Robust Electrostatic-Templated Polymerization for Controllable Synthesis of Stable and Permeable Polyelectrolyte Vesicles.

Polymer vesicles are of profound interest for designing delivery vehicles and nanoreactors toward a variety of biomedical and catalytic applications, yet robust synthesis of stable and permeable vesicles remains challenging. Here, we propose an electrostatic-templated polymerization that enables fabrication of polyelectrolyte vesicles with simultaneously regulated stability and permeability. In our design, cationic monomers were copolymerized with cross-linkers in the presence of a polyanionic-neutral diblock copolymer as a template. By properly choosing the block length ratio of the template, we fabricated a type of polyion complex vesicle consisting of a cross-linked cationic membrane, electrostatically assembled with the template copolymer which can be removed by sequential dissociation and separation under concentrated salt. We finally obtained stable polyelectrolyte vesicles of regulated size, membrane permeability, and response properties by tuning the synthesis factors including ionic strength, cross-linker type, and fraction as well as different monomers and concentrations. As a proof-of-concept, lipase was loaded in the designed cationic vesicles, which exhibited enhanced enzyme stability and activity. Our study has developed a novel and robust strategy for controllable synthesis of a new class of stable and permeable polymer (polyelectrolyte) vesicles that feature great potential applications as functional delivery carriers and nanoreactors.

Ischemic insular damage and stress ulcer in patients of acute ischemic stroke.

BACKGROUND AND AIMS: Stress ulcer (SU) is a common complication in patients with acute ischemic stroke. The relationship of infarction location and the incidence of SU was unclear. Herein, we aim to investigate the association between ischemic insular damage and the development of SU. METHODS: Data were retrieved from the SPARK study (Effect of Cardiac Function on Short-Term Functional Prognosis in Patients with Acute Ischemic Stroke). We included the patients who had experienced an ischemic stroke within 7 days. The diagnosis of SU was based on clinical manifestations, including hematemesis, bloody nasogastric tube aspirate, or hematochezia. Evaluation of ischemic insular damage was conducted through magnetic resonance imaging. Cyclo-oxygenase regression analysis and Kaplan-Meier survival curves were used to assess the relationship between ischemic insular damage and the occurrence of SU. RESULTS: Among the 1357 patients analyzed, 110 (8.1%) developed SUs during hospitalization, with 69 (6.7%) experiencing infarctions in the anterior circulation. After adjusting for potential confounders, patients with ischemic insular damage exhibited a 2.16-fold higher risk of developing SUs compared to those without insular damage (p = .0206). Notably, among patients with infarctions in the anterior circulation, those with insular damage had a 2.21-fold increased risk of SUs (p = .0387). Moreover, right insular damage was associated with a higher risk of SUs compared to left insular damage or no insular damage (p for trend = .0117). Kaplan-Meier curves demonstrated early separation among groups, persisting throughout the follow-up period (all p < .0001). CONCLUSIONS: This study identified a significant independent correlation between ischemic insular damage, particularly on the right side, and the development of SU during hospitalization, indicating the need to consider prophylactic acid-suppressive treatment for patients with ischemic insular damage.

Hydrophobic core evolution of major histocompatibility complex class I chain-related protein a for dramatic enhancing binding affinity.

Interface residues at sites of protein-protein interaction (PPI) are the focus for affinity optimisation. However, protein hydrophobic cores (HCs) play critical roles and shape the protein surface. We hypothesise that manipulating protein HCs can enhance PPI interaction affinities. A cell stress molecule, major histocompatibility complex class I chain-related protein A (MICA), binds to the natural killer group 2D (NKG2D) homodimer to form three molecule interactions. MICA was used as a study subject to support our hypothesis. We redesigned MICA HCs by directed mutagenesis and isolated high-affinity variants through a newly designed partial-denature panning (PDP) method. A few mutations in MICA HCs increased the NKG2D-MICA interaction affinity by 325-5613-fold. Crystal structures of the NKG2D-MICA variant complexes indicated that mutagenesis of MICA HCs stabilised helical elements for decreasing intermolecular interactive free energy (ΔG) of the NKG2D-MICA heterotrimer. The repacking of MICA HC mutants maintained overall surface residues and the authentic binding specificity of MICA. In conclusion, this study provides a new method for MICA redesign and affinity optimisation through HC manipulation without mutating PPI interface residues. Our study introduces a novel approach to protein manipulation, potentially expanding the toolkit for protein affinity optimisation.

