Methodological validation of sedimentation velocity analytical ultracentrifugation method for Adeno-Associated Virus and collaborative calibration of system suitability substance.

Currently, adeno-associated virus (AAV) is one of the primary gene delivery vectors in gene therapy, facilitating long-term in vivo gene expression. Despite being imperative, it is incredibly challenging to precisely assess AAV particle distribution according to the sedimentation coefficient and identify impurities related to capsid structures. This study performed the systematic methodological validation of quantifying the AAV empty and full capsid ratio. This includes specificity, accuracy, precision, linearity, and parameter variables involving the sedimentation velocity analytical ultracentrifugation (SV-AUC) method. Specifically, SV-AUC differentiated among the empty, partial, full, and High Sedimentation Coefficient Substance (HSCS) AAV particles while evaluating their sedimentation heterogeneity. The intermediate precision analysis of HE (high percentage of empty capsid) and HF( high percentage of full capsid) samples revealed that the specific species percentage, such as empty or full, was more significant than 50%. Moreover, the RSD (relative standard deviation) could be within 5%. Even for empty or partial less than 15%, the RSD could be within 10%. The accuracy recovery rates of empty capsid were between 103.9% and 108.7% across three different mixtures. When the measured percentage of specific species was more significant than 14%, the recovery rate was between 77.9% and 106.6%. Linearity analysis revealed an excellent linear correlation between the empty, partial, and full in the HE samples. The AAV samples with as low as 7.4×1011 cp/mL AAV could be accurately quantified with SV-AUC. The parameter variable analyses revealed that variations in cell alignment significantly affected the overall results. Still, the detection wavelength of 235nm slightly influenced the empty, partial, and full percentages. Minor detection wavelength changes showed no impact on the sedimentation coefficient of these species. However, the temperature affected the measured sedimentation coefficient. These results validated the SV-AUC method to quantify AAV. This study provides solutions to AAV empty and full capsid ratio quantification challenges and the subsequent basis for calibrating the AAV empty capsid system suitability substance. Due to the AAV structure and potential variability complexity in detection, we jointly calibrated empty capsid system suitability substance with three laboratories to accurately detect the quantitative AAV empty and full capsid ratio. The empty capsid system suitability substance could be used as an external reference to measure the performance of the instrument. The results could be compared with multiple QC (quality control)laboratories based on the AAV vector and calibration accuracy. This is crucial for AUC to be used for QC release and promote gene therapy research worldwide.

Gold core@CeO2 halfshell Janus nanocomposites catalyze targeted sulfate radical for periodontitis therapy.

The sulfate radical (SO4•-), known for its high reactivity and long lifespan, has emerged as a potent antimicrobial agent. Its exceptional energy allows for the disruption of vital structures and metabolic pathways in bacteria that are usually inaccessible to common radicals. Despite its promising potential, the efficient generation of this radical, particularly through methods involving enzymes and photocatalysis, remains a substantial challenge. Here, we capitalized on the peroxidase (POD)-mimicking activity and photocatalytic properties of cerium oxide (CeO2) nanozymes, integrating these properties with the enhanced concept of plasma gold nanorod (GNR) to develop a half-encapsulated core@shell GNRs@CeO2 Janus heterostructure impregnated with persulfate. Under near-infrared irradiation, the GNRs generate hot electrons, thereby boosting the CeO2's enzyme-like activity and initiating a potent reactive oxygen species (ROS) storm. This distinct nanoarchitecture facilitates functional specialization, wherein the heterostructure and efficient light absorption ensured continuous hot electron flow, not only enhancing the POD-like activity of CeO2 for the production of SO4•- effectively, but also contributing a significant photothermal effect, disrupting periodontal plaque biofilm and effectively eradicating pathogens. Furthermore, the local temperature elevation synergistically enhances the POD-like activity of CeO2. Transcriptomics analysis, as well as animal experiments of the periodontitis model, have revealed that pathogens undergo genetic information destruction, metabolic disorders, and pathogenicity changes in the powerful ROS system, and profound therapeutic outcomes in vivo, including anti-inflammation and bone preservation. This study demonstrated that energy transfer to augment nanozyme activity, specifically targeting ROS generation, constitutes a significant advancement in antibacterial treatment.

