Low-Temperature Plasma Radiofrequency Ablation for Congenital Epiglottic Cysts.

Objectives: Congenital epiglottic cysts are rare disorders of the larynx with symptoms such as laryngeal stridor and inspiratory dyspnea and are life-threatening in severe cases. This study aimed to investigate the usefulness of low-temperature plasma radiofrequency ablation for congenital epiglottic cysts and provide a reference for clinicians to develop treatment options. Methods: The clinical data of children (n = 7, 4 males and 3 females) with congenital epiglottic cysts, who were admitted to the Second Affiliated Hospital of Wenzhou Medical University and Yuying Children's Hospital from March 2018 to March 2023, were analyzed retrospectively. Following preoperative examinations, all patients underwent low-temperature plasma radiofrequency ablation under general anesthesia, and the curative effect was evaluated. Following surgery, regular patient follow-up examinations were conducted to monitor recurrence. Results: The age at the time of operation ranged from 1 day to 99 days, with an average of 37.57 ± 35.01 days. The surgical procedure was successfully completed in all the children; dyspnea disappeared and no surgical complications were observed. In addition, during the postoperative follow-up period of 6 months to 5 years, recurrence was not observed. Conclusions: Low-temperature plasma radiofrequency ablation is a safe and effective procedure for treating congenital epiglottic cysts and deserves clinical application and promotion.

Branched glycopolymer prodrug-derived nanoassembly combined with a STING agonist activates an immuno-supportive status to boost anti-PD-L1 antibody therapy.

Despite the great potential of anti-PD-L1 antibodies for immunotherapy, their low response rate due to an immunosuppressive tumor microenvironment has hampered their application. To address this issue, we constructed a cell membrane-coated nanosystem (mB4S) to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor effect. In this system, Epirubicin (EPI) as an immunogenic cell death (ICD) inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes (STING) agonist was encapsulated into mB4S. After internalization of mB4S, EPI was acidic-responsively released to induce ICD, which was characterized by an increased level of calreticulin (CRT) exposure and enhanced ATP secretion. Meanwhile, diABZI effectively activated the STING pathway. Treatment with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells (DCs) and CD8+ T cells, promoting cytokines secretion, up-regulating M1-like tumor-associated macrophages (TAMs) and down-regulating immunosuppressive myeloid-derived suppressor cells (MDSCs). Therefore, this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+ T cells infiltration, creating an immuno-supportive microenvironment, thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.

Using an Interpretable Amino Acid-Based Machine Learning Method to Enhance the Diagnosis of Major Depressive Disorder.

Background: Major depressive disorder (MDD) is a leading cause of disability worldwide. At present, however, there are no established biomarkers that have been validated for diagnosing and treating MDD. This study sought to assess the diagnostic and predictive potential of the differences in serum amino acid concentration levels between MDD patients and healthy controls (HCs), integrating them into interpretable machine learning models. Methods: In total, 70 MDD patients and 70 HCs matched in age, gender, and ethnicity were recruited for the study. Serum amino acid profiling was conducted by means of chromatography-mass spectrometry. A total of 21 metabolites were analysed, with 17 from a preset amino acid panel and the remaining 4 from a preset kynurenine panel. Logistic regression was applied to differentiate MDD patients from HCs. Results: The best-performing model utilised both feature selection and hyperparameter optimisation and yielded a moderate area under the receiver operating curve (AUC) classification value of 0.76 on the testing data. The top five metabolites identified as potential biomarkers for MDD were 3-hydroxy-kynurenine, valine, kynurenine, glutamic acid, and xanthurenic acid. Conclusions: Our study highlights the potential of using an interpretable machine learning analysis model based on amino acids to aid and increase the diagnostic accuracy of MDD in clinical practice.

A Survey of Emerging Memory in a Microcontroller Unit.