Oropharyngeal swallowing hydrodynamics of thin and mildly thick liquids in an anatomically accurate throat-epiglottis model.

Understanding the mechanisms underlying dysphagia is crucial in devising effective, etiology-centered interventions. However, current clinical assessment and treatment of dysphagia are still more symptom-focused due to our limited understanding of the sophisticated symptom-etiology associations causing swallowing disorders. This study aimed to elucidate the mechanisms giving rise to penetration flows into the laryngeal vestibule that results in aspirations with varying symptoms. Methods: Anatomically accurate, transparent throat models were prepared with a 45° down flapped epiglottis to simulate the instant of laryngeal closure during swallowing. Fluid bolus dynamics were visualized with fluorescent dye from lateral, rear, front, and endoscopic directions to capture key hydrodynamic features leading to aspiration. Three influencing factors, fluid consistency, liquid dispensing site, and dispensing speed, were systemically evaluated on their roles in liquid aspirations. Results: Three aspiration mechanisms were identified, with liquid bolus entering the airway through (a) the interarytenoid notch (notch overflow), (b) cuneiform tubercle recesses (recess overflow), and (c) off-edge flow underneath the epiglottis (off-edge capillary flow). Of the three factors considered, liquid viscosity has the most significant impact on aspiration rate, followed by the liquid dispensing site and the dispensing speed. Water had one order of magnitude higher aspiration risks than 1% w/v methyl cellulose solution, a mildly thick liquid. Anterior dispensing had higher chances for aspiration than posterior oropharyngeal dispensing for both liquids and dispensing speeds considered. The effects of dispending speed varied. A lower speed increased aspiration for anterior-dispensed liquids due to increased off-edge capillary flows, while it significantly reduced aspiration for posterior-dispensed liquids due to reduced notch overflows. Visualizing swallowing hydrodynamics from multiple orientations facilitates detailed site-specific inspections of aspiration mechanisms.

Deep learning-based detection of irreversible pulpitis in primary molars.

BACKGROUND: Changes in healthy and inflamed pulp on periapical radiographs are traditionally so subtle that they may be imperceptible to human experts, limiting its potential use as an adjunct clinical diagnostic feature. AIM: This study aimed to investigate the feasibility of an image-analysis technique based on the convolutional neural network (CNN) to detect irreversible pulpitis in primary molars on periapical radiographs (PRs). DESIGN: This retrospective study was performed in two health centres. Patients who received indirect pulp therapy at Peking University Hospital for Stomatology were retrospectively identified and randomly divided into training and validation sets (8:2). Using PRs as input to an EfficientNet CNN, the model was trained to categorise cases into either the success or failure group and externally tested on patients who presented to our affiliate institution. Model performance was evaluated using sensitivity, specificity, accuracy and F1 score. RESULTS: A total of 348 PRs with deep caries were enrolled from the two centres. The deep learning model achieved the highest accuracy of 0.90 (95% confidence interval: 0.79-0.96) in the internal validation set, with an overall accuracy of 0.85 in the external test set. The mean greyscale value was higher in the failure group than in the success group (p = .013). CONCLUSION: The deep learning-based model could detect irreversible pulpitis in primary molars with deep caries on PRs. Moreover, this study provides a convenient and complementary method for assessing pulp status.

Several inaccurate or erroneous conceptions and misleading propaganda about brain-computer interfaces.

