Effect of moxibustion on plasma amino acid metabolism in rats with knee osteoarthritis. / è‰¾ç¸å¯¹è†å ³èŠ‚éª¨å ³èŠ‚ç‚Žå¤§é¼ è¡€æµ†æ°¨åŸºé ¸ä»£è°¢çš„å½±å“.

OBJECTIVES: To observe the effect of moxibustion at "Zusanli "(ST36) on the plasma amino acid metabolism in rats with knee osteoarthritis (KOA), and to explore the amino acid metabolism mechanism of moxibustion in repairing cartilage injury in KOA. METHODS: A total of 30 SD rats were randomly divided into normal, model and moxibustion groups, with 10 rats in each group. Rats in the model and moxibustion groups were injected with the mixture of L-cysteine and papain into bilateral knee joint cavity to make the KOA model. The moxibustion group received moxibustion at bilateral ST36 for 30 min, once daily for 30 days. At the end of the experiment, the swelling degree of knee joint was calculated, the mechanical pain threshold was measured by the Von Frey filament, the cartilage tissue injury was observed by HE staining, the matrix metalloproteinase-13 (MMP-13) content in the synovial tissue was detected by enzyme-linked immunosorbent assay (ELISA), and the differential amino acid metabolites in plasma were detected and screened by liquid chromatography-mass spectrometry (LC-MS). RESULTS: Compared with the normal group, the model group showed irregular cartilage surface, decreased number of chondrocytes, uneven distribution, and local clusters of chondrocytes；the contour of the tide line was blurred. The degree of joint swelling in the model group was higher than that in the normal group (P<0.01), the mechanical pain threshold was lower (P<0.01), and the content of MMP-13 in synovial tissue was higher (P<0.01). The contents of proline and tryptophan in the model group were down-regulated (P<0.01, P<0.05). Compared with the model group, the cartilage tissue damage and knee joint swelling were decreased(P<0.05), mechanical pain threshold was increased(P<0.05), MMP-13 content in synovial tissue and levels of glutamate and histidine expression were decreased (P<0.01, P<0.05). CONCLUSIONS: Moxibustion at ST36 significantly alleviated arthritis-related swelling and pain in KOA model rats, attenuated cartilage damage, and regulated levels of certain plasma amino acid metabolites. Moxibustion may regulate KOA cartilage synthesis and degradation through amino acid metabolic pathways such as proline, tryptophan, glutamate and histidine, exerting anti-inflammatory, analgesic, and protection of cartilage injury effects.

A simple and efficient approach for preparing cationic coating with tunable electroosmotic flow for capillary zone electrophoresis-mass spectrometry-based top-down proteomics.

BACKGROUND: Capillary zone electrophoresis-tandem mass spectrometry (CZE-MS/MS) has become a valuable analytical technique in top-down proteomics (TDP). CZE-MS/MS-based TDP typically employs separation capillaries with neutral coatings (i.e., linear polyacrylamide, LPA). However, issues related to separation resolution and reproducibility remain with the LPA-coated capillaries due to the unavoidable non-specific protein adsorption onto the capillary wall. Cationic coatings can be critical alternatives to LPA coating for CZE-MS/MS-based TDP due to the electrostatic repulsion between the positively charged capillary inner wall and proteoform molecules in the acidic separation buffer. Unfortunately, there are only very few studies using cationic coating-based CZE-MS/MS for TDP studies. RESULTS: In this work, we aimed to develop a simple and efficient approach for preparing separation capillaries with a cationic coating, i.e., poly (acrylamide-co-(3-acrylamidopropyl) trimethylammonium chloride [PAMAPTAC]) for CZE-MS/MS-based TDP. The PAMAPTAC coating-based CZE-MS produced significantly better separation resolution of proteoforms compared to the traditionally used LPA-coated approach. It achieved reproducible separation and measurement of a simple proteoform mixture and a complex proteome sample (i.e., a yeast cell lysate) regarding migration time, proteoform intensity, and the number of proteoform identifications. The PAMAPTAC coating-based CZE-MS enabled the detection of large proteoforms (≥30 kDa) from the yeast cell lysate reproducibly without any size-based prefractionation. Interestingly, the mobility of proteoforms using the PAMAPTAC coating can be predicted accurately using a simple semi-empirical model. SIGNIFICANCE: The results render the PAMAPTAC coating as a valuable alternative to the LPA coating to advance CZE-MS-based TDP towards high-resolution separation and highly reproducible measurement of proteoforms in complex samples.

