Quantitatively Dissecting Triple Roles of Dynactin in Dynein-Driven Transport of Influenza Virus by Quantum Dot-Based Single-Virus Tracking.

After entering host cells by endocytosis, influenza A virus (IAV) is transported along microfilaments and then transported by dynein along microtubules (MTs) to the perinuclear region for genome release. Understanding the mechanisms of dynein-driven transport is significant for a comprehensive understanding of IAV infection. In this work, the roles of dynactin in dynein-driven transport of IAV were quantitatively dissected in situ using quantum dot-based single-virus tracking. It was revealed that dynactin was essential for dynein to transport IAV toward the nucleus. After virus entry, virus-carrying vesicles bound to dynein and dynactin before being delivered to MTs. The attachment of dynein to the vesicles was dependent on dynactin and its subunits, p150Glued and Arp1. Once viruses reached MTs, dynactin-assisted dynein initiates retrograde transport of IAV. Importantly, the retrograde transport of viruses could be initiated at both plus ends (32%) and other regions on MTs (68%). Subsequently, dynactin accompanied and assisted dynein to persistently transport the virus along MTs in the retrograde direction. This study revealed the dynactin-dependent dynein-driven transport process of IAV, enhancing our understanding of IAV infection and providing important insights into the cell's endocytic transport mechanism.

Simultaneous Mapping of the Nanoscale Organization and Redox State of Extracellular Space in Living Brain Tissue.

The spatial organization characteristics and redox status of the extracellular space (ECS) are crucial in the development of brain diseases. However, it remains a challenge to simultaneously capture dynamic changes in microstructural features and redox states at the submicron level within the ECS. Here, we developed a reversible glutathione (GSH)-responsive nanoprobe (RGN) for mapping the spatial organization features and redox status of the ECS in brain tissues with nanoscale resolution. The RGN is composed of polymer nanoparticles modified with GSH-responsive molecules and amino-functionalized methoxypoly(ethylene glycol), which exhibit exceptional single-particle brightness and excellent free diffusion capability in the ECS of brain tissues. Tracking single RGNs in acute brain slices allowed us to dynamically map spatial organizational features and redox levels within the ECS of brain tissues in disease models. This provides a powerful super-resolution imaging method that offers a potential opportunity to study the dynamic changes in the ECS microenvironment and to understand the physiological and pathological roles of the ECS in vivo.

Silica nanoparticle design for colorectal cancer treatment: Recent progress and clinical potential.

Colorectal cancer (CRC) is the third most common cancer worldwide and the second most common cause of cancer death. Nanotherapies are able to selectively target the delivery of cancer therapeutics, thus improving overall antitumor efficiency and reducing conventional chemotherapy side effects. Mesoporous silica nanoparticles (MSNs) have attracted the attention of many researchers due to their remarkable advantages and biosafety. We offer insights into the recent advances of MSNs in CRC treatment and their potential clinical application value.

Assessing the suitability of video-assisted anal fistula treatment for obese patients compared to conventional surgery: a question worth investigating.