Brain-computer interface (BCI) is a revolutionizing human-computer interaction, which has potential applications for specific individuals or groups in specific scenarios. Extensive research has been conducted on the principles and implementation methods of BCI, and efforts are currently being made to bridge the gap from research to real-world applications. However, there are inaccurate or erroneous conceptions about BCI among some members of the public, and certain media outlets, as well as some BCI researchers, developers, manufacturers, and regulators, propagate misleading or overhyped claims about BCI technology. Therefore, this article summarizes the several misconceptions and misleading propaganda about BCI, including BCI being capable of "mind-controlled," "controlling brain," "mind reading," and the ability to "download" or "upload" information from or to the brain using BCI, among others. Finally, the limitations (shortcomings) and limits (boundaries) of BCI, as well as the necessity of conducting research aimed at countering BCI systems are discussed, and several suggestions are offered to reduce misconceptions and misleading claims about BCI.

Blocking the MIF-CD74 axis augments radiotherapy efficacy for brain metastasis in NSCLC via synergistically promoting microglia M1 polarization.

BACKGROUND: Brain metastasis is one of the main causes of recurrence and death in non-small cell lung cancer (NSCLC). Although radiotherapy is the main local therapy for brain metastasis, it is inevitable that some cancer cells become resistant to radiation. Microglia, as macrophages colonized in the brain, play an important role in the tumor microenvironment. Radiotherapy could activate microglia to polarize into both the M1 and M2 phenotypes. Therefore, searching for crosstalk molecules within the microenvironment that can specifically regulate the polarization of microglia is a potential strategy for improving radiation resistance. METHODS: We used databases to detect the expression of MIF in NSCLC and its relationship with prognosis. We analyzed the effects of targeted blockade of the MIF/CD74 axis on the polarization and function of microglia during radiotherapy using flow cytometry. The mouse model of brain metastasis was used to assess the effect of targeted blockade of MIF/CD74 axis on the growth of brain metastasis. RESULT: Our findings reveals that the macrophage migration inhibitory factor (MIF) was highly expressed in NSCLC and is associated with the prognosis of NSCLC. Mechanistically, we demonstrated CD74 inhibition reversed radiation-induced AKT phosphorylation in microglia and promoted the M1 polarization in combination of radiation. Additionally, blocking the MIF-CD74 interaction between NSCLC and microglia promoted microglia M1 polarization. Furthermore, radiation improved tumor hypoxia to decrease HIF-1α dependent MIF secretion by NSCLC. MIF inhibition enhanced radiosensitivity for brain metastasis via synergistically promoting microglia M1 polarization in vivo. CONCLUSIONS: Our study revealed that targeting the MIF-CD74 axis promoted microglia M1 polarization and synergized with radiotherapy for brain metastasis in NSCLC.

Left ventricular ejection fraction <60 % is associated with short-term functional disability in patients of acute ischemic stroke.

Background and objective: The association between cardiac dysfunction and functional outcome in acute ischemic stroke (AIS) is not clear. We aimed to investigate the relationship between the routinely assessed left ventricular ejection fraction (LVEF) and functional outcomes in patients with AIS. Methods: Data came from a prospective, observational, single-center study (Effect of Cardiac Function on Short-term Functional Prognosis in Patients with Acute Ischemic Stroke, SPARK). The LVEF was assessed with transthoracic echocardiography within 7 days of stroke onset. The primary outcome was functional disability, defined as a modified Rankin Scale score of 3-6 at 90 days (range: 0-6, with higher scores indicating greater disability). We also investigated the association of the LVEF with mortality, early neurological deterioration, hospital stay, and costs. Multivariate logistic regression analysis and 2:1 propensity score matching (PSM) were performed to compare the differences in outcomes. Results: A total of 1181 patients were included in this analysis, of which 87 (7.4 %) patients were found to have LVEF of <60 %. In the entire study population, LVEF<60 % was significantly associated with functional disability at 90 days (odds ratio [OR]: 1.85, 95 % confidence intervals (CI): 1.01-3.40) after adjusting for all confounders. After PSM, the association was consistently significant (OR: 5.32, 95 % CI: 3.04-9.30). However, associations of the LVEF with mortality, early neurological deterioration, hospital stay, and costs were not consistently significant across all analyses. In the subgroup analysis, the association of LVEF of <60 % with functional disability was statistically significant in patients with non-cardioembolic stroke, but not in patients with cardioembolic stroke (P for interaction = 0.872). Conclusions: An LVEF of <60 % will likely increase the risk of functional disability in patients with AIS. Future strategies to prevent cardiac dysfunction in the acute phase are needed.

