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Simple Summary: This study investigates the potential of small extracellular vesicles (sEVs) as vehicles for delivering therapeutic agents, with a focus on the p53 tumor suppressor gene. Fusion with CD63 or ARRDC1 was found to facilitate the overexpression and proper localization of p53 and significantly increase the yield and loading efficiency of sEVs with p53 mRNA and proteins. Moreover, the functional assessment of these engineered sEVs on H1299 cells demonstrated an enhanced anti-tumor effect, particularly with ARP-sEVs, suggesting a superior inhibition of cell proliferation and promotion of apoptosis. These results are expected to be informative in the application of EV therapy. Small extracellular vesicles (sEVs) have emerged as promising therapeutic agents and drug delivery vehicles. Targeted modification of sEVs and their contents using genetic modification strategies is one of the most popular methods. This study investigated the effects of p53 fusion with arrestin domain-containing protein 1 (ARRDC1) and CD63 on the generation of sEVs, p53 loading efficiency, and therapeutic efficacy. Overexpression of either ARRDC1–p53 (ARP) or CD63–p53 (CDP) significantly elevated p53 mRNA and protein levels. The incorporation of ARRDC1 and CD63 significantly enhanced HEK293T-sEV biogenesis, evidenced by significant increases in sEV-associated proteins TSG101 and LAMP1, resulting in a boost in sEV production. Importantly, fusion with ARRDC1 or CD63 substantially increased the efficiency of loading both p53 fusion proteins and its mRNA into sEVs. sEVs equipped with ARP or CDP significantly enhanced the enrichment of p53 fusion proteins and mRNA in p53-null H1299 cells, resulting in a marked increase in apoptosis and a reduction in cell proliferation, with ARP-sEVs demonstrating greater effectiveness than CDP-sEVs. These findings underscore the enhanced functionality of ARRDC1- and CD63-modified sEVs, emphasizing the potential of genetic modifications in sEV-based therapies for targeted cancer treatment. [ABSTRACT FROM AUTHOR]

Nonagenarians with acute ischemic stroke tend to have a higher mortality and morbidity than younger patients. Tirofiban is a glycoprotein IIb/IIIa antagonist that has a therapeutic potential for ischemic stroke. Here, we provide a case report of a 93-year-old male patient with acute ischemic stroke. He presented with right-sided hemiparesis for 2 hours (National Institute of Health Stroke Scale, NIHSS = 23). Immediate treatment with endovascular tirofiban infusion achieved an improvement of intracranial blood flow and a progressively decreased NIHSS one day after admission (NIHSS = 16) and then seven days after admission (NIHSS = 7). After a follow-up of 90 days, the modified ranking score was 2. This case report suggests that endovascular application with tirofiban may be a favorable option for treating nonagenarians presenting with acute ischemic stroke and warrants further study.

Cancer stands as a serious malady, posing substantial risks to human well‐being and survival. This underscores the paramount necessity to explore and investigate novel antitumor medications. Nitrogen‐containing compounds, especially those derived from natural sources, form a highly significant category of antitumor agents. Among these, antitumor agents with six‐membered aromatic nitrogen heterocycles have consistently attracted the attention of chemists and pharmacologists. Accordingly, we present a comprehensive summary of synthetic strategies and clinical implications of these compounds in this review. This entails an in‐depth analysis of synthesis pathways for pyridine, quinoline, pyrimidine, and quinazoline. Additionally, we explore the historical progression, targets, mechanisms of action, and clinical effectiveness of small molecule inhibitors possessing these structural features. [ABSTRACT FROM AUTHOR]

Molecular aggregation affects the electronic interactions between molecules and has emerged as a powerful tool in material science. Aggregate effect finds wide applications in the research of new physical phenomena; however, its value for chemical reaction development has been far less explored. Herein, we report the development of aggregation‐enabled alkene insertion into carbon–halogen bonds. The spontaneous cleavage of C–X (X = Cl, Br, or I) bonds generates an intimate ion pair, which can be quickly captured by alkenes in an aggregated state. Additional catalysts or promoters are not necessary under such circumstances, and solvent quenching experiments indicate that the aggregated state is critical for achieving such sequences. The ionic insertion mode is supported by mechanistic studies, density functional theory calculations, and symmetry‐adapted perturbation theory analysis. Results also show that the non‐aggregated state may quench the transition state and terminate the insertion process. [ABSTRACT FROM AUTHOR]