In the era of widespread edge computing, energy conservation modes like complete power shutdown are crucial for battery-powered devices, but they risk data loss in volatile memory. Energy autonomous systems, relying on ambient energy, face operational challenges due to power losses. Recent advancements in emerging nonvolatile memories (NVMs) like FRAM, RRAM, MRAM, and PCM offer mature solutions to sustain work progress with minimal energy overhead during outages. This paper thoroughly reviews utilizing emerging NVMs in microcontroller units (MCUs), comparing their key attributes to describe unique benefits and potential applications. Furthermore, we discuss the intricate details of NVM circuit design and NVM-driven compute-in-memory (CIM) architectures. In summary, integrating emerging NVMs into MCUs showcases promising prospects for next-generation applications such as Internet of Things and neural networks.

Morphology and optical properties of Au-Ag hybrid nanoparticles regulation and its ultra-sensitive SERS immunoassay detection in carbohydrate antigen 19-9.

The development of an ultra-sensitive detection method for carbohydrate antigen 19-9 (CA19-9) is very important for the early diagnosis of pancreatic cancer. In this work, we developed a new strategy to achieve a variety of Au-Ag hybrid nanoparticles from janus to core-satellite which is controlled by the volume of AgNO3 and the concentration of benzimidazolecarboxylic acid (MBIA). With the volume of AgNO3 increased, Au-Ag hybrid nanoparticles changed from janus to core-satellite and the characteristic absorption peak showed two opposite trends. The size and number of Ag islands were determined by the concentration of MBIA. Au-Ag core-satellites nanoparticles with a large number of small-sized Ag have the highest SERS intensity. Then we used them as SERS nanotags and Au-Polystyrene nanospheres modified by captured anti-CA19-9 antibody as solid substrates to realize the ultra-sensitive detection of CA19-9 with a low limit of detection of 1.25 × 10-6 IU/mL and a wide linear range of 1.00 × 10-5 -1.00 × 104 IU/mL. This work not only demonstrates that MBIA and AgNO3 were the key factors in the growth of Au-Ag hybrid nanoparticles from 2D to 3D structure but also supplies an ultra-sensitive detection method for CA19-9 which has a potential practicability in the clinical early diagnoses of pancreatic cancer.

Highly sensitive dual-function sensor for refractive index and temperature using D-shaped microchannel photonic crystal fiber.

An innovative ultra-sensitive, dual-functional sensor employing a D-shaped microchannel photonic crystal fiber (PCF) for refractive index (RI) and temperature measurements is proposed and comprehensively investigated. Its high-sensitivity is achieved through the incorporation of gold (Au) and magnesium fluoride (MgF2) as plasmonic materials in the micro-rectangular channel. This configuration significantly enhances the interaction between the surface plasmon polaritons (SPPs) field and y-polarized evanescent field on external surfaces. Additionally, the integration of a temperature-sensitive fluid within the sensor allows for precise detection of temperature changes. Our simulations demonstrate a broad detection spectrum, covering RI values from 1.27 to 1.43 and temperatures ranging from 45°C to 100°C. The sensor achieves peak sensitivities of 31800nm/RIU for RI and 49 nm/°C for temperature. Besides, the sensor only has a cladding consisting of three air holes to enhance coupling and reduce the difficulty of preparation. Importantly, the sensor's performance remains robust against minor structural alterations in the PCF, indicating high fault tolerance. Given its high sensitivity, extensive detection range, and strong fabrication stability, this PCF-SPR sensor offers significant potential for applications in biochemical sensing and environmental monitoring.

Sialic Acid Mediated Endothelial and Hepatic Uptake: A Mechanism based Mathematic Model Elucidating the Complex Pharmacokinetics and Pharmacodynamics of Efmarodocokin Alfa, a Variably Glycosylated Fusion Protein.