Mass Spectrometry-Based Top-Down Proteomics in Nanomedicine: Proteoform-Specific Measurement of Protein Corona.

Conventional mass spectrometry (MS)-based bottom-up proteomics (BUP) analysis of the protein corona [i.e., an evolving layer of biomolecules, mostly proteins, formed on the surface of nanoparticles (NPs) during their interactions with biomolecular fluids] enabled the nanomedicine community to partly identify the biological identity of NPs. Such an approach, however, fails to pinpoint the specific proteoforms─distinct molecular variants of proteins in the protein corona. The proteoform-level information could potentially advance the prediction of the biological fate and pharmacokinetics of nanomedicines. Recognizing this limitation, this study pioneers a robust and reproducible MS-based top-down proteomics (TDP) technique for characterizing proteoforms in the protein corona. Our TDP approach has successfully identified about 900 proteoforms in the protein corona of polystyrene NPs, ranging from 2 to 70 kDa, revealing proteoforms of 48 protein biomarkers with combinations of post-translational modifications, signal peptide cleavages, and/or truncations─details that BUP could not fully discern. This advancement in MS-based TDP offers a more advanced approach to characterize NP protein coronas, deepening our understanding of NPs' biological identities. We, therefore, propose using both TDP and BUP strategies to obtain more comprehensive information about the protein corona, which, in turn, can further enhance the diagnostic and therapeutic efficacy of nanomedicine technologies.

PNLDC1 catalysis and postnatal germline function are required for piRNA trimming, LINE1 silencing, and spermatogenesis in mice.

PIWI-interacting RNAs (piRNAs) play critical and conserved roles in transposon silencing and gene regulation in the animal germline. Three distinct piRNA populations are present during mouse spermatogenesis: fetal piRNAs in fetal/perinatal testes, pre-pachytene and pachytene piRNAs in postnatal testes. PNLDC1 is required for piRNA 3' end maturation in multiple species. However, whether PNLDC1 is the bona fide piRNA trimmer and the physiological role of 3' trimming of different piRNA populations in spermatogenesis in mammals remain unclear. Here, by inactivating Pnldc1 exonuclease activity in vitro and in mice, we reveal that the PNLDC1 trimmer activity is essential for spermatogenesis and male fertility. PNLDC1 catalytic activity is required for both fetal and postnatal piRNA 3' end trimming. Despite this, postnatal piRNA trimming but not fetal piRNA trimming is critical for LINE1 transposon silencing. Furthermore, conditional inactivation of Pnldc1 in postnatal germ cells causes LINE1 transposon de-repression and spermatogenic arrest in mice, indicating that germline-specific postnatal piRNA trimming is essential for transposon silencing and germ cell development. Our findings highlight the germ cell-intrinsic role of PNLDC1 and piRNA trimming in mammals to safeguard the germline genome and promote fertility.

Native Proteomics by Capillary Zone Electrophoresis-Mass Spectrometry.

Native proteomics measures endogenous proteoforms and protein complexes under a near physiological condition using native mass spectrometry (nMS) coupled with liquid-phase separations. Native proteomics should provide the most accurate bird's-eye view of proteome dynamics within cells, which is fundamental for understanding almost all biological processes. nMS has been widely employed to characterize well-purified protein complexes. However, there are only very few trials of utilizing nMS to measure proteoforms and protein complexes in a complex sample (i.e., a whole cell lysate). Here, we pioneer the native proteomics measurement of large proteoforms or protein complexes up to 400 kDa from a complex proteome via online coupling of native capillary zone electrophoresis (nCZE) to an ultra-high mass range (UHMR) Orbitrap mass spectrometer. The nCZE-MS technique enabled the measurement of a 115-kDa standard protein complex while consuming only about 0.1 ng of protein material. nCZE-MS analysis of an E.coli cell lysate detected 72 proteoforms or protein complexes in a mass range of 30-400 kDa in a single run while consuming only 50-ng protein material. The mass distribution of detected proteoforms or protein complexes agreed well with that from mass photometry measurement. This work represents a technical breakthrough in native proteomics for measuring complex proteomes.