BACKGROUND AND AIMS: Video-assisted anal fistula treatment (VAAFT) is an innovative surgical approach enabling the direct visualization of the fistula tract structure. This study aims to assess the efficacy of VAAFT in comparison with that of traditional surgical methods and explore potential risk factors contributing to fistula recurrence to provide new recommendations for surgical selection. MATERIALS AND METHODS: Information was collected from 100 patients with complex anal fistula (CAF) in our hospital who underwent surgical treatment from January 2021 to January 2023. We compared the baseline information and surgical outcomes of two groups, analyzed the risk factors for fistula recurrence by using logistic regression analysis, and conducted further exploration by using the body mass index. RESULTS: Equal numbers of patients underwent VAAFT and traditional surgeries, and no significant differences in baseline information were observed. Patients who received VAAFT experienced less intraoperative bleeding (15.5 (14.0-20.0) vs. 32.0 (25.0-36.0)), shorter hospital stays (2.0 (2.0-2.5) vs. 3.0 (3.0-3.5)), reduced postoperative pain and wound discharge, but longer operative times (43.3 ± 6.9 vs. 35.0 (31.5-40.0)) compared with patients who underwent traditional surgeries. No significant differences in recurrence rates were found three and six months after operation (the p-values were 0.790 and 0.806, respectively). However, the Wexner scores of the VAAFT group were significantly low in the first follow-up (0 (0-1.0) vs. 2.0 (1.0-2.0)). Postoperative recurrence of fistulas may be associated with obesity (p-value = 0.040), especially in patients undergoing traditional surgeries (p-value = 0.036). CONCLUSION: VAAFT offers advantages, such as less pain, less trauma, and faster recovery, compared with traditional surgical treatment. Obese patients with CAF are prone to recurrence, and we recommend that they undergo VAAFT treatment rather than traditional surgeries.

Metal nanozymes modulation of reactive oxygen species as promising strategies for cancer therapy.

Nanozymes, nanostructured materials emulating natural enzyme activities, exhibit potential in catalyzing reactive oxygen species (ROS) production for cancer treatment. By facilitating oxidative reactions, elevating ROS levels, and influencing the tumor microenvironment (TME), nanozymes foster the eradication of cancer cells. Noteworthy are their superior stability, ease of preservation, and cost-effectiveness compared to natural enzymes, rendering them invaluable for medical applications. This comprehensive review intricately explores the interplay between ROS and tumor therapy, with a focused examination of metal-based nanozyme strategies mitigating tumor hypoxia. It provides nuanced insights into diverse catalytic processes, mechanisms, and surface modifications of various metal nanozymes, shedding light on their role in intra-tumoral ROS generation and applications in antioxidant therapy. The review concludes by delineating specific potential prospects and challenges associated with the burgeoning use of metal nanozymes in future tumor therapies.

NIR-II Fluorescence Imaging for In Vivo Quantitative Analysis.

In vivo real-time qualitative and quantitative analysis is essential for the diagnosis and treatment of diseases such as tumors. Near-infrared-II (NIR-II, 1000-1700 nm) bioimaging is an emerging visualization modality based on fluorescent materials. The advantages of NIR-II region fluorescent materials in terms of reduced photon scattering and low tissue autofluorescence enable NIR-II bioimaging with high resolution and increasing depth of tissue penetration, and thus have great potential for in vivo qualitative and quantitative analysis. In this review, we first summarize recent advances in NIR-II imaging, including fluorescent probe selection, quantitative analysis strategies, and imaging. Then, we describe in detail representative applications to illustrate how NIR-II fluorescence imaging has become an important tool for in vivo quantitative analysis. Finally, we describe the future possibilities and challenges of NIR-II fluorescence imaging.

Regulation of Protein Conformation Enables Cell-Selective Targeting of Virus-Mimicking Nanoparticles for siRNA Therapy of Glioblastoma.

Orthotopic glioblastoma (GBM) has an aggressive growth pattern and complex pathogenesis, becoming one of the most common and deadly tumors of the central nervous system (CNS). The emergence of RNA therapies offers promise for the treatment of GBM. However, the efficient and precise delivery of RNA drugs to specific tumor cells in the brain with high cellular heterogeneity remains ongoing. Here, a strategy is proposed to regulate protein conformation through lipid nanoenvironments to custom-design virus-mimicking nanoparticles (VMNs) with excellent selective cell targeting capabilities, leading to efficient and precise delivery of small interfering RNA for effective treatment of GBM. The optimized VMNs not only retain the ability to cross the blood-brain barrier and release the RNA by lysosomal escape like natural viruses but also ensure precise enrichment in the GBM area. This study lays the conceptual foundation for the custom design of VMNs with superior cell-selective targeting capabilities and opens up the possibility of RNA therapies for the efficient treatment of GBM and CNS tumors.