A convenient method for synthesizing aryl-containing trisubstituted alkenes through direct alkylation of alkenes was successfully achieved under solvent-free and catalyst-free conditions. The absence of solvents was found to be crucial in initiating this sequence. Moreover, this protocol stands out due to its minimal waste production and straightforward operation. The radical capture experiment provided evidence for an ionic reaction mechanism. [ABSTRACT FROM AUTHOR]

A HKUST-1 derivative composite based on LDH was synthesized to efficiently adsorb iodide anions in aqueous solutions. Specifically, Cu/Al-LDH, HKUST-1, HKUST-1@Cu/Al-LDH, Cu/Al-CLDH, Cu-C and Cu2O@Cu/Al-CLDH were synthesized and characterized. HKUST-1@Cu/Al-LDH kept the desirable characteristics of both Cu/Al-LDH and HKUST-1. Cu2O@Cu/Al-CLDH maintained the morphology of HKUST-1@Cu/Al-LDH, with its iodine anions absorption mechanism being chemical adsorption. Cu2O@Cu/Al-CLDH exhibited a significantly higher adsorption capacity than previously reported Cu-based adsorbents, with an adsorption capacity of 240.7 mg g−1 at pH 3, taking about 240 min to reach adsorption equilibrium. Thus, Cu2O@Cu/Al-CLDH is a promising adsorbent for removing iodide anions from aqueous solutions. [ABSTRACT FROM AUTHOR]

Radioactive iodine is one of the inevitable by-products of nuclear energy application. However, it is a great threat to public health and the adsorbent needs to be adopted for removing the radioactive iodine. The iodine adsorbent needs to have some advantages, such as simple preparation method, low cost, high absorption capacity, and recyclable utilization. In order to meet the above requirements, the etched material of institute Lavoisier 101 (MIL-101) was prepared to absorb the gaseous iodine. After the MIL-101 is etched, the iodine adsorption performance has been greatly improved. The iodine adsorption experiment of etched MIL-101 with different etching time (1 h, 3 h, 4 h, and 6 h) was completed, the results show that the optimal etching time is 4 hours and the capture capacity of the etched MIL-101 is 371 wt%, which is about 22% higher than that of original MIL-101. The experiment results of XRD, FT-IR, and XPS prove that the components and structure of etched MIL-101 are accordable with those of MIL-101. The surface roughness is introduced in this work. The pore roughness is also an important factor to the adsorption capacity, and the related research also supports this conclusion. Furthermore, after iodine is absorbed, etched MIL-101 can be treated by ethanol for iodine release, and the etched MIL-101 has satisfied recyclability within three cycles. Compared with MIL-101, etched MIL-101 not only had good reversible adsorption of iodine but also can adsorb low-concentration iodine. The etched MIL-101 has a broad application prospect in nuclear emergency response and radiation detection. [ABSTRACT FROM AUTHOR]

Ubiquilin-2 (UBQLN2) mutations lead to familial amyotrophic lateral sclerosis (FALS)/and frontotemporal dementia (FTLD) through unknown mechanisms. The combination of iPSC technology and CRISPR-mediated genome editing technology can generate an iPSC-derived motor neuron (iPSC-MN) model with disease-relevant mutations, which results in increased opportunities for disease mechanism research and drug screening. In this study, we introduced a UBQLN2-P497H mutation into a healthy control iPSC line using CRISPR/Cas9, and differentiated into MNs to study the pathology of UBQLN2-related ALS. Our in vitro MN model faithfully recapitulated specific aspects of the disease, including MN apoptosis. Under sodium arsenite (SA) treatment, we found differences in the number and the size of UBQLN2+ inclusions in UBQLN2P497H MNs and wild-type (WT) MNs. We also observed cytoplasmic TAR DNA-binding protein (TARDBP, also known as TDP-43) aggregates in UBQLN2P497H MNs, but not in WT MNs, as well as the recruitment of TDP-43 into stress granules (SGs) upon SA treatment. We noted that UBQLN2-P497H mutation induced MNs DNA damage, which is an early event in UBQLN2-ALS. Additionally, DNA damage led to an increase in compensation for FUS, whereas UBQLN2-P497H mutation impaired this function. Therefore, FUS may be involved in DNA damage repair signaling. [ABSTRACT FROM AUTHOR]

