Mapping of cytosol-facing organelle outer membrane proximity proteome by proximity-dependent biotinylation in living Arabidopsis cells.

The cytosol-facing outer membrane (OM) of organelles communicates with other cellular compartments to exchange proteins, metabolites, and signaling molecules. Cellular surveillance systems also target OM-resident proteins to control organellar homeostasis and ensure cell survival under stress. However, the OM proximity proteomes have never been mapped in plant cells since using traditional approaches to discover OM proteins and identify their dynamically interacting partners remains challenging. In this study, we developed an OM proximity labeling (OMPL) system using biotin ligase-mediated proximity biotinylation to identify the proximity proteins of the OMs of mitochondria, chloroplasts, and peroxisomes in living Arabidopsis (Arabidopsis thaliana) cells. Using this approach, we mapped the OM proximity proteome of these three organelles under normal conditions and examined the effects of the ultraviolet-B (UV-B) or high light (HL) stress on the abundances of OM proximity proteins. We demonstrate the power of this system with the discovery of cytosolic factors and OM receptor candidates potentially involved in local protein translation and translocation. The candidate proteins that are involved in mitochondrion-peroxisome, mitochondrion-chloroplast, or peroxisome-chloroplast contacts, and in the organellar quality control system are also proposed based on OMPL analysis. OMPL-generated OM proximity proteomes are valuable sources of candidates for functional validation and suggest directions for further investigation of important questions in cell biology.

Charge-Reversal NaCl/G-Quartets for Aggregation-Induced Mitochondrial MicroRNA Imaging and Ion-Interference Therapy.

Mitochondrial therapy is a promising new strategy that offers the potential to achieve precise disease diagnosis or maximum therapeutic response. However, versatile mitochondrial theranostic platforms that integrate biomarker detection and therapy have rarely been exploited. Here, we report a charge-reversal nanomedicine activated by an acidic microenvironment for mitochondrial microRNA (mitomiR) detection and ion-interference therapy. The transporter liposome (DD-DC) was constructed from a pH-responsive polymer and a positively charged phospholipid, encapsulating NaCl nanoparticles with coloading of the aggregation-induced emission (AIE) fluorogens AIEgen-DNA/G-quadruplexes precursor and brequinar (NAB@DD-DC). The negatively charged nanomedicine ensured good blood stability and high tumor accumulation, while the charge-reversal to positive in response to the acidic pH in the tumor microenvironment (TME) and lysosomes enhanced the uptake by tumor cells and lysosome escape, achieving accumulation in mitochondria. The subsequently released Na+ in mitochondria not only contributed to the formation of mitomiR-494 induced G-quadruplexes for AIE imaging diagnosis but also led to an osmolarity surge that was enhanced by brequinar to achieve effective ion-interference therapy.

A Novel Hydrated Iron Vanadate Cathode Material for Advanced Aqueous Nickel-Ion Batteries.

Aqueous nickel-ion batteries (ANIBs) as an emerging energy storage device attracted much attention owing to their multielectron redox reaction and dendrite-free Ni anode, yet their development is hindered by the divalent properties of Ni2+ and the lack of suitable cathode materials. Herein, a hydrated iron vanadate (Fe2V3O10.5∙1.5H2O, FOH) with a preferred orientation along the (200) plane is innovatively proposed and used as cathode material for ANIBs. The FOH cathode exhibits a remarkable capacity of 129.3 mAh g-1 at 50 mA g-1 and a super-high capacity retention of 95% at 500 mA g-1 after 700 cycles. The desirable Ni2+ storage capacity of FOH can be attributed to the preferentially oriented and tunnel structures, which offer abundant reaction active planes and a broad Ni2+ diffusion path, the abundant vacancies and high specific surface area further increase ion storage sites and accelerate ion diffusion in the FOH lattice. Furthermore, the Ni2+ storage mechanism and structural evolution in the FOH cathode are explored through ex situ XRD, ex situ Raman, ex situ XPS and other ex situ characteristics. This work opens a new way for designing novel cathode materials to promote the development of ANIBs.

Linkage-Mediated Electronic Structure Modulation in Multicomponent Covalent Organic Frameworks for Dramatically Promoted Photocatalytic Hydrogen Evolution.

