Robust Tunability and Newly Emerged Q Resonance of Ba0.8Sr0.2TiO3-Based Microwave Capacitors under Gamma Irradiations.

The complex resonance of dielectric quality factor Q, combined with a capacitance tunability n higher than 3:1 without any dispersion, was achieved in the voltage-tunable interdigital capacitors (IDCs) based on epitaxial Ba0.8Sr0.2TiO3 ferroelectric thin films across the microwave L (1-2 GHz), S (2-4 GHz), and C (4-8 GHz) bands at room temperature. The resonant Q and n features were driven by the microwave responses of the ferroelectric nanodomains engineered in the films. To promote their application in space radiation environments, the evolutions of Q and n both as functions of frequency f (1-8 GHz) and applied electric field E (0-240 kV/cm) were systematically investigated under a series of gamma-ray irradiations up to 100 kGy. The robust capacitance tunability was accompanied by the emergence of an additional Q resonance at 2.3 GHz in most post-irradiated devices, which is ascribed to extra polar nanoregions of expanded surface lattices associated with oxygen vacancies induced by irradiations.

Primary pulmonary meningioma and minute pulmonary meningothelial-like nodules: Rare pulmonary nodular lesions requiring more awareness in clinical practice.

In this editorial, we comment on an article by Ruan et al published in a recent issue of the World Journal of Clinical Case. Pulmonary meningothelial proliferative lesions, including primary pulmonary meningiomas, minute pulmonary meningothelial-like nodules, and metastatic pulmonary meningiomas are rare pulmonary lesions. These lesions are difficult to differentiate from lung cancers based on clinical and imaging manifestations. Herein, we briefly introduce the clinical, imaging, and pathological characteristics of these lesions and discuss their pathogenesis to strengthen the current understanding of pulmonary meningothelial proliferative lesions in clinical diagnosis and therapy.

Surface functionalization of exosomes for chondrocyte-targeted siRNA delivery and cartilage regeneration.

Osteoarthritis (OA) is the most prevalent degenerative cartilage disease, but no effective treatment is currently available to ameliorate the dysregulation of cartilage catabolism. Cartilage degeneration is closely related to the change in the physiology of chondrocytes: for example, chondrocytes of the OA patients overexpress matrix metallopeptidase 13 (MMP13), a.k.a. collagenase 3, which damages the extracellular matrix (ECM) of the cartilage and deteriorate the disease progression. Inhibiting MMP13 has shown to be beneficial for OA treatments, but delivering therapeutics to the chondrocytes embedded in the dense cartilage is a challenge. Here, we engineered the exosome surface with the cartilage affinity peptide (CAP) through lipid insertion to give chondrocyte-targeting exosomes, CAP-Exo, which was then loaded with siRNA against MMP13 (siMMP13) in the interior to give CAP-Exo/siMMP13. Intra-articular administration of CAP-Exo/siMMP13 reduced the MMP13 level and increased collagen COL2A1 and proteoglycan in cartilage in a rat model of anterior cruciate ligament transection (ACLT)-induced OA. Proteomic analysis showed that CAP-Exo/siMMP13 treatment restored the altered protein levels in the IL-1ß-treated chondrocytes. Taken together, a facile exosome engineering method enabled targeted delivery of siRNA to chondrocytes and chondrocyte-specific silencing of MMP13 to attenuate cartilage degeneration.

Chondrocyte-Targeted Delivery System of Sortase A-Engineered Extracellular Vesicles Silencing MMP13 for Osteoarthritis Therapy.

