Encapsulation of antioxidants with colloidal lipid particles for enhancing the photooxidation stability of phytosterol in Pickering emulsions.

In order to prevent the photooxidation of phytosterols, a new type of Pickering emulsion was developed by regulating the oriented distribution of antioxidants in colloidal lipid particles (CLPs) at the oil-water interface. High-melting-point and low-melting-point lipids were tested to modulate their protective effect against phytosterols photooxidation. Results showed that CLPs could stabilize Pickering emulsion and encapsulate antioxidants, providing a dual functional delivery system for phytosterols protection. The Pickering emulsion formed had a particle size of around 350-820 nm, and the crystallization and melting temperatures of tripalmitin particles were approximately 32 °C and 63.8 °C, respectively. The addition of tributyrin or tricaprylin reduced the crystallization and melting temperatures of Pal CLPs and improved the photooxidation emulsion stability. The prepared Pickering emulsion remained stable for a maximum of 12 days under accelerated light-induced oxidation. Among all formulations, the emulsion primarily composed of tripalmitin CLPs, with added tributyrin and resveratrol, exhibited the highest photooxidation stability.

Methods and clinical biomarker discovery for targeted proteomics using Olink technology.

PURPOSE: This paper is to offer insights for designing research utilizing Olink technology to identify biomarkers and potential therapeutic targets for disease treatment. EXPERIMENTAL DESIGN: We discusses the application of Olink technology in oncology, cardiovascular, respiratory and immune-related diseases, and Outlines the advantages and limitations of Olink technology. RESULTS: Olink technology simplifies the search for therapeutic targets, advances proteomics research, reveals the pathogenesis of diseases, and ultimately helps patients develop precision treatments. CONCLUSIONS: Although proteomics technology has been rapidly developed in recent years, each method has its own disadvantages, so in the future research, more methods should be selected for combined application to verify each other.

Design and characterization of Fe(II) complexes with tetradentate ligands exhibiting spin-crossover near room temperature.

Construction of spin-crossover (SCO) materials is very appealing for applications such as molecular switches and information storage. This study focuses on the design of Fe(II) complexes using N,N'-bis(2-pyridinylmethyl)-1,2-ethanediamine-based ligands with an N4 structure for SCO material development. By incorporating para-substituted benzene groups into the ligand's pyridine moiety, two polymorphs, α and ß, were obtained, both exhibiting SCO activity. Notably, the ß polymorph displayed a spin crossover temperature of 270 K, which is approaching room temperature. Structural analyses were conducted to compare the differences between the polymorphs, along with a literature review of related complexes, providing insights into the characteristics of SCO behavior.

Prediction of Potential Suitable Distribution Areas for an Endangered Salamander in China.

Climate change has been considered to pose critical threats for wildlife. During the past decade, species distribution models were widely used to assess the effects of climate change on the distribution of species' suitable habitats. Among all the vertebrates, amphibians are most vulnerable to climate change. This is especially true for salamanders, which possess some specific traits such as cutaneous respiration and low vagility. The Wushan salamander (Liua shihi) is a threatened and protected salamander in China, with its wild population decreasing continuously. The main objective of this study was to predict the distribution of suitable habitat for L. shihi using the ENMeval parameter-optimized MaxEnt model under current and future climate conditions. Our results showed that precipitation, cloud density, vegetation type, and ultraviolet radiation were the main environmental factors affecting the distribution of L. shihi. Currently, the suitable habitats for L. shihi are mainly concentrated in the Daba Mountains, including northeastern Chongqing and western Hubei Provinces. Under the future climate conditions, the area of suitable habitats increased, which mainly occurred in central Guizhou Province. This study provided important information for the conservation of L. shihi. Future studies can incorporate more species distribution models to better understand the effects of climate change on the distribution of L. shihi.

Two-dimensional monolayer C5-10-16: a metallic carbon allotrope as an anode material for high-performance sodium/potassium-ion batteries.

