A gut-derived hormone regulates cholesterol metabolism.

The reciprocal coordination between cholesterol absorption in the intestine and de novo cholesterol synthesis in the liver is essential for maintaining cholesterol homeostasis, yet the mechanisms governing the opposing regulation of these processes remain poorly understood. Here, we identify a hormone, Cholesin, which is capable of inhibiting cholesterol synthesis in the liver, leading to a reduction in circulating cholesterol levels. Cholesin is encoded by a gene with a previously unknown function (C7orf50 in humans; 3110082I17Rik in mice). It is secreted from the intestine in response to cholesterol absorption and binds to GPR146, an orphan G-protein-coupled receptor, exerting antagonistic downstream effects by inhibiting PKA signaling and thereby suppressing SREBP2-controlled cholesterol synthesis in the liver. Therefore, our results demonstrate that the Cholesin-GPR146 axis mediates the inhibitory effect of intestinal cholesterol absorption on hepatic cholesterol synthesis. This discovered hormone, Cholesin, holds promise as an effective agent in combating hypercholesterolemia and atherosclerosis.

OGA mutant aberrantly hydrolyzes O-GlcNAc modification from PDLIM7 to modulate p53 and cytoskeleton in promoting cancer cell malignancy.

O-GlcNAcase (OGA) is the only human enzyme that catalyzes the hydrolysis (deglycosylation) of O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) from numerous protein substrates. OGA has broad implications in many challenging diseases including cancer. However, its role in cell malignancy remains mostly unclear. Here, we report that a cancer-derived point mutation on the OGA's noncatalytic stalk domain aberrantly modulates OGA interactome and substrate deglycosylation toward a specific set of proteins. Interestingly, our quantitative proteomic studies uncovered that the OGA stalk domain mutant preferentially deglycosylated protein substrates with +2 proline in the sequence relative to the O-GlcNAcylation site. One of the most dysregulated substrates is PDZ and LIM domain protein 7 (PDLIM7), which is associated with the tumor suppressor p53. We found that the aberrantly deglycosylated PDLIM7 suppressed p53 gene expression and accelerated p53 protein degradation by promoting the complex formation with E3 ubiquitin ligase MDM2. Moreover, deglycosylated PDLIM7 significantly up-regulated the actin-rich membrane protrusions on the cell surface, augmenting the cancer cell motility and aggressiveness. These findings revealed an important but previously unappreciated role of OGA's stalk domain in protein substrate recognition and functional modulation during malignant cell progression.

Observation of Chiral Channels in Helical Covalent Organic Frameworks.

Unraveling the mechanism of chirality transfer across length scales is crucial to the rational development of functional materials with hierarchical chirality. The key obstacle is the lack of structural information, especially at the mesoscopic level. We report herein the structural identification of helical covalent organic frameworks (heliCOFs) with hierarchical chirality, which integrate molecular chirality, channel chirality, and morphology chirality into one crystalline entity. Specifically, benefiting from the highly ordered structure of heliCOFs, the existence of chiral channels at the mesoscopic level has been confirmed by electron crystallography, and the handedness of these chiral channels has been directly determined through the stereopair imaging technique. Accordingly, the chirality transfer in heliCOFs from microscopic to macroscopic levels could be rationalized with a layer-rotating model that has been supported by both crystal structure analysis and theoretical calculations. Observation of chiral channels in heliCOFs not only provides unprecedented data for the understanding of the chirality transfer process but also sheds new light on the rational construction of highly ordered polymeric materials with hierarchical chirality.