A Cyanine with 83.2% Photothermal Conversion Efficiency and Absorption Wavelengths over 1200 nm for Photothermal Therapy.

Developing small-molecule photothermal agents (PTAs) with good near-infrared-II (NIR-II) response for deeper tissue penetration and minimizing damage to healthy tissues has attracted much attention in photothermal therapy (PTT). However, concentrating ultra-long excitation wavelengths and high photothermal conversion efficiencies (PCEs) into a single organic small molecule is still challenging due to the lack of suitable molecular structures. Here, six polymethine cyanine molecules based on the structure of indocyanine green are synthesized by increasing the conjugated structure of the two-terminal indole salts and the number of rigid methine units, and incorporating longer alkyl side chains into the indole salts. Ultimately, IC-1224 is obtained with an absorption wavelength of more than 1200 nm, which has a high PCE up to 83.2% in the NIR-II window and exhibits excellent PTT tumor ablation performance. This provides a high-performance NIR-II-responsive PTA, and offers further possibilities for the application of PTT in biomedical fields.

A radiomics model of contrast-enhanced computed tomography for predicting post-acute pancreatitis diabetes mellitus.

Background: Diabetes mellitus can occur after acute pancreatitis (AP), but the accurate quantitative methods to predict post-acute pancreatitis diabetes mellitus (PPDM-A) are lacking. This retrospective study aimed to establish a radiomics model based on contrast-enhanced computed tomography (CECT) for predicting PPDM-A. Methods: A total of 374 patients with first-episode AP were retrospectively enrolled from two tertiary referral centers. There were 224 patients in the training cohort, 56 in the internal validation cohort, and 94 in the external validation cohort, and there were 86, 22, and 27 patients with PPDM-A in these cohorts, respectively. The clinical characteristics were collected from the hospital information system. A total of 2,398 radiomics features, including shape-based features, first-order histogram features, high order textural features, and transformed features, were extracted from the arterial- and venous-phase CECT images. Intraclass correlation coefficients were used to assess the intraobserver reliability and interobserver agreement. Random forest-based recursive feature elimination, collinearity analysis, and least absolute shrinkage and selection operator (LASSO) were used for selecting the final features. Three classification methods [eXtreme Gradient Boosting (XGBoost), Adaptive Boosting, and Decision Tree] were used to build three models and performances of the three models were compared. Each of the three classification methods were used to establish the clinical model, radiomics model, and combined model for predicting PPDM-A, resulting in a total of nine classifiers. The predictive performances of the models were evaluated by the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and F1-score. Results: Eleven radiomics features were selected after a reproducibility test and dimensionality reduction. Among the three classification methods, the XGBoost classifier showed better and more consistent performances. The AUC of the XGBoost's radiomics model to predict PPDM-A in the training, internal, and external cohorts was good (0.964, 0.901, and 0.857, respectively). The AUC of the XGBoost's combined model to predict PPDM-A in the training, internal, and external cohorts was good (0.980, 0.901, and 0.882, respectively). The AUC of the XGBoost's clinical model to predict PPDM-A in the training, internal, and external cohorts did not perform well (0.685, 0.733, and 0.619, respectively). In the external validation cohort, the AUC of the XGBoost's radiomics model was significantly higher than that of the clinical model (0.857 vs. 0.619, P<0.001), but there was no significant difference between the combined and radiomics models (0.882 vs. 0.857, P=0.317). Conclusions: The radiomics model based on CECT performs well and can be used as an early quantitative method to predict the occurrence of PPDM-A.

One-Step Dual-Color Labeling of Viral Envelope and Intraviral Genome with Quantum Dots Harnessing Virus Infection.