Carbonaceous materials are promising candidates as anode materials for non-lithium-ion batteries (NLIBs) due to their appealing properties such as good electrical conductivity, low cost, and high safety. However, graphene, a classic two-dimensional (2D) carbon material, is chemically inert to most metal atoms, hindering its application as an electrode material for metal-ion batteries. Inspired by the unique geometry of a four-penta unit, we explore a metallic 2D carbon allotrope C5-10-16 composed of 5-10-16 carbon rings. The C5-10-16 monolayer is free from any imaginary frequencies in the whole Brillouin zone. Due to the introduction of a non-sp2 hybridization state into C5-10-16, the extended conjugation of π-electrons is disrupted, leading to the enhanced surface activity toward metal ions. We investigate the performance of C5-10-16 as the anode for sodium/potassium-ion batteries by using first-principles calculations. The C5-10-16 sheet has high theoretical specific capacities of Na (850.84 mA h g-1) and K (743.87 mA h g-1). Besides, C5-10-16 exhibits a moderate migration barrier of 0.63 (0.32) eV for Na (K), ensuring rapid charging/discharging processes. The average open-circuit voltages of Na and K are 0.33 and 0.62 V, respectively, which are within the voltage acceptance range of anode materials. The fully sodiated (potassiated) C5-10-16 shows tiny lattice expansions of 1.4% (1.3%), suggesting the good reversibility. Moreover, bilayer C5-10-16 significantly affects both the adsorption strength and the mobility of Na or K. All these results show that C5-10-16 could be used as a promising anode material for NLIBs.

Molecular dynamics simulations of the interfacial behaviors and photo-oxidation of phytosterol under different emulsion oil content.

Phytosterol, recognized for its health benefits, is predominantly extracted from plants and exhibits significantly reduced stability under varying light conditions. Their photooxidation is significantly influenced by emulsion interfaces. This study examined the mechanism of interface structure on phytosterol photooxidation with unparalleled molecular precision, utilizing molecular dynamics simulations and experimental procedures. Hydrogen bonding between the hydroxyl group at the C3 position of phytosterols and water molecules, coupled with van der Waals forces between the hydrophobic regions and the oil phase, induced phytosterol molecules to disperse toward the interface. The elevated polarity of the oil phase, specifically in tributyrin, facilitated the permeation of water molecules into the oil phase. This was achieved by diminishing the emulsion's interfacial tension, thereby fostering the development of more interface or micelles, and accelerating the photooxidation process of phytosterols. These simulations unraveled that the preponderance of phytosterol distribution is localized and oxidized at the oil-water interface.

0.36BiScO3-0.64PbTiO3/Epoxy 1-3-2 High-Temperature Composite Ultrasonic Transducer for Non-destructive Testing Applications.

The development of high-temperature nondestructive testing (NDT) requires ultrasonic transducers with good temperature resistance and high sensitivity for improved detection efficiency. Piezoelectric composite can improve the performance of transducers because of its high electromechanical coupling coefficient and adjustable acoustic impedance. In this study, 1-3-2 composites and 1-3-2 high-temperature composite ultrasonic transducers (HTCUTs) based on 0.36BiScO3-0.64PbTiO3 (BSPT), which are preferred piezoelectric materials at 200°C-300°C, and high-temperature epoxy with a center frequency of 6 MHz were designed and fabricated. From 25°C to 250°C, 1-3-2 composites show a higher electromechanical coupling coefficient kt especially at high temperatures (~0.53 at 25°C, and ~0.64 at 250°C) than monolithic BSPT (~0.5). The signal of the pulse-echo response of 1-3-2 HTCUTs is distinguishable up to 250 °C and remains stable (Vpp~500 mV) below 150°C, exhibiting higher sensitivity (improved by 7 dB) than that of monolithic BSPT high-temperature ultrasonic transducers (HTUTs). Bandwidth has been greatly enhanced especially at high temperatures (~103250°C) compared with that of monolithic BSPT HTUTs(~30250°C). To verify the excellent performance, B-mode scanning imaging measurement of a stepped steel block and defect location detection of a steel block were performed, showing the potential for high-temperature NDT applications.

Patterns of Tadpole ß Diversity in Temperate Montane Streams.