Emotion Classification Based on Transformer and CNN for EEG Spatial-Temporal Feature Learning.

OBJECTIVES: The temporal and spatial information of electroencephalogram (EEG) signals is crucial for recognizing features in emotion classification models, but it excessively relies on manual feature extraction. The transformer model has the capability of performing automatic feature extraction; however, its potential has not been fully explored in the classification of emotion-related EEG signals. To address these challenges, the present study proposes a novel model based on transformer and convolutional neural networks (TCNN) for EEG spatial-temporal (EEG ST) feature learning to automatic emotion classification. METHODS: The proposed EEG ST-TCNN model utilizes position encoding (PE) and multi-head attention to perceive channel positions and timing information in EEG signals. Two parallel transformer encoders in the model are used to extract spatial and temporal features from emotion-related EEG signals, and a CNN is used to aggregate the EEG's spatial and temporal features, which are subsequently classified using Softmax. RESULTS: The proposed EEG ST-TCNN model achieved an accuracy of 96.67% on the SEED dataset and accuracies of 95.73%, 96.95%, and 96.34% for the arousal-valence, arousal, and valence dimensions, respectively, for the DEAP dataset. CONCLUSIONS: The results demonstrate the effectiveness of the proposed ST-TCNN model, with superior performance in emotion classification compared to recent relevant studies. SIGNIFICANCE: The proposed EEG ST-TCNN model has the potential to be used for EEG-based automatic emotion recognition.

Terahertz Radiation Modulates Neuronal Morphology and Dynamics Properties.

Terahertz radiation falls within the spectrum of hydrogen bonding, molecular rotation, and vibration, as well as van der Waals forces, indicating that many biological macromolecules exhibit a strong absorption and resonance in this frequency band. Research has shown that the terahertz radiation of specific frequencies and energies can mediate changes in cellular morphology and function by exciting nonlinear resonance effects in proteins. However, current studies have mainly focused on the cellular level and lack systematic studies on multiple levels. Moreover, the mechanism and law of interaction between terahertz radiation and neurons are still unclear. Therefore, this paper analyzes the mechanisms by which terahertz radiation modulates the nervous system, and it analyzes and discusses the methods by which terahertz radiation modulates neurons. In addition, this paper reviews the laws of terahertz radiation's influence on neuronal morphology and kinetic properties and discusses them in detail in terms of terahertz radiation frequency, energy, and time. In the future, the safety of the terahertz radiation system should be considered first to construct the safety criterion of terahertz modulation, and the spatial resolution of the terahertz radiation system should be improved. In addition, the systematic improvement of the laws and mechanisms of terahertz modulation of the nervous system on multiple levels is the key to applying terahertz waves to neuroscience. This paper can provide a platform for researchers to understand the mechanism of the terahertz-nervous system interaction, its current status, and future research directions.

Osteocyte mitochondria regulate angiogenesis of transcortical vessels.

Transcortical vessels (TCVs) provide effective communication between bone marrow vascular system and external circulation. Although osteocytes are in close contact with them, it is not clear whether osteocytes regulate the homeostasis of TCVs. Here, we show that osteocytes maintain the normal network of TCVs by transferring mitochondria to the endothelial cells of TCV. Partial ablation of osteocytes causes TCV regression. Inhibition of mitochondrial transfer by conditional knockout of Rhot1 in osteocytes also leads to regression of the TCV network. By contrast, acquisition of osteocyte mitochondria by endothelial cells efficiently restores endothelial dysfunction. Administration of osteocyte mitochondria resultes in acceleration of the angiogenesis and healing of the cortical bone defect. Our results provide new insights into osteocyte-TCV interactions and inspire the potential application of mitochondrial therapy for bone-related diseases.

1-Selector 1-Memristor Configuration with Multifunctional a-IGZO Memristive Devices Fabricated at Room Temperature.

