Exploring the potential molecular intersection of stroke and major depression disorder.

Stroke and major depression disorder are common neurological diseases, and a large number of clinical studies have shown that there is a close relationship between the two diseases, but whether the two diseases are linked at the genetic level needs to be further explored. The purpose of this study was to explore the comorbidity mechanism of stroke and major depression by using bioinformatics technology and animal experiments. From the GEO database, we gathered transcriptome data of stroke and depression mice (GSE104036, GSE131712, GSE81672, and GSE146845) and identified comorbid gene set through edgR and WGCNA analyses. Further analysis revealed that these genes were enriched in pathways associated with cell death. Programmed cell death gene sets (PCDGs) are generated from genes related to apoptosis, necroptosis, pyroptosis and autophagy. The intersection of PCDGs and comorbid gene set resulted in two hub genes, Mlkl and Nlrp3. Single-cell sequencing analysis indicated that Mlkl and Nlrp3 are mainly influential on endothelial cells and microglia, suggesting that the impairment of these two cell types may be a factor in the relationship between stroke and major depression. This was experimentally confirmed by RT-PCR and immunofluorescence staining. Our research revealed that two specific genes, namely, Mlkl and Nlrp3, play crucial roles in the complex mechanism that links stroke and major depression. Additionally, we have predicted six possible therapeutic agents and the outcomes of docking simulations of target proteins and drug molecules.

A novel capsid-XL32-derived adeno-associated virus serotype prompts retinal tropism and ameliorates choroidal neovascularization.

Gene therapy has been adapted, from the laboratory to the clinic, to treat retinopathies. In contrast to subretinal route, intravitreal delivery of AAV vectors displays the advantage of bypassing surgical injuries, but the viral particles are more prone to be nullified by the host neutralizing factors. To minimize such suppression of therapeutic effect, especially in terms of AAV2 and its derivatives, we introduced three serine-to-glycine mutations, based on the phosphorylation sites identified by mass spectrum analysis, to the XL32 capsid to generate a novel serotype named AAVYC5. Via intravitreal administration, AAVYC5 was transduced more effectively into multiple retinal layers compared with AAV2 and XL32. AAVYC5 also enabled successful delivery of anti-angiogenic molecules to rescue laser-induced choroidal neovascularization and astrogliosis in mice and non-human primates. Furthermore, we detected fewer neutralizing antibodies and binding IgG in human sera against AAVYC5 than those specific for AAV2 and XL32. Our results thus implicate this capsid-optimized AAVYC5 as a promising vector suitable for a wide population, particularly those with undesirable AAV2 seroreactivity.

Thioredoxin1 Binding Metastasis-Associated Lung Adenocarcinoma Transcript 1 Attenuates Inflammation and Apoptosis after Intracerebral Hemorrhage.

Post-transcriptional regulation and RNA-binding proteins (RBPs) play vital roles in the occurrence of secondary injury after intracerebral hemorrhage (ICH). Therefore, we identified RBPs distinctively expressed after ICH by screening and determined thioredoxin1 (Txn1) as one of the most distinctive RBPs. We employed an ICH model and in vitro experiments to investigate the role of Txn1 in ICH. Firstly, we found that Txn1 was mainly expressed in microglia and neurons in the central nervous system, and its expression was significantly reduced in perihematomal tissue. Additionally, adeno-associated virus (AAV) carrying Txn1 was injected into the ICH rat model. Our results showed that overexpression of Txn1 reduced secondary injury and improved outcome in the ICH rat model. Moreover, to understand the therapeutic mechanism of Txn1 after ICH, we performed RNA immunoprecipitation combined with high-throughput sequencing. The results showed that Txn1 binds to inflammation- and apoptosis-related mRNAs and affects gene expression through RNA splicing and translation. Finally, RNA pull-down assays and in vitro experiments confirmed that Txn1 binds to metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), leading to reduced inflammation and apoptosis. Our study suggests that Txn1 is a potential therapeutic target for alleviating ICH-induced brain injury.

Single-cell RNA sequencing of peripheral blood reveals that monocytes with high cathepsin S expression aggravate cerebral ischemia-reperfusion injury.