Sialic acid (SA) is crucial for protecting glycoproteins from clearance. Efmarodocokin alfa (IL-22Fc), a fusion protein agonist that links IL-22 to the crystallizable fragment (Fc) of human IgG4, contains 8 N-glycosylation sites and exhibits heterogeneous and variable terminal sialylation biodistribution. This presents a unique challenge for Pharmacokinetic (PK) and Pharmacodynamic (PD) analysis and cross-species translation. In this study, we sought to understand how varying SA levels and heterogeneous distribution contribute to IL-22Fc's complex PKPD properties. We initially used homogenous drug material with varying SA levels to examine PKPD in mice. Population PKPD analysis based on mouse data revealed that SA was a critical covariate simultaneously accounting for the substantial between subject variability (BSV) in clearance (CL), distribution clearance (CLd), and volume of distribution (Vd). In addition to the well-established mechanism by which SA inhibits ASGPR activity, we hypothesized a novel mechanism by which decrease in SA increases the drug uptake by endothelial cells. This decrease in SA, leading to more endothelial uptake, was supported by the neonatal Fc receptor (FcRn) dependent cell-based transcytosis assay. The population analysis also suggested in vivo EC50 (IL-22Fc stimulating Reg3ß) was independent on SA, while the in-vitro assay indicated a contradictory finding of SA-in vitro potency relationship. We created a mechanism based mathematical (MBM) PKPD model incorporating the decrease in SA mediated endothelial and hepatic uptake, and successfully characterized the SA influence on IL-22Fc PK, as well as the increased PK exposure being responsible for increased PD. Thereby, the MBM model supported that SA has no direct impact on EC50, aligning with the population PKPD analysis. Subsequently, using the MBM PKPD model, we employed 5 subpopulation simulations to reconstitute the heterogeneity of drug material. The simulation accurately predicted the PKPD of heterogeneously and variably sialylated drug in mouse, monkey and human. The successful prospective validation confirmed the MBM's ability to predict IL-22Fc PK across variable SA levels, homogenous to heterogeneous material, and across species (R2=0.964 for clearance prediction). Our model prediction suggests an average of 1 mol/mol SA increase leads to a 50% increase in drug exposure. This underlines the significance of controlling sialic acid levels during lot-to-lot manufacturing.

Hypoxia-inducible factor-2α promotes fibrosis in non-alcoholic fatty liver disease by enhancing glutamine catabolism and inhibiting yes-associated protein phosphorylation in hepatic stellate cells.

Non-alcoholic fatty liver disease (NAFLD) has a high global prevalence and affects approximately one-third of adults, owing to high-fat dietary habits and a sedentary lifestyle. The role of hypoxia-inducible factor 2α (HIF-2α) in NAFLD progression remains unknown. This study aimed to investigate the effects of chronic hypoxia on NAFLD progression by examining the role of hypoxia-inducible factor 2α (HIF-2α) activation and that of hepatic stellate cell (HSC)-derived myofibroblasts through glutaminolysis. We hypothesised that hypoxia exacerbates NAFLD by promoting HIF-2α upregulation and inhibiting phosphorylated yes-associated protein (YAP), and that increasing YAP expression enhances HSC-derived myofibroblasts. We studied patients with NAFLD living at high altitudes, as well as animal models and cultured cells. The results revealed significant increases in HSC-derived myofibroblasts and collagen accumulation caused by HIF-2α and YAP upregulation, both in patients and in a mouse model for hypoxia and NAFLD. HIF-2α and HIF-2α-dependent YAP downregulation reduced HSC activation and myofibroblast levels in persistent chronic hypoxia. Furthermore, hypoxia-induced HIF-2α upregulation promoted YAP and inhibited YAP phosphorylation, leading to glutaminase 1 (GLS1), SLC38A1, α-SMA, and Collagen-1 overexpression. Additionally, hypoxia restored mitochondrial adenosine triphosphate production and reactive oxygen species (ROS) overproduction. Thus, chronic hypoxia-induced HIF-2α activation enhances fibrosis and NAFLD progression by restoring mitochondrial ROS production and glutaminase-1-induced glutaminolysis, which is mediated through the inhibition of YAP phosphorylation and increased YAP nuclear translocation. In summary, HIF-2α plays a pivotal role in NAFLD progression during chronic hypoxia.

