Optimising Complex Surgical Trays Based on PDSA Cycles.

Objective: To investigate the application of a multidisciplinary collaboration model to optimise the configuration management of orthopaedic external device sets in general hospitals. Methods: A pretest-post-test study design was used. Sixty patients who underwent unilateral total knee arthroplasty and 60 patients who underwent posterior lumbar interbody fusion between March and May 2022 were recruited as the control stage. Additionally, a total of 120 patients, 60 of each, who underwent the two procedures between September and November 2022, were recruited as the experimental stage. For the control stage, conventional external equipment management was used, and for the experimental stage, an external device management programme was implemented based on multidisciplinary collaboration with the control stage. Based on the PDSA cycle, the configuration management of orthopaedic external device sets was optimised, and the differences in collating and counting external devices, nurses' overtime in the external device stage and orthopaedic surgeon satisfaction were compared between the two stages. Results: Compared with the control stage, the collation count took less time (8.65 ± 0.25 min vs 5.37 ± 0.13 min; 13.55 ± 1.10 min vs 7.85 ± 0.82 min), the number of overtime hours was shorter (175.80 ± 12.19 min vs 96.68 ± 13.66 min) and orthopaedic surgeon satisfaction was improved (4.58 ± 0.62 vs 4.10 ± 0.68; 4.33 ± 0.73 vs 3.87 ± 0.77; 4.20 ± 0.71 vs 3.82 ± 0.71; 4.12 ± 0.69 vs 3.87 ± 0.72; 4.05 ± 0.68 vs 3.79 ± 0.68) in the experimental stage (all P < 0.05). Conclusion: Multidisciplinary collaboration offers various benefits for optimising the configuration of external device sets, such as reducing the time taken for the preoperative sorting and counting of external devices, enhancing nurses' work efficiency and improving surgeons' job satisfaction; therefore, it is worthy of reference in clinical practice.

Piperonyl-Tethered Rhodanine Derivatives Potently Inhibit Chitinolytic Enzymes of Ostrinia furnacalis.

Insect pest chitinases are potential target for developing new insect growth regulators. Piperine was found first to inhibit the insect chitinase (OfChi-h) from Ostrinia furnacalis (Asian corn borer) in this work, except for previously reported OfChtI. Novel piperonyl-tethered rhodanine derivatives 7a-j were rationally designed with piperine as lead and synthesized by introducing a unique rhodanine moiety into the piperine scaffold based on the similar binding cavity of OfChtI and OfChi-h. Compared to piperine, compounds 7a-j showed approximately 100- to 400-fold or 110- to 210-fold higher inhibitory capacity against two chitinases, respectively. Molecular mechanism studies indicated that π interactions are crucial for improving inhibitory activity against two chitinases due to the introduction of the conjugated rhodanine ring. Moreover, compounds 7a-c could dramatically inhibit the growth and development of O. furnacalis larvae by in vivo activity evaluation. This study provides novel piperonyl-tethered rhodanine derivatives inhibiting dual chitinases as insect growth regulator candidates.

Novel brain-targeted nanomicelles for anti-glioma therapy mediated by the ApoE-enriched protein corona in vivo.