Linkage chemistry is an essential aspect to covalent organic framework (COF) applications; it is highly desirable to precisely modulate electronic structure mediated directly by linkage for efficient COF-based photocatalytic hydrogen evolution, which however, remains substantially challenging. Herein, as a proof of concept, a collection of robust multicomponent pyrene-based COFs with abundant donor-acceptor (D-A) interactions has been judiciously designed and synthesized through molecularly engineering linkage for photogeneration of hydrogen. Controlled locking and conversion of linkage critically contribute to continuously regulating COFs' electronic structures further to optimize photocatalytic activities. Remarkably, the well-modulated optoelectronic properties turn on the average hydrogen evolution rate from zero to 15.67 mmol g-1 h-1 by the protonated quinoline-linked COF decorated with the trifluoromethyl group (TT-PQCOF-CF3). Using diversified spectroscopy and theoretical calculations, we show that multiple modifications toward linkage synergistically lead to the redistribution of charge on COFs with extended π-conjugation and reinforced D-A effect, making TT-PQCOF-CF3 a promising material with significantly boosted carrier separation and migration. This study provides important guidance for the design of high-performance COF photocatalysts based on the strategy of linkage-mediated electronic structure modulation in COFs.

Chemical and Structural Engineering of Gelatin-Based Delivery Systems for Therapeutic Applications: A Review.

As a biodegradable and biocompatible protein derived from collagen, gelatin has been extensively exploited as a fundamental component of biological scaffolds and drug delivery systems for precise medicine. The easily engineered gelatin holds great promise in formulating various delivery systems to protect and enhance the efficacy of drugs for improving the safety and effectiveness of numerous pharmaceuticals. The remarkable biocompatibility and adjustable mechanical properties of gelatin permit the construction of active 3D scaffolds to accelerate the regeneration of injured tissues and organs. In this Review, we delve into diverse strategies for fabricating and functionalizing gelatin-based structures, which are applicable to gene and drug delivery as well as tissue engineering. We emphasized the advantages of various gelatin derivatives, including methacryloyl gelatin, polyethylene glycol-modified gelatin, thiolated gelatin, and alendronate-modified gelatin. These derivatives exhibit excellent physicochemical and biological properties, allowing the fabrication of tailor-made structures for biomedical applications. Additionally, we explored the latest developments in the modulation of their physicochemical properties by combining additive materials and manufacturing platforms, outlining the design of multifunctional gelatin-based micro-, nano-, and macrostructures. While discussing the current limitations, we also addressed the challenges that need to be overcome for clinical translation, including high manufacturing costs, limited application scenarios, and potential immunogenicity. This Review provides insight into how the structural and chemical engineering of gelatin can be leveraged to pave the way for significant advancements in biomedical applications and the improvement of patient outcomes.

Prognostic Significance of Biventricular and Biatrial Strain in Dilated Cardiomyopathy: Strain Analysis Derived from Cardiovascular Magnetic Resonance.

Background: Dilated cardiomyopathy (DCM) has a poor prognosis and high mortality. The relationship between the deformation capacity of the biatrial and biventricular regions in patients with DCM remains unclear. Methods: This retrospective study used cardiovascular magnetic resonance (CMR) to assess patient enrollment between September 2020 to May 2022. Feature tracking (FT) was used to evaluate biventricular global radial strain (GRS), global circumferential strain (GCS) and global longitudinal strain (GLS). Fast long-axis method was used to evaluate biatrial GLS by analyzing balanced steady-state free precession cine images. The median follow-up period was 362 days (interquartile range: 234 to 500 days). DCM patients were divided into two groups based on the occurrence or non-occurrence of major adverse cardiac event (MACE). The primary endpoint was defined as all-cause death, heart transplantation, and adverse ventricular arrhythmia. The secondary end point included hospitalizations due to heart failure. Cox regression analysis was utilized for variables and Kaplan-Meier survival was utilized for clinical outcomes. Results: There were 124 DCM patients (52.82 ± 12.59 years, 67.74% male) and 53 healthy volunteers (53.17 ± 14.67 years, 52.83% male) recruited in this study. Biventricular GRS, GCS, GLS, and biatrial GLS were significantly impaired in the DCM group compared with the healthy group. In receiver-operating characteristic curve, biatrial GLS and biventricular GRS, GCS, and GLS showed significant prognostic value in predicting MACEs (all p < 0.05). In multivariate Cox regression analysis, left ventricular (LV) GLS offered a significant and independent prognostic value surpassing other CMR parameters in predicting MACE. In Kaplan-Meier analysis, patients with a LV GLS > -4.81% had a significantly higher rate of MACE (Log-rank p < 0.001). Conclusions: LV GLS was independently associated with MACEs in DCM patients by using FT and fast long-axis method derived from CMR. Comprehensive CMR examination including biatrial and biventricular functions should be systematically performed, to understand disease characteristics, as well as improve the risk stratification and therapeutic management for patients with DCM.