Causal role of lipid metabolism in pulmonary alveolar proteinosis: an observational and mendelian randomisation study.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease characterised by the accumulation of lipoprotein material in the alveoli. Although dyslipidaemia is a prominet feature, the causal effect of lipid traits on PAP remains unclear. This study aimed to explore the role of lipid traits in PAP and evaluate the potential of lipid-lowering drug targets in PAP. METHODS: Clinical outcomes, lipid profiles and lung function tests were analysed in a clinical cohort of diagnosed PAP patients and propensity score-matched healthy controls. Genome-wide association study data on PAP, lipid metabolism, blood cells and variants of genes encoding potential lipid-lowering drug targets were obtained for Mendelian randomisation (MR) and mediation analyses. FINDINGS: Observational results showed that higher levels of total cholesterol (TC), triglycerides and low-density lipoprotein (LDL) were associated with increased risks of PAP. Higher levels of TC and LDL were also associated with worse PAP severity. In MR analysis, elevated LDL was associated with an increased risk of PAP (OR: 4.32, 95% CI: 1.63 to 11.61, p=0.018). Elevated monocytes were associated with a lower risk of PAP (OR 0.34, 95% CI: 0.18 to 0.66, p=0.002) and mediated the risk impact of LDL on PAP. Genetic mimicry of PCSK9 inhibition was associated with a reduced risk of PAP (OR 0.03, p=0.007). INTERPRETATION: Our results support the crucial role of lipid and metabolism-related traits in PAP risk, emphasising the monocyte-mediated, causal effect of elevated LDL in PAP genetics. PCSK9 mediates the development of PAP by raising LDL. These finding provide evidence for lipid-related mechanisms and promising lipid-lowering drug target for PAP.

11-Plex DiLeu Isobaric Labeling Enables Quantitative Assessment of Brain Region Protein Association Networks Impacted by the Gut Microbiome.

Gut microbiota can regulate host brain functions and influence various physiological and pathological processes through the brain-gut axis. To systematically elucidate the intervention of different gut environments on different brain regions, we implemented an integrated approach that combines 11-plex DiLeu isobaric tags with a "BRIDGE" normalization strategy to comparatively analyze the proteome of six brain regions in germ-free (GF)- and conventionally raised (ConvR)-mice. A total of 5945 proteins were identified and 5656 were quantifiable, while 1906 of them were significantly changed between GF- and ConvR-mice; 281 proteins were filtered with FC greater than 1.2 in at least one brain region, of which heatmap analysis showed clear protein profile disparities, both between brain regions and gut microbiome conditions. Gut microbiome impact is most overt in the hypothalamus and the least in the thalamus region. Collectively, this approach allows an in-depth investigation of the induced protein changes by multiple gut microbiome environments in a brain region-specific manner. This comprehensive proteomic work improves the understanding of the brain region protein association networks impacted by the gut microbiome and highlights the critical roles of the brain-gut axis.

Ru-Doped NiFe-MIL-53 with Facilitated Reconstruction and Active Hydrogen Supplement for Enhanced Nitrate Reduction.

The Electrochemical reduction of nitrate to ammonia (NH3) is a process of great significance to energy utilization and environmental protection. However, it suffers from sluggish multielectron/proton-involved steps involving coupling reactions between different reaction intermediates and active hydrogen species (Hads) produced by water decomposition. In this study, a Ru-doped NiFe-MIL-53 (NiFeRu-MIL-53) supported on Ni foam (NF) has been designed for the nitrate reduction reaction (NO3RR). The NiFeRu-MIL-53 exhibits excellent NO3RR activity with a maximum Faradaic efficiency (FE) of 100% at -0.4 V vs. RHE for NH3 and a maximum NH3 yield of 62.39 mg h-1 cm-2 at -0.7 V vs. RHE in alkaline media. This excellent performance for the NO3RR is attributed to a strong synergistic effect between Ru and reconstructed NiFe(OH)2. Additionally, the doped Ru facilitates water dissociation, leading to an appropriate supply of Hads required for N species hydrogenation during NO3RR, thereby further enhancing its performance. Furthermore, in situ Raman analysis reveals that incorporating Ru facilitates the reconstruction of MOFs and promotes the formation of hydroxide active species during the NO3RR process. This work provides a valuable strategy for designing electrocatalysts to improve the efficiency of the reduction of electrochemical nitrate to ammonia.