Aims: The ubiquilin‐like protein ubiquilin 2 (UBQLN2) is associated with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD). The biological function of UBQLN2 has previously been shown to be related to stress granules (SGs). In this study, we aimed to clarify the regulatory relationship between UBQLN2 and SGs. Methods: In this study, we transfected UBQLN2‐WT or UBQLN2‐P497H plasmids into cell lines (HEK293T, HeLa), and observed the process of SG dynamics by immunofluorescence. Meanwhile, immunoblot analyses the protein changes of stress granules related components. Results: We observed that ubiquilin 2 colocalizes with the SG component proteins G3BP1, TIA‐1, ATXN2, and PABPC1. In cells expressing WT UBQLN2 or P497H mutants, in the early stages of SG formation under oxidative stress, the percentage of cells with SGs and the number of SGs per cell decreased to varying degrees. Between WT and mutant, there was no significant difference in eIF2α activity after stress treatment. Interestingly, the UBQLN2 P497H mutant downregulates the level of TIA‐1. In addition, the overexpression of the UBQLN2 P497H mutant inhibited the phosphorylation of 4E‐BP1 and affected the nucleoplasmic distribution of TDP‐43. Conclusions: Ubiquilin 2 colocalizes with the SG component proteins G3BP1, TIA‐1, ATXN2, and PABPC1. It participates in regulating SG dynamics. And UBQLN2 mutation affects the assembly of stress granules by regulating TIA‐1. In addition, the overexpression of the UBQLN2 P497H mutant inhibited the phosphorylation of 4E‐BP1 and affected the nuclear and cytoplasmic distribution of TDP‐43. These provide new insights into the role of UBQLN2 in oxidative stress and the pathogenesis of ALS. [ABSTRACT FROM AUTHOR]

Aluminum alloy materials have been extensively used in long-span roof structures, especially in coastal and industrial buildings containing corrosive matters. In this study, new-type aluminum alloy bolt-sphere joints were taken as research objects and evaluated through tensile test and numerical simulation. The tensile properties and failure mechanism of the aluminum alloy bolt-sphere joints were explored. A calculation formula for the tension capacity of aluminum alloy bolt-sphere joints was proposed. The following conclusions were drawn based on the test data and the numerical simulation results: (1) the tension capacity of aluminum alloy bolt-sphere joints is controlled by the tensile properties of seal plates and the uplift-resistant properties of stainless steel bolts; (2) as the thickness of the seal plate increases, its main tensile failure modes are the combined tensile and shear failures at the ring crush part of the aluminum pipe, the tensile failure at the ring crush part of the aluminum pipe, and the tensile failure of the stainless steel bolt; (3) the tensile failure modes of the bolts are mainly the rupture failure of the bolt member and the shear failure of the thread according to the different screwing depths of the bolts into the sphere; and (4) the screwing depth of the bolt into the sphere should be more than 1.6d (d is the diameter of the stainless steel bolt); (5) the proposed calculation formula is accurate and effective. [ABSTRACT FROM AUTHOR]

This article, titled "Cover Picture: Six-Membered Aromatic Nitrogen Heterocyclic Anti-Tumor Agents: Synthesis and Applications," discusses the synthesis strategies and clinical applications of nitrogen-containing heterocyclic antitumor agents. The cover picture showcases various classes of these antitumor skeletons, including pyridine, quinoline, pyrimidine, and quinazoline. The article provides a detailed review of the small molecule inhibitors based on these scaffolds and their use in the field of anti-tumor research. The authors of the article are Jiatong Li, Ao Gu, Xiao-Mei Nong, Shuyang Zhai, Zhu-Ying Yue, Meng-Yao Li, and Yingbin Liu. [Extracted from the article]

Genipin, a natural compound derived from the fruit of Gardenia jasminoides, possesses numerous biological properties. The aim of the present study was to investigate the anticancer effects of genipin in human bladder cancer. T24 and 5637 bladder cancer cells were treated with different concentrations of genipin (0-200 μM) and tested for cell viability, colony formation, cell cycle progression and apoptosis. A xenograft model of bladder cancer was established to determine the anticancer effect of genipin in vivo. The involvement of the phosphoinositide-3 kinase (PI3K)/Akt pathway in the action of genipin was examined. Genipin treatment significantly inhibited the viability and clonogenic growth of bladder cancer cells and inhibited the growth of T24 xenograft tumors, compared with vehicle controls (P<0.05). Genipin-treated cells exhibited a cell cycle arrest at the G0/G1-phase, which was accompanied by a deregulation of numerous cell cycle regulators. Genipin-treated cells demonstrated a significant increase in the percentage of apoptotic cells, loss of mitochondrial membrane potential, Bax translocation to the mitochondria and the release of cytochrome c to the cytosol. Additionally, genipin treatment significantly (P<0.05) reduced the phosphorylation levels of PI3K and Akt in bladder cancer cells. Importantly, genipin-mediated anticancer effects were reversed by the overexpression of constitutively active Akt. In conclusion, to the best of our knowledge, the present study demonstrates for the first time the growth inhibitory effects of genipin in bladder cancer cells, and indicates its potential as a natural anticancer agent for bladder cancer. [ABSTRACT FROM AUTHOR]