Multi-Tissue Integrated Tissue-Engineered Trachea Regeneration Based on 3D Printed Bioelastomer Scaffolds.

Functional segmental trachea reconstruction is a critical concern in thoracic surgery, and tissue-engineered trachea (TET) holds promise as a potential solution. However, current TET falls short in fully restoring physiological function due to the lack of the intricate multi-tissue structure found in natural trachea. In this research, a multi-tissue integrated tissue-engineered trachea (MI-TET) is successfully developed by orderly assembling various cells (chondrocytes, fibroblasts and epithelial cells) on 3D-printed PGS bioelastomer scaffolds. The MI-TET closely resembles the complex structures of natural trachea and achieves the integrated regeneration of four essential tracheal components: C-shaped cartilage ring, O-shaped vascularized fiber ring, axial fiber bundle, and airway epithelium. Overall, the MI-TET demonstrates highly similar multi-tissue structures and physiological functions to natural trachea, showing promise for future clinical advancements in functional TETs.

[Long-term effect observation after 10 years of tonsillotomy （Histological analysis of one case of secondary operation）].

Objective:To investigate the long-term effect of partial tonsillectomy in children with tonsil hypertrophy. Methods:A total of 146 children with obstructive sleep apnea（OSA） who received surgical treatment for tonsil hyperplasia from January 2010 to January 2013 were selected and divided into the observation group（n=69） and the control group（n=77）. The observation group was received tonsillotomy（TT）, and the control group was received total tonsillectomy（TE）. Parental satisfaction and OSA quality of life questionnaire for children（OSA-18） were surveyed. Residual tonsil size was measured, and polysomnography（PSG） was monitored after 10 years. HE and immunohistochemical analysis were performed on tonsil tissues of one patient who performed a second operation after TT in 2017 year. Results:The results of questionnaire survey showed that the symptoms of respiratory obstruction were significantly improved in both groups, and the satisfaction of TT group was higher than that in the TE group. No increase in the number of respiratory tract infections was observed in all patients. In the TT group, nine cases（13.04%） had tonsil hyperplasia toⅡ°, and the remaining patients had tonsil hyperplasia to Ⅰ°. In addition, one case hadtonsil suppurative infection at the 14th month after surgery, and no recurrence or reoperation was found after treatment. There were seven cases in the TT group and eight cases in the TE group with occasional snoring and mouth breathing after surgery, but the PSG examination of the patients did not meet the diagnosis of OSA. The main causes were obesity and allergic rhinitis. Compared with the first operation, the cicatricial obstruction and infection of tonsil tissue in the second operation were not significantly changed, and the immunohistochemical results also demonstrated that the expression of CD20 was not changed, and the expression of CD3 was decreased. Conclusion:Both TT and TE can effectively improve the symptoms of OSA obstruction in children. TT has less trauma, less postoperative pain, faster recovery and lower rate of hyperplasia, which can be used as one of the main methods for the treatment of tonsil hypertrophy in children.

Effects of air pollutants exposure on frailty risk: A systematic review and meta-analysis.

Air pollutants have been investigated to be associated with many health issues. Recently, increasing epidemiological studies have suggested the association between air pollution exposure and risk of frailty with inconsistent findings. This systematic review and meta-analysis was to summarize and evaluate effects of exposure to various air pollutants on risk of frailty. PubMed, Embase, Scopus and Web of Science were systematically searched for relevant studies published before May 11, 2024. Studies that explored the potential relationship between exposure to air pollutants (PM2.5, PM10, O3, NOx, solid fuel, secondhand tobacco, and air quality) and risk of frailty were included. The quality of cross-sectional and cohort studies was evaluated using an eight-item assessment instrument for epidemiological studies and Newcastle-Ottawa Scale, respectively. A total of 9,929 papers were retrieved, of which 20 met the inclusion criteria. Meta-analysis indicated that PM2.5 exposure was significantly associated with frailty assessed by the frailty index [OR (95% CI): 1.24 (1,11-1.38) per 10 µg/m3 increment]. Moreover, solid fuel exposures were significantly associated with an increased risk of frailty assessed by the frailty phenotype [OR (95% CI): 1.91 (1.09-3.34)] or the frailty index [OR (95% CI): 1.25 (1.11-1.41)]. Exposure to PM2.5 and solid fuel increases the risk of frailty. Environmental protection policies and public health measures should be developed to reduce PM2.5 concentrations. Effective measures, such as improving stoves and using clean fuels, should be taken to reduce indoor air pollution levels.