Serving as neuromorphic hardware accelerators, memristors play a crucial role in large-scale neuromorphic computing. Herein, two-terminal memristors utilizing amorphous indium-gallium-zinc oxide (a-IGZO) are fabricated through room-temperature sputtering. The electrical characteristics of these memristors are effectively modulated by varying the oxygen flow during the deposition process. The optimized a-IGZO memristor, fabricated under 3 sccm oxygen flow, presents a 5 × 103 ratio between its high- and low-resistance states, which can be maintained over 1 × 104 s with minimal degradation. Meanwhile, desirable properties such as electroforming-free and self-compliance, crucial for low-energy consumption, are also obtained in the a-IGZO memristor. Moreover, analog conductance switching is observed, demonstrating an interface-type behavior, as evidenced by its device-size-dependent performance. The coexistence of negative differential resistance with analog switching is attributed to the migration of oxygen vacancies and the trapping/detrapping of charges. Furthermore, the device demonstrates optical storage capabilities by exploiting the optical properties of a-IGZO, which can stably operate for up to 50 sweep cycles. Various synaptic functions have been demonstrated, including paired-pulse facilitation and spike-timing-dependent plasticity. These functionalities contribute to a simulated recognition accuracy of 90% for handwritten digits. Importantly, a one-selector one-memristor (1S1M) architecture is successfully constructed at room temperature by integrating a-IGZO memristor on a TaOx-based selector. This architecture exhibits a 107 on/off ratio, demonstrating its potential to suppress sneak currents among adjacent units in a memristor crossbar.

Towards clinically applicable automated mandibular canal segmentation on CBCT.

OBJECTIVES: To develop a deep learning-based system for precise, robust, and fully automated segmentation of the mandibular canal on cone beam computed tomography (CBCT) images. METHODS: The system was developed on 536 CBCT scans (training set: 376, validation set: 80, testing set: 80) from one center and validated on an external dataset of 89 CBCT scans from 3 centers. Each scan was annotated using a multi-stage annotation method and refined by oral and maxillofacial radiologists. We proposed a three-step strategy for the mandibular canal segmentation: extraction of the region of interest based on 2D U-Net, global segmentation of the mandibular canal, and segmentation refinement based on 3D U-Net. RESULTS: The system consistently achieved accurate mandibular canal segmentation in the internal set (Dice similarity coefficient [DSC], 0.952; intersection over union [IoU], 0.912; average symmetric surface distance [ASSD], 0.046 mm; 95% Hausdorff distance [HD95], 0.325 mm) and the external set (DSC, 0.960; IoU, 0.924; ASSD, 0.040 mm; HD95, 0.288 mm). CONCLUSIONS: These results demonstrated the potential clinical application of this AI system in facilitating clinical workflows related to mandibular canal localization. CLINICAL SIGNIFICANCE: Accurate delineation of the mandibular canal on CBCT images is critical for implant placement, mandibular third molar extraction, and orthognathic surgery. This AI system enables accurate segmentation across different models, which could contribute to more efficient and precise dental automation systems.

Inferior vena cava hemangioma resected using a novel Toumai robotic surgical platform.

This study aims to investigate the significance of using the Toumai robotic platform for the resection of inferior vena cava (IVC) hemangiomas. Our objective is to provide information on the potential benefits of this innovative approach in managing these uncommon vascular tumors and to contribute to the growing body of knowledge in the field of surgical oncology and vascular surgery. A 37-year-old female patient with an incidental finding of a right retroperitoneal mass underwent contrast-enhanced magnetic resonance imaging, which confirmed the diagnosis of an IVC hemangioma. Due to the rarity and complexity of this vascular tumor, the medical team opted for a novel approach using the Toumai robotic surgical platform (Shanghai MicroPort MedBot Group Co, Ltd). Under general anesthesia, the patient was placed in the left lateral decubitus position, and the robotic arms were controlled remotely through the Toumai platform. A transperitoneal approach was adopted, and the surgeon meticulously resected the tumor while preserving the integrity of the IVC. The use of the Toumai robotic platform facilitated precise tumor resection, minimizing the risk of damage to surrounding structures. The minimally invasive nature of the robotic surgery contributed to a reduced incidence of postoperative complications and accelerated patient recovery. Furthermore, the remote fifth-generation mobile network surgical capabilities of the Toumai platform allow for expert care to be provided to patients despite geographic barriers. The robotic-assisted surgical approach using the Toumai platform demonstrates its potential benefits in managing rare and complex vascular tumors such as IVC hemangiomas. Robotic technology has the potential to revolutionize the field of surgical oncology and vascular surgery, leading to improved patient outcomes and healthcare delivery. However, more extensive clinical studies and larger case series are needed to validate the long-term safety and efficacy of this innovative surgical approach. Continued research and collaboration between clinicians and robotic technology experts are essential to fully realize the potential of robotic-assisted surgery for the benefit of patients with rare and challenging medical conditions.

