Nanotheranostic Trojan Horse for visualization and photo-immunotherapy of multidrug-resistant bacterial infection.

Effective diagnosis and therapy for bacterial infections, especially those caused by multidrug-resistant (MDR) species, greatly challenge current antimicrobial stewardship. Monocytes, which can chemotactically migrate from the blood to infection site and elicit a robust infection infiltration, provide a golden opportunity for bacterial theranostics. Here, a nano-Trojan Horse was facilely engineered using mannose-functionalized manganese-eumelanin coordination nanoparticles (denoted as MP-MENP) for precise two-step localization and potent photothermal-immunotherapy of MDR bacterial infection. Taking advantage of the selective recognition between mannose and inflammation-associated monocytes, the MP-MENP could be passively piggybacked to infection site by circulating monocytes, and also actively target infiltrated monocytes that are already accumulated in infection microenvironment. Such dual-pronged targeting enabled an efficient imaging diagnosis of bacterial infection. Upon laser irradiation, the MP-MENP robustly produced local hyperemia to ablate bacteria, both extracellularly and intracellularly. Further combined with photothermal therapy-induced immunogenic cell death and MP-MENP-mediated macrophage reprogramming, the immunosuppressive infection microenvironment was significantly relieved, allowing an enhanced antibacterial immunity. Collectively, the proposed nanotheranostic Trojan Horse, which integrates dual-pronged targeting, precise imaging diagnosis, and high-performance photothermal immunotherapy, promises a new way for complete eradication of MDR bacterial infection.

ZnO Additive Boosts Charging Speed and Cycling Stability of Electrolytic Zn-Mn Batteries.

Electrolytic aqueous zinc-manganese (Zn-Mn) batteries have the advantage of high discharge voltage and high capacity due to two-electron reactions. However, the pitfall of electrolytic Zn-Mn batteries is the sluggish deposition reaction kinetics of manganese oxide during the charge process and short cycle life. We show that, incorporating ZnO electrolyte additive can form a neutral and highly viscous gel-like electrolyte and render a new form of electrolytic Zn-Mn batteries with significantly improved charging capabilities. Specifically, the ZnO gel-like electrolyte activates the zinc sulfate hydroxide hydrate assisted Mn2+ deposition reaction and induces phase and structure change of the deposited manganese oxide (Zn2Mn3O8·H2O nanorods array), resulting in a significant enhancement of the charge capability and discharge efficiency. The charge capacity increases to 2.5 mAh cm-2 after 1 h constant-voltage charging at 2.0 V vs. Zn/Zn2+, and the capacity can retain for up to 2000 cycles with negligible attenuation. This research lays the foundation for the advancement of electrolytic Zn-Mn batteries with enhanced charging capability.

Seed the Views: Hierarchical Semantic Alignment for Contrastive Representation Learning.

Self-supervised learning based on instance discrimination has shown remarkable progress. In particular, contrastive learning, which regards each image as well as its augmentations as an individual class and tries to distinguish them from all other images, has been verified effective for representation learning. However, conventional contrastive learning does not model the relation between semantically similar samples explicitly. In this paper, we propose a general module that considers the semantic similarity among images. This is achieved by expanding the views generated by a single image to Cross-Samples and Multi-Levels, and modeling the invariance to semantically similar images in a hierarchical way. Specifically, the cross-samples are generated by a data mixing operation, which is constrained within samples that are semantically similar, while the multi-level samples are expanded at the intermediate layers of a network. In this way, the contrastive loss is extended to allow for multiple positives per anchor, and explicitly pulling semantically similar images together at different layers of the network. Our method, termed as CSML, has the ability to integrate multi-level representations across samples in a robust way. CSML is applicable to current contrastive based methods and consistently improves the performance. Notably, using MoCo v2 as an instantiation, CSML achieves 76.6% top-1 accuracy with linear evaluation using ResNet-50 as backbone, 66.7% and 75.1% top-1 accuracy with only 1% and 10% labels, respectively. All these numbers set the new state-of-the-art. The code is available at https://github.com/haohang96/CSML.