Delicate and thin fibrous septa indicate a regression tendency in metabolic dysfunction-associated steatohepatitis patients with advanced fibrosis.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH)-related fibrosis is reversible. However, the dynamic morphology change in fibrosis regression remains unclear. We aim to explore the morphological characteristics of fibrosis regression in advanced MASH patients. METHODS: Clinical and histological data of 79 biopsy-proved MASH patients with advanced fibrosis (F3-F4) were reviewed. The second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) image technology was used to quantitatively identify the R (regressive) septa from P (progressive) septa and PS (perisinusoidal) fibrosis. Non-invasive tests were used to compare the fibrosis level with and without R septa groups. Transcriptomics was used to explore hub genes and the underlying mechanism of the formation of R septa. RESULTS: The R septa were different from the P septa and PS fibrosis in detail collagen quantitation identified by SHG/TPEF technology. The R septa were found in MASH fibrosis-regressed patients, which met the definition of the "Beijing classification". Therefore, patients were divided into two groups according to septa morphology: with R septa (n = 10, 12.7%), and without R septa (n = 69, 87.3%). Patients with R septa had lower values in most non-invasive tests, especially for liver stiffness assessed by TE (12.3 vs. 19.4 kPa, p = 0.010) and FAST (FibroScan®-AST) score (0.43 vs. 0.70, p = 0.003). Transcriptomics analysis showed that the expressions of five hub fibrogenic genes, including Col3A1, BGN, Col4A1, THBS2, and Col4A2 in the R septa group, were significantly lower. CONCLUSIONS: The R septa can be differentiated from the P septa and PS fibrosis by quantitative assessment of SHG/TPEF, and it represents a tendency of fibrosis regression in MASH patients. TRIAL REGISTRATION: NCT03386890, 29/12/2017.

Combining SDS-PAGE to capillary zone electrophoresis-tandem mass spectrometry for high-resolution top-down proteomics analysis of intact histone proteoforms.

Mass spectrometry (MS)-based top-down proteomics (TDP) analysis of histone proteoforms provides critical information about combinatorial post-translational modifications (PTMs), which is vital for pursuing a better understanding of epigenetic regulation of gene expression. It requires high-resolution separations of histone proteoforms before MS and tandem MS (MS/MS) analysis. In this work, for the first time, we combined SDS-PAGE-based protein fractionation (passively eluting proteins from polyacrylamide gels as intact species for mass spectrometry, PEPPI-MS) with capillary zone electrophoresis (CZE)-MS/MS for high-resolution characterization of histone proteoforms. We systematically studied the histone proteoform extraction from SDS-PAGE gel and follow-up cleanup as well as CZE-MS/MS, to determine an optimal procedure. The optimal procedure showed reproducible and high-resolution separation and characterization of histone proteoforms. SDS-PAGE separated histone proteins (H1, H2, H3, and H4) based on their molecular weight and CZE provided additional separations of proteoforms of each histone protein based on their electrophoretic mobility, which was affected by PTMs, for example, acetylation and phosphorylation. Using the technique, we identified over 200 histone proteoforms from a commercial calf thymus histone sample with good reproducibility. The orthogonal and high-resolution separations of SDS-PAGE and CZE made our technique attractive for the delineation of histone proteoforms extracted from complex biological systems.

Causal effects of denture wearing on epigenetic age acceleration and the mediating pathways: a mendelian randomization study.

