The catalytic activity of 3-mercaptopyruvate (3MP) sulfurtransferase (MPST) converts 3MP to hydrogen sulfide (H₂S). However, the regulatory mechanisms governing MPST and its impact on the brain remain largely unexplored. Our study reveals the neuroprotective role of endothelial MPST-generated H₂S, regulated by protein phosphatase 2A (PP2A). Bioinformatics analysis and RNA sequencing demonstrated that endothelial PP2A is associated with neurodegenerative disease pathways. Cerebral ischemic mice exhibited significant inactivation of endothelial PP2A, evidenced by the reduction of PP2Acα in the brain endothelium. Mice with endothelium-specific null PP2A (PP2A^EC-cKO) exhibited neuronal loss, cognitive dysfunction, and long-term potentiation deficits. Postnatal inactivation of endothelial PP2A also contributes to cognitive dysfunction and neuronal loss. However, regaining endothelial PP2A activity by overexpressing Ppp2ca rescued neuronal dysfunction. Mechanistically, PP2A deficiency is intricately linked to the MPST-H₂S signaling pathway. A robust reduction in endothelial MPST-dependent H₂S production followed PP2A deficiency. Exogenous H₂S treatment and AAV-mediated overexpression of MPST in brain endothelial cells significantly mitigated neuronal dysfunction in PP2A^EC-cKO mice. Furthermore, PP2A deficiency promotes an increase in calcium influx and calpain2 phosphorylation, subsequently leading to MPST degradation. The PP2A activator (FTY720) and MPST activator (3MP sodium) both remarkably restored endothelial MPST-dependent H₂S production, subsequently rescuing ischemia-induced neurological deficits. In conclusion, our study demonstrates that endothelial PP2A deficiency leads to MPST degradation by activating calpain2, thus damaging neuronal function.

Cardiac fibrosis is characterized by an elevated amount of extracellular matrix (ECM) within the heart. However, the persistence of cardiac fibrosis ultimately diminishes contractility and precipitates cardiac dysfunction. Circular RNAs (circRNAs) are emerging as important regulators of cardiac fibrosis. Here, we elucidate the functional role of a specific circular RNA CELF1 in cardiac fibrosis and delineate a novel feedback loop mechanism. Functionally, circ-CELF1 was involved in enhancing fibrosis-related markers' expression and promoting the proliferation of cardiac fibroblasts (CFs), thereby exacerbating cardiac fibrosis. Mechanistically, circ-CELF1 reduced the ubiquitination-degradation rate of BRPF3, leading to an elevation of BRPF3 protein levels. Additionally, BRPF3 acted as a modular scaffold for the recruitment of histone acetyltransferase KAT7 to facilitate the induction of H3K14 acetylation within the promoters of the Celf1 gene. Thus, the transcription of Celf1 was dramatically activated, thereby inhibiting the subsequent response of their downstream target gene Smad7 expression to promote cardiac fibrosis. Moreover, Celf1 further promoted Celf1 pre-mRNA transcription and back-splicing, thereby establishing a feedback loop for circ-CELF1 production. Consequently, a novel feedback loop involving CELF1/circ-CELF1/BRPF3/KAT7 was established, suggesting that circ-CELF1 may serve as a potential novel therapeutic target for cardiac fibrosis.

BACKGROUND: Several studies have demonstrated the occurrence of secondary tumors as a rare but significant complication of chimeric antigen receptor T (CAR-T) cell therapy, underscoring the need for a detailed investigation. Given the limited variety of secondary tumor types reported to date, a comprehensive characterization of the various secondary tumors arising after CAR-T therapy is essential to understand the associated risks and to define the role of the immune microenvironment in malignant transformation. This study aims to characterize the immune microenvironment of a newly identified secondary tumor post-CAR-T therapy, to clarify its pathogenesis and potential therapeutic targets. METHODS: In this study, the bone marrow (BM) samples were collected by aspiration from the primary and secondary tumors before and after CD19 CAR-T treatment. The CD45 + BM cells were enriched with human CD45 microbeads. The CD45 + cells were then sent for 10× genomics single-cell RNA sequencing (scRNA-seq) to identify cell populations. The Cell Ranger pipeline and CellChat were used for detailed analysis. RESULTS: In this study, a rare type of secondary chronic myelomonocytic leukemia (CMML) were reported in a patient with diffuse large B-cell lymphoma (DLBCL) who had previously received CD19 CAR-T therapy. The scRNA-seq analysis revealed increased inflammatory cytokines, chemokines, and an immunosuppressive state of monocytes/macrophages, which may impair cytotoxic activity in both T and natural killer (NK) cells in secondary CMML before treatment. In contrast, their cytotoxicity was restored in secondary CMML after treatment. CONCLUSIONS This finding delineates a previously unrecognized type of secondary tumor, CMML, after CAR-T therapy and provide a framework for defining the immune microenvironment of secondary tumor occurrence after CAR-T therapy. In addition, the results provide a rationale for targeting macrophages to improve treatment strategies for CMML treatment.
Humans ; Lymphoma, Large B-Cell, Diffuse/therapy* ; Tumor Microenvironment/genetics* ; Antigens, CD19/metabolism* ; Leukemia, Myelomonocytic, Chronic/genetics* ; Immunotherapy, Adoptive/adverse effects* ; Male ; Single-Cell Analysis/methods* ; Female ; Sequence Analysis, RNA/methods* ; Receptors, Chimeric Antigen ; Middle Aged

Poly(lactic-co-glycolide)(PLGA)is a key excipient in long-acting sustained-release preparations,and its degradation properties directly affect the drug release behavior.In this study,PLGA microspheres were prepared by microfluidic techniques,and the morphology changes of the microspheres were observed by scanning electron microscopy(SEM).In alkaline environment,due to the accelerated hydrolysis of ester bonds,the surface of the microspheres was rapidly dissolved and eroded,and the degradation rate was significantly higher than that in acidic environment.High temperature accelerated the degradation of PLGA microspheres