Labeling the genome and envelope of a virus with multicolor quantum dots (QDs) simultaneously enables real-time monitoring of viral uncoating and genome release, contributing to our understanding of virus infection mechanisms. However, current labeling techniques require genetic modification, which alters the virus's composition and infectivity. To address this, we utilized the CRISPR/Cas13 system and a bioorthogonal metabolic method to label the Japanese encephalitis virus (JEV) genome and envelopes with different-colored QDs in situ. This technique allows one-step two-color labeling of the viral envelope and intraviral genome with QDs harnessing virus infection. In combination with single-virus tracking, we visualized JEV uncoating and genome release in real time near the endoplasmic reticulum of live cells. This labeling strategy allows for real-time visualization of uncoating and genome release at the single-virus level, and it is expected to advance the study of other viral infection mechanisms.

Transcription factor PbNAC71 regulates xylem and vessel development to control plant height.

Dwarfism is an important agronomic trait in fruit breeding programs. However, the germplasm resources required to generate dwarf pear (Pyrus spp.) varieties are limited. Moreover, the mechanisms underlying dwarfism remain unclear. In this study, "Yunnan" quince (Cydonia oblonga Mill.) had a dwarfing effect on "Zaosu" pear. Additionally, the dwarfism-related NAC transcription factor gene PbNAC71 was isolated from pear trees comprising "Zaosu" (scion) grafted onto "Yunnan" quince (rootstock). Transgenic Nicotiana benthamiana and pear OHF-333 (Pyrus communis) plants overexpressing PbNAC71 exhibited dwarfism, with a substantially smaller xylem and vessel area relative to the wild-type controls. Yeast one-hybrid, dual-luciferase, chromatin immunoprecipitation-qPCR, and electrophoretic mobility shift assays indicated that PbNAC71 downregulates PbWalls are thin 1 expression by binding to NAC-binding elements in its promoter. Yeast two-hybrid assays showed that PbNAC71 interacts with the E3 ubiquitin ligase PbRING finger protein 217 (PbRNF217). Furthermore, PbRNF217 promotes the ubiquitin-mediated degradation of PbNAC71 by the 26S proteasome, thereby regulating plant height as well as xylem and vessel development. Our findings reveal a mechanism underlying pear dwarfism and expand our understanding of the molecular basis of dwarfism in woody plants.

Predicting intraoperative hemorrhage during curettage treatment of cesarean scar pregnancy using free-breathing GRASP DCE-MRI.

OBJECTIVE: To explore the feasibility of the golden-angle radial sparse parallel (GRASP) dynamic magnetic resonance imaging (MRI) technique in predicting the intraoperative bleeding risk of scar pregnancy. METHODS: A total of 49 patients with cesarean scar pregnancy (CSP) who underwent curettage and GRASP-MRI imaging were retrospectively selected between January 2021 and July 2022. The pharmacokinetic parameters, including Wash-in, Wash-out, time to peck (TTP), initial area under the curve (iAUC), the transfer rate constant (Ktrans), constant flow rate (Kep), and volume of extracellular space (Ve), were calculated. The amount of intraoperative bleeding was recorded by a gynecologist who performed surgery, after which patients were divided into non-hemorrhage (blood loss ≤ 200 mL) and hemorrhage (blood loss > 200 mL) groups. The measured pharmacokinetic parameters were statistically compared using the t-test or Mann-Whitney U test with a significant level set to be p < 0.05. The receiver operating characteristic (ROC) curve was constructed, and the area under the curve (AUC) was calculated to evaluate each parameter's capability in intraoperative hemorrhage subgroup classification. RESULTS: Twenty patients had intraoperative hemorrhage (blood loss > 200 mL) during curettage. The hemorrhage group had larger Wash-in, iAUC, Ktrans, Ve, and shorter TTP than the non-hemorrhage group (all P > 0.05). Wash-in had the highest AUC value (0.90), while Ktrans had the lowest value (0.67). Wash-out and Kep were not significantly different between the two groups. CONCLUSION: GRASP DCE-MRI has the potential to forecast intraoperative hemorrhage during curettage treatment of CSP, with Wash-in exhibiting the highest predictive performance. This data holds promise for advancing personalized treatment. However, further study is required to compare its effectiveness with other risk factors identified through anatomical MRI and ultrasound.