BACKGROUND: The interactions between nanoparticles (NPs) and plasma proteins form a protein corona around NPs after entering the biological environment, which provides new biological properties to NPs and mediates their interactions with cells and biological barriers. Given the inevitable interactions, we regard nanoparticle‒protein interactions as a tool for designing protein corona-mediated drug delivery systems. Herein, we demonstrate the successful application of protein corona-mediated brain-targeted nanomicelles in the treatment of glioma, loading them with paclitaxel (PTX), and decorating them with amyloid ß-protein (Aß)-CN peptide (PTX/Aß-CN-PMs). Aß-CN peptide, like the Aß1-42 peptide, specifically binds to the lipid-binding domain of apolipoprotein E (ApoE) in vivo to form the ApoE-enriched protein corona surrounding Aß-CN-PMs (ApoE/PTX/Aß-CN-PMs). The receptor-binding domain of the ApoE then combines with low-density lipoprotein receptor (LDLr) and LDLr-related protein 1 receptor (LRP1r) expressed in the blood-brain barrier and glioma, effectively mediating brain-targeted delivery. METHODS: PTX/Aß-CN-PMs were prepared using a film hydration method with sonication, which was simple and feasible. The specific formation of the ApoE-enriched protein corona around nanoparticles was characterized by Western blotting analysis and LC-MS/MS. The in vitro physicochemical properties and in vivo anti-glioma effects of PTX/Aß-CN-PMs were also well studied. RESULTS: The average size and zeta potential of PTX/Aß-CN-PMs and ApoE/PTX/Aß-CN-PMs were 103.1 nm, 172.3 nm, 7.23 mV, and 0.715 mV, respectively. PTX was efficiently loaded into PTX/Aß-CN-PMs, and the PTX release from rhApoE/PTX/Aß-CN-PMs exhibited a sustained-release pattern in vitro. The formation of the ApoE-enriched protein corona significantly improved the cellular uptake of Aß-CN-PMs on C6 cells and human umbilical vein endothelial cells (HUVECs) and enhanced permeability to the blood-brain tumor barrier in vitro. Meanwhile, PTX/Aß-CN-PMs with ApoE-enriched protein corona had a greater ability to inhibit cell proliferation and induce cell apoptosis than taxol. Importantly, PTX/Aß-CN-PMs exhibited better anti-glioma effects and tissue distribution profile with rapid accumulation in glioma tissues in vivo and prolonged median survival of glioma-bearing mice compared to those associated with PMs without the ApoE protein corona. CONCLUSIONS: The designed PTX/Aß-CN-PMs exhibited significantly enhanced anti-glioma efficacy. Importantly, this study provided a strategy for the rational design of a protein corona-based brain-targeted drug delivery system. More crucially, we utilized the unfavorable side of the protein corona and converted it into an advantage to achieve brain-targeted drug delivery.

Effects of bronchial thermoplasty and cryoablation on airway smooth muscle.

BACKGROUND: The effectiveness of bronchial thermoplasty (BT) has been reported in patients with severe asthma. This study compared the effects of BT and cryoballoon ablation (CBA) therapy on the airway smooth muscle (ASM). METHODS: Eight healthy male beagle dogs were included in this experiment. In the preliminary experiment, one dog received BT treatment for both lower lobe bronchus, another dog received CBA treatment for 7 s on the upper and lower lobe of right bronchus, and 30 s on the left upper and lower lobe. The treatments were performed twice at an interval of 1 month. In subsequent experiments, the right lower lobe bronchus was treated with BT, and the left lower lobe bronchus was treated with CBA. The effects of treatment were observed after 1 (n = 3) month and 6 months (n = 3). Hematoxylin-eosin staining, Masson trichrome staining, and immunohistochemical staining were used to compare the effects of BT and CBA therapy on the ASM thickness, collagen fibers synthesis, and M3 receptor expression after treatment. One-way analysis of variance with Dunnett post hoc test was used to analyze the differences among groups. RESULTS: In the preliminary experiment, the ASM ablation effect of 30-s CBA was equivalent to that of 7-s CBA (ASM thickness: 30.52 ±â€Š7.75 µm vs. 17.57 ±â€Š15.20 µm, P = 0.128), but the bronchial mucociliary epithelium did not recover, and large numbers of inflammatory cells had infiltrated the mucosal epithelium at 1-month post-CBA with 30-s freezing. Therefore, we chose 7 s as the CBA treatment time in our follow-up experiments. Compared with the control group (35.81 ±â€Š11.02 µm), BT group and CBA group (13.41 ±â€Š4.40 µm and 4.81 ±â€Š4.44 µm, respectively) had significantly decreased ASM thickness after 1 month (P < 0.001). Furthermore, the ASM thickness was significantly lower in the 1-month post-CBA group than in the 1-month post-BT group (P = 0.015). There was no significant difference in ASM thickness between the BT and CBA groups after six months (9.92 ±â€Š4.42 µm vs. 7.41 ±â€Š7.20 µm, P = 0.540). Compared with the control group (0.161 ±â€Š0.013), the average optical density of the ASM M3 receptor was significantly decreased in 6-month post-BT, 1-month post-CBA, and 6-month post-CBA groups (0.070 ±â€Š0.022, 0.072 ±â€Š0.012, 0.074 ±â€Š0.008, respectively; all P < 0.001). There was no significant difference in the average optical density of ASM M3 receptor between the BT and CBA therapy groups after six months (P = 0.613). CONCLUSIONS: CBA therapy effectively ablates the ASM, and its ablation effect is equivalent to that of BT with a shorter onset time. A neural mechanism is involved in both BT and CBA therapy.