Revisiting the Surface Brightness Profile of the Stellar Disk with the Statistical Mechanics of the Self-Gravitating System with the Central Body.

We have explored the exponential surface brightness profile (SBP) of stellar disks, a topic extensively discussed by many authors yet seldom integrated with the study of correlations between black holes, bulges, and entire disks. Building upon our prior work in the statistical mechanics of disk-shaped systems and aligning with methodologies from other research, we analyze the influence of the central body. This analysis reveals analytical relationships among black holes, bulges, and the entire stellar disk. Additionally, we incorporate a specific angular momentum distribution (SAMD) that aligns more closely with observational data, showing that for the self-gravitating disk, with the same surface density, a reduction in its spin results in only a slight decrease in its radius, whereas with the same SAMD, an increment in its spin significantly limits its extent. A key feature of our model is its prediction that the surface density profile of an isolated disk will invariably exhibit downbending at a sufficient distance, a hypothesis that future observations can test. Our refined equations provide a notably improved fit for SBPs, particularly in the central regions of stellar disks. While our findings underscore the significance of statistical mechanics in comprehending spiral galaxy structures, they also highlight areas in our approach that warrant further discussion and exploration.

Near-infrared light triggered upconversion nanocomposites with multifunction of enhanced antimicrobial photodynamic therapy and gas therapy for inflammation regulation.

Antibacterial photodynamic therapy (aPDT) is highly effective in killing bacteria, while the problem of hypoxia and limited light penetration in deep tissue has not been properly solved. In addition, few aPDT works take into account the regulation of inflammation, which is an important regulatory process after antimicrobial therapy and the final purpose of treatment. In this work, to address the above isssues, we have designed a multi-functional composite UCNPs-Ce6-Mn(CO)5Br@Silane (referred to as UCM@Si), which consists of several key components: Up-conversion nanoparticles (UCNPs: NaErF4:Tm3+@NaYF4:Yb3+), Chlorin e6 (Ce6) and Manganese pentacarbonyl bromide (Mn(CO)5Br). When exposed to near-infrared (NIR) light (980 nm), the UCNPs can emit strong red light at 655 nm which further trigger the aPDT of Ce6. The generated reactive oxygen (ROS) subsequently break the metal carbonyl bond of Mn(CO)5Br, leading to the production of carbon monoxide (CO) molecules as well as manganese ions (Mn2+), which further decomposes hydrogen peroxide (H2O2) in the microenvironment to oxygen (O2). Therefore, this simple nanocomposite not only provides substantial self-oxygen replenishment for enhanced aPDT, but also facilitates effective inflammation regulation via CO across a wide range of deep infections. This approach leverages the unique properties of these materials to combat bacterial infections by simultaneously killing bacteria, regulating inflammation, and enhancing the oxygen levels in the affected microenvironment. This O2 and CO gas based aPDT treatment system offers a promising approach to comprehensively address microbial-induced infectious diseases, particularly deep infections, holding the potential clinical applications.

NIR-Triggered Multifunctional NO Nanoplatform for Conquering Thermal Resistance in Biofilms.

Photothermal treatment (PTT) has emerged as a promising avenue for biofilm elimination, yet its potential drawbacks, such as local hyperpyrexia and bacterial heat resistance, have posed challenges. To address these concerns, an innovative nanoplatform (Au@mSiO2 -arg/ICG) is devised that integrates phototherapeutic and gas therapeutic functionalities. This multifaceted nanoplatform is composed of mesoporous silica-coated Au nanorods (Au@mSiO2 ), supplemented with l-arginine (l-arg) and indocyanine green (ICG), and is engineered for mild temperature PTT aimed at biofilm eradication. Au@mSiO2 -arg/ICG nanoparticles (NPs) show excellent antibacterial effects through the generation of nitric oxide (NO) gas, heat, and reactive oxygen species (ROS) under 808 nm light irradiation. The ROS generated by ICG initiates a cascade reaction with l-arg, ultimately yielding NO gas molecules. This localized release of NO not only effectively curbs the expression of heat shock proteins 70 mitigating bacterial thermoresistance, but also reduces extracellular polymeric substance allowing better penetration of the therapeutic agents. Furthermore, this nanoplatform achieves an outstanding biofilm elimination rate of over 99% in an abscess model under 808 nm light irradiation (0.8 W·cm-2 ), thereby establishing its potential as a dependable strategy for NO-enhanced mild PTT and antibacterial photodynamic therapy (aPDT) in clinical settings.