Functional and structural abnormalities of the speech disorders: a multimodal activation likelihood estimation meta-analysis.

Speech disorders are associated with different degrees of functional and structural abnormalities. However, the abnormalities associated with specific disorders, and the common abnormalities shown by all disorders, remain unclear. Herein, a meta-analysis was conducted to integrate the results of 70 studies that compared 1843 speech disorder patients (dysarthria, dysphonia, stuttering, and aphasia) to 1950 healthy controls in terms of brain activity, functional connectivity, gray matter, and white matter fractional anisotropy. The analysis revealed that compared to controls, the dysarthria group showed higher activity in the left superior temporal gyrus and lower activity in the left postcentral gyrus. The dysphonia group had higher activity in the right precentral and postcentral gyrus. The stuttering group had higher activity in the right inferior frontal gyrus and lower activity in the left inferior frontal gyrus. The aphasia group showed lower activity in the bilateral anterior cingulate gyrus and left superior frontal gyrus. Across the four disorders, there were concurrent lower activity, gray matter, and fractional anisotropy in motor and auditory cortices, and stronger connectivity between the default mode network and frontoparietal network. These findings enhance our understanding of the neural basis of speech disorders, potentially aiding clinical diagnosis and intervention.

3D multi-robot olfaction in naturally ventilated indoor environments: Locating a time-varying source at unknown heights.

Source localization is significant for mitigating indoor air pollution and safeguarding the well-being and safety of occupants. While most study focuses on mechanical ventilation and static sources, this study explores the less-explored domain of locating time-varying sources in naturally ventilated spaces. We have developed an innovative 3D localization system that adjusts to varying heights, significantly enhancing capabilities beyond traditional fixed-height 2D systems. To ensure consistency in experimental conditions, we conducted comparative analyses of 2D and 3D methods, using a swinging fan to simulate natural ventilation. Our findings reveal a substantial disparity in performance: the 2D method had a success rate below 46.7% in cases of height mismatches, while our 3D methods consistently achieved success rates above 66.7%, demonstrating their superior effectiveness in complex environments. Furthermore, we validated the 3D strategies in real naturally ventilated settings, confirming their wider applicability. This research extends the scope of indoor source localization and offers valuable insights and strategies for more effective pollution control.

Erratum: ß-elemene promotes the senescence of glioma cells through regulating YAP-CDK6 signaling.

[This corrects the article on p. 370 in vol. 11, PMID: 33575077.].

Serum CXCL13 level is related to treatment response and predicts disease prognosis in Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a type of B-cell lymphoma that produces IgM. Our study aimed to investigate the role of CXCL13, a chemokine essential for B lymphocytes, in the evaluation of treatment response and prognosis in WM. We collected serum samples and clinical data from 72 WM patients, with 69 patients receiving systemic therapy and 3 patients opting not to receive treatment. Serum CXCL13 levels at baseline and after six months of treatments were measured by enzyme-linked immunosorbent assay. The median serum level of CXCL13 was 1 539.2 pg/ml (range 10.0-21 389.9) at baseline and significantly decreased to 123.1 pg/ml (range 0.0-6 741.5) after 6 months of treatments. At baseline, higher CXCL13 levels were associated with lower hemoglobin levels (p = 0.001), higher ß2-microglobulin levels (p = 0.001), lower albumin levels (p = 0.046), and higher IPSS-WM scores (p = 0.013). After 6 months of treatment, patients who achieved PR/VGPR had significantly lower CXCL13 levels compared to those with SD (70.2 pg/ml vs 798.6 pg/ml, p = 0.002). The median follow-up period was 40 months (range 4.2-188). Eight patients died during the follow-up period. Overall survival differed based on CXCL13 levels. When grouped by baseline CXCL13 levels, the median OS was 60.0 months in patients with serum CXCL13 > 2 000 pg/ml, while it was not reached in patients with low CXCL13 levels (p < 0.001). Based on CXCL13 levels after the treatments, the median OS was 74.0 months in patients with serum CXCL13 > 200 pg/ml, while it was not reached in patients with CXCL13 ≤ 200 pg/ml. In a subgroup of 28 patients with a series of serum samples, the increase of serum CXCL13 level was associated with disease progression or the start of next-line therapy (p < 0.001). Our study concludes that serum CXCL13 levels decrease in WM patients treated with various regimens and correlate with treatment response. Detecting serum CXCL13 at baseline or after treatment help in predicting prognosis.