Understanding the spatial variation and formation mechanism of biological diversity is a hot topic in ecological studies. Comparing with α diversity, ß diversity is more accurate in reflecting community dynamics. During the past decades, ß diversity studies usually focused on plants, mammals, and birds. Studies of amphibian ß diversity in montane ecosystems, in particular, tadpoles, are still rare. In this study, Mount Emei, located in southwestern China, was selected as the study area. We explored the tadpole ß diversity in 18 streams, based on a two-year survey (2018-2019). Our results indicated a high total ß diversity in tadpole assemblages, which was determined by both turnover and nestedness processes, and the dominant component was turnover. Both the total ß diversity and turnover component were significantly and positively correlated with geographical, elevational, and environmental distances, but no significant relationship was detected between these and the nestedness component. Moreover, the independent contributions of river width, current velocity, and chlorophyll α were larger than that of geographical and elevational distance. Overall, tadpole ß diversity was determined by both spatial and environmental factors, while the contribution of environmental factors was larger. Future studies can focus on functional and phylogenetic structures, to better understand the tadpole assembly process.

Large-scale uterine myoma MRI dataset covering all FIGO types with pixel-level annotations.

Uterine myomas are the most common pelvic tumors in women, which can lead to abnormal uterine bleeding, abdominal pain, pelvic compression symptoms, infertility, or adverse pregnancy. In this article, we provide a dataset named uterine myoma MRI dataset (UMD), which can be used for clinical research on uterine myoma imaging. The UMD is the largest publicly available uterine MRI dataset to date including 300 cases of uterine myoma T2-weighted imaging (T2WI) sagittal patient images and their corresponding annotation files. The UMD covers 9 types of uterine myomas classified by the International Federation of Obstetrics and Gynecology (FIGO), which were annotated and reviewed by 11 experienced doctors to ensure the authority of the annotated data. The UMD is helpful for uterine myomas classification and uterine 3D reconstruction tasks, which has important implications for clinical research on uterine myomas.

Phosphorylation-regulated phase separation of syndecan-4 and syntenin promotes the biogenesis of exosomes.

The biogenesis of exosomes that mediate cell-to-cell communication by transporting numerous biomolecules to neighbouring cells is an essential cellular process. The interaction between the transmembrane protein syndecan-4 (SDC4) and cytosolic protein syntenin plays a key role in the biogenesis of exosomes. However, how the relatively weak binding of syntenin to SDC4 efficiently enables syntenin sorting for packaging into exosomes remains unclear. Here, we demonstrate for the first time that SDC4 can undergo liquid-liquid phase separation (LLPS) to form condensates both in vitro and in the cell membrane and that, the SDC4 cytoplasmic domain (SDC4-CD) is a key contributor to this process. The phase separation of SDC4 greatly enhances the recruitment of syntenin to the plasma membrane (PM) despite the weak SDC4-syntenin interaction, facilitating syntenin sorting for inclusion in exosomes. Interestingly, phosphorylation at the only serine (179) in the SDC4-CD (Ser179) disrupts SDC4 LLPS, and inhibited phosphorylation or dephosphorylation restores the SDC4 LLPS to promote its recruitment of syntenin to the PM and syntenin inclusion into exosomes. This research reveals a novel phosphorylation-regulated phase separation property of SDC4 in the PM through which SDC4 efficiently recruits cytosolic syntenin and facilitates the biogenesis of exosomes, providing potential intervention targets for exosome-mediated biomedical events.

A machine learning algorithm based on circulating metabolic biomarkers offers improved predictions of neurological diseases.