Preparation of a Sunitinib loaded microemulsion for ocular delivery and evaluation for the treatment of corneal neovascularization in vitro and in vivo.

Background: Corneal neovascularization (CNV) is a pathological condition that can disrupt corneal transparency, thus harming visual acuity. However, there is no effective drug to treat CNV. Sunitinib (STB), a small-molecule multiple receptor tyrosine kinase inhibitor, was shown to have an effect on CNV. The purpose of this study was to develop an STB microemulsion (STB-ME) eye drop to inhibit CNV by topical application. Methods: We successfully prepared an STB-ME by the phase inversion emulsification method, and the physicochemical properties of STB-MEs were investigated. The short-term storage stability, cytotoxicity to human corneal epithelial cells, drug release, ocular irritation, ocular pharmacokinetics and the inhibitory effect on CNV were evaluated in vitro and in vivo. Results: The optimal formulation of STB-ME is composed of oleic acid, CRH 40, Transcutol P, water and sodium hyaluronate (SH). It is a uniform spherical particle with a mean droplet size of 18.74 ± 0.09 nm and a polydispersity index of 0.196 ± 0.004. In the in vitro drug release results, STB-ME showed sustained release and was best fitted by a Korsmeyer-Peppas model (R 2 = 0.9960). The results of the ocular pharmacokinetics in rabbits showed that the formulation containing SH increased the bioavailability in the cornea (2.47-fold) and conjunctiva (2.14-fold). STB-ME (0.05% and 0.1%), administered topically, suppressed alkali burn-induced CNV in mice more effectively than saline, and high-dose (0.1%) STB-ME had similar efficacy to dexamethasone (0.025%). Conclusion: This study provides a promising formulation of STB-ME for the inhibition of CNV by topical administration, which has the excellent characteristics of effectiveness, sustained release and high ocular bioavailability.

K-Shot Contrastive Learning of Visual Features With Multiple Instance Augmentations.

In this paper, we propose the K-Shot Contrastive Learning (KSCL) of visual features by applying multiple augmentations to investigate the sample variations within individual instances. It aims to combine the advantages of inter-instance discrimination by learning discriminative features to distinguish between different instances, as well as intra-instance variations by matching queries against the variants of augmented samples over instances. Particularly, for each instance, it constructs an instance subspace to model the configuration of how the significant factors of variations in K-shot augmentations can be combined to form the variants of augmentations. Given a query, the most relevant variant of instances is then retrieved by projecting the query onto their subspaces to predict the positive instance class. This generalizes the existing contrastive learning that can be viewed as a special one-shot case. An eigenvalue decomposition is performed to configure instance subspaces, and the embedding network can be trained end-to-end through the differentiable subspace configuration. Experiment results demonstrate the proposed K-shot contrastive learning achieves superior performances to the state-of-the-art unsupervised methods.

Preparation and in vitro and in vivo evaluation of an isoliquiritigenin-loaded ophthalmic nanoemulsion for the treatment of corneal neovascularization.

Isoliquiritigenin (ISL), as a natural flavonoid, has been proven to have therapeutic potential for corneal neovascularization (CNV) treatment; however, its therapeutic use is restricted due to its poor aqueous solubility and limited bioavailability. To overcome these limitations, a novel ISL-loaded nanoemulsion (ISL-NE) was designed for inhibiting CNV in this study. ISL-NE formulation was composed of propylene glycol dicaprylate (PGD), Cremophor® EL (EL35), polyethylene glycol 400 (PEG 400) and adding water with sodium hyaluronate, its particle size was 34.56 ± 0.80 nm with a low polydispersity index of less than 0.05, which suggested a narrow size distribution. The results demonstrated that ISL-NE released higher and permeated more drug than ISL suspension (ISL-Susp) in in vitro drug release and ex vivo corneal permeation study. ISL-NE showed no cytotoxicity in human corneal epithelial cells toxicity study, which was consistent with the result of ocular irritation study in rabbit eyes. ISL-NE had bioavailability 5.76-fold, 7.80-fold and 2.13-fold higher than ISL-Sups in tears, cornea and aqueous humor after a single dose of ISL-NE, respectively. Furthermore, the efficacy of ISL-NE treatment (0.2% ISL) was comparable to that of dexamethasone treatment (0.025%) in the inhibition of CNV in mice model. Enzyme-linked immunosorbent assay (ELISA) showed that the expressions of corneal vascular endothelial growth factor (VEGF-A) and matrix metalloproteinase (MMP-2) were decreased. In conclusion, the ISL-NE demonstrated excellent physicochemical properties, good tolerance, and enhanced ocular bioavailability. It could be a promising, safe, and effective treatment for CNV.