A superior heterologous prime-boost vaccination strategy against COVID-19: A bivalent vaccine based on yeast-derived RBD proteins followed by a heterologous vaccine.

Various vaccines have been challenged by SARS-CoV-2 variants. Here, we reported a yeast-derived recombinant bivalent vaccine (Bivalent wild-type [Wt]+De) based on the wt and Delta receptor-binding domain (RBD). Yeast derived RBD proteins based on the wt and Delta mutant were used as the prime vaccine. It was found that, in the presence of aluminium hydroxide (Alum) and unmethylated CpG-oligodeoxynucleotides (CpG) adjuvants, more cross-protective immunity against SARS-CoV-2 prototype and variants were elicited by bivalent vaccine than monovalent wtRBD or Delta RBD. Furthermore, a heterologous boosting strategy consisting of two doses of bivalent vaccines followed by one dose adenovirus vectored vaccine exhibited cross-neutralization capacity and specific T cell responses against Delta and Omicron (BA.1 and BA.4/5) variants in mice, superior to a homologous vaccination strategy. This study suggested that heterologous prime-boost vaccination with yeast-derived bivalent protein vaccine could be a potential approach to address the challenge of emerging variants.

Assessing the Feasibility and Safety of the Toumai® Robotic System in Urologic Surgery: Initial Experience.

Purpose Robotic surgery using da Vinci surgical system has gained prominence in urology, emerging robotic platforms are expanding its applications and increasing affordability. We assess the feasibility and safety of a novel system, the Toumai® robotic system in various urological surgeries. Methods This prospective study was conducted at the first affiliated hospital of Zhengzhou university. Twenty consecutive patients underwent renal and prostatic surgery with the Toumai®. The study assessed technical feasibility (conversion rate) and safety (perioperative complications) of the procedures as primary outcomes. Secondary endpoints included key surgical perioperative outcomes; functional and oncologic results. The Endoscopic Surgical System operates within a master-slave protocol, comprising a Surgeon Console, Patient Platform, and Vision Platform Results Seventeen patients underwent various nephrectomy procedures and three underwent radical prostatectomy. There was no conversion to alternative surgical approach, a single (Clavien-Dindo grade ≥3b) complication occurred and no readmission was recorded within 30 days. The median operative time was 120, 140, and 210 minutes for partial nephrectomy, radical nephrectomy and radical prostatectomy respectively. Off clamp partial nephrectomy was performed in one case and the warm ischemia time in the remaining two case was eighteen minutes. The median docking time was 22 minutes for nephrectomy and 20 minutes for radical prostatectomy, no major robotic malfunction was encountered. At three months follow-up, no tumor recurrence was recorded, renal function was well preserved and the continence status was satisfactory. Conclusions We present the initial clinical utilization of an innovative robotic platform. Complex urological interventions were successfully completed without conversions and with minimal complications. Further investigations are warranted to confirm these initial findings.

Approximation method for yielding support analysis in high ground stress soft surrounding rock tunnels.

In solving the whole process of interaction between soft rock and yielding support in high-stress environments in tunnels using mechanical analysis methods, it is challenging to simultaneously satisfy both displacement coordination and static equilibrium at the contact surface between the rock and the support structure. This paper, based on the mechanical analysis of rock and rigid support, considers the impact of the circumferential installation of yielding elements on radial displacement, and proposes displacement approximation and support force approximation methods using displacement coordination and static equilibrium as approximation conditions. The study fits curves of numerical simulation results and laboratory test results of yielding elements, and attempts to directly use the laboratory test data set of yielding elements as computational data. By calculating two circular tunnel examples and comparing the effects of the trisection method, bisection method, and substitution method on the convergence of the displacement approximation method, the effectiveness of the methods proposed in this paper is verified. The research results show that the two approximation algorithms proposed in this paper have good accuracy and reliability in calculating the relative displacement of rock and yielding support structure contact surfaces, and the support force of yielding support. The bisection method outperforms the trisection and substitution methods in terms of stability and convergence. However, there are certain limitations in this study, such as the effectiveness of the algorithm may be influenced by geological conditions; the complexity of actual geological conditions may exceed the assumptions of the current rock-support mechanical analysis model.