Diagnostic value of D-dimer to fibrinogen ratio for pulmonary embolism in postpartum women.

BACKGROUND: Pulmonary embolism is a common disease associated with high mortality and morbidity. Diagnosing pulmonary embolism is challenging due to diverse clinical presentations and the lack of specific biomarkers. The study aimed to investigate the diagnostic value on pulmonary embolism for postpartum women by D-dimer to fibrinogen ratio, and it combined with neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio. METHODS: A total of 537 women with suspected pulmonary embolism were selected as the research subjects from the Shanghai First Maternity and Infant Hospital between 1 January 2019 and 31 October 2022. The D-dimer to fibrinogen ratio and it combined with neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio were applied to evaluate the clinical probability of pulmonary embolism, and the positive predictive value of both scores were calculated using computed tomography pulmonary arteriography as a gold standard. The diagnostic value of D-dimer to fibrinogen ratio, combined with neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio was evaluated by the area under the curve, sensitivity, specificity, and other indicators in the receiver operator characteristic curve. RESULTS: Among the 502 women included for analysis, 194 (38.65%) were definitely diagnosed as pulmonary embolism. The positive predictive values of D-dimer to fibrinogen ratio and it combined with platelet-to-lymphocyte ratio or neutrophil-to-lymphocyte ratio were 70.1%, 50.5%, and 56.5%, respectively in the postpartum women, the area under the curve for the D-dimer to fibrinogen ratio and it combined with platelet-to-lymphocyte ratio or neutrophil-to-lymphocyte ratio were 0.606 (95%CI: 0.562-0.650), 0.624 (95%CI: 0.575-0.673), and 0.639 (95%CI: 0.592-0.686), respectively. The negative predictive values of D-dimer to fibrinogen ratio, it combined with platelet-to-lymphocyte ratio or neutrophil-to-lymphocyte ratio were 50.5%, 70.1%, and 69.8%, respectively. CONCLUSION: The diagnostic value of the D-dimer to fibrinogen ratio was higher than the D-dimer for the postpartum women with suspected pulmonary embolism. The combination of either the neutrophil-to-lymphocyte ratio or the platelet-to-lymphocyte ratio with D-dimer to fibrinogen ratio is an appropriate strategy to rule out pulmonary embolism.

High-performance pyrite nano-catalyst driven photothermal/chemodynamic synergistic therapy for Osteosarcoma.

Osteosarcoma (OS) is an aggressive bone tumor with strong invasiveness, rapid metastasis, and dreadful mortality. Chemotherapy is a commonly used approach for OS treatment but is limited by the development of drug resistance and long-term adverse effects. To date, OS still lacks the curative treatment. Herein, we fabricated pyrite-based nanoparticles (FeS2@CP NPs) as synergetic therapeutic platform by integrating photothermal therapy (PTT) and chemo-dynamic therapy (CDT) into one system. The synthetic FeS2@CP NPs showed superior Fenton reaction catalytic activity. FeS2@CP NPs-based CDT efficaciously eradicated the tumor cells by initiating dual-effect of killing of apoptosis and ferroptosis. Furthermore, the generated heat from FeS2@CP under near-infrared region II (NIR-II) laser irradiation could not only inhibit tumor's growth, but also promote tumor cell apoptosis and ferroptosis by accelerating •OH production and GSH depletion. Finally, the photothermal/NIR II-enhanced CDT synergistic therapy showed excellent osteosarcoma treatment effects both in vitro and in vivo with negligible side effects. Overall, this work provided a high-performance and multifunctional Fenton catalyst for osteosarcoma synergistic therapy, which provided a pathway for the clinical application of PTT augmented CDT.

The transcriptional elongation factor CTR9 demarcates PRC2-mediated H3K27me3 domains by altering PRC2 subtype equilibrium.