Targeted drug delivery and the reduction of off-target effects are crucial for the promising clinical application of nucleic acid drugs. To address this challenge, a new approach for treating osteoarthritis (OA) that accurately delivers antisense oligonucleotides (ASO) targeting matrix metalloproteinase-13 (ASO-MMP13) to chondrocytes, is developed. Small extracellular vesicles (exos) are ligated with chondrocyte affinity peptide (CAP) using Sortase A and subsequently incubated with cholesterol-modified ASO-MMP13 to construct a chondrocyte-targeted drug delivery exo (CAP-exoASO). Compared with exos without CAP (ExoASO), CAP-exoASOs attenuate IL-1ß-induced chondrocyte damage and prolong the retention time of ASO-MMP13 in the joint without distribution in major organs following intra-articular injection. Notably, CAP-exoASOs decrease MMP13 expression (P < 0.001) and upregulate COL2A1 expression (P = 0.006), resulting in reorganization of the cartilage matrix and alleviation of progression in the OA model. Furthermore, the Osteoarthritis Research Society International (OARSI) score of articular cartilage tissues treated with CAP-exoASO is comparable with that of healthy rats (P = 0.148). A mechanistic study demonstrates that CAP-exoASO may reduce inflammation by suppressing the IL-17 and TNF signaling pathways. Based on the targeted delivery effect, CAP-exoASOs successfully accomplish cartilage repair and have considerable potential for development as a promising therapeutic modality for satisfactory OA therapy.

NEK2 affects the ferroptosis sensitivity of gastric cancer cells by regulating the expression of HMOX1 through Keap1/Nrf2.

NEK2 is a serine/threonine protein kinase that is involved in regulating the progression of various tumors. Our previous studies have found that NEK2 is highly expressed in gastric cancer and suggests that patients have a worse prognosis. However, its role and mechanism in gastric cancer are only poorly studied. In this study, we established a model of ferroptosis induced by RSL3 or Erastin in AGS cells in vitro, and konckdown NEK2, HOMX1, Nrf2 by siRNA. The assay kit was used to analyzed cell viability, MDA levels, GSH and GSSG content, and FeRhoNox™-1 fluorescent probe, BODIPY™ 581/591 C11 lipid oxidation probe, CM-H2DCFDA fluorescent probe were used to detected intracellular Fe2+, lipid peroxidation, and ROS levels, respectively. Calcein-AM/PI staining was used to detect the ratio of live and dead cells, qRT-PCR and Western blot were used to identify the mRNA and protein levels of genes in cells, immunofluorescence staining was used to analyze the localization of Nrf2 in cells, RNA-seq was used to analyze changes in mRNA expression profile, and combined with the FerrDb database, ferroptosis-related molecules were screened to elucidate the impact of NEK2 on the sensitivity of gastric cancer cells to ferroptosis. We found that inhibition of NEK2 could enhance the sensitivity of gastric cancer cells to RSL3 and Erastin-induced ferroptosis, which was reflected in the combination of inhibition of NEK2 and ferroptosis induction compared with ferroptosis induction alone: cell viability and GSH level were further decreased, while the proportion of dead cells, Fe2+ level, ROS level, lipid oxidation level, MDA level, GSSG level and GSSG/GSH ratio were further increased. Mechanism studies have found that inhibiting NEK2 could promote the expression of HMOX1, a gene related to ferroptosis, and enhance the sensitivity of gastric cancer cells to ferroptosis by increasing HMOX1. Further mechanism studies have found that inhibiting NEK2 could promote the ubiquitination and proteasome degradation of Keap1, increase the level of Nrf2 in the nucleus, and thus promote the expression of HMOX1. This study confirmed that NEK2 can regulate HMOX1 expression through Keap1/Nrf2 signal, and then affect the sensitivity of gastric cancer cells to ferroptosis, enriching the role and mechanism of NEK2 in gastric cancer.

Bioinspired Selenium-Nitrogen Exchange (SeNEx) Click Chemistry Suitable for Nanomole-Scale Medicinal Chemistry and Bioconjugation.