Age-, sex- and proximal-distal-resolved multi-omics identifies regulators of intestinal aging in non-human primates.

The incidence of intestinal diseases increases with age, yet the mechanisms governing gut aging and its link to diseases, such as colorectal cancer (CRC), remain elusive. In this study, while considering age, sex and proximal-distal variations, we used a multi-omics approach in non-human primates (Macaca fascicularis) to shed light on the heterogeneity of intestinal aging and identify potential regulators of gut aging. We explored the roles of several regulators, including those from tryptophan metabolism, in intestinal function and lifespan in Caenorhabditis elegans. Suggesting conservation of region specificity, tryptophan metabolism via the kynurenine and serotonin (5-HT) pathways varied between the proximal and distal colon, and, using a mouse colitis model, we observed that distal colitis was more sensitive to 5-HT treatment. Additionally, using proteomics analysis of human CRC samples, we identified links between gut aging and CRC, with high HPX levels predicting poor prognosis in older patients with CRC. Together, this work provides potential targets for preventing gut aging and associated diseases.

Breaking Iron Homeostasis: Iron Capturing Nanocomposites for Combating Bacterial Biofilm.

Given the scarcity of novel antibiotics, the eradication of bacterial biofilm infections poses formidable challenges. Upon bacterial infection, the host restricts Fe ions, which are crucial for bacterial growth and maintenance. Having coevolved with the host, bacteria developed adaptive pathways like the hemin-uptake system to avoid iron deficiency. Inspired by this, we propose a novel strategy, termed iron nutritional immunity therapy (INIT), utilizing Ga-CT@P nanocomposites constructed with gallium, copper-doped tetrakis (4-carboxyphenyl) porphyrin (TCPP) metal-organic framework, and polyamine-amine polymer dots, to target bacterial iron intakes and starve them. Owing to the similarity between iron/hemin and gallium/TCPP, gallium-incorporated porphyrin potentially deceives bacteria into uptaking gallium ions and concurrently extracts iron ions from the surrounding bacteria milieu through the porphyrin ring. This strategy orchestrates a "give and take" approach for Ga3+/Fe3+ exchange. Simultaneously, polymer dots can impede bacterial iron metabolism and serve as real-time fluorescent iron-sensing probes to continuously monitor dynamic iron restriction status. INIT based on Ga-CT@P nanocomposites induced long-term iron starvation, which affected iron-sulfur cluster biogenesis and carbohydrate metabolism, ultimately facilitating biofilm eradication and tissue regeneration. Therefore, this study presents an innovative antibacterial strategy from a nutritional perspective that sheds light on refractory bacterial infection treatment and its future clinical application.

A versatile upconversion-based multimode lateral flow platform for rapid and ultrasensitive detection of microRNA towards health monitoring.

MicroRNAs are small single-stranded RNA molecules associated with gene expression and immune response, suggesting their potential as biomarkers for health monitoring. Herein, we designed a novel upconversion-based multimode lateral flow assay (LFA) system to detect microRNAs in body fluids by simultaneously producing three unique signals within a detection strip. The core-shell Au-DTNB@Ag nanoparticles act as both the Raman reporters and acceptors, quenching fluorescence from upconversion nanoparticles (UCNPs, NaYF4: Yb3+, Er3+) via the Förster resonance energy transfer mechanism. Using microRNA-21 as a representative analyte, the LFA system offers remarkable detection range from 2 nM to 1 fM, comparable to outcomes from signal amplification methods, due to the successful single-layer self-assembly of UCNPs on the NC membrane, which greatly enhances both the convenience and sensitivity of the LFA technique. Additionally, our proprietary fluorescence-Raman detection platform simplifies result acquisition by reducing procedural intricacies. The biosensor, when evaluated with diverse bodily fluids, showed remarkable selectivity and sustained stability. Importantly, our LFA biosensor effectively identified periodontitis and lung cancer patients from healthy subjects in genuine samples, indicating significant potential for disease prediction, early diagnosis, and progression tracking. This system holds promise as a multifunctional tool for various biomarker assays.

Efficient and Stable Multicolor Emissions of the Coumarin-Modified Cs3LnCl6 Lead-Free Perovskite Nanocrystals and LED Application.