BACKGROUND: The epigenetic-age acceleration (EAA) represents the difference between chronological age and epigenetic age, reflecting accelerated biological aging. Observational studies suggested that oral disorders may impact DNA methylation patterns and aging, but their causal relationship remains largely unexplored. This study aimed to investigate potential causal associations between dental traits and EAA, as well as to identify possible mediators. METHODS: Using summary statistics of genome-wide association studies of predominantly European ancestry, we conducted univariable and multivariable Mendelian randomization (MR) to estimate the overall and independent effects of ten dental traits (dentures, bleeding gums, painful gums, loose teeth, toothache, ulcers, periodontitis, number of teeth, and two measures of caries) on four EAA subtypes (GrimAge acceleration [GrimAA], PhenoAge acceleration [PhenoAA], HannumAge acceleration [HannumAA] and intrinsic EAA [IEAA]), and used two-step Mendelian randomization to evaluate twelve potential mediators of the associations. Comprehensive sensitivity analyses were used to verity the robustness, heterogeneity, and pleiotropy. RESULTS: Univariable inverse variance weighted MR analyses revealed a causal effect of dentures on greater GrimAA (ß: 2.47, 95% CI: 0.93-4.01, p = 0.002), PhenoAA (ß: 3.00, 95% CI: 1.15-4.85, p = 0.001), and HannumAA (ß: 1.96, 95% CI: 0.58-3.33, p = 0.005). In multivariable MR, the associations remained significant after adjusting for periodontitis, caries, number of teeth and bleeding gums. Three out of 12 aging risk factors were identified as mediators of the association between dentures and EAA, including body mass index, body fat percentage, and waist circumference. No evidence for reverse causality and pleiotropy were detected (p > 0.05). CONCLUSIONS: Our findings supported the causal effects of genetic liability for denture wearing on epigenetic aging, with partial mediation by obesity. More attention should be paid to the obesity-monitoring and management for slowing EAA among denture wearers.

No genetic association between sleep traits and periodontitis: A bidirectional two-sample Mendelian randomization study.

OBJECTIVE: This study aimed to investigate the potential genetic link between sleep traits and periodontitis. METHODS: A two-sample bidirectional Mendelian randomization (MR) analysis was conducted using publicly available genome-wide association studies data on chronotype, daytime sleepiness, daytime napping frequency, insomnia, sleep duration, snoring, and the apnea-hypopnea index (AHI), along with a separate dataset on periodontitis. RESULTS: Chronotype (OR = 0.929, 95% CI = 0.788-1.095), daytime sleepiness (OR = 0.492, 95% CI = 0.186-1.306), daytime napping frequency (OR = 1.178, 95% CI = 0.745-1.863), sleep duration (OR = 0.868, 95% CI = 0.644-1.169), AHI (OR = 1.124, 95% CI = 0.980-1.289), insomnia (OR = 0.832, 95% CI = 0.440-1.573), and snoring (OR = 0.641, 95% CI = 0.198-2.075) had no effect on periodontitis. Similarly, periodontitis demonstrated no significant effect on sleep traits. CONCLUSIONS: There is no evidence of a bidirectional genetic relationship between sleep traits and the risk of periodontitis.

Mass spectrometry-intensive top-down proteomics: an update on technology advancements and biomedical applications.

Proteoforms are all forms of protein molecules from the same gene because of variations at the DNA, RNA, and protein levels, e.g., alternative splicing and post-translational modifications (PTMs). Delineation of proteins in a proteoform-specific manner is crucial for understanding their biological functions. Mass spectrometry (MS)-intensive top-down proteomics (TDP) is promising for comprehensively characterizing intact proteoforms in complex biological systems. It has achieved substantial progress in technological development, including sample preparation, proteoform separations, MS instrumentation, and bioinformatics tools. In a single TDP study, thousands of proteoforms can be identified and quantified from a cell lysate. It has also been applied to various biomedical research to better our understanding of protein function in regulating cellular processes and to discover novel proteoform biomarkers of diseases for early diagnosis and therapeutic development. This review covers the most recent technological development and biomedical applications of MS-intensive TDP.

Causal effects of autoimmune diseases on temporomandibular disorders and the mediating pathways: a Mendelian randomization study.

