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Objective To investigate the morphological and proteomic differences in exosomes (EXOs) during the storage of leukocyte-free apheresis platelets (LFA-Plt), evaluate the quality of platelets in storage and predict the function of EXOs at different storage periods. Methods EXOs were isolated by ultracentrifugation, then the morphological observation was performed by electron microscope. Particle size analysis and WB protein index detection were performed. 4D Label-free quantitative proteomics technology was used to perform quantitative and bioinformatics analysis on identified proteins. Protein differential analysis on the LFA- Plt EXO between group day 3 and day 5 was performed, and GO function and KEGG pathway enrichment analysis on differential proteins was conducted. Results Cup shaped, CD9/TSG101 enriched and Calnexin (-) EXO was successfully obtained. The particle size (nm) of LFA-Plt EXO for day 3 and day 5 were (82.2±19.6) and (83.4±19.4) respectively, and the protein concentration(μ g/uL) were (0.55±0.13) and (0.51±0.08) respectively, with no statistically significant difference between two groups (P>0.05). 1 504 proteins were identified in all samples. GO functional enrichment analysis showed that the LFA-Plt EXO proteins were mainly concentrated in the cell membrane, extracellular domain and proteasome core complex, and were related to the binding ability of proteins, ATP, calcium ions and GTP, and mainly participated in processes such as redox, protein hydrolysis and signal transduction. KEGG functional annotation showed that the EXO proteins mainly participated in material transportation and catabolism, genetic information processing, and were closely related to human tumors and viral bacterial infections, affecting the metabolism of human immune system. Compared with day 3, day 5 EXO showed significant up-regulation in 16 proteins. The GO enrichment analysis showed that 16 upregulated proteins were mainly associated with adenosine homocysteine activity and 6-phosphofructose kinase activity, and were mainly involved in the metabolism of organic nitrogen compound. KEGG enrichment pathway analysis showed that the most important function of upregulated proteins was participating in signaling pathway for oocyte maturation mediated by progesterone. Conclusion Under the preparation and storage conditions of LFA-Plt in our center, platelet quality can be relatively stable. The functions of EXO proteins varies with different storage periods, which may affect the effectiveness of platelet transfusion.

Ammonium iodides are intensively investigated as effective interfacial passivation agents in perovskite solar cells (PSCs) while facing a major challenge of their high reactivity with perovskites that undermines the operational stability of the PSCs. Exemplified by involving rationally designed/selected peptide into the widely adopted phenethylammonium iodide (PEAI), the present work demonstrates that the bespoke peptide‐PEAI can effectively inhibit the deprotonation of ammonium iodides and thus hinder the formation of 2D perovskite, facilitating the stability enhancement in perovskite films by multi hydrogen bonding. The additional lone pair electrons provided by peptide molecules can also enhance the passivation ability of the modified layer. Attributed to the stable co‐modifier peptide‐PEAI, the small‐area FAPbI3‐based PSCs yield a high efficiency of 25.02% with robust light and thermal stabilities. Moreover, the peptide‐PEAI‐based minimodules with an efficiency of 19.06% for a total area of 36 cm2 manifested the great application potential of this co‐modification strategy in the perovskite photovoltaics. [ABSTRACT FROM AUTHOR]

Ripretinib, a broad‐spectrum inhibitor of the KIT and PDGFRA receptor tyrosine kinases, is designated as a fourth‐line treatment for gastrointestinal stromal tumor (GIST). It is tailored for patients resistant to imatinib, sunitinib, and regorafenib. As its increasing use, instances of resistance to ripretinib are becoming more frequent. Unfortunately, there are currently no scientifically mature treatment options available for patients resistant to ripretinib. Posttranslational modifications (PTMs) such as ubiquitination, in conjunction with its interplay with other modifications, play a collective role in regulating tumor initiation and progression. However, the specific association between ubiquitination and ripretinib resistance is not reported. Through proteome–ubiquitinome sequencing, increased levels of the USP5 protein and decreased ubiquitination in ripretinib‐resistant GISTs are detected. Subsequent examination of the mass spectrometry findings validated the interaction through which TRIM21 governs USP5 expression via ubiquitination, and USP5 regulates MDH2 expression through deubiquitination, consequently fostering ripretinib resistance in GIST. Moreover, ZDHHC18 can palmitoylate MDH2, preventing its ubiquitination and further increasing its protein stability. The research underscores the correlation between posttranslational modifications, specifically ubiquitination, and drug resistance, emphasizing the potential of targeting the USP5‐MDH2 axis to counteract ripretinib resistance in GIST. [ABSTRACT FROM AUTHOR]

The innate immune system is the body's natural defense system, which recognizes a wide range of microbial molecules (such as bacterial DNA and RNA) and abnormal molecules within cells (such as misplaced DNA, self-antigens) to play its role. DNA released into the cytoplasm activates the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway to initiate an immune response. Ischemia–reperfusion injury (IRI) after acute myocardial infarction refers to the phenomenon where myocardial tissue suffers further damage upon the restoration of blood flow. This issue is a significant clinical problem in the treatment of myocardial infarction, as it can diminish the effectiveness of reperfusion therapy and lead to further deterioration of cardiac function. Studies have found that the cGAS-STING signaling pathway is closely related to this phenomenon. Therefore, this review aims to describe the role of the cGAS-STING signaling pathway in ischemia–reperfusion injury after myocardial infarction and summarize the current development status of cGAS-STING pathway inhibitors and the application of nanomaterials to further elucidate the potential of this pathway as a therapeutic target. [ABSTRACT FROM AUTHOR]