Accurate Cancer Screening and Prediction of PD-L1-Guided Immunotherapy Efficacy Using Quantum Dot Nanosphere Self-Assembly and Machine Learning.

Accurate quantification of exosomal PD-L1 protein in tumors is closely linked to the response to immunotherapy, but robust methods to achieve high-precision quantitative detection of PD-L1 expression on the surface of circulating exosomes are still lacking. In this work, we developed a signal amplification approach based on aptamer recognition and DNA scaffold hybridization-triggered assembly of quantum dot nanospheres, which enables bicolor phenotyping of exosomes to accurately screen for cancers and predict PD-L1-guided immunotherapeutic effects through machine learning. Through DNA-mediated assembly, we utilized two aptamers for simultaneous ultrasensitive detection of exosomal antigens, which have synergistic roles in tumor diagnosis and treatment prediction, and thus, we achieved better sample classification and prediction through machine-learning algorithms. With a drop of blood, we can distinguish between different cancer patients and healthy individuals and predict the outcome of immunotherapy. This approach provides valuable insights into the development of personalized diagnostics and precision medicine.

Lipid-Centric Design of Plasma Membrane-Mimicking Nanocarriers for Targeted Chemotherapeutic Delivery.

The plasma membranes (PM) of mammalian cells contain diverse lipids, proteins, and carbohydrates that are important for systemic recognition and communication in health and disease. Cell membrane coating technology that imparts unique properties of natural plasma membranes to the surface of encapsulated nanoparticles is thus becoming a powerful platform for drug delivery, immunomodulation, and vaccination. However, current coating methods fail to take full advantage of the natural systems because they disrupt the complex and functionally essential features of PMs, most notably the chemical diversity and compositional differences of lipids in two leaflets of the PM. Herein, a new lipid coating approach is reported in which the lipid composition is optimized through a combination of biomimetic and systematic variation approaches for the custom design of nanocarrier systems for precision drug delivery. Nanocarriers coated with the optimized lipids offer unique advantages in terms of bioavailability and efficiency in tumor targeting, tumor penetration, cellular uptake, and drug release. This pilot study provides new insight into the rational design and optimization of nanocarriers for cancer chemotherapeutic drugs and lays the foundation for further customization of cell membrane-mimicking nanocarriers through systematic incorporation of other components.

Near-Infrared II Hemicyanine Dye with Large Stokes Shift Designed by TICT Regulation for Boosting Imaging-Guided Photothermal Therapy.

The serious threat that cancer poses to human health highlights the significance of early detection and effective treatment. The integration of fluorescence diagnosis and photothermal therapy in NIR-II has gained attention due to its high sensitivity, fast response, and noninvasiveness. Fluorescence, produced by the radiative relaxation process of electrons in a molecule, and photothermal, generated by the nonradiative relaxation process of electrons in a molecule, are competing photophysical processes. Hence, it is a challenge for the molecule to balance between the properties of fluorescence and photothermal. In this study, a NIR-II hemicyanine with TICT character is designed to obtain molecules with both better fluorescence and photothermal properties, utilizing positively charged pyridine salt and triphenylamine as electron acceptor and donor, respectively, and oxole as the conjugated π-bridge. HCY-995, one of the synthesized compounds, has a quantum yield of 0.09%, photothermal conversion efficiency of 54.90%, and a significant Stoke shift of 232 nm, which makes it appropriate for the integration of photothermal therapy and high-resolution imaging. This study provides new insights into the development of NIR-II molecules with fluorescent and photothermal integrated properties.

A gas-selective Zn-MOF exhibits selective sensing of Fe3+ ions by doping with Tb3.