Decreased histone expression in chronic rhinosinusitis with nasal polyps.

Background: Histones have been associated with human diseases. However, the implication of extranuclear histone proteins and their potential mechanism in the pathophysiology of chronic rhinosinusitis (CRS) have not been thoroughly investigated. This study was designed to evaluate the role of histones in patients with CRS by comparing histone expression between patients and controls. Methods: Nasal polyp (NP) tissues were obtained, and their comprehensive gene expression profiles were investigated by microarray analysis. Differences in expression were verified by reverse transcriptase polymerase chain reaction and immunohistochemical staining. Cell culture and flow cytometry were used to evaluate the role of histones in the pathogenesis of polyps. Results: Significant differences in the microarray analysis were observed between the patient and control groups (P < 0.01). It was found by flow cytometry that the histone (H2BK) can promote cell apoptosis in NPs. Conclusion: Our results indicate that reduced expression of H2BK may contribute to the imbalance process of cell proliferation and apoptosis in CRS with NP.

The Neurovascular Unit Dysfunction in the Molecular Mechanisms of Epileptogenesis and Targeted Therapy.

Epilepsy is a multifaceted neurological syndrome characterized by recurrent, spontaneous, and synchronous seizures. The pathogenesis of epilepsy, known as epileptogenesis, involves intricate changes in neurons, neuroglia, and endothelium, leading to structural and functional disorders within neurovascular units and culminating in the development of spontaneous epilepsy. Although current research on epilepsy treatments primarily centers around anti-seizure drugs, it is imperative to seek effective interventions capable of disrupting epileptogenesis. To this end, a comprehensive exploration of the changes and the molecular mechanisms underlying epileptogenesis holds the promise of identifying vital biomarkers for accurate diagnosis and potential therapeutic targets. Emphasizing early diagnosis and timely intervention is paramount, as it stands to significantly improve patient prognosis and alleviate the socioeconomic burden. In this review, we highlight the changes and molecular mechanisms of the neurovascular unit in epileptogenesis and provide a theoretical basis for identifying biomarkers and drug targets.

Surgical treatment and prognosis of recurrent and radiotherapy insensitive nasopharyngeal carcinoma.

OBJECTIVE: To explore the effect of surgical treatment and related prognostic factors for recurrent Nasopharyngeal Carcinoma (NPC) after radiotherapy and the pathological types of nasopharyngeal carcinoma insensitive to radiotherapy. METHODS: A total of 70 NPC patients who underwent surgery at the Department of Otolaryngology, head and neck surgery, from January 2005 to December 2020 were retrospectively included: 41 males and 29 females, aged 21-75 years, 47 patients were pathologically classified as NPC (nonkeratinizing, undifferentiated type), 10 patients as adenoid cystic carcinoma, 13 patients as other types, 45 patients had received radiotherapy preoperatively, and 25 patients had not received radiotherapy preoperatively. All patients underwent surgical treatment under general anesthesia. Fifty-six patients underwent nasoendoscopic NPC resection, seven patients underwent open surgery, and seven patients underwent combined nasoendoscopic and open surgery. The median follow-up was 39 months. Tumor volume, extent of involvement, lymph node metastasis, imaging characteristics, surgical approach and efficacy, postoperative complications, and 2-, 3-, and 5-year postoperative survival rates were calculated for all patients. Statistical analysis was performed using spss22 Kaplan Meier survival analysis and Cox regression analysis were performed. RESULTS: Among the 70 patients, the overall 2-year survival rate was 93.4%, the 3-year survival rate was 90.8%, and the 5-year survival rate was 80.3%. Multivariate analysis showed that TNM stage and age at onset were independent prognostic factors for NPC outcome. CONCLUSION: Depending on the size and location of the tumor, endoscopic surgery, open surgery, and combined open surgery with nasoendoscopy may be considered for recurrent and radiotherapy insensitive NPC. LEVEL OF EVIDENCE: Level 4.

Human Umbilical Cord Mesenchymal Stem Cell-derived Exosomes Induce Macrophage M2 Polarization by Antagonizing LPS-mediated Stimulation of the NF-κB and STAT3 Pathways.