Lanthanide-based lead-free perovskite materials hold great promise for the development of high-resolution full-color displays in the future. Here, various Cs3LnCl6 perovskite nanocrystals (NCs) emitting light across the visible to near-infrared spectrum with remarkably high photoluminescence quantum yield (PLQY) are systemically prepared. Especially, by introducing multifunctional coumarin small molecules into Cs3EuCl6 NCs as an intermediate state, Cs3EuCl6 NCs can achieve an impressive PLQY of 92.4% with pure red emission and an exceptional energy transfer efficiency of nearly 93.2%. Furthermore, the lanthanide-based electroluminescent devices in red, green, and blue are successfully fabricated. Among them, the Cs3EuCl6-NC-based red light-emitting diode (LED) demonstrates a FWHM of 18 nm at 617 nm, an external quantum efficiency up to 5.17%, and a maximum brightness of 2373 cd m-2, which is the most excellent reported for lead-free narrowband (within 20 nm) emission devices. Notably, these devices exhibit an operating half-life of 440 h at a brightness level of 100 cd m-2, surpassing the performance of most reported lead-free perovskite LEDs (PLEDs). This work opens up exciting possibilities for the future commercialization of lanthanide-based PLEDs in the display industry, paving the way for more vibrant, energy-efficient, and long-lasting display technologies.

New mechanism for the participation of aromatic oxidation products in atmospheric nucleation.

Oxygenated organic molecules (OOMs) are recognized as important precursors for new particle formation (NPF) in the urban atmosphere. The paper theoretically studied the formation of OOMs by styrene oxidation processes initiated by OH radicals, focusing on the OOMs nucleation mechanism. The results found that in the presence of an H2SO4 molecule, lowly oxygenated organic molecules containing a benzene ring (LOMBs) can form stable clusters and grow to the scale of a critical nucleus through pi-pi stacking and OH hydrogen bonding. In addition, LOMBs are more readily generated in a styrene-oxidized system in the presence/absence of NOx than highly oxygenated organic molecules (HOMs). The reaction of OH radicals with other aromatics containing a branched chain on the benzene ring produces LOMBs to varying degrees, with pi-pi stacking playing an essential role. This result suggests that, in the presence of H2SO4 molecules, LOMBs may play a more significant role in promoting nucleation than HOMs. Our findings serve as a pivotal foundation for future investigations into the oxidation and nucleation processes of diverse aromatics in urban environments.

Machine Learning Developed a MYC Expression Feature-Based Signature for Predicting Prognosis and Chemoresistance in Pancreatic Adenocarcinoma.

MYC has been identified to profoundly influence a wide range of pathologic processes in cancers. However, the prognostic value of MYC-related genes in pancreatic adenocarcinoma (PAAD) remains unclarified. Gene expression data and clinical information of PAAD patients were obtained from The Cancer Genome Atlas (TCGA) database (training set). Validation sets included GSE57495, GSE62452, and ICGC-PACA databases. LASSO regression analysis was used to develop a risk signature for survival prediction. Single-cell sequencing data from GSE154778 and CRA001160 datasets were analyzed. Functional studies were conducted using siRNA targeting RHOF and ITGB6 in PANC-1 cells. High MYC expression was found to be significantly associated with a poor prognosis in patients with PAAD. Additionally, we identified seven genes (ADGRG6, LINC00941, RHOF, SERPINB5, INSYN2B, ITGB6, and DEPDC1) that exhibited a strong correlation with both MYC expression and patient survival. They were then utilized to establish a risk model (MYCsig), which showed robust predictive ability. Furthermore, MYCsig demonstrated a positive correlation with the expression of HLA genes and immune checkpoints, as well as the chemotherapy response of PAAD. RHOF and ITGB6, expressed mainly in malignant cells, were identified as key oncogenes regulating chemosensitivity through EMT. Downregulation of RHOF and ITGB6 reduced cell proliferation and invasion in PANC-1 cells. The developed MYCsig demonstrates its potential in enhancing the management of patients with PAAD by facilitating risk assessment and predicting response to adjuvant chemotherapy. Additionally, our study identifies RHOF and ITGB6 as novel oncogenes linked to EMT and chemoresistance in PAAD.

High-Performance Blue Perovskite Light-Emitting Diodes Enabled by Synergistic Effect of Additives.