BACKGROUND: Stroke is a major cause of morbidity and mortality worldwide. After cerebral ischemia, peripheral immune cells infiltrate the brain and elicit an inflammatory response. However, it is not clear when and how these peripheral immune cells affect the central inflammatory response, and whether interventions that target these processes can alleviate ischemia-reperfusion (I/R) injury. METHODS: Single-cell transcriptomic sequencing and bioinformatics analysis were performed on peripheral blood of mice at different times after I/R to analyze the key molecule of cell subsets. Then, the expression pattern of this molecule was determined through various biological experiments, including quantitative RT-PCR, western blot, ELISA, and in situ hybridization. Next, the function of this molecule was assessed using knockout mice and the corresponding inhibitor. RESULTS: Single-cell transcriptomic sequencing revealed that peripheral monocyte subpopulations increased significantly after I/R. Cathepsin S (Ctss)was identified as a key molecule regulating monocyte activation by pseudotime trajectory analysis and gene function analysis. Next, Cathepsin S was confirmed to be expressed in monocytes with the highest expression level 3 days after I/R. Infarct size (p < 0.05), neurological function scores (p < 0.05), and apoptosis and vascular leakage rates were significantly reduced after Ctss knockout. In addition, CTSS destroyed the blood-brain barrier (BBB) by binding to junctional adhesion molecule (JAM) family proteins to cause their degradation. CONCLUSIONS: Cathepsin S inhibition attenuated cerebral I/R injury; therefore, cathepsin S can be used as a novel target for drug intervention after stroke.

New Hydrophobic Organic Coating Based Triboelectric Nanogenerator for Efficient and Stable Hydropower Harvesting.

Liquid-solid triboelectrification technology provides a new way to collect hydropower, while the high cost, complexity, and easily damaged microstructures of the triboelectric nanogenerator electrode materials highly limit their practical applications. In this study, a new type of organic coating triboelectric nanogenerator is fabricated using acrylate resin as the friction layer material. To further improve the solid-liquid triboelectrification performance and the hydrophobicity of the coating, fluorine-containing materials were added to the acrylic resin. As a non-microstructure-dependent film, its preparation process is simple and large area prepared, which can be achieved by modifying some commonly used anticorrosion and antifouling coatings in engineering. This packaged organic coating triboelectric nanogenerator provides good stability and high-output performance, which can easily light several commercial light-emitting diodes (LEDs) on a model ship by collecting the wave energy during the voyage. This new type of triboelectric nanogenerator based on the coating material has the advantages of simple process, low cost, and large-area preparation, which combines the performance of the coating itself with the power generation function, and have potential promising practical applications in ocean energy collection and utilization, self-powered sensing, and other fields.

New Coating TENG with Antiwear and Healing Functions for Energy Harvesting.

In view of the limitations of practical applications of current triboelectric nanogenerators (TENGs), a new type of coating TENGs with antiwear and healing properties have been fabricated to collect the large-scale dissipative energy in the environment. To enhance the triboelectrification performance of the coating TENG, mesoporous silica filled with perfluorooctylethanol is added to the acrylate resin material, in addition to improving the antiwear properties of the frictional coating. The result shows that when the mesoporous silica is used as a carrier and perfluorooctylethanol is loaded, the short-circuit current (Isc) and output voltage (Vo) of the coating TENG reach as high as 10 µA and 220 V, respectively, which are 4-5 times higher than those of pure acrylate. More importantly, the coefficient of friction of the new coating decreases from 0.11 to 0.04 with the wear volume reducing by approximately 89%, indicating a better friction-reducing property of the coating for long-term working. As a new coating material based on the traditional acrylic resin, it can be widely sprayed onto various walls, metals, and hulls as protection coating as well as power-generation coating. Interestingly, when the coating is damaged due to long-term aging or external mechanical forces, it can restore its triboelectric performance by encapsulating the repair agent within the pore structure of silica. Owing to the large-area fabrication, low cost, high output performance, and antiwear properties, the new coating TENGs have promising potential for practical applications in energy-harvesting, self-energy supplies, and self-powered sensors.

One-Step Regioselective Synthesis of Benzofurans from Phenols and α-Haloketones.

Reported here is the direct synthesis of naphthofurans and benzofurans from readily available phenols and α-haloketones promoted by titanium tetrachloride which combines Friedel-Crafts-like alkylation and intramolecular cyclodehydration into one step. This simple protocol allows for the formation of a variety of high value naphthofurans and benzofurans within which a series of cyclic and acyclic groups are readily incorporated. This process demonstrates the advantages of high levels of regioselectivity, broad substrate scope, and moderate to excellent yields.