BACKGROUND AND AIMS: A machine learning algorithm based on circulating metabolic biomarkers for the predictions of neurological diseases (NLDs) is lacking. To develop a machine learning algorithm to compare the performance of a metabolic biomarker-based model with that of a clinical model based on conventional risk factors for predicting three NLDs: dementia, Parkinson's disease (PD), and Alzheimer's disease (AD). MATERIALS AND METHODS: The eXtreme Gradient Boosting (XGBoost) algorithm was used to construct a metabolic biomarker-based model (metabolic model), a clinical risk factor-based model (clinical model), and a combined model for the prediction of the three NLDs. Risk discrimination (c-statistic), net reclassification improvement (NRI) index, and integrated discrimination improvement (IDI) index values were determined for each model. RESULTS: The results indicate that incorporation of metabolic biomarkers into the clinical model afforded a model with improved performance in the prediction of dementia, AD, and PD, as demonstrated by NRI values of 0.159 (0.039-0.279), 0.113 (0.005-0.176), and 0.201 (-0.021-0.423), respectively; and IDI values of 0.098 (0.073-0.122), 0.070 (0.049-0.090), and 0.085 (0.068-0.101), respectively. CONCLUSION: The performance of the model based on circulating NMR spectroscopy-detected metabolic biomarkers was better than that of the clinical model in the prediction of dementia, AD, and PD.

Phytosterol organic acid esters: Characterization, anti-inflammatory properties and a delivery strategy to improve mitochondrial function.

Phytosterol organic acid esters are important food resources and the components of biomembrane structure. Due to the lack of extraction and synthesis techniques, more research has been focused on phytosterols, and the research on phytosterol acid esters have encountered a bottleneck, but phytosterol acid esters confer substantial benefits to human health. In this study, stigmasteryl vanillate (VAN), stigmasteryl protocatechuate (PRO) and stigmasteryl sinapate (SIN) were prepared through the Steglich reaction. The processes are promotable and the products reach up to 95% purity. In addition, their stability was evaluated by differential scanning calorimetry and thermogravimetric analysis. HPLC analysis revealed an enhancement in water solubility after esterification with phenolic acid. In an in vitro digestion model, the bioaccessibility of stigmasteryl phenolates was significantly higher than that of stigmasterols (STIs). Regarding the anti-inflammatory properties, VAN, PRO, and SIN exhibit superior effects against TNF-α induced pro-inflammatory responses compared to STI. All stigmasteryl phenolates supplementation increased the ATP production, the basal, and maximal oxygen consumption rate in mitochondrial stress test. Overall, we present a synthesis method for stigmasteryl phenolates. It will contribute to the development and research of phytosterol acid ester analysis, functions and utilization in food. Moreover, the nutrient-stigmasterol hybrids tactic we have constructed is practical and can become a targeted mitochondrial delivery strategy with enhanced anti-inflammatory effects.

Clinical Implications of Interleukin-4 and C-reactive Protein in Atopic Dermatitis and Their Changes Before and after Dupilumab Treatment.

Objective: To analyze the clinical implications of C-reactive protein (C-reactive protein) and interleukin-4 (IL-4) in atopic dermatitis and their correlations with the therapeutic effect of Dupilumab (DU). Methods: Seventy-four cases of atopic dermatitis (intervention group) were admitted to Xingtai Third Hospital between May 2021 and January 2023, and 55 concurrent healthy controls (control group) were selected as research participants. Atopic dermatitis patients were treated with a DU injection of 600 mg for the first time after diagnosis. Peripheral blood IL-4 and C-reactive protein levels before and after treatment in the intervention group and their levels at admission in the control group were comparatively analyzed, and their predictive value for the occurrence, clinical efficacy, and adverse reactions of atopic dermatitis were determined. Additionally, alterations in C-reactive protein and IL-4 levels before and after treatment in the intervention group and their relationship with the Scoring Atopic Dermatitis (SCORAD) index were discussed. Results: The intervention group exhibited higher C-reactive protein and IL-4 levels than the control group. The diagnostic sensitivity and specificity of C-reactive protein + IL-4 detection for atopic dermatitis were 74.32% and 94.55%, respectively (P < .05). The post-treatment C-reactive protein and IL-4 were lower in the intervention group, and the test results were positively correlated with SCORAD before and after treatment (P < .05). In addition, C-reactive protein + IL-4 detection showed excellent predictive effects on the therapeutic efficacy of DU and adverse reactions. Conclusions: IL-4 and C-reactive protein are closely related to atopic dermatitis, which can be used as the evaluation indexes for disease development of atopic dermatitis and therapeutic effects of DU in the future.

Cell-Cycle-related Protein Centromere Protein F Deficiency Inhibits Cervical Cancer Cell Growth by Inducing Ferroptosis Via Nrf2 Inactivation.