Bibliometric analysis of intestinal microbiota and lung diseases.

Background: Increasing evidence suggests a close association between the intestinal microbiome and the respiratory system, drawing attention to studying the gut-lung axis. This research employs bibliometric methods to conduct a visual analysis of literature in the field of intestinal microbiota and lung diseases over the past two decades. It offers scientific foundations for research directions and critical issues in this field. Methods: We retrieved all articles on intestinal microbiota and lung diseases from the SCI-Expanded of WoSCC on October 25, 2023. The analysis included original articles and reviews published in English from 2011 to 2023. We utilized Python, VOSviewer, and CiteSpace to analyze the retrieved data visually. Results: A total of 794 publications were analyzed. China ranked first in the number of publications, while the United States had the highest citations and H-index. Jian Wang was the most prolific author. Zhejiang University was the institution with the highest number of publications. Frontiers in Microbiology was the journal with the most publications. Author keywords appearing more than 100 times included "intestinal microbiota/microbiome", "microbiota/microbiome", and "gut-lung axis". Conclusion: The correlation and underlying mechanisms between intestinal microbiota and lung diseases, including asthma, COPD, lung cancer, and respiratory infections, remain hot topics in research. However, understanding the mechanisms involving the gut-lung axis is still in its infancy and requires further elucidation.

Prenatal antibiotics exposure and preschoolers' internalizing and externalizing problems: A biomonitoring-based prospective birth cohort study.

BACKGROUND: Biomonitoring-based epidemiological studies on prenatal antibiotic exposure and behavioral problems in preschoolers are lacking. The present study aimed to investigate the relationship between prenatal antibiotic exposure and internalizing and externalizing problems in preschoolers. METHODS: Data from 2449 mother-child pairs were analyzed. Urine samples were repeatedly collected across three trimesters, and 43 antibiotics and 2 metabolites were measured, including preferred as veterinary antibiotics (PVAs), VAs, preferred as human antibiotics and human antibiotics. Preschoolers' internalizing and externalizing problems were evaluated by the Achenbach Child Behavior Checklist. Poisson regression models with generalized estimating equations were used to estimate risk ratios (RRs) and 95 % confidence intervals (CIs) for preschoolers' internalizing, externalizing and total problems across tertiles of antibiotic concentrations during three periods of pregnancy, and performed several subgroup analyses. RESULTS: First-trimester urinary oxytetracycline (RR = 1.69, 95%CI: 1.20, 2.39, P-FDR = 0.011), tetracycline (RR = 1.91, 95%CI: 1.36, 2.68, P-FDR < 0.001), doxycycline (RR = 1.66, 95%CI: 1.28, 2.17, P-FDR < 0.001) and PVAs (RR = 1.79, 95%CI: 1.29, 2.48, P-FDR < 0.001) concentrations in the highest tertile were related to an elevated risk of internalizing problems compared with concentrations in the lowest tertile. First-trimester urinary doxycycline concentrations in the third tertile were also associated with an increased risk of externalizing problems compared with the first tertile (RR = 2.00, 95%CI: 1.28, 3.15, P-FDR = 0.042). Compared with concentrations in the lowest tertile, first-trimester urinary doxycycline (RR = 1.63, 95%CI: 1.19, 2.22, P-FDR = 0.028) and PVAs (RR = 1.67, 95%CI: 1.14, 2.43, P-FDR = 0.047) concentrations in the middle tertile were related to an increased risk of total problems. Furthermore, the type of main caregiver and children's outdoor activities time modified the relationships between specific prenatal antibiotic exposure and preschoolers' behavioral problems. CONCLUSIONS: Exposure to specific antibiotics during the first trimester may be related to an increased risk of internalizing and externalizing problems in preschoolers.