Click chemistry is a powerful molecular assembly strategy for rapid functional discovery. The development of click reactions with new connecting linkage is of great importance for expanding the click chemistry toolbox. We report the first selenium-nitrogen exchange (SeNEx) click reaction between benzoselenazolones and terminal alkynes (Se-N to Se-C), which is inspired by the biochemical SeNEx between Ebselen and cysteine (Cys) residue (Se-N to Se-S). The formed selenoalkyne connection is readily elaborated, thus endowing this chemistry with multidimensional molecular diversity. Besides, this reaction is modular, predictable, and high-yielding, features fast kinetics (k2≥14.43 M-1 s-1), excellent functional group compatibility, and works well at miniaturization (nanomole-scale), opening up many interesting opportunities for organo-Se synthesis and bioconjugation, as exemplified by sequential click chemistry (coupled with ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) and sulfur-fluoride exchange (SuFEx)), selenomacrocycle synthesis, nanomole-scale synthesis of Se-containing natural product library and DNA-encoded library (DEL), late-stage peptide modification and ligation, and multiple functionalization of proteins. These results indicated that SeNEx is a useful strategy for new click chemistry developments, and the established SeNEx chemistry will serve as a transformative platform in multidisciplinary fields such as synthetic chemistry, material science, chemical biology, medical chemistry, and drug discovery.

Highly active probiotic hydrogels matrixed on bacterial EPS accelerate wound healing via maintaining stable skin microbiota and reducing inflammation.

Skin microbiota plays an important role in wound healing, but skin injuries are highly susceptible to wound infections, leading to disruption of the skin microbiota. However, conventional antibacterial hydrogels eliminate both probiotics and pathogenic bacteria, disrupting the balance of the skin microbiota. Therefore, it is important to develop a wound dressing that can fend off foreign pathogenic bacteria while preserving skin microbiota stability. Inspired by live bacteria therapy, we designed a probiotic hydrogel (HAEPS@L.sei gel) with high viability for promoting wound healing. Lactobacillus paracasei TYM202 encapsulated in the hydrogel has the activity of promoting wound healing, and the hydrogel matrix EPS-M76 has the prebiotic activity that promotes the proliferation and metabolism of Lactobacillus paracasei TYM202. During the wound healing process, HAEPS@L.sei gel releases lactic acid and acetic acid to resist the growth of pathogenic bacteria while maintaining Firmicutes and Proteobacteria balance at the phylum level, thus preserving skin microbiota stability. Our results showed that live probiotic hydrogels reduce the incidence of inflammation during wound healing while promoting angiogenesis and increasing collagen deposition. This study provides new ideas for developing wound dressings predicated on live bacterial hydrogels.

Evolution of chemistry and selection technology for DNA-encoded library.

DNA-encoded chemical library (DEL) links the power of amplifiable genetics and the non-self-replicating chemical phenotypes, generating a diverse chemical world. In analogy with the biological world, the DEL world can evolve by using a chemical central dogma, wherein DNA replicates using the PCR reactions to amplify the genetic codes, DNA sequencing transcripts the genetic information, and DNA-compatible synthesis translates into chemical phenotypes. Importantly, DNA-compatible synthesis is the key to expanding the DEL chemical space. Besides, the evolution-driven selection system pushes the chemicals to evolve under the selective pressure, i.e., desired selection strategies. In this perspective, we summarized recent advances in expanding DEL synthetic toolbox and panning strategies, which will shed light on the drug discovery harnessing in vitro evolution of chemicals via DEL.

Bifidobacterium breve Protects the Intestinal Epithelium and Mitigates Inflammation in Colitis via Regulating the Gut Microbiota-Cholic Acid Pathway.

In this study, we aimed to explore the protective effects of Bifidobacterium in colitis mice and the potential mechanisms. Results showed that Bifidobacterium breve (B. breve) effectively colonized the intestinal tract and alleviated colitis symptoms by reducing the disease activity index. Moreover, B. breve mitigated intestinal epithelial cell damage, inhibited the pro-inflammatory factors, and upregulated tight junction (TJ)-proteins. Gut microbiota and metabolome analysis found that B. breve boosted bile acid-regulating genera (such as Bifidobacterium and Clostridium sensu stricto 1), which promoted bile acid deconjugation in the intestine. Notably, cholic acid (CA) was closely associated with the expression levels of inflammatory factors and TJ-proteins (p < 0.05). Our in vitro cell experiments further confirmed that CA (20.24 ± 4.53 pg/mL) contributed to the inhibition of lipopolysaccharide-induced tumor necrosis factor-α expression (49.32 ± 5.27 pg/mL) and enhanced the expression of TJ-proteins (Occludin and Claudin-1) and MUC2. This study suggested that B. breve could be a probiotic candidate for use in infant foods.