Background: The role of autoimmune diseases (ADs) in temporomandibular disorders (TMDs) has been emphasized in observational studies. However, whether the causation exists is unclear, and controversy remains about which specific disorder is destructive in TMDs. This Mendelian randomization (MR) study aims to estimate the causal effect of common ADs on TMDs. Methods: Genetic data from published genome-wide association studies for fourteen common ADs, specifically multiple sclerosis (MS, N = 15,283), ankylosing spondylitis (AS, N = 22,647), asthma (N = 408,422), celiac disease (N = 15,283), Graves' disease (N = 458,620), Hashimoto thyroiditis (N = 395,640), primary biliary cirrhosis (PBC, N = 11,375), primary sclerosing cholangitis (PSC, N = 14,890), psoriasis vulgaris (N = 483,174), rheumatoid arthritis (RA, N = 417,256), systemic lupus erythematosus (SLE, N = 23,210), Type 1 diabetes (T1D, N = 520,580), inflammatory bowel disease (IBD, N = 34,652), and Sjogren's syndrome (SS, N = 407,746) were collected. Additionally, the latest summary-level data for TMDs (N = 228,812) were extracted from the FinnGen database. The overall effects of each immune traits were assessed via inverse-variance weighted (IVW), weighted median, and MR-Egger methods, and performed extensive sensitivity analyses. Finally, 731 immune cell phenotypes (N = 3,757) were analyzed for their mediating role in the significant causality. Results: Univariable MR analyses revealed that genetically predicted RA (IVW OR: 1.12, 95% CI: 1.05-1.19, p < 0.001) and MS (IVW OR: 1.06, 95% CI: 1.03-1.10, p = 0.001) were associated with increased risk of TMDs. Two out of 731 immune cell phenotypes were identified as causal mediators in the associations of RA with TMDs, including "CD25++ CD8+ T cell % CD8+ T cell" (mediation proportion: 6.2%) and "CD3 on activated CD4 regulatory T cell" (5.4%). Additionally, "CD127 on granulocyte" mediated 10.6% of the total effect of MS on TMDs. No reverse directions, heterogeneity, and pleiotropy were detected in the analyses (p > 0.05). Conclusion: This MR study provides new evidence regarding the causal impact of genetic predisposition to RA or MS on the increased risk of TMDs, potentially mediated by the modulation of immune cells. These findings highlight the importance for clinicians to pay more attention to patients with RA or MS when consulting for temporomandibular discomfort. The mediating role of specific immune cells is proposed but needs further investigation.

Native Proteomics by Capillary Zone Electrophoresis-Mass Spectrometry.

Native proteomics measures endogenous proteoforms and protein complexes under a near physiological condition using native mass spectrometry (nMS) coupled with liquid-phase separations. Native proteomics should provide the most accurate bird's-eye view of proteome dynamics within cells, which is fundamental for understanding almost all biological processes. nMS has been widely employed to characterize well-purified protein complexes. However, there are only very few trials of utilizing nMS to measure proteoforms and protein complexes in a complex sample (i.e., a whole cell lysate). Here, we pioneer the native proteomics measurement of large proteoforms or protein complexes up to 400 kDa from a complex proteome via online coupling of native capillary zone electrophoresis (nCZE) to an ultra-high mass range (UHMR) Orbitrap mass spectrometer. The nCZE-MS technique enabled the measurement of a 115-kDa standard protein complex while consuming only about 0.1 ng of protein material. nCZE-MS analysis of an E . coli cell lysate detected 72 proteoforms or protein complexes in a mass range of 30-400 kDa in a single run while consuming only 50-ng protein material. The mass distribution of detected proteoforms or protein complexes agreed well with that from mass photometry measurement. This work represents a technical breakthrough in native proteomics for measuring complex proteomes.

Integrating Radiomics and Neural Networks for Knee Osteoarthritis Incidence Prediction.