CTR9 is the scaffold subunit in polymerase-associated factor complex (PAFc), a multifunctional complex employed in multiple steps of RNA Polymerase II (RNAPII)-mediated transcription. CTR9/PAFc is well known as an evolutionarily conserved elongation factor that regulates gene activation via coupling with histone modifications enzymes. However, little is known about its function to restrain repressive histone markers. Using inducible and stable CTR9 knockdown breast cancer cell lines, we discovered that the H3K27me3 levels are strictly controlled by CTR9. Quantitative profiling of histone modifications revealed a striking increase of H3K27me3 levels upon loss of CTR9. Moreover, loss of CTR9 leads to genome-wide expansion of H3K27me3, as well as increased recruitment of PRC2 on chromatin, which can be reversed by CTR9 restoration. Further, CTR9 depletion triggers a PRC2 subtype switch from the less active PRC2.2, to the more active PRC2.1 with higher methyltransferase activity. As a consequence, CTR9 depletion generates vulnerability that renders breast cancer cells hypersensitive to PRC2 inhibitors. Our findings that CTR9 demarcates PRC2-mediated H3K27me3 levels and genomic distribution provide a unique mechanism that explains the transition from transcriptionally active chromatin states to repressive chromatin states and sheds light on the biological functions of CTR9 in development and cancer.

Real-world effectiveness and predictors of super-responders to dupilumab in a Chinese uncontrolled asthma cohort.

Background: Dupilumab has been shown to be effective in clinical trials for moderate-to-severe uncontrolled asthma. However, the efficacy of dupilumab in the real world and the prediction of treatment response have not been well studied in patients with asthma. Objective: To investigate the efficacy of dupilumab and explore predictors of super-responders in a Chinese retrospective cohort. Methods: From January 2021 through December 2022, the patients with uncontrolled asthma who were treated with dupilumab for 4 months were included. Symptom control, type 2 inflammatory biomarkers, and lung function were collected at baseline and follow-up for efficacy assessment. Super-responders were defined as exacerbation-free, off maintenance of oral corticosteroids (mOCS), and with a score of the five-item Asthma Control Questionnaire (ACQ-5) of <0.5. The uni- and multivariable logistic regressions were used to construct predictive models for super-responders based on baseline features. Results: A total of 53 patients were included. After 4 months treatment, the median (interquartile range [IQR]) ACQ-5 score decreased from 1.8 (1.6-2.4) to 0.4 (0.2-0.8) (p < 0.001), the median (IQR) number of exacerbations, from 0.0 (0.0-1.0) to 0.0 (0.0-0.0) (p = 0.005). The median (IQR) dose of mOCS (prednisone equivalent) decreased from 15.0 mg/day (8.8-22.5 mg/day) to 2.5 mg/day (0.0-10.0 mg/day) (p = 0.008) in nine patients who were receiving mOCS. All efficacy assessment parameters, including sputum eosinophil were significantly improved, while blood eosinophil count did not decline (530 cells/mm³ [300-815 cells/mm³] versus 560 cells/mm³ [220-938 cells/mm³], p = 0.710). After taking dupilumab, 25 of 53 patients (47.2%) achieved a super-response. The age of onset < 42 years (odds ratio [OR] 7.471 [95% confidence interval {CI}, 1.286-43.394) and the baseline fractional exhaled nitric oxide (FeNO) of 25-50 ppb (OR 35.038 [95% CI, 3.104-395.553]) predicted super-responders, which showed a C-index of 0.822 (95% CI, 0.697-0.947). Conclusion: Dupilumab significantly improved symptom control, type 2 inflammatory markers, and lung function in Chinese patients with uncontrolled asthma. Airway eosinophils, rather than blood eosinophils, can be a reliable indicator of therapeutic efficacy. The early-onset asthma as well as the medium-high level of baseline FeNO contributed to the prediction of super-responders.

Structure and Defect Engineering Synergistically Boost High Solar-to-Chemical Conversion Efficiency of Cerium oxide/Au Hollow Nanomushrooms for Nitrogen Photofixation.