Cervical cancer (CC) is one of the severe cancers that pose a threat to women's health and result in death. CENPF, the centromere protein F, plays a crucial role in mitosis by regulating numerous cellular processes, such as chromosome segregation during mitosis. According to bioinformatics research, CENPF serves as a master regulator that is upregulated and activated in cervical cancer. Nevertheless, the precise biological mechanism that CENPF operates in CC remains unclear. The aim of this study was to analyze the function of CENPF on cervical cancer and its mechanism. We conducted immunohistochemistry and western blot analysis to examine the expression levels of CENPF in both cervical cancer tissues and cells. To explore the hidden biological function of CENPF in cell lines derived from CC, we applied lentivirus transfection to reduce CENPF manifestation. CENPF's main role is to regulate ferroptosis which was assessed by analyzing Reactive Oxygen Species (ROS), malonaldehyde (MDA), etc. The vitro findings were further validated through a subcutaneous tumorigenic nude mouse model. Our research finding indicates that there is an apparent upregulation of CENPF in not merely tumor tissues but also cell lines in the carcinomas of the cervix. In vitro and vivo experimental investigations have demonstrated that the suppression of CENPF can impede cellular multiplication, migration, and invasion while inducing ferroptosis. The ferroptosis induced by CENPF inhibition in cervical cancer cell lines is likely mediated through the Nrf2/HO-1 pathway. The data herein come up with the opinion that CENPF may have a crucial role in influencing anti-cervical cancer effects by inducing ferroptosis via the triggering of the Nrf2/HO-1 signaling pathway.

Exploring the microbial ecosystem of Berchemia polyphylla var. leioclada: a comprehensive analysis of endophytes and rhizospheric soil microorganisms.

Endophytic and rhizospheric microorganisms associated with plants play a crucial role in plant health, pest and disease defense, and fruit yield by actively participating in the plant's adaptation to its environment. In this study, high-throughput sequencing technology was employed to analyze the community structure and diversity of endophytic and rhizospheric soil microorganisms in Berchemia polyphylla var. leioclada. The results revealed significant differences in microbial diversity and community structure between the soil and plant compartments within the same geographic region. Microbial diversity and species composition varied among different geographic locations. The dominant bacteria in plants were Cyanobacteria and Proteobacteria, with dominant genera including Methylobacterium-Methylorubrum, Escherichia-Shigella and Sphingomonas. In contrast, the dominant bacteria in soil were Proteobacteria, Acidobacteriota, and Actinobacteriota, with dominant genera such as Sphingomonas, Conexibacter and Vicinamibacteraceae, with Sphingomonas was considered core groups present in all plant and soil samples. As for fungi, the dominant phyla in both plants and soil were Ascomycota, Basidiomycota, and Mortierellomycota, with different dominant genera between the two compartments, including Fusarium, Septoria, and Mortierella, totaling 59 genera. Linear discriminant analysis at the genus level identified 102 bacterial and 54 fungal indicator taxa associated with plants and soil. Co-occurrence network analysis indicated close interactions among soil bacterial microorganisms. Functional prediction of the top 10 microbial genes revealed three bacterial metabolic pathways shared between soil and plants, while the predominant fungal metabolic types were similar between the two compartments but with varying abundances. This study elucidates the diversity and interplay of endophytic and rhizospheric microorganisms in Berchemia polyphylla var. leioclada across diverse geographical regions, providing insights crucial for the plant's conservation and development.

Clinical evolution of antisynthetase syndrome-associated interstitial lung disease after COVID-19 in a man with Klinefelter syndrome: A case report.