Tumor microenvironment-activatable nanocatalysts with chemodynamic therapy and enhanced autophagy for specific treatment of oral squamous cell carcinoma.

Adjuvant therapy following surgery is imperative for enhancing the prognosis of patients with oral squamous cell carcinoma (OSCC) in the clinical setting. Nevertheless, challenges such as treatment resistance mediated by the tumor microenvironment (TME), systemic toxicity, and adverse side effects hinder the effectiveness of conventional adjuvant therapy. In this context, we introduce a novel nanocatalyst denoted as MnO2-x@HA-CCM (MnHA@CCM NC) designed specifically for treating OSCC. This nanocatalyst exerts targeted anti-tumor effects through TME-activatable chemodynamic therapy (CDT) and tumoricidal autophagy. The MnHA@CCM NCs exploit the biocompatibility of hyaluronic acid (HA) coating and the homologous targeting effect of cancer cell membrane (CCM) camouflage, ensuring safe in vivo delivery and specific accumulation at tumor sites. Following intracellular uptake, Fenton-like Mn2+ is generated by consuming glutathione (GSH) within the TME. Subsequently, Mn2+ catalyzes the overproduced H2O2 to generate reactive oxygen species (ROS), inducing cell apoptosis through mitochondrial damage. Additionally, phagocytized NCs and the resultant ROS accumulation in tumor cells elevate the autophagy flux, leading to autophagosome overload and consequent tumoricidal autophagy. Notably, normal cells without TME-catalytic CDT undergo mild protective autophagy to rebalance the stimulation of NCs. As a result, the TME-activatable MnHA@CCM NCs demonstrate a therapeutic efficacy in inhibiting cancer cell growth both in vitro and in vivo. This study presents a targeted treatment strategy for OSCC tumors while sparing normal cells, offering a potential alternative in the realm of adjuvant therapy.

Design, synthesis, and bioactivity evaluation of novel indole-selenide derivatives as P-glycoprotein inhibitors against multi-drug resistance in MCF-7/ADR cell.

The inhibition of P-glycoprotein (P-gp) has emerged as an intriguing strategy for circumventing multidrug resistance (MDR) in anticancer chemotherapy. In this study, we have designed and synthesized 30 indole-selenides as a new class of P-gp inhibitors based on the scaffold hopping strategy. Among them, the preferred compound H27 showed slightly stronger reversal activity (reversal fold: 271.7 vs 261.6) but weaker cytotoxicity (inhibition ratio: 33.7% vs 45.1%) than the third-generation P-gp inhibitor tariquidar on the tested MCF-7/ADR cells. Rh123 accumulation experiments and Western blot analysis demonstrated that H27 displayed excellent MDR reversal activity by dose-dependently inhibiting the efflux function of P-gp rather than its expression. Besides, UIC-2 reactivity shift assay revealed that H27 could bind to P-gp directly and induced a conformation change of P-gp. Moreover, docking study revealed that H27 matched well in the active pockets of P-gp by forming some key H-bonding interactions, arene-H interactions and hydrophobic contacts. These results suggested that H27 is worth to be a starting point for the development of novel Se-containing P-gp inhibitors for clinic use.

Vitamin D improves autoimmune diseases by inhibiting Wnt signaling pathway.