BACKGROUND: Many studies have documented the protective effects of regulating macrophage M1/M2 polarization in inflammatory diseases characterized by their imbalance state. In pathological diseases associated with inflammation, mesenchymal stem cells (MSCs) regulate macrophages, thereby having anti-inflammatory and tissue regenerative effects. Exosomes have been suggested as an alternative mechanism that underlies the paracrine function of MSCs. Thus, this study explored the anti-inflammatory impact of human umbilical cord MSCssecreted exosomes (hucMSCs-EX) by influencing macrophage polarization in normal and inflammatory environments in vitro. METHODS: In this study, hucMSCs-conditioned medium (hucMSCs-CM) and hucMSCs- EX were used to treat RAW264.7 macrophages with or without LPS. The expressions of TNF- α, IL-10, IL-6, IL-1ß, and Arg-1 were quantified by qPCR. The expressions of IL-6 and IL-10 were evaluated by ELISAs. Western blots (WB) were performed to observe the expressions of CD206, NF-κB P65, NF-κB p-p65, p-STAT3, STAT3, and NF-κB phosphorylation. The number of cells expressing CD206 and the fluorescence intensity were measured via flow cytometry (FC) and immunofluorescence staining. Cell propagation and migration were examined via MTT and transwell assays, respectively. RESULTS: The inhibition of LPS-induced inflammatory polarization by hucMSCs-EX or hucMSCs- CM led to increases in IL-10 and arginase (Arg) levels and decreases in those of IL-6 and TNF-α. Moreover, hucMSCs-EX enhanced the CD206 expression in RAW264.7 cells and accelerated the propagation and migration of LPS-induced cells. The suppressive impact of hucMSCs-EX on the LPS-induced phenotypic polarization of M1 macrophages was linked with the reduction of NF-κB signaling. They stimulated the transition of M2 macrophages by enhancing the activity of STAT3 in RAW264.7 cells. CONCLUSION: This study indicated that hucMSCs-EX enhances the macrophage transition into the M2 phenotype by inhibiting the NF-κB p65 axis and stimulating that of STAT3.

Fabrication of hyaluronic acid-altered gold complex delivery for head and neck squamous cell carcinoma therapy with high antitumor efficacy and low in vivo toxicity.

The use of multifunctional nanomedicines in the treatment of tumors is gaining popularity. Here, we constructed a nanodrug delivery system (HA/Au-PDA@CZT) that targets tumors and responds to pH and near-infrared (NIR) dual stimuli. By precisely interacting with an overexpressed CD44 receptor in specific cancer cells, hyaluronic acid (HA) is coated on the Au-PDA NP surface for tumor-targeting abilities. When exposed to NIR radiation, polydopamine (PDA) and gold nanoshells exhibit exceptional photothermal performance that has the potential to both accelerate and kill HLAC 78 head and neck squamous cell carcinoma cells. Antitumor investigations conducted in vivo and in vitro demonstrated that nanomedicine had remarkable synergistic benefits with chemotherapy and photothermal treatment. Only 25.2% of the cells in the HA/Au-PDA@CZT with a NIR irradiation group were viable. Any group's lowest tumor volume was shown in the tumor mice subjected to HA/Au-PDA@CZT with NIR at 0.3 ± 0.1. Consequently, for synergistic chemo-photothermal therapy, our logically designed nanoplatform would be the potential for a head and neck squamous tumor-targeting drug delivery system.

Genetic predisposition to milder forms of COVID-19 may provide some resilience to head and neck cancers.

Introduction: The impact of the COVID-19 pandemic on head and neck cancer (HNC) has been suggested, but the causal relationship remains unclear. Methods: We explore this connection by utilizing the Mendelian randomization (MR) approach applied to publicly available genome-wide association study (GWAS) summary datasets for COVID-19 and HNC. The datasets included critical COVID-19 (13,769 cases, 1,072,442 controls), hospitalized COVID-19 (32,519 cases, 2,062,805 controls), SARS-CoV-2 infection (122,616 cases, 2,475,240 controls), and HNC (2,131 cases, 287,137 controls). Mechanistic underpinnings of the causal relationships identified by MR analysis were explored through functional annotation augmented by AI-based literature data mining. Results: Surprisingly, a genetic predisposition to contracting a milder form of COVID-19 substantially reduced the risks of developing HNC (OR: 0.52, 95% CI: 0.35-0.78, p = 1.42E-03), with no significant association between genetic liability to severe COVID-19 and the risk of HNC detected. Additionally, our findings highlighted 14 genes linked to SARS-CoV-2 infection, potentially playing a protective role in the context of HNC. These genes include OAS1, LOC107985887, BCL11A, DPP9, LOC107984685, LINC02326, MUC4, NXPE3, IFNAR2, LZTFL1, LOC105372437, NAPSA, LOC105376622, LOC107986082, and SLC6A20. Conclusion: Our study emphasizes the protective role of the genetic liability to milder COVID-19 in reducing the risk of HNC while refuting a causal relationship between severe COVID-19 and HNC.