Photocatalytic nitrogen fixation using solar illumination under ambient conditions is a promising strategy for production of the indispensable chemical NH3 . However, due to the catalyst's limitations in solar energy utilization, loss of hot electrons during transfer, and low nitrogen adsorption and activation capacity, the unsatisfactory solar-to-chemical conversion (SCC) efficiencies of most photocatalysts limit their practical applications. Herein, cerium oxide nanosheets with abundant strain-VO defects were anchored on Au hollow nanomushroom through atomically sharp interfaces to construct a novel semiconductor/plasmonic metal hollow nanomushroom-like heterostructure (denoted cerium oxide-AD/Au). Plasmonic Au extended the absorption of light from the visible to the second near-infrared region. The superior interface greatly enhanced the transfer efficiency of hot electrons. Abundant strain-VO defects induced by interfacial compressive strain promoted adsorption and in situ activation of nitrogen, and such synergistic promotion of strain and VO defects was further confirmed by density functional theory calculations. The judicious structural and defect engineering co-promoted the efficient nitrogen photofixation of the cerium oxide-AD/Au heterostructures with a SCC efficiency of 0.1 % under simulated AM 1.5G solar illumination, which is comparable to the average solar-to-biomass conversion efficiency of natural photosynthesis by typical plants, thus exhibiting significant potential as a new candidate for artificial photosynthesis.

ATP-Coated Dual-Functionalized Titanium(IV) IMAC Material for Simultaneous Enrichment and Separation of Glycopeptides and Phosphopeptides.

Protein glycosylation and phosphorylation are two of the most common post-translational modifications (PTMs), which play an important role in many biological processes. However, low abundance and poor ionization efficiency of phosphopeptides and glycopeptides make direct MS analysis challenging. In this study, we developed a hydrophilicity-enhanced bifunctional Ti-IMAC (IMAC: immobilized metal affinity chromatography) material with grafted adenosine triphosphate (denoted as epoxy-ATP-Ti4+) to enable simultaneous enrichment and separation of common N-glycopeptides, phosphopeptides, and M6P glycopeptides from tissue/cells. The enrichment was achieved through a dual-mode mechanism based on the electrostatic and hydrophilic properties of the material. The epoxy-ATP-Ti4+ IMAC material was prepared from epoxy-functionalized silica particles via a convenient two-step process. The ATP molecule provided strong and active phosphate sites for binding phosphopeptides in the conventional IMAC mode and also contributed significantly to the hydrophilicity, which permitted the enrichment of glycopeptides via hydrophilic interaction chromatography. The two modes could be implemented simultaneously, allowing glycopeptides and phosphopeptides to be collected sequentially in a single experiment from the same sample. In addition to standard protein samples, the material was further applied to glycopeptide and phosphopeptide enrichment and characterization from HeLa cell digests and mouse lung tissue samples. In total, 2928 glycopeptides and 3051 phosphopeptides were identified from the mouse lung tissue sample, supporting the utility of this material for large-scale PTM analysis of complex biological samples. Overall, the newly developed epoxy-ATP-Ti4+ IMAC material and associated fractionation method enable simple and effective enrichment and separation of glycopeptides and phosphopeptides, offering a useful tool to study potential crosstalk between these two important PTMs in biological systems. The MS data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD029775.

Structural basis of Blastomyces Endoglucanase-2 adjuvancy in anti-fungal and -viral immunity.