OBJECTIVE: In this study, we investigated the development of the Wnt signaling pathway in vitamin D (VitD) to improve systemic lupus erythematosus in mice to breakthrough clinical treatment approaches. METHODS: Body weight changes were recorded during rearing. Antinuclear antibodies (ANA), anti-dsDNA, and anti-snRNP were detected in the mouse serum using an enzyme-linked immunosorbent assay. Apoptosis of Th1 and Th2 immune cells in mice was detected using flow cytometry. Reverse transcription polymerase chain reaction was used to detect the expression of T-bet, GATA3, and Wnt3a mRNA in the spleens of each group. Western blot analysis was performed to detect the expression of Wnt1, p-ß-catenin, ß-catenin, glycogen synthase kinsase3ß (GSK-3ß), Wnt3a, c-myc, and cyclin D1 protein in mice spleens. ß-catenin in mice spleen was visualized using immunohistochemistry. RESULTS: VitD did not substantial reduce the body weight of MRL/LPR mice, whereas the inhibitor did. VitD notably decreased the concentrations of ANA, anti-double-stranded DNA, and anti-snRNP in the serum of MRL/LPR mice and alleviated apoptosis of Th1 and Th2 cells. VitD markedly increased the expression of T-bet and GATA mRNA in the spleen of MRL/LPR mice and consequently increased the levels of Wnt3a and ß-catenin. Western blot analysis revealed that the levels of GSK-3ß, p-ß-catenin, Wnt1, Wnt3a, c-myc, and cyclin D1 could be reduced by VitD, compared with MRL/LPR. Immunohistochemistry demonstrated that the expression of ß-catenin was the most pronounced in the spleen of MRL/LPR mice, and the expression level of ß-catenin decreased substantially after VitD intervention. CONCLUSIONS: VitD can further inhibit the nuclear translocation of ß-catenin by downregulating the expression of Wnt ligands (Wnt1 and Wnt3a), which reduces the expression of the downstream target gene cyclin D1. Systemic lupus erythematosus in mice was improved by inhibiting the activation of Wnt/ß-catenin signal pathway.

Fall Detection System Based on Point Cloud Enhancement Model for 24 GHz FMCW Radar.

Automatic fall detection plays a significant role in monitoring the health of senior citizens. In particular, millimeter-wave radar sensors are relevant for human pose recognition in an indoor environment due to their advantages of privacy protection, low hardware cost, and wide range of working conditions. However, low-quality point clouds from 4D radar diminish the reliability of fall detection. To improve the detection accuracy, conventional methods utilize more costly hardware. In this study, we propose a model that can provide high-quality three-dimensional point cloud images of the human body at a low cost. To improve the accuracy and effectiveness of fall detection, a system that extracts distribution features through small radar antenna arrays is developed. The proposed system achieved 99.1% and 98.9% accuracy on test datasets pertaining to new subjects and new environments, respectively.

Utilizing nanotechnology and advanced machine learning for early detection of gastric cancer surgery.

Nanotechnology has emerged as a promising frontier in revolutionizing the early diagnosis and surgical management of gastric cancers. The primary factors influencing curative efficacy in GIC patients are drug inefficacy and high surgical and pharmacological therapy recurrence rates. Due to its unique optical features, good biocompatibility, surface effects, and small size effects, nanotechnology is a developing and advanced area of study for detecting and treating cancer. Considering the limitations of GIC MRI and endoscopy and the complexity of gastric surgery, the early diagnosis and prompt treatment of gastric illnesses by nanotechnology has been a promising development. Nanoparticles directly target tumor cells, allowing their detection and removal. It also can be engineered to carry specific payloads, such as drugs or contrast agents, and enhance the efficacy and precision of cancer treatment. In this research, the boosting technique of machine learning was utilized to capture nonlinear interactions between a large number of input variables and outputs by using XGBoost and RNN-CNN as a classification method. The research sample included 350 patients, comprising 200 males and 150 females. The patients' mean ± SD was 50.34 ± 13.04 with a mean age of 50.34 ± 13.04. High-risk behaviors (P = 0.070), age at diagnosis (P = 0.034), distant metastasis (P = 0.004), and tumor stage (P = 0.014) were shown to have a statistically significant link with GC patient survival. AUC was 93.54%, Accuracy 93.54%, F1-score 93.57%, Precision 93.65%, and Recall 93.87% when analyzing stomach pictures. Integrating nanotechnology with advanced machine learning techniques holds promise for improving the diagnosis and treatment of gastric cancer, providing new avenues for precision medicine and better patient outcomes.