OBJECTIVE: Accurately predicting knee osteoarthritis (KOA) is essential for early detection and personalized treatment. We aimed to develop and test a magnetic resonance imaging (MRI)-based joint space (JS) radiomic model (RM) to predict radiographic KOA incidence through neural networks by integrating meniscus and femorotibial cartilage radiomic features. METHODS: In the Osteoarthritis Initiative cohort, participants with knees without radiographic KOA at baseline but at high risk for radiographic KOA were included. Patients' knees developed radiographic KOA, whereas control knees did not over four years. We randomly split the participants into development and test cohorts (8:2) and extracted features from baseline three-dimensional double-echo steady-state sequence MRI. Model performance was evaluated using an area under the receiver operating characteristic curve (AUC), sensitivity, and specificity in both cohorts. Nine resident surgeons performed the reader experiment without/with the JS-RM aid. RESULTS: Our study included 549 knees in the development cohort (275 knees of patients with KOA vs 274 knees of controls) and 137 knees in the test cohort (68 knees of patients with KOA vs 69 knees of controls). In the test cohort, JS-RM had a favorable accuracy for predicting the radiographic KOA incidence with an AUC of 0.931 (95% confidence interval [CI] 0.876-0.963), a sensitivity of 84.4% (95% CI 83.9%-84.9%), and a specificity of 85.6% (95% CI 85.2%-86.0%). The mean specificity and sensitivity of resident surgeons through MRI reading in predicting radiographic KOA incidence were increased from 0.474 (95% CI 0.333-0.614) and 0.586 (95% CI 0.429-0.743) without the assistance of JS-RM to 0.874 (95% CI 0.847-0.901) and 0.812 (95% CI 0.742-0.881) with JS-RM assistance, respectively (P < 0.001). CONCLUSION: JS-RM integrating the features of the meniscus and cartilage showed improved predictive values in radiographic KOA incidence.

Copy number deletion of PLA2G4A affects the susceptibility and clinical phenotypes of schizophrenia.

Phospholipase A2(PLA2) superfamily is recognized as being involved in the pathogenesis of schizophrenia by affecting lipid homeostasis in cell membranes. We hypothesized that PLA2 gene copy number variation (CNV) may affect PLA2 enzyme expression and be associated with schizophrenia risk. This study indicated that in the discovery stage, an increased copy number of PLA2G6 and the deletion of PLA2G3, PLA2G4A, PLA2G4F and PLA2G12F was associated with increased risk of schizophrenia. CNV segments involving six PLA2 genes were detected in publicly available datasets, including two deletion segments specific to the PLA2G4A gene. The relationship between the deletion of PLA2G4A and susceptibility to schizophrenia was then reaffirmed in the validation group of 806 individuals. There was a significant correlation between PLA2G4A deletion and the symptoms of poverty of thought in male patients and erotomanic delusion in females. Furthermore, ELISA results demonstrate a significant decrease in peripheral blood cytosolic PLA2(cPLA2) levels in patients with the PLA2G4A deletion genotype compared to those with normal and copy number duplicate genotypes. These data suggest that the functional copy number deletion in the PLA2G4A gene is associated with the risk of schizophrenia and clinical phenotypes by reducing the expression of cPLA2, which may be an indicator of susceptibility to schizophrenia.

Quantitative proteomics reveals the dynamic proteome landscape of zebrafish embryos during the maternal-to-zygotic transition.

Maternal-to-zygotic transition (MZT) is central to early embryogenesis. However, its underlying molecular mechanisms are still not well described. Here, we revealed the expression dynamics of 5,000 proteins across four stages of zebrafish embryos during MZT, representing one of the most systematic surveys of proteome landscape of the zebrafish embryos during MZT. Nearly 700 proteins were differentially expressed and were divided into six clusters according to their expression patterns. The proteome expression profiles accurately reflect the main events that happen during the MZT, i.e., zygotic genome activation (ZGA), clearance of maternal mRNAs, and initiation of cellular differentiation and organogenesis. MZT is modulated by many proteins at multiple levels in a collaborative fashion, i.e., transcription factors, histones, histone-modifying enzymes, RNA helicases, and P-body proteins. Significant discrepancies were discovered between zebrafish proteome and transcriptome profiles during the MZT. The proteome dynamics database will be a valuable resource for bettering our understanding of MZT.

Modulating synovial macrophage pyroptosis and mitophagy interactions to mitigate osteoarthritis progression using functionalized nanoparticles.

