA-PUSS-gimi-mPEG micelles could enhance the cellular uptake under acid condition and the micelles could accelerate the drug release in tumor cells due to the presence of disulfide bonds in the polymer. Therefore, FA-PUSS-gimi-mPEG micelles could efficiently deliver anticancer drug into tumor cells and enhance the inhibition of cellular proliferation through multi-effect synergy.

Acid-sensitive charge-reversal co-assembled polyurethane nanomicelles as drug delivery carriers.

In order to obtain drug delivery carriers with good stability in blood and high cellular uptake efficiency, carboxyl groups and tertiary amine groups were respectively introduced into polyurethane to synthesize two kinds of amphiphilic polyurethanes with opposite charges (PUC and PUN). Their structures were characterized by Fourier transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (1H NMR) spectroscopy and gel permeation chromatography (GPC). PUC-PUN co-assembled nanomicelles were prepared by electrostatic interaction between PUC and PUN micelles, which showed acid-sensitive property. When the pH of the solution was decreased from 7.4 to 6.5, PUC-PUN-1 micelles showed negative-to-positive charge-reversal property among these micelles. The results of stability and cell experiments demonstrated that PUC-PUN-1 micelles not only had excellent stability in simulated normal physiological environment but also could obviously enhance the cellular uptake efficiency. PUC-PUN-1 micelles had low cytotoxicity against SGC-7901 and MGC-803 cells, whereas PUC-PUN-1/DOX micelles had higher cytotoxicity compared to pure DOX and PUN-1/DOX micelles. Moreover, the results of in vivo antitumor activity experiments showed that PUC-PUN-1/DOX micelles had better tumor inhibition ability and safety than pure DOX. In addition, the results of in vitro drug release experiments indicated that PUC-PUN-1/DOX micelles had almost no burst release or leakage of drugs in pH 7.4 environment. However, the drug release was accelerated in pH 5.0, which followed Fickian diffusion mechanism.

Immobilization of bovine hemoglobin on Au nanoparticles/MoS2 nanosheets - Chitosan modified screen-printed electrode as chlorpyrifos biosensor.

In this paper a quick and disposable electrochemical biosensor based on bovine hemoglobin (BHb) is proposed for the determination of chlorpyrifos (CP). The bioelectrode (denoted as AuNPs/MoS2-CS/BHb/SPE) has been designed by immobilizing BHb on the screen printed electrode (SPE) surface modified by gold nanoparticles (AuNPs) and Molybdenum disulfide (MoS2) nanosheets - chitosan (CS) mixture (MoS2-CS). Field emission scanning electron microscopy (FESEM) and electrochemical characterization demonstrate the successful grafting of AuNPs/MoS2-CS/BHb/SPE. Detailed electrochemical impedance spectroscopy (EIS) analysis and cyclic voltammetry (CV) tests show that the proposed bioelectrode exhibits decent electrochemical properties, such as well conductivity and large specific surface area. In-depth electrochemical analysis reveals the redox reaction occurring on the surface of the bioelectrode and the mechanism that CP binds with BHb forming the thin film to inhibit the peak current. The proposed biosensor exhibits sensitive and stable responses for electrochemical assay of CP ranging from 0.004 µM to 28.52 µM, with a limit of detection (LOD) as 5.6 nM. The electrochemical biosensor passes the repeatability, reproducibility, stability and anti-interference ability test experiments with good performance. The biosensor also shows its credibility for detecting CP in real vegetable samples (Cabbage and Leek) with recovery (%) ranging from 87% to 109%. The proposed biosensor is of great potential application values for detecting CP and the study is of great reference value for the research and development of biosensors for quantitative detection of organophosphate pesticides (OPs).

Network Pharmacology-Based Strategy for Predicting Active Ingredients and Potential Targets of Gegen Qinlian Decoction for Rotavirus Enteritis.

MATERIALS AND METHODS: In this study, a network pharmacology-based strategy was used to elucidate the mechanism of GGQLD for the treatment of RVE. Oral bioavailability and drug-likeness were taken as the judgment criteria to search the active ingredients of GGQLD in traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). The affinity between protein and ingredients was further determined using the similarity ensemble approach to find the corresponding targets. According to the genes related to enteritis in GeneCards database, the key targets were screened by intersections between drug and disease targets. And the therapeutic mechanism was predicted using the protein-protein interactions (PPIs), the Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, which was verified by detecting calcium ion concentration with the fluorescent probe. RESULT: 130 active ingredients were screened from GGQLD, including (R)-canadine, moupinamide, formononetin, and other flavonoids. They act on a total of 366 targets, which is mainly distributed in the biological process of hormone binding or signaling pathways of neuroactive ligand receptor interaction, serotonergic synapse, and calcium signaling pathway. Furthermore, serotonin receptors, adrenergic receptors, cholinergic receptors, and dopamine receptors in the enteric nervous system may be the key targets of RVE treatment by GGQLD. CONCLUSION: This study demonstrated that the potential mechanism that GGQLD can effectively improve the symptoms of RVE may depend on the regulation of calcium ions, serotonin, and gastrointestinal hormone ion that could mutually affect the intestinal nervous system.