BPKEM: A biometric-based private key encryption and management framework for blockchain.

The fundamental technology behind bitcoin, known as blockchain, has been studied and used in a variety of industries especially in finance. The security of blockchain is extremely important as it will affects the assets of the clients as well as it is the lifeline feature of the entire system that needs to be guaranteed. Currently, there is a lack of a methodical approach to guarantee the security and dependability of the private key during its whole life. Furthermore, there is no quick, easy, or secure way to create the encryption key. A biometric-based private key encryption and management framework (BPKEM) for blockchain is proposed not only to solve the private key lifecycle manag- ement problem, but also it maintains compatibility with existing blockchain systems. For the problem of private key encryption, a biometric-based stable key generation method is proposed. By using the relative invariance between facial and fingerprint feature points, this measure can convert feature points into stable and distinguishable descriptors, then using a reusable fuzzy extractor to create a stable key. The correct- ness and efficiency of the newly proposed biometric-based blockchain encryption tech- nique in this paper has been validated in the experiments.

Aqueous-phase product treatment and monetization options of wet waste hydrothermal liquefaction: Comprehensive techno-economic and life-cycle GHG emission assessment unveiling research opportunities.

While wet waste hydrothermal liquefaction technology has a high biofuel yield, a significant amount of the carbon and nitrogen in the feedstock reports to the aqueous-phase product. Pretreatment of this stream before sending to a conventional wastewater plant is essential or at the very least, advisable. In this work, techno-economic and life-cycle assessments were conducted for the state-of-technology baseline and four aqueous-phase product treatment and monetization options based on experimental data. These options can cut minimum fuel selling prices by up to 13 % and life-cycle greenhouse gas emissions by up to 39 % compared to the baseline. These findings highlight the substantial influence of aqueous produce treatment strategies on the entire wet waste hydrothermal liquefaction process, demonstrating the potential for optimizing economic viability and environmental impact through further research and development of milder treatment methods and diversified by-product valorization pathways.

Phase 2 study using low dose cytarabine for adult patients with newly diagnosed Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) lacks a standardized first-line therapy. This single-center, phase 2 prospective study (NCT04121819) enrolled 61 newly diagnosed adult LCH patients with multisystem or multifocal single system disease from October 2019 to June 2022. Subcutaneous cytarabine (100 mg/m2 for 5 days) was administered in 35-day cycles for 12 total cycles. The primary endpoint was event-free survival (EFS). The median age was 33 years (range 18-66). Twelve patients (19.7%) had liver involvement, of which 2 also had spleen involvement. Among 43 patients undergoing next-generation sequencing, BRAF alterations (44.2%) were most frequent, followed by TP53 (16.3%), MAP2K1 (14.0%) and IDH2 (11.6%). MAPK pathway alterations occurred in 28 patients (65.1%). The overall response rate was 93.4%, with 20 (32.7%) achieving complete response and 37 (60.7%) partial response. After a median 30 months follow-up, 21 (34.4%) relapsed without deaths. Estimated 3-year OS and EFS were 100.0% and 58.5%, respectively. Multivariate analysis identified ≥3 involved organs (P = 0.007; HR 3.937, 95% CI: 1.456-9.804) and baseline lung involvement (P = 0.028; HR 2.976, 95% CI: 1.126-7.874) as poor prognostic factors for EFS. The most common grade 3-4 toxicities were neutropenia (27.9%), thrombocytopenia (1.6%), and nausea (1.6%). In conclusion, cytarabine monotherapy is an effective and safe regimen for newly diagnosed adults, while baseline lung or ≥3 involved organs confers poor prognosis.