The development of safe subunit vaccines requires adjuvants that augment immunogenicity of non-replicating protein-based antigens. Current vaccines against infectious diseases preferentially induce protective antibodies driven by adjuvants such as alum. However, the contribution of antibody to host defense is limited for certain classes of infectious diseases such as fungi, whereas animal studies and clinical observations implicate cellular immunity as an essential component of the resolution of fungal pathogens. Here, we decipher the structural bases of a newly identified glycoprotein ligand of Dectin-2 with potent adjuvancy, Blastomyces endoglucanase-2 (Bl-Eng2). We also pinpoint the developmental steps of antigen-specific CD4+ and CD8+ T responses augmented by Bl-Eng2 including expansion, differentiation and tissue residency. Dectin-2 ligation led to successful systemic and mucosal vaccination against invasive fungal infection and Influenza A infection, respectively. O-linked glycans on Bl-Eng2 applied at the skin and respiratory mucosa greatly augment vaccine subunit- induced protective immunity against lethal influenza and fungal pulmonary challenge.

Integrated analyzes identify CCT3 as a modulator to shape immunosuppressive tumor microenvironment in lung adenocarcinoma.

BACKGROUND: Chaperonin-containing tailless complex polypeptide 1 (TCP1) subunit 3 (CCT3) has tumor-promoting effects in lung adenocarcinoma (LUAD). This study aims to investigate the molecular mechanisms of CCT3 in LUAD oncogenesis. METHODS: The UALCAN databases, Human Protein Atlas (HPA) and The Cancer Genome Atlas (TCGA) data were used to analyze CCT3 expression in LUAD. Both the Wilcoxon rank-sum test and the regression model were used to investigate the connection between clinicopathologic characteristics of LUAD patients and CCT3 expression. The prognostic value of CCT3 was determined by Cox regression models, the Kaplan-Meier method and Nomogram prediction. Next, we identified the most related genes with CCT3 via GeneMANIA and String databases, and the association between CCT3 and infiltrated immune cells using single-sample Gene Set Enrichment Analysis (ssGSEA). CCT3-related pathway enrichment analysis was investigated by GSEA. Finally, CCT3 roles in cell proliferation and apoptosis of LUAD A549 cells was verified by siRNA (small interfering RNA) mediated CCT3 knockdown. RESULTS: CCT3 was upregulated in LUAD both in mRNA and protein levels. CCT3 overexpression was associated with clinicopathological characteristics including sex, smoking, T- and N-categories, pathological staging, and a poor prognosis of LUAD patients. GeneMANIA and String databases found a set of CCT3-related genes that are connected to the assembly and stability of proteins involved in proteostasis of cytoskeletal filaments, DNA repair and protein methylation. Furthermore, CCT3 was found to be positively correlated with the infiltrating Th2 cells (r = 0.442, p < 0.01) while negatively correlated with mast cells (r = -0.49, p < 0.01) and immature dendritic cells (iDCs, r = -0.401, p < 0.001) according to ssGSEA analyzes. The pathway analysis based on GSEA method showed that the cell cycle pathway, the protein export pathway, the proteasome pathway and the ribosome pathway are enriched in CCT3 high group, whereas the JAK/STAT pathway, B cell receptor pathway, T cell receptor pathway and toll like receptor pathway were enriched in CCT3 low group. Finally, CCT3 knockdown substantially inhibited proliferation while promoted apoptosis of A549 cells. CONCLUSION: Integrated analyzes identify CCT3 as a modulator to shape immunosuppressive tumor microenvironment in LUAD and therefore, a prognostic factor for LUAD.

Selenite-Decorated Polycrystalline NiO Nanosheets Generated from Cathodic Reconstruction for Electrocatalytic Hydrogen Production.

Precatalyst reconstruction in alkaline hydrogen evolution reaction (HER) usually leads to changes in the morphology, composition, and structure, thus improving the catalytic activity, which recently receives intensive attention. However, the design strategies of cathodic reconstruction and the structural features of reconstruction products have not achieved a profound understanding. Here, from the point of thermodynamic stability, metastable nickel selenite dihydrate (NiSeO3·2H2O) is deliberately fabricated as a precatalyst to comprehensively study the reconstruction dynamics in alkaline HER. Multiple in/ex situ techniques capture the geometric, component, and phase evolutions, proving that NiSeO3·2H2O can be transformed into SeO32--decorated polycrystalline NiO nanosheets with rich active sites and good conductivity under alkaline HER conditions, which act as a real catalytic active species. Density functional theory calculations demonstrate that the adsorption of SeO32- can further promote the HER activity of NiO due to the optimized free energy of water activation and hydrogen adsorption. As a result, the SeO32--NiO catalyst exhibits a low overpotential at -10 mA cm-2 (90 mV) and long-term stability (>100 h). This work highlights the targeted design of precatalyst to trigger and utilize cathodic reconstruction and provides an available method for the development of adsorption-modulated efficient electrocatalysts.