Here, a new Zn2+ metal organic framework, {[Me2NH2][Zn2(L)(DTZ)]·2DMF·3H2O}n (Zn-MOF), has been synthesized with low-symmetric carboxylic acid ligand 2,6 bis(2',5'-dicarboxyphenyl)pyridine (H4L) as the main ligand and 3,5-diamino-1,2,4-riazole (DTZ) containing an electron-rich N atom as an auxiliary ligand. Because of its high structural stability and adsorption properties, it can be used to efficiently separate CO2/CH4 and C2H2/CH4. In addition, Tb@Zn-MOF was obtained by doping with Tb3+ to partially replace Zn2+. A study of its luminescence sensing performance demonstrated that Tb@Zn-MOF showed intense luminescence properties and can be used for the directional detection of Fe3+ in aqueous solution. Furthermore, PXRD analysis, UV-vis spectroscopy and X-ray photoelectron spectroscopy (XPS) were also used to study possible luminescence sensing mechanisms. The recognition mechanism for Fe3+ ions is believed to be caused by electron transfer.

Engineered Lipidic Nanomaterials Inspired by Sphingomyelin Metabolism for Cancer Therapy.

Sphingomyelin (SM) and its metabolites are crucial regulators of tumor cell growth, differentiation, senescence, and programmed cell death. With the rise in lipid-based nanomaterials, engineered lipidic nanomaterials inspired by SM metabolism, corresponding lipid targeting, and signaling activation have made fascinating advances in cancer therapeutic processes. In this review, we first described the specific pathways of SM metabolism and the roles of their associated bioactive molecules in mediating cell survival or death. We next summarized the advantages and specific applications of SM metabolism-based lipidic nanomaterials in specific cancer therapies. Finally, we discussed the challenges and perspectives of this emerging and promising SM metabolism-based nanomaterials research area.

[Effects of electroacupuncture pretreatment on long-term postoperative cognitive dysfunction and neuron-inflammation in aged rats].

OBJECTIVE: To observe the effects of electroacupuncture pretreatment on postoperative cognitive dysfunction (POCD), neuronal apoptosis and neuron-inflammation in aged rats. METHODS: Thirty-six male SD rats aged 20 months were randomly divided into sham operation group, model group and electroacupuncture (EA) group, with 12 rats in each group. The POCD rats model was prepared by internal fixation of left tibial fracture. Five days before modeling, EA stimulation (2 Hz/15 Hz, 1 mA, 30 min) was applied to "Zusanli" (ST36), "Hegu" (LI4) and "Neiguan" (PC6) on the unaffected side of rats in the EA group, once a day for consecutive 5 d. The learning and memory abilities of rats were evaluated by water maze test 31-35 days after operation. The apoptosis of hippocampal neurons was observed by Tunel/NeuN double staining. The expressions of high mobility group protein B1 (HMGB1) and phosphorylated (p)-nuclear factor (NF)-κB in microglia cells in hippocampal dentate gyrus were detected by immunofluorescence staining. The expression levels of interleukin (IL)-6 and IL-1ß in the hippocampus were detected by Western blot. RESULTS: Compared with the sham operation group, the escape latency was prolonged (P<0.05); the frequency of crossing the original platform, ratio of the swimming distance and the time in the target quadrant of the Morris water maze were significantly decreased (P<0.05); the apoptosis rate of hippocampal neurons was significantly increased (P<0.05); the expressions of HMGB1 and p-NF-κB in microglia cells in the dentate gyrus and the expression levels of IL-6 and IL-1ß in hippocampus were increased (P<0.05) in the model group. Compared with the model group, the results of the above indexes were all opposite (P<0.05) in the EA group. CONCLUSION: EA preconditioning can regulate hippocampal inflammatory response, alleviate neuronal apoptosis rate and long-term cognitive dysfunction in aged rats with POCD, the mechanisms may be related to the inhibition of microglia HMGB1/NF-κB pathway in hippocampal dentate gyrus.