This paper focuses on the finite-time tracking control problem of shield tunneling systems in the presence of constraints on the states and control input. By modeling the system based on the LuGre friction model, an effective method of tracking control in finite time is designed to overcome these actual constraints at the same time. First, the constraint on the system state is transformed into a symmetric constraint on the tracking error, and the constraint on control input is handled by designing an auxiliary differential equation. Then, radial basis function (RBF) neural networks are introduced to approximate the uncertainties. Next, using an adaptive finite-time backstepping method and choosing a logarithmic barrier Lyapunov function (BLF), a finite-time controller is designed to realize the finite-time stability of the closed-loop system. Finally, a simulation example is given to verify the correctness and validity of the theoretical results. [ABSTRACT FROM AUTHOR]

Previous research highlighted the involvement of the cannabinoid CB1 receptor in regulating the physiology of hepatocytes and hepatic stellate cells. The inhibition of the CB1 receptor via peripherally restricted CB1 receptor inverse agonist JD5037 has shown promise in inhibiting liver fibrosis in mice treated with CCl4. However, its efficacy in phospholipid transporter-deficiency-induced liver fibrosis remains uncertain. In this study, we investigated the effectiveness of JD5037 in Mdr2−/− mice. Mdr2 (Abcb4) is a mouse ortholog of the human MDR3 (ABCB4) gene encoding for the canalicular phospholipid transporter. Genetic disruption of the Mdr2 gene in mice causes a complete absence of phosphatidylcholine from bile, leading to liver injury and fibrosis. Mdr2−/− mice develop spontaneous fibrosis during growth. JD5037 was orally administered to the mice for four weeks starting at eight weeks of age. Liver fibrosis, bile acid levels, inflammation, and injury were assessed. Additionally, JD5037 was administered to three-week-old mice to evaluate its preventive effects on fibrosis development. Our findings corroborate previous observations regarding global CB1 receptor inverse agonists. Four weeks of JD5037 treatment in eight-week-old Mdr2−/− mice with established fibrosis led to reduced body weight gains. However, contrary to expectations, JD5037 significantly exacerbated liver injury, evidenced by elevated serum ALT and ALP levels and exacerbated liver histology. Notably, JD5037-treated Mdr2−/− mice exhibited significantly heightened serum bile acid levels. Furthermore, JD5037 treatment intensified liver fibrosis, increased fibrogenic gene expression, stimulated ductular reaction, and upregulated hepatic proinflammatory cytokines. Importantly, JD5037 failed to prevent liver fibrosis formation in three-week-old Mdr2−/− mice. In summary, our study reveals the exacerbating effect of JD5037 on liver fibrosis in genetically MDR2-deficient mice. These findings underscore the need for caution in the use of peripherally restricted CB1R inverse agonists for liver fibrosis treatment, particularly in cases of dysfunctional hepatic phospholipid transporter. [ABSTRACT FROM AUTHOR]

Genome editing, which allows for the artificial modification of genes in organisms, has received significant attention in recent years. Currently, various genome editing tools have been developed based on different principles. ZFNs (zinc finger nucleases), TALENs (transcription activator-like effector nucleases), and CRISPR-Cas9 are the three genome editing technologies that are predominantly utilized. This article reviews the principles and characteristics of these three genome editing tools and summarizes the advantages and disadvantages of each of them accordingly. Genome editing is also playing an increasingly important role in yeast, opening up unforeseen applications for human beings. Tup1, a crucial transcriptional corepressor factor in yeast, is associated with multiple metabolic pathways and plays a key role in gene expression regulation. Currently, our understanding of how Tup1 regulates gene transcription remains limited. To gain a better understanding of the detailed mechanisms of Tup1, genome editing can be utilized to deepen our knowledge of its function. Therefore, this article proposes a method that utilizes CRISPR-Cas9 to construct mutant variants of Tup1 in yeast. The main process of this method involves introducing plasmids containing artificially designed sgRNA and Cas9 protein sequences into yeast cells, allowing them to express and edit the yeast Tup1 sequence, ultimately generating yeast Tup1 mutants. This method allows for the efficient construction of engineered Tup1 mutants, facilitating further research on Tup1.

Long non-coding RNAs (lncRNAs) serve as vital candidates to mediate cancer risk. Here, we aimed to identify the risk single-nucleotide polymorphisms (SNPs)-induced lncRNAs and to investigate their roles in gastric cancer (GC) development. Through integrating the differential expression analysis of lncRNAs in GC tissues and expression quantitative trait loci analysis in normal stomach tissues and GC tissues, as well as genetic association analysis based on GC genome-wide association studies and an independent validation study, we identified four lncRNA-related SNPs consistently associated with GC risk, including SNHG7 [odds ratio (OR) = 1.16, 95% confidence interval (CI): 1.09–1.23], NRAV (OR = 1.11, 95% CI: 1.05–1.17), LINC01082 (OR = 1.16, 95% CI: 1.08–1.22) and FENDRR (OR = 1.16, 95% CI: 1.07–1.25). We further found that a functional SNP rs6489786 at 12q24.31 increases binding of MEOX1 or MEOX2 at a distal enhancer and results in up-regulation of NRAV. The functional assays revealed that NRAV accelerates GC cell proliferation while inhibits GC cell apoptosis. Mechanistically, NRAV decreases the expression of key subunit genes through the electron transport chain, thereby driving the glucose metabolism reprogramming from aerobic respiration to glycolysis. These findings suggest that regulating lncRNA expression is a crucial mechanism for risk-associated variants in promoting GC development. [ABSTRACT FROM AUTHOR]