BACKGROUND: This study presents a case of rapidly developing respiratory failure due to antisynthetase syndrome (AS) following coronavirus disease 2019 (COVID-19) in a 33-year-old man diagnosed with Klinefelter syndrome (KS). CASE SUMMARY: A 33-year-old man with a diagnosis of KS was admitted to the Department of Pulmonary and Critical Care Medicine of a tertiary hospital in China for fever and shortness of breath 2 wk after the onset of COVID-19. Computed tomography of both lungs revealed diffuse multiple patchy heightened shadows in both lungs, accompanied by signs of partial bronchial inflation. Metagenomic next-generation sequencing of the bronchoalveolar lavage fluid suggested absence of pathogen. A biopsy specimen revealed organizing pneumonia with alveolar septal thickening. Additionally, extensive auto-antibody tests showed strong positivity for anti-SSA, anti-SSB, anti-Jo-1, and anti-Ro-52. Following multidisciplinary discussions, the patient received a final diagnosis of AS, leading to rapidly progressing respiratory failure. CONCLUSION: This study underscores the clinical progression of AS-associated interstitial lung disease subsequent to viral infections such as COVID-19 in patients diagnosed with KS.

ZNF862 induces cytostasis and apoptosis via the p21-RB1 and Bcl-xL-Caspase 3 signaling pathways in human gingival fibroblasts.

OBJECTIVE: This study investigates the effects of ZNF862 on the proliferation and apoptosis of human gingival fibroblasts and their related mechanisms. BACKGROUND: As a major transcription factor family, zinc finger proteins (ZFPs) regulate cell differentiation, growth, and apoptosis through their conserved zinc finger motifs, which allow high flexibility and specificity in gene regulation. In our previous study, ZNF862 mutation was associated with hereditary gingival fibromatosis. Nevertheless, little is known about the biological function of ZNF862. Therefore, this study was aimed to reveal intracellular localization of ZNF862, the influence of ZNF862 on the growth and apoptosis of human gingival fibroblasts (HGFs) and its potential related mechanisms. METHODS: Immunohistochemistry, immunofluorescence staining, and western blotting were performed to determine the intracellular localization of ZNF862 in HGFs. HGFs were divided into three groups: ZNF862 overexpression group, ZNF862 interference group, and the empty vector control group. Then, the effects of ZNF862 on cell proliferation, migration, cell cycle, and apoptosis were evaluated. qRT-PCR and western blotting were performed to further explore the mechanism related to the proliferation and apoptosis of HGFs. RESULTS: ZNF862 was found to be localized in the cytoplasm of HGFs. In vitro experiments revealed that ZNF862 overexpression inhibited HGFs proliferation and migration, induced cell cycle arrest at the G0/G1-phase and apoptosis. Whereas, ZNF862 knockdown promoted HGFs proliferation and migration, accelerated the transition from the G0/G1 phase into the S and G2/M phase and inhibited cell apoptosis. Mechanistically, the effects of ZNF862 on HGFs proliferation and apoptosis were noted to be dependent on inhibiting the cyclin-dependent kinase inhibitor 1A (p21)-retinoblastoma 1 (RB1) signaling pathway and enhancing the B-cell lymphoma-extra-large (Bcl-xL)-Caspase 3 signaling pathway. CONCLUSION: Our results for the first time reveal that ZNF862 is localized in the cytoplasm of HGFs. ZNF862 can inhibit the proliferation of HGFs by inhibiting the p21-RB1 signaling pathway, and it also promotes the apoptosis of HGFs by enhancing the Bcl-xL-Caspase 3 signaling pathway.

[Research Progress on the Influence of Tumor Extracellular Matrix Mechanic Properties on Nanodrug Delivery]. / è‚¿ç˜¤åŸºè´¨åŠ›å­¦ç‰¹æ€§å½±å“çº³ç±³è¯ç‰©é€’é€çš„ç ”ç©¶è¿›å±•.