[Ethical considerations for medical applications of implantable brain-computer interfaces].

Implantable brain-computer interfaces (BCIs) have potentially important clinical applications due to the high spatial resolution and signal-to-noise ratio of electrodes that are closer to or implanted in the cerebral cortex. However, the surgery and electrodes of implantable BCIs carry safety risks of brain tissue damage, and their medical applications face ethical challenges, with little literature to date systematically considering ethical norms for the medical applications of implantable BCIs. In order to promote the clinical translation of this type of BCI, we considered the ethics of practice for the medical application of implantable BCIs, including: reducing the risk of brain tissue damage from implantable BCI surgery and electrodes, providing patients with customized and personalized implantable BCI treatments, ensuring multidisciplinary collaboration in the clinical application of implantable BCIs, and the responsible use of implantable BCIs, among others. It is expected that this article will provide thoughts and references for the research and development of ethics of the medical application of implantable BCI.

Cancer-Thylakoid Hybrid Membrane Camouflaged Thulium Oxide Nanoparticles with Oxygen Self-Supply Capability for Tumor-Homing Phototherapy.

Nanomaterials that generate reactive oxygen species (ROS) upon light irradiation have significant applications in various fields, including photodynamic therapy (PDT) that is widely recognized as a highly momentous strategy for the eradication of cancer cells. However, the ROS production rate of photosensitizers, as well as the tumor hypoxia environment, are two major challenges that restrict the widespread application of PDT. In this study, a cancer-thylakoid hybrid membrane-camouflaged thulium oxide nanoparticles (Tm2O3) for tumor-homing phototherapy through dual-stage-light-guided ROS generation and oxygen self-supply is developed. Tm2O3 as a type II photosensitizer are viable for NIR-stimulated ROS generation due to the unique energy levels, large absorption cross section, and long lifetime of the 3H4 state of Tm ions. The thylakoid membrane (TK) plays a catalase-like role in converting hydrogen peroxide into oxygen and also acts as a natural photosensitizer that can generate lethal ROS through electron transfer when exposed to light. In addition, fluorescence dye DiR is embedded in the hybrid membrane for in vivo tracing as well as photothermal therapy. Results show that tumors in Tm2O3@TK-M/DiR group are effectively ablated following dual-stage-light irradiation, highlighting the promising potential of rare-earth element-based type II photosensitizers in various applications.

CCDC92 promotes podocyte injury by regulating PA28α/ABCA1/cholesterol efflux axis in type 2 diabetic mice.

Podocyte lipotoxicity mediated by impaired cellular cholesterol efflux plays a crucial role in the development of diabetic kidney disease (DKD), and the identification of potential therapeutic targets that regulate podocyte cholesterol homeostasis has clinical significance. Coiled-coil domain containing 92 (CCDC92) is a novel molecule related to metabolic disorders and insulin resistance. However, whether the expression level of CCDC92 is changed in kidney parenchymal cells and the role of CCDC92 in podocytes remain unclear. In this study, we found that Ccdc92 was significantly induced in glomeruli from type 2 diabetic mice, especially in podocytes. Importantly, upregulation of Ccdc92 in glomeruli was positively correlated with an increased urine albumin-to-creatinine ratio (UACR) and podocyte loss. Functionally, podocyte-specific deletion of Ccdc92 attenuated proteinuria, glomerular expansion and podocyte injury in mice with DKD. We further demonstrated that Ccdc92 contributed to lipid accumulation by inhibiting cholesterol efflux, finally promoting podocyte injury. Mechanistically, Ccdc92 promoted the degradation of ABCA1 by regulating PA28α-mediated proteasome activity and then reduced cholesterol efflux. Thus, our studies indicate that Ccdc92 contributes to podocyte injury by regulating the PA28α/ABCA1/cholesterol efflux axis in DKD.