Redox-Activatable Magnetic Nanoarchitectonics for Self-Enhanced Tumor Imaging and Synergistic Photothermal-Chemodynamic Therapy.

Oral squamous cell carcinoma (OSCC) is a prevalent malignancy of the head and neck region associated with high recurrence rates and poor prognosis under current diagnostic and treatment methods. The development of nanomaterials that can improve diagnostic accuracy and therapeutic efficacy is of great importance for OSCC. In this study, a redox-activatable nanoarchitectonics is designed via the construction of dual-valence cobalt oxide (DV-CO) nanospheres, which can serve as a contrast agent for magnetic resonance (MR) imaging, and exhibit enhanced transverse and longitudinal relaxivities through the release and redox of Co3+ /Co2+ in an acidic condition with glutathione (GSH), resulting in self-enhanced T1 /T2 -weighted MR contrast. Moreover, DV-CO demonstrates properties of intracellular GSH-depletion and hydroxyl radicals (•OH) generation through a Fenton-like reaction, enabling strengthened chemodynamic (CD) effect. Additionally, DV-CO displays efficient near-infrared laser-induced photothermal (PT) effect, thereby exhibiting synergistic PT-CD therapy for suppressing OSCC tumor cells. It further investigates the tumor-specific self-enhanced MR imaging of DV-CO both in subcutaneous and orthotopic OSCC mouse models, and demonstrate the therapeutic effects of DV-CO in orthotopic OSCC mouse models. Overall, the in vitro and in vivo findings highlight the excellent theranositc potentials of DV-CO for OSCC and offer new prospects for future advancement of nanomaterials.

Mask and Release Strategy-Enabled Diversity-Oriented Synthesis for DNA-Encoded Library.

An ideal DNA-encoded library (DEL) selection requires the library to consist of diverse core skeletons and cover chemical space as much as possible. However, the lack of efficient on-DNA synthetic approaches toward core skeletons has greatly restricted the diversity of DEL. To mitigate this issue, this work disclosed a "Mask & Release" strategy to streamline the challenging on-DNA core skeleton synthesis. N-phenoxyacetamide is used as a masked phenol and versatile directing group to mediate diversified DNA-compatible C-H functionalization, introducing the 1st-dimensional diversity at a defined site, and simultaneously releasing the phenol functionality, which can facilitate the introduction of the 2nd diversity. This work not only provides a set of efficient syntheses toward DNA-conjugated drug-like core skeletons such as ortho-alkenyl/sulfiliminyl/cyclopropyl phenol, benzofuran, dihydrobenzofuran but also provides a paradigm for on-DNA core skeleton synthetic method development.

Abietane diterpenoids and iridoids from Caryopteris mongolica.

Six new abietane diterpenoids (1-6) and five undescribed iridoids (7-11) have been isolated from the aerial parts of Caryopteris mongolica. The intricate structural characterization of these compounds was meticulously undertaken using an array of advanced spectroscopic techniques. This process was further enhanced by the application of DP4+ probability analyses and electronic circular dichroism (ECD) calculations. Following isolation and structural elucidation, the cytotoxicity of these compounds was evaluated. Among them, compound 3 stood out, displaying significant cytotoxic activity against HeLa cells with an IC50 value of 7.83 ± 1.28 µmol·L-1. Additionally, compounds 1, 2, 4, 9, and 10 manifested moderate cytotoxic effects on specific cell lines, with IC50 values ranging from 11.7 to 20.9 µmol·L-1.