Nanodrugs are widely utilized in the biomedical fields, exhibiting immense potential in cancer therapy in particular. However, tumors exist in an extremely complicated microenvironment where substances like collagen are continuously deposited and remodeled, leading to significant alterations in the mechanical properties of the extracellular matrix (ECM) during tumor development. Previous research has primarily focused on the specific physicochemical properties of nanodrugs, such as particle size, electric charge, shape, surface chemistry, etc., and their effects on cellular uptake, cytotoxicity, and in vivo pharmacokinetics. Limited studies have been done to explore the impact of ECM mechanical properties on nanodrug delivery. In this review, we systematically summarized the relevant research findings on this topic from the perspective of the characteristics and testing methods of tumor ECM mechanics. Additionally, we made a thorough discussion of the potential mechanical and biological mechanisms involved in nanodrug delivery. We proposed several noteworthy research directions. Regarding the overall strategy, there is a need to emphasize targeted delivery that combines ECM mechanics and nanomechanics to achieve precise drug delivery. Regarding the spatial aspect, attention should be given to the nonlinear spatial mechanical heterogeneity within the interior of solid tumors and the construction of mechanic microenvironment-adaptive nanocarriers to improve the delivery efficiency. Regarding the temporal aspect, emphasis should be placed on the dynamic development and changes in the mechanical microenvironment during solid tumor growth and treatment processes. Based on the stromal mechanical characteristics of the tumor tissues of individual patients, personalized treatment strategies can be formulated, which will enhance treatment specificity and efficacy. In addition, issues such as mechanically targeted nanodrug delivery, degradation, and metabolism under dynamic ECM mechanical conditions warrant further investigation.

Marginal zone B cells produce 'natural' atheroprotective IgM antibodies in a T cell-dependent manner.

AIMS: The adaptive immune response plays an important role in atherosclerosis. In response to a high-fat/high-cholesterol (HF/HC) diet, marginal zone B (MZB) cells activate an atheroprotective programme by regulating the differentiation and accumulation of 'poorly differentiated' T follicular helper (Tfh) cells. On the other hand, Tfh cells activate the germinal centre response, which promotes atherosclerosis through the production of class-switched high-affinity antibodies. We therefore investigated the direct role of Tfh cells and the role of IL18 in Tfh differentiation in atherosclerosis. METHODS AND RESULTS: We generated atherosclerotic mouse models with selective genetic deletion of Tfh cells, MZB cells, or IL18 signalling in Tfh cells. Surprisingly, mice lacking Tfh cells had increased atherosclerosis. Lack of Tfh not only reduced class-switched IgG antibodies against oxidation-specific epitopes (OSEs) but also reduced atheroprotective natural IgM-type anti-phosphorylcholine (PC) antibodies, despite no alteration of natural B1 cells. Moreover, the absence of Tfh cells was associated with an accumulation of MZB cells with substantially reduced ability to secrete antibodies. In the same manner, MZB cell deficiency in Ldlr-/- mice was associated with a significant decrease in atheroprotective IgM antibodies, including natural anti-PC IgM antibodies. In humans, we found a positive correlation between circulating MZB-like cells and anti-OSE IgM antibodies. Finally, we identified an important role for IL18 signalling in HF/HC diet-induced Tfh. CONCLUSION: Our findings reveal a previously unsuspected role of MZB cells in regulating atheroprotective 'natural' IgM antibody production in a Tfh-dependent manner, which could have important pathophysiological and therapeutic implications.

Serum Olink Proteomics-Based Identification of Protein Biomarkers Associated with the Immune Response in Ischemic Stroke.

The immune response is considered essential for pathology of ischemic stroke (IS), but it remains unclear which immune response-related proteins exhibit altered expression in IS patients. Here, we used Olink proteomics to examine the expression levels of 92 immune response-related proteins in the sera of IS patients (n = 88) and controls (n = 88), and we found that 59 of these proteins were differentially expressed. Feature variables were screened from the differentially expressed proteins by the least absolute shrinkage and selection operator (LASSO) and the random forest and by determining whether their proteins had an area under the curve (AUC) greater than 0.8. Ultimately, we identified six potential protein biomarkers of IS, namely, MASP1, STC1, HCLS1, CLEC4D, PTH1R, and PIK3AP1, and established a logistic regression model that used these proteins to diagnose IS. The AUCs of the models in the internal validation and the test set were 0.962 (95% confidence interval (CI): 0.895-1.000) and 0.954 (95% CI: 0.884-1.000), respectively, and the same protein detection method was performed in an external independent validation set (AUC: 0.857 (95% CI: 0.801-0.913)). These proteins may play a role in immune regulation via the C-type lectin receptor signaling pathway, the PI3K-AKT signaling pathway, and the B-cell receptor signaling pathway.