In-depth Site-specific Analysis of N-glycoproteome in Human Cerebrospinal Fluid and Glycosylation Landscape Changes in Alzheimer's Disease.

As the body fluid that directly interchanges with the extracellular fluid of the central nervous system (CNS), cerebrospinal fluid (CSF) serves as a rich source for CNS-related disease biomarker discovery. Extensive proteome profiling has been conducted for CSF, but studies aimed at unraveling site-specific CSF N-glycoproteome are lacking. Initial efforts into site-specific N-glycoproteomics study in CSF yield limited coverage, hindering further experimental design of glycosylation-based disease biomarker discovery in CSF. In the present study, we have developed an N-glycoproteomic approach that combines enhanced N-glycopeptide sequential enrichment by hydrophilic interaction chromatography (HILIC) and boronic acid enrichment with electron transfer and higher-energy collision dissociation (EThcD) for large-scale intact N-glycopeptide analysis. The application of the developed approach to the analyses of human CSF samples enabled identifications of a total of 2893 intact N-glycopeptides from 511 N-glycosites and 285 N-glycoproteins. To our knowledge, this is the largest site-specific N-glycoproteome dataset reported for CSF to date. Such dataset provides molecular basis for a better understanding of the structure-function relationships of glycoproteins and their roles in CNS-related physiological and pathological processes. As accumulating evidence suggests that defects in glycosylation are involved in Alzheimer's disease (AD) pathogenesis, in the present study, a comparative in-depth N-glycoproteomic analysis was conducted for CSF samples from healthy control and AD patients, which yielded a comparable N-glycoproteome coverage but a distinct expression pattern for different categories of glycoforms, such as decreased fucosylation in AD CSF samples. Altered glycosylation patterns were detected for a number of N-glycoproteins including alpha-1-antichymotrypsin, ephrin-A3 and carnosinase CN1 etc., which serve as potentially interesting targets for further glycosylation-based AD study and may eventually lead to molecular elucidation of the role of glycosylation in AD progression.

The Novel Application of Robotic-Assisted Bronchoscopy Combined with Photodynamic Therapy for Adenoid Cystic Carcinoma of the Trachea.

Robotic platforms have been widely used in the various fields of clinical diagnosis and therapy of diseases in the past decade. Robotic-assisted bronchoscopy (RAB) demonstrates its advantages of visibility, flexibility, and stability in comparison to conventional bronchoscopic techniques. Improving diagnostic yield and navigation yield for peripheral pulmonary lesions has been defined; however, RAB platform of treatment was not reported. In this article, we report a case of a 52-year-old woman who was diagnosed with the tracheal adenoid cystic carcinoma and recurred in the second postoperative year, leading to the involvement of the entire tracheal wall and lumen obstruction. Since the lesion was inoperable, we combined RAB and photodynamic therapy (PDT) for the patient. The potential advantages of using RAB for PDT delivery include precise light irradiation of target lesions and stable intra-operative control over the long term. This is a novel application of RAB combined with PDT for airway diseases. The case report may provide a new insight into the diagnosis and treatment of pulmonary diseases. In addition to improving the diagnostic rates, the RAB platform may also play an important role in the treatment of airway and lung disease in the future.

5G-Based Remote Virtual Bronchoscopic Navigation-Guided Transbronchial Lung Biopsy for Diagnosis of Lung Cancer: Description of 2 Cases.