Efficient Anti-Glioma Therapy Through the Brain-Targeted RVG15-Modified Liposomes Loading Paclitaxel-Cholesterol Complex.

BACKGROUND: Glioma is the most common primary malignant brain tumor with a dreadful overall survival and high mortality. One of the most difficult challenges in clinical treatment is that most drugs hardly pass through the blood-brain barrier (BBB) and achieve efficient accumulation at tumor sites. Thus, to circumvent this hurdle, developing an effectively traversing BBB drug delivery nanovehicle is of significant clinical importance. Rabies virus glycoprotein (RVG) is a derivative peptide that can specifically bind to nicotinic acetylcholine receptor (nAChR) widely overexpressed on BBB and glioma cells for the invasion of rabies virus into the brain. Inspired by this, RVG has been demonstrated to potentiate drugs across the BBB, promote the permeability, and further enhance drug tumor-specific selectivity and penetration. METHODS: Here, we used the RVG15, rescreened from the well-known RVG29, to develop a brain-targeted liposome (RVG15-Lipo) for enhanced BBB permeability and tumor-specific delivery of paclitaxel (PTX). The paclitaxel-cholesterol complex (PTX-CHO) was prepared and then actively loaded into liposomes to acquire high entrapment efficiency (EE) and fine stability. Meanwhile, physicochemical properties, in vitro and in vivo delivery efficiency and therapeutic effect were investigated thoroughly. RESULTS: The particle size and zeta potential of PTX-CHO-RVG15-Lipo were 128.15 ± 1.63 nm and -15.55 ± 0.78 mV, respectively. Compared with free PTX, PTX-CHO-RVG15-Lipo exhibited excellent targeting efficiency and safety in HBMEC and C6 cells, and better transport efficiency across the BBB in vitro model. Furthermore, PTX-CHO-RVG15-Lipo could noticeably improve the accumulation of PTX in the brain, and then promote the chemotherapeutic drugs penetration in C6luc orthotopic glioma based on in vivo imaging assays. The in vivo antitumor results indicated that PTX-CHO-RVG15-Lipo significantly inhibited glioma growth and metabasis, therefore improved survival rate of tumor-bearing mice with little adverse effect. CONCLUSION: Our study demonstrated that the RVG15 was a promising brain-targeted specific ligands owing to the superior BBB penetration and tumor targeting ability. Based on the outstanding therapeutic effect both in vitro and in vivo, PTX-CHO-RVG15-Lipo was proved to be a potential delivery system for PTX to treat glioma in clinic.

A Piperine-Based Scaffold as a Novel Starting Point to Develop Inhibitors against the Potent Molecular Target OfChtI.

The insect chitinase OfChtI from the agricultural pest Ostrinia furnacalis (Asian corn borer) is a promising target for green insecticide design. OfChtI is a critical chitinolytic enzyme for the cuticular chitin degradation at the stage of molting. In this study, piperine, a natural amide compound isolated from black pepper, Piper nigrum L., was discovered for the first time to have inhibitory activity toward OfChtI. The compound-enzyme interaction was presumed to take place between the piperine benzo[d][1,3] dioxole skeleton and subsite -1 of the substrate-binding pocket of OfChtI. Hence, on the basis of the deduced inhibitory mechanism and crystal structure of the substrate-binding cavity of OfChtI, compounds 5a-f were designed and synthesized by introducing a butenolide scaffold into the lead compound piperine. The enzymatic activity assay indicated that compounds 5a-f (Ki = 1.03-2.04 µM) exhibited approximately 40-80-fold higher inhibitory activity than the lead compound piperine (I) (Ki = 81.45 µM) toward OfChtI. The inhibitory mechanism of the piperonyl butenolide compounds was elucidated by molecular dynamics, which demonstrated that the introduced butenolide skeleton improved the binding affinity to OfChtI. Moreover, the in vivo activity assay indicated that these compounds also displayed moderate insecticidal activity toward O. furnacalis. This work introduces the natural product piperine as a starting point for the development of novel insecticides targeting OfChtI.