The uniform dispersion of graphene oxide (GO) and strong interfacial bonding are the key factors in achieving the high mechanical strength of GO/polymer composites. It is still challenging to prepare GO/PA66 composites with uniform GO dispersion by the in situ polymerization method. In this paper, we prepare GO/PA66 salt nanocomposite by in situ precipitating PA66 salt with GO in ethanol. The GO/PA66 nanocomposite fibers are then fabricated using the as-prepared GO/PA66 salt by in situ polymerizing and melt spinning. By tuning the GO content, the tensile strength and Young's modulus of the GO/PA66 fibers are increased from 265 ± 18 to 710 ± 14 MPa (containing 0.3 wt% GO) and from 1.1 ± 0.08 to 3.8 ± 0.19 GPa (containing 0.5 wt% GO), respectively. The remarkable improvements are attributed to the uniform dispersion of GO in the GO/PA66 salt nanocomposite via ionic bonding and hydrogen bonding in the in situ precipitation process, and the covalent interfacial bonding between the GO and PA66 during the in situ polymerization process. This work sheds light on the easy fabrication of high-performance PA66-based nanocomposites. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD), the most common lethal muscular disorder, affects 1 in 5000 male births. It is caused by mutations in the X-linked dystrophin gene (DMD), and there is no effective treatment currently. Gene addition is a promising strategy owing to its universality for patients with all gene mutations types. In this study, we describe a site-specific gene addition strategy in induced pluripotent stem cells (iPSCs) derived from a DMD patient with exon 50 deletion. By using transcription activator-like effector nickases (TALENickases), the mini-dystrophin cassette was precisely targeted at the ribosomal RNA gene (rDNA) locus via homologous recombination with high targeting efficiency. The targeted clone retained the main pluripotent properties and was differentiated into cardiomyocytes. Significantly, the dystrophin expression and membrane localization were restored in the genetic corrected iPSCs and their derived cardiomyocytes. More importantly, the enhanced spontaneous contraction was observed in modified cardiomyocytes. These results provide a proof of principle for an efficient targeted gene addition for DMD gene therapy and represents a significant step toward precisely therapeutic for DMD. • Site-specific integrated mini-dystrophin into rDNA locus in DMD-iPSCs. • Dystrophin expression and localization were restored in targeted iPSCs and iCMs. • The enhanced spontaneous contraction was observed in the targeted iCMs. [ABSTRACT FROM AUTHOR]

Pancreatobililary cancers are fatal solid tumors that pose a significant threat to human life. It is imperative to investigate novel small molecule active compounds for controlling these cancers. Heterocyclic compounds (e.g. gemcitabine) and multi-substituted alkenes (e.g. resveratrol) are commonly applied in tumor treatment. Researchers have proposed that the synthesis of new trisubstituted alkenes containing heteroaromatic rings by combining these two scaffolds may be a fresh strategy to develop new active molecules. In this study, we utilized alkenyl bromide and heteroaryl boronic acid as substrates, employing Suzuki coupling to generate a series of triarylethylenes featuring nitrogen, oxygen, and sulfur atoms. Through in vitro experiments, the results indicated that some compounds exhibited remarkable anti-tumor efficacy (e.g. IC50[3be, GBC-SD] = 0.13 µM and IC50[3be, PANC-1] = 0.27 µM). The results further demonstrated that the antitumor efficacy of these compounds was dependent on the heteroatom, π-system, skeleton-bonding site, and substituent type., (© 2024 Wiley‐VCH GmbH.)

Pancreatic cancer (PC) is a highly malignant cancer characterized by poor prognosis, high heterogeneity, and intricate heterocellular systems. Selecting an appropriate experimental model for studying its progression and treatment is crucial. Patient-derived models provide a more accurate representation of tumor heterogeneity and complexity compared to cell line-derived models. This review initially presents relevant patient-derived models, including patient-derived xenografts (PDXs), patient-derived organoids (PDOs), and patient-derived explants (PDEs), which are essential for studying cell communication and pancreatic cancer progression. We have emphasized the utilization of these models in comprehending intricate intercellular communication, drug responsiveness, mechanisms underlying tumor growth, expediting drug discovery, and enabling personalized medical approaches. Additionally, we have comprehensively summarized single-cell analyses of these models to enhance comprehension of intercellular communication among tumor cells, drug response mechanisms, and individual patient sensitivities.