Sorafenib-loaded nanostructured lipid carriers for topical ocular therapy of corneal neovascularization: development, in-vitro and in vivo study.

Sorafenib (SRB), a multikinase inhibitor, is effective in reducing experimental corneal neovascularization (CNV) after oral administration; however, its therapeutic use in ocular surface disorders is restricted due to poor solubility and limited bioavailability. This study aimed to develop and optimize SRB-loaded nanostructured lipid carriers (SRB-NLCs) for topical ocular delivery by a central composite design response surface methodology (CCD-RSM). It was spherical and uniform in morphology with an average particle size of 111.87 ± 0.93 nm and a narrow size distribution. The in vitro drug release from the released SRB-NLC formulation was well fitted to Korsmeyer Peppas release kinetics. The cell counting kit-8 (CCK-8) cell viability assay demonstrated that SRB-NLC was not obviously cytotoxic to human corneal epithelial cells (HCECs). An in vivo ocular irritation test showed that SRB-NLC was well tolerated by rabbit eyes. Ocular pharmacokinetics revealed 6.79-fold and 1.24-fold increase in the area under concentration-time curves (AUC0-12h) over 12 h in rabbit cornea and conjunctiva, respectively, treated with one dose of SRB-NLC compared with those treated with SRB suspension. Moreover, SRB-NLC (0.05% SRB) and dexamethasone (0.025%) similarly suppressed corneal neovascularization in mice. In conclusion, the optimized SRB-NLC formulation demonstrated excellent physicochemical properties and good tolerance, sustained release, and enhanced ocular bioavailability. It is safe and potentially effective for the treatment of corneal neovascularization.

Baicalin suppresses glaucoma pathogenesis by regulating the PI3K/AKT signaling in vitro and in vivo.

Glaucoma, characterized with progressive degeneration of retinal ganglion cells (RGCs), is the second frequently leading cause of sight loss in the word after cataract. Baicalin plays a protective role in age-related macular degeneration, retinopathy of prematurity, branch retinal vein occlusion, and ischemia-induced neurodegeneration in the retina. The present study aimed to investigate the role of baicalin in glaucoma. RGCs were stimulated with N-methyl-D-aspartate (NMDA) to mimic the in vitro model of glaucoma. A mouse model of glaucoma induced by chronic elevated intraocular pressure was also established. The apoptosis, oxidative stress, and autophagy of RGCs were detected by flow cytometry analysis, 2,7-dichlorodihydrofluorescein diacetate staining, and Western blotting, respectively. Retinal pathological changes were exhibited by hemotoxylin and eosin staining. Baicalin restrained the NMDA-induced cell apoptosis, autophagy, and oxidative stress of RGCs by activating the PI3K/AKT signaling in vitro. The elevated intraocular pressure-induced pathological changes in retinas of glaucoma mice were attenuated by baicalin. Moreover, the number of RGCs was significantly decreased in glaucoma mice, and then increased by baicalin treatment. Baicalin also inhibited autophagy and activated PI3K/AKT signaling in vivo. In conclusion, baicalin suppresses glaucoma pathogenesis by regulating the PI3K/AKT signaling in vitro and in vivo.