Bioactivities of synthetic salicylate-substituted carboxyl (E)-ß-Farnesene derivatives as ecofriendly agrochemicals and their binding mechanism with potential targets in aphid olfactory system.

BACKGROUND: The aphid alarm pheromone, (E)-ß-farnesene (EßF), is a natural product secreted from the aphid cornicle as a signal to warn companions of danger. Odorant binding proteins (OBPs) are the vital targets in insect signal transduction pathways. To improve bioactivity of EßF as more economic and stable aphid control agents, EßF derivatives containing an active substructure, salicylic acid moiety, were designed, synthesized, and evaluated for their bioactivities in a structure-function study under laboratory conditions. RESULTS: EßF derivatives, (E)-3,7-dimethylocta-2,6-dien-1-yl-2-hydroxy-3-methylbenzoate and (E)-3,7-dimethylocta-2,6-dien-1-yl-2-hydroxy-3-methoxybenzoate showed outstanding aphid-repellent activity at a dose of 5 µg against Acyrthosiphon pisum (repellency proportions of 67.3% and 71.2%, respectively) and Myzus persicae (repellency proportions of 80.0% and 74.4%, respectively) in laboratory. EßF and most of its derivatives bound strongly to ApisOBP9 with a higher affinity than those of the reported potential targets AphisOBP3 and ApisOBP7. The binding affinities to these three ApisOBPs were generally consistent with the in vivo aphid-repellent activity. A molecular docking study suggested that the hydrophobic effect was crucial for the interactions between the derivatives and the OBPs. CONCLUSION: New EßF derivatives containing salicylic acid moiety and their repellent activity, binding mechanism with three potential OBPs are presented. A new OBP, ApisOBP9, was characterized as a potential EßF and EßF derivatives binding protein for the first time. The hydrophobic nature of these analogues is responsible for their activity. Two analogues 3b and 3e with outstanding aphid-repellent activity could be new leads for aphid control agents.

The mechanism underlying OBP heterodimer formation and the recognition of odors in Holotrichia oblita Faldermann.

Insect odorant-binding proteins (OBPs) play key roles in transport odors to receptors and contribute to insect survival. The cooperative interaction of HoblOBP1 and HoblOBP2 in Holotrichia oblita Faldermann (Coleoptera: Melolonthidae) could increase their binding capacity for ligands. In present study, molecular docking results showed that OBP1/OBP2 complex formed a large binding pocket and interacted with the ligands by hydrogen bonds and hydrophobic interactions. Then, nine amino acids for single site mutations, three paired for double sites, and negative control were mutated into alanine successfully by site-directed mutagenesis. Finally, fluorescence binding assays of these mutants showed that breaking one or two pairs of hydrogen bonds between HoblOBP1 and HoblOBP2 or formed with the ligands significantly decrease the binding affinity with the ligands. However, hydrophobic site mutants still showed slight binding affinity to the ligands. Therefore, the three pairs of hydrogen bonds involved in heterodimer formation and the five hydrogen bonding sites in binding pocket played a key role in response to odors in H. oblita. Our findings may promote further understanding of the mechanisms underlying OBP dimer formation and the role of OBP dimers in odor perception and discrimination.

Key site residues of pheromone-binding protein 1 involved in interacting with sex pheromone components of Helicoverpa armigera.