Synovial macrophages play an important role in the progression of osteoarthritis (OA). In this study, we noted that synovial macrophages can activate pyroptosis in a gasdermin d-dependent manner and produce reactive oxygen species (ROS), aberrantly activating the mammalian target of rapamycin complex 1 (mTORC1) pathway and matrix metalloproteinase-9 (MMP9) expression in synovial tissue samples collected from both patients with OA and collagen-induced osteoarthritis (CIOA) mouse model. To overcome this, we constructed rapamycin- (RAPA, a mTORC1 inhibitor) loaded mesoporous Prussian blue nanoparticles (MPB NPs, for catalyzing ROS) and modified the NPs with MMP9-targeted peptides (favor macrophage targeting) to develop RAPA@MPB-MMP9 NPs. The inherent enzyme-like activity and RAPA released from RAPA@MPB-MMP9 NPs synergistically impeded the pyroptosis of macrophages and the activation of the mTORC1 pathway. In particular, the NPs decreased pyroptosis-mediated ROS generation, thereby inhibiting cGAS-STING signaling pathway activation caused by the release of mitochondrial DNA. Moreover, the NPs promoted macrophage mitophagy to restore mitochondrial stability, alleviate pyroptosis-related inflammatory responses, and decrease senescent synoviocytes. After the as-prepared NPs were intra-articularly injected into the CIOA mouse model, they efficiently attenuated synovial macrophage pyroptosis and cartilage degradation. In conclusion, our study findings provide a novel therapeutic strategy for OA that modulates the pyroptosis and mitophagy of synovial macrophage by utilizing functionalized NPs. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) presents a significant global challenge owing to its complex pathogenesis and finite treatment options. Synovial macrophages have emerged as key players in the progression of OA, managing inflammation and tissue destruction. In this study, we discovered a novel therapeutic strategy in which the pyroptosis and mitophagy of synovial macrophages are targeted to mitigate OA pathology. For this, we designed and prepared rapamycin-loaded mesoporous Prussian blue nanoparticles (RAPA@MPB-MMP9 NPs) to specifically target synovial macrophages and modulate their inflammatory responses. These NPs could efficiently suppress macrophage pyroptosis, diminish reactive oxygen species production, and promote mitophagy, thereby alleviating inflammation and protecting cartilage integrity. Our study findings not only clarify the intricate mechanisms underlying OA pathogenesis but also present a promising therapeutic approach for effectively managing OA by targeting dysregulation in synovial macrophages.

Protective effects of oyster polypeptide on cyclophosphamide-induced immunosuppressed rats.

BACKGROUND: Oyster polypeptide (OP) is a mixture of oligopeptides extracted from oysters through enzyme lysis, separation, and purification. It is associated with immunomodulatory effects, but the underlying mechanisms are not known. This study therefore combined proton nuclear magnetic resonance (1H-NMR) urinary metabolomics and 16S rRNA gene sequencing of the gut microbiome to determine the immunoprotective mechanisms of OP in rats subjected to cyclophosphamide-induced immunosuppression. RESULTS: Oyster polypeptide restored the body weight and the structure of spleen and thymus in rats with cyclophosphamide-induced immunosuppression. It upregulated the levels of white blood cells (WBCs), hemoglobin (HGB), platelets (PLT), red blood cells (RBCs), immunoglobulin G (IgG), immunoglobulin M (IgM), cytokines such as interleukin­6 (IL-6) and tumor necrosis factor-α (TNF-α), and increased the numbers of CD3+ and CD4+ T cells in the immunosuppressed rats. The 1H-NMR metabolomics results showed that OP significantly reversed the levels of ten metabolites in urine, including 2-oxoglutarate, citrate, dimethylamine, taurine, N-phenylacetylglycine, alanine, betaine, creatinine, uracil, and benzoate. The 16S rRNA gene sequencing results showed that OP restored the gut microbiome homeostasis by increasing the abundance of beneficial bacteria and reducing the abundance of pathogenic bacteria. Finally, a combination of metabolomics and microbiomics found that the metabolism of taurine and hypotaurine, and the metabolism of alanine, aspartate, and glutamate were disturbed, but these metabolic pathways were restored by OP. CONCLUSION: This study demonstrated that OP had immunoprotective effects in rats with cyclophosphamide-induced immunosuppression by restoring key metabolic pathways and the gut microbiome homeostasis. Our findings provide a framework for further research into the immunoregulatory mechanisms of OP and its potential use in drugs and nutritional supplements. © 2024 Society of Chemical Industry.