Coronary CT Angiography-Based Radiomics to Predict Vessel-Specific Ischemia by Stress Dynamic CT Myocardial Perfusion Imaging.

RATIONALE AND OBJECTIVES: To investigate the predictive value of coronary CT angiography (CCTA)-based radiomics for vessel-specific ischemia by stress dynamic CT myocardial perfusion imaging (MPI). MATERIALS AND METHODS: Patients with typical angina/atypical angina/non-angina chest pain who underwent both stress dynamic CT MPI and CCTA scans were retrospectively enrolled. The following models were constructed for ischemic prediction using logistic regression and CCTA-derived quantitative and radiomic features: plaque quantitative model, lumen quantitative model, CT-fractional flow reserve (CT-FFR) model, integrative quantitative model, plaque radiomic model, peri-coronary adipose tissue (pCAT) radiomic model, integrative radiomic model, and quantitative and radiomic fusion model. A relative myocardial blood flow ≤ 0.75 on stress dynamic CT MPI was considered ischemic. The models' performances were quantified by the area under the receiver-operating characteristic curve (AUC). RESULTS: 386 coronary vessels (stenosis grade: 25%∼75%; training set: 200 [ischemia/non-ischemia=96/104]; test set:186 [ischemia/non-ischemia=79/107]) from 326 patients were included. The plaque radiomic model (training/test set: AUC=0.81/0.80) outperformed (p < .05) both the plaque quantitative (training/test set: AUC=0.71/0.68) model and the lumen quantitative (training/test set: AUC=0.69/0.65) model in identifying ischemia. The integrative radiomic model (training/test set: AUC=0.83/0.82) outperformed (p < .05) the CT-FFR model (training/test set: AUC=0.74/0.73) for ischemic prediction. The quantitative and radiomic fusion model (training/test set: AUC=0.86/0.84) outperformed (p < .05) the integrative quantitative model (training/test set: AUC=0.79/0.77) for ischemic detection. CONCLUSION: The plaque and pCAT radiomic features were superior to the plaque and pCAT quantitative features in predicting ischemia and the addition of the radiomic features to the quantitative features for ischemic identification yielded incremental discriminatory value.

Surgical treatment and prognosis of recurrent and radiotherapy insensitive nasopharyngeal carcinoma

Abstract Objective To explore the effect of surgical treatment and related prognostic factors for recurrent Nasopharyngeal Carcinoma (NPC) after radiotherapy and the pathological types of nasopharyngeal carcinoma insensitive to radiotherapy. Methods A total of 70 NPC patients who underwent surgery at the Department of Otolaryngology, head and neck surgery, from January 2005 to December 2020 were retrospectively included: 41 males and 29 females, aged 21-75 years, 47 patients were pathologically classified as NPC (nonkeratinizing, undifferentiated type), 10 patients as adenoid cystic carcinoma, 13 patients as other types, 45 patients had received radiotherapy preoperatively, and 25 patients had not received radiotherapy preoperatively. All patients underwent surgical treatment under general anesthesia. Fifty-six patients underwent nasoendoscopic NPC resection, seven patients underwent open surgery, and seven patients underwent combined nasoendoscopic and open surgery. The median follow-up was 39 months. Tumor volume, extent of involvement, lymph node metastasis, imaging characteristics, surgical approach and efficacy, postoperative complications, and 2-, 3-, and 5-year postoperative survival rates were calculated for all patients. Statistical analysis was performed using spss22 Kaplan Meier survival analysis and Cox regression analysis were performed. Results Among the 70 patients, the overall 2-year survival rate was 93.4%, the 3-year survival rate was 90.8%, and the 5-year survival rate was 80.3%. Multivariate analysis showed that TNM stage and age at onset were independent prognostic factors for NPC outcome. Conclusion Depending on the size and location of the tumor, endoscopic surgery, open surgery, and combined open surgery with nasoendoscopy may be considered for recurrent and radiotherapy insensitive NPC. Level of Evidence: Level 4.