Pheromone binding proteins (PBPs) are widely distributed in insect antennae, and play important roles in the perception of sex pheromones. However, the detail mechanism of interaction between PBPs and odorants remains in a black box. Here, a predicted 3D structure of PBP1 of the serious agricultural pest, Helicoverpa armigera (HarmPBP1) was constructed, and the key residues that contribute to binding with the major sex pheromone components of this pest, (Z)-11- hexadecenal (Z11-16:Ald) and (Z)-9- hexadecenal (Z9-16:Ald), were predicted by molecular docking. The results of molecular simulation suggest that hydrophobic interactions are the main linkage between HarmPBP1 and the two aldehydes, and four residues in the binding pocket (Phe12, Phe36, Trp37, and Phe119) may participate in binding with these two ligands. Then site-directed mutagenesis and fluorescence binding assays were performed, and significant decrease of the binding ability to both Z11-16:Ald and Z9-16:Ald was observed in three mutants of HarmPBP1 (F12A, W37A, and F119A). These results revealed that Phe12, Trp37, and Phe119 are the key residues of HarmPBP1 in binding with the Z11-16:Ald and Z9-16:Ald. This study provides new insights into the interactions between pheromone and PBP, and may serve as a foundation for better understanding of the pheromone recognition in moths.

Adhesion molecule CD146 and its soluble form correlate well with carotid atherosclerosis and plaque instability.

AIMS: Intraplaque neovascularization and foam cell infiltration contribute to the development of unstable plaque, leading to thromboembolism and stroke. Cell adhesion molecules (CAMs) have been reported to be involved in the progression of atherosclerosis and plaque vulnerability. The aim of this study was to assess the association of adhesion molecule CD146 with carotid plaque instability. METHODS: We collected forty atherosclerotic plaques from 40 patients undergoing carotid endarterectomy. The clinical information of each patient was obtained, and the plaque morphology and characteristics were examined by the ultrasound. The CD146 expressions of the plaques were graded by using semiquantitative scales. The serum level of soluble form of CD146 was detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: CD146 expression was mainly on the intraplaque blood vessels and infiltrated macrophages. The CD146 expression was strongly correlated with the matrix metalloproteinase-9(MMP-9)expressions (P < 0.001) in the plaques. Soluble CD146 (sCD146) was also elevated in patients with atherosclerotic plaques. There was significant correlation between the increased CD146 expression and sCD146 level (P = 0.0057). sCD146 correlated well with serum MMP-9 (P < 0.0044), IL-6 (P = 0.0044) and high sensitivity C-reactive protein (hsCRP) (P = 0.005). CONCLUSIONS: Adhesion molecules CD146 and its soluble form strongly correlated with the development of inflammation of atherosclerosis and plaque instability. CD146 may be a promising biomarker for monitoring the development and instability of atherosclerotic plaque in patients with carotid diseases.

Density functional theoretical study of a series of binary azides M(N3)n (n = 3, 4).

Geometrical structures of a series of binary azides M(N3)n (M = elements in groups 3 and 13 (n = 3) and in groups 4 and 14 (n = 4)) were investigated at the B3LYP/6-311+G level of theory. Our calculations found that binary group 3 triazides M(N3)3 (M = Sc, Y, La) and binary group 4 tetraazides M(N3)4 (M = Ti, Zr, Hf) turn out to be stable with all frequencies real having a similar linear M-N-NN structural feature, as previously reported for M(N3)4 (M = Ti, Zr, Hf). However, binary azides of group 13 M(N3)3 (M = B, Al, Ga, In, Tl) and group 14 elements M(N3)4 (C, Si, Ge, Sn, Pb) with bent M-N-NN bond angles differ obviously from binary group 3 and 4 azides in geometrical structure. These facts are mainly explained by the difference in electronic density overlap between the central atom and the alpha-N atoms of the azido groups. Two lone-pair electrons on the sp hybridization alpha-N atoms in the binary group 3 and 4 azides donate electron density into two empty d orbitals of the central transition metal atom and a pair of valence bonding electrons, resulting in the alpha-N atoms acting as a tridentate ligand. The sp2 hybridization alpha-N atoms of the binary group 13 and 14 azides only give one valence electron to form one valence bonding electron pair acting virtually as monodentate donors.