While quasi-two-dimensional (quasi-2D) perovskites have good properties of cascade energy transfer, high exciton binding energy, and high quantum efficiency, which will benefit high-efficiency blue PeLEDs, inefficient domain distribution management and unbalanced carrier transport impede device performance improvement. Herein, (2-(9H-carbazol-9-yl)ethyl)phosphonic acid (2PACz) and methyl 2-aminopyridine-4-carboxylate (MAC) were simultaneously introduced to a blue quasi-2D perovskite film. Relying on the synergistic effect of 2PACz and MAC, it not only modulates the phase distribution inhibiting the n = 2 phase but also greatly improves the electrical property of the quasi-2D perovskite film. As a result, the as-modified blue quasi-2D PeLED demonstrated an external quantum efficiency (EQE) of 17.08% and a luminance of 10142 cd m-2. This study exemplifies the synergistic effect among dual additives and offers a new effective additive strategy modulating phase distribution and building balanced carrier transport, which paves the way for the fabrication of highly efficient blue PeLEDs.

Bacteroides thetaiotaomicron ameliorates mouse hepatic steatosis through regulating gut microbial composition, gut-liver folate and unsaturated fatty acids metabolism.

Gut microbiota plays an essential role in the progression of nonalcoholic fatty liver disease (NAFLD), making the gut-liver axis a potential therapeutic strategy. Bacteroides genus, the enriched gut symbionts, has shown promise in treating fatty liver. However, further investigation is needed to identify specific beneficial Bacteroides strains for metabolic disorders in NAFLD and elucidate their underlying mechanisms. In this study, we observed a positive correlation between the abundance of Bacteroides thetaiotaomicron (B. theta) and the alleviation of metabolic syndrome in the early and end stages of NAFLD. Administration of B. theta to HFD-fed mice for 12 weeks reduced body weight and fat accumulation, decreased hyperlipidemia and insulin resistance, and prevented hepatic steatohepatitis and liver injury. Notably, B. theta did not affect these indicators in low-fat diet (LFD)-fed mice and exhibited good safety. Mechanistically, B. theta regulated gut microbial composition, characterized by a decreased Firmicutes/Bacteroidetes ratio in HFD-Fed mice. It also increased gut-liver folate levels and hepatic metabolites, alleviating metabolic dysfunction. Additionally, treatment with B. theta increased the proportion of polyunsaturated fatty acid in the mouse liver, offering a widely reported benefit for NAFLD improvement. In conclusion, this study provides evidence that B. theta ameliorates NAFLD by regulating gut microbial composition, enhancing gut-liver folate and unsaturated fatty acid metabolism, highlighting the therapeutic role of B. theta as a potential probiotic for NAFLD.

Species pool, local assembly processes: Disentangling the mechanisms determining bacterial α- and ß-diversity during forest secondary succession.

Across ecology, and particularly within microbial ecology, there is limited understanding how the generation and maintenance of diversity. Although recent work has shown that both local assembly processes and species pools are important in structuring microbial communities, the relative contributions of these mechanisms remain an important question. Moreover, the roles of local assembly processes and species pools are drastically different when explicitly considering the potential for saturation or unsaturation, yet this issue is rarely addressed. Thus, we established a conceptual model that incorporated saturation theory into the microbiological domain to advance the understanding of mechanisms controlling soil bacterial diversity during forest secondary succession. Conceptual model hypotheses were tested by coupling soil bacterial diversity, local assembly processes and species pools using six different forest successional chronosequences distributed across multiple climate zones. Consistent with the unsaturated case proposed in our conceptual framework, we found that species pool consistently affected α-diversity, even while local assembly processes on local richness operate. In contrast, the effects of species pool on ß-diversity disappeared once local assembly processes were taken into account, and changes in environmental conditions during secondary succession led to shifts in ß-diversity through mediation of the strength of heterogeneous selection. Overall, this study represents one of the first to demonstrate that most local bacterial communities might be unsaturated, where the effect of species pool on α-diversity is robust to the consideration of multiple environmental influences, but ß-diversity is constrained by environmental selection.

Investigation of rare earth-based magnetic nanocomposites for specific enrichment of exosomes from human plasma.