Germline defects of familial hemophagocytic lymphohistiocytosis-related genes presenting as adult-onset peripheral T-cell lymphoma.

Germline mutations in genes involved in perforin-granzyme-mediated cytotoxicity such as PRF1, UNC13D, STX11, and STXBP2 were known to cause familial hemophagocytic lymphohistiocytosis (FHL). In this study, we reported a unique group of 3 patients with germline mutations of UNC13D and STX11 genes and presented as adult-onset peripheral T-cell lymphoma (PTCL) with cytotoxic T-cell phenotype and atypical lymphoma presentations. CD107a degranulation assay and NK-cell activity analysis demonstrated impaired cytotoxic function of the NK/T-cells of the patients with FHL-related mutations. Gene expression profile study revealed that up-regulated genes of the cytotoxic T-cells were enriched in autoimmune-related pathways. It was possible that impaired cytotoxic lymphocyte-mediated immune surveillance and autoantigen stimulation may both participate in PTCL oncogenesis. Germline defects of FLH-related genes may represent a novel predisposing factor for PTCLs.

ALOX5 drives the pyroptosis of CD4+ T cells and tissue inflammation in rheumatoid arthritis.

Pyroptosis, an inflammatory form of programmed cell death, is linked to the pathology of rheumatoid arthritis (RA). Here, we investigated the molecular mechanism underlying pyroptosis in T cells isolated from patients with RA. Compared with healthy individuals, patients with RA had more pyroptotic CD4+ T cells in blood and synovia, which correlated with clinical measures of disease activity. Moreover, the mRNA expression and protein abundance of arachidonate 5-lipoxygenase (ALOX5), which converts arachidonic acid to leukotriene A4 (LTA4), were increased in CD4+ T cells from patients with RA and, among patients with RA, were lowest in those in clinical remission. Knockdown or pharmacological inhibition of ALOX5 suppressed CD4+ T cell pyroptosis and improved symptoms in two rodent models of RA. Mechanistically, the increase in ALOX5 activity in RA CD4+ T cells enhanced the production of the LTA4 derivative LTB4, which stimulated Ca2+ influx through ORAI3 channels, leading to the activation of NLRP3 inflammasomes and pyroptosis. Our findings reveal a role for ALOX5 in RA and provide a molecular basis for further exploring the clinical utility of ALOX5 inhibition in RA and for using ALOX5 as a biomarker to distinguish active disease and remission in RA.

Core-shell structured carbon dots with up-conversion fluorescence and photo-triggered nitric oxide-releasing properties.

Cancer-targeted nanotechnology has a new trend in the design and preparation of new materials with functions for imaging and therapeutic applications simultaneously. As a new type of carbon nanomaterial, the inherent core-shell structured carbon dots (CDs) can be designed to provide a modular nanoplatform for integration of bioimaging and therapeutic capabilities. Here, core-shell structured CDs are designed and synthesized from levofloxacin and arginine and named Arg-CDs, in which levofloxacin-derived chromophores with up-conversion fluorescence are densely packed into the carbon core while guanidine groups are located on the shell, providing nitric oxide (NO) for photodynamic therapy of tumors. Moreover, the chromophores in the carbon core irradiated by visible LED light generate large amounts of reactive oxygen species (ROSs) that will oxidize the guanidine groups located on the shell of the Arg-CDs and further increase the NO releasing capacity remarkably. The as-synthesized Arg-CDs show excellent biocompatibility, bright up-conversion fluorescence, and a light-controlled ROS & NO releasing ability, which can be a potential light-modulated nanoplatform to integrate bioimaging and therapeutic functionalities.