INTRODUCTION: Bronchoscopic navigation combined with endobronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB) is an important approach for the diagnosis of peripheral pulmonary lesions (PPL). The fifth-generation (5G) network, characterized by low latency and high stability, has shown promising possibilities in telemedicine for remote areas. METHODS: We present two cases of PPL in primary hospitals without navigation equipment. The EBUS-TBLB was performed with the guidance of remote augmented reality virtual bronchoscopic navigation (VBN) based on a 5G network. In practice, the 5G network could enable the matching of actual/virtual bronchoscopic images and navigation paths in real time, as well as high-speed transmission at long distances (>20 km), without any visual delay (<500 ms). CONCLUSION: Both patients were successfully diagnosed with lung cancer after accurate positioning and obtaining biopsies of target lesions. This 5G-based remote VBN-guided EBUS-TBLB appears to be safe with reliable connections in both cases and shows potential for cost-effectiveness. It would be an optimal resource for undeveloped regions and/or regions lacking endoscopists with extensive experience in navigation-related procedures.

The Association Between Insulin Use and Asthma: An Epidemiological Observational Analysis and Mendelian Randomization Study.

BACKGROUND: Asthma is a common respiratory disease caused by genetic and environmental factors, but the contribution of insulin use to the risk of asthma remains unclear. This study aimed to investigate the association between insulin use and asthma in a large population-based cohort, and further explore their causal relationship by Mendelian randomization (MR) analysis. METHODS: An epidemiological study including 85,887 participants from the National Health and Nutrition Examination Survey (NHANES) 2001-2018 was performed to evaluate the association between insulin use and asthma. Based on the inverse-variance weighted approach, MR analysis were conducted to estimate the causal effect of insulin use on asthma from the UKB and FinnGen datasets, respectively. RESULTS: In the NHANES cohort, we found that insulin use was associated with an increased risk of asthma [odd ratio (OR) 1.38; 95% CI 1.16-1.64; p < 0.001]. For the MR analysis, we found a causal relationship between insulin use and a higher risk of asthma in both Finn (OR 1.10; p < 0.001) and UK Biobank cohorts (OR 1.18; p < 0.001). Meanwhile, there was no causal association between diabetes and asthma. After multivariable adjustment for diabetes in UKB cohort, the insulin use remained significantly associated with an increased risk of asthma (OR 1.17, p < 0.001). CONCLUSIONS: An association between insulin use and an increased risk of asthma was found via the real-world data from the NHANES. In addition, the current study identified a causal effect and provided a genetic evidence of insulin use and asthma. More studies are needed to elucidate the mechanisms underlying the association between insulin use and asthma.

Selective Enrichment of Sialylglycopeptides Enabled by Click Chemistry and Dynamic Covalent Exchange.

Despite the important roles of protein sialylation in biological processes such as cellular interaction and cancer progression, simple and effective methods for the analysis of intact sialylglycopeptides (SGPs) are still limited. Analyses of low-abundance SGPs typically require efficient enrichment prior to comprehensive liquid chromatography-mass spectrometry (LC-MS)-based analysis. Here, a novel workflow combining mild periodate oxidation, hydrazide chemistry, copper-catalyzed azide/alkyne cycloaddition (CuAAC) click chemistry, and dynamic covalent exchange has been developed for selective enrichment of SGPs. The intact SGPs could be separated easily from protein tryptic digests, and the signature ions were produced during LC-MS/MS for unambiguous identification. The structure of the signature ions and corresponding dynamic covalent exchange were confirmed by using an isotopic reagent. Under the optimized condition, over 70% enrichment efficiency of SGPs was achieved using bovine fetuin digests, and the method was successfully applied to complex biological samples, such as a mouse lung tissue extract. The high enrichment efficiency, good reproducibility, and easily adopted procedure without the need to generate specialized materials make this method a promising tool for broad applications in SGP analysis.