Exosomes, also known as small extracellular vesicles, are widely present in a variety of body fluids (e.g., blood, urine, and saliva). Exosomes are becoming an alternative promising source of diagnostic markers for disease rich in cargo of metabolites, proteins, and nucleic acids. However, due to the low abundance and structure similarity with protein complex, the efficient isolation of exosomes is one of the most important issues for biomedical applications. With a higher order of f-orbitals in rare earth element, it will have strong adsorption toward the phosphate group on the surface of the phospholipid bilayer of exosomes. In this study, we systematically investigated the ability of various rare earths interacting with phosphate-containing molecules and plasma exosomes. One of the best binding europium was selected and used to synthesize core-shell magnetic nanomaterials (Fe3O4@SiO2@Eu2O3) for the enrichment of exosomes from human plasma. The developed nanomaterials exhibited higher enrichment capacity, less time consumption and more convenient handling compared to commonly used ultracentrifugation method. The nanomaterials were applied to separate exosomes from the plasma of patients with hepatocellular carcinoma and healthy controls for metabolomics study with high-resolution mass spectrometry, where 70 differentially expressed metabolites were identified, involving amino acid and lipid metabolic pathway. We anticipated the rare earth-based materials to be an alternative approach on exosome isolation for disease diagnosis or postoperative clinical monitoring.

Pathogen-Activated Macrophage Membrane Encapsulated CeO2 -TCPP Nanozyme with Targeted and Photo-Enhanced Antibacterial Therapy.

Nanozymes with peroxidase-mimic activity have recently emerged as effective strategies for eliminating infections. However, challenges in enhancing catalytic activities and the ability to target bacteria have hindered the broader application of nanozymes in bacterial infections. Herein, a novel nanozyme based on mesoporous CeO2 nanosphere and meso-tetra(4-carboxyphenyl)porphine (TCPP) encapsulated within pathogen-activated macrophage membranes, demonstrates photodynamic capability coupled with photo-enhanced chemodynamic therapy for selective and efficient antibacterial application against infected wounds. Interestingly, the expression of Toll-like receptors accordingly upregulates when macrophages are co-cultured with specific bacteria, thereby facilitating to recognition of the pathogen-associated molecular patterns originating from bacteria. The CeO2 not only serve as carriers for TCPP, but also exhibit intrinsic peroxidase-like catalytic activity. Consequently, Staphylococcus aureus (S. aureus)-activated macrophage membrane-coated CeO2 -TCPP (S-MM@CeO2 -TCPP) generated singlet oxygen, and simultaneously promoted photo-enhanced chemodynamic therapy, significantly boosting reactive oxygen species (ROS) to effectively eliminate bacteria. S-MM@CeO2 -TCPP specifically targeted S. aureus via Toll-like receptor, thereby directly disrupting bacterial structural integrity to eradicate S. aureus in vitro and relieve bacteria-induced inflammation to accelerate infected wound healing in vivo. By selectively targeting specific bacteria and effectively killing pathogens, such strategy provides a more efficient and reliable alternative for precise elimination of pathogens and inflammation alleviation in microorganism-infected wounds.

ALS-linked C9orf72-SMCR8 complex is a negative regulator of primary ciliogenesis.

Massive GGGGCC (G4C2) repeat expansion in C9orf72 and the resulting loss of C9orf72 function are the key features of ~50% of inherited amyotrophic lateral sclerosis and frontotemporal dementia cases. However, the biological function of C9orf72 remains unclear. We previously found that C9orf72 can form a stable GTPase activating protein (GAP) complex with SMCR8 (Smith-Magenis chromosome region 8). Herein, we report that the C9orf72-SMCR8 complex is a major negative regulator of primary ciliogenesis, abnormalities in which lead to ciliopathies. Mechanistically, the C9orf72-SMCR8 complex suppresses the primary cilium as a RAB8A GAP. Moreover, based on biochemical analysis, we found that C9orf72 is the RAB8A binding subunit and that SMCR8 is the GAP subunit in the complex. We further found that the C9orf72-SMCR8 complex suppressed the primary cilium in multiple tissues from mice, including but not limited to the brain, kidney, and spleen. Importantly, cells with C9orf72 or SMCR8 knocked out were more sensitive to hedgehog signaling. These results reveal the unexpected impact of C9orf72 on primary ciliogenesis and elucidate the pathogenesis of diseases caused by the loss of C9orf72 function.