Personalized differential expression analysis in triple-negative breast cancer.

Identification of individual-level differentially expressed genes (DEGs) is a pre-step for the analysis of disease-specific biological mechanisms and precision medicine. Previous algorithms cannot balance accuracy and sufficient statistical power. Herein, RankCompV2, designed for identifying population-level DEGs based on relative expression orderings, was adjusted to identify individual-level DEGs. Furthermore, an optimized version of individual-level RankCompV2, named as RankCompV2.1, was designed based on the assumption that the rank positions of genes and relative rank differences of gene pairs would influence the identification of individual-level DEGs. In comparison to other individualized analysis algorithms, RankCompV2.1 performed better on statistical power, computational efficiency, and acquired coequal accuracy in both simulation and real paired cancer-normal data from ten cancer types. Besides, single sample GSEA and Gene Set Variation Analysis analysis showed that pathways enriched with up-regulated and down-regulated genes presented higher and lower enrichment scores, respectively. Furthermore, we identified 16 genes that were universally deregulated in 966 triple-negative breast cancer (TNBC) samples and interacted with Food and Drug Administration (FDA)-approved drugs or antineoplastic agents, indicating notable therapeutic targets for TNBC. In addition, we also identified genes with highly variable deregulation status and used these genes to cluster TNBC samples into three subgroups with different prognoses. The subgroup with the poorest outcome was characterized by down-regulated immune-regulated pathways, signal transduction pathways, and apoptosis-related pathways. Protein-protein interaction network analysis revealed that OAS family genes may be promising drug targets to activate tumor immunity in this subgroup. In conclusion, RankCompV2.1 is capable of identifying individual-level DEGs with high accuracy and statistical power, analyzing mechanisms of carcinogenesis and exploring therapeutic strategy.

Endoplasmic reticulum aminopeptidase 2 regulates CD4+ T cells pyroptosis in rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease with a complex pathogenesis that has not yet been fully elucidated, and T-cell pyroptosis is an important pathogenetic factor in RA. This study aimed to investigate the role of endoplasmic reticulum aminopeptidase 2 (ERAP2) in the pyroptosis of CD4+ T cells in RA and the specific molecular mechanism. METHODS: Peripheral venous blood was collected from human subjects, and CD4+ T cells were isolated and activated to measure the level of pyroptosis and ERAP2 expression. Pyroptosis levels were assessed using immunofluorescence, flow cytometry, qRT-PCR, and Western blotting. Changes in pyroptosis levels were observed upon knockdown or overexpression of ERAP2. To detect activated Caspase-1 in tissues, chimeric mice were engrafted with human synovial tissue and reconstituted with human CD4+ T cells. CD4 + T cells were treated with GLI1 antagonists and SMO receptor agonists to detect changes in pyroptosis levels. RESULTS: CD4+ T cell levels undergoing pyroptosis were found to be elevated in the blood and synovium of RA patients. The gene and protein expression of ERAP2 were significantly higher in CD4+ T cells from RA patients. Deletion of ERAP2 suppressed pyroptosis of these cells, attenuated the activation of Caspase-1 in tissue T cells, and reduced tissue inflammatory responses. Reciprocally, overexpression of ERAP2 triggered inflammasome assembly, activated Caspase-1, and induced pyroptosis in CD4+ T cells. Mechanistically, ERAP2 inhibits the Hedgehog signaling pathway and upregulates the expression of nucleotide-binding oligomerization segment-like receptor family 3(NLRP3), cleaved Caspase-1, and Gasdermin D to promote pyroptosis in CD4+ T cells. CONCLUSIONS: Taken together, our results identify a novel mechanism by which ERAP2 regulates RA development and document the effect of the ERAP2/Hedgehog signaling axis on pyroptosis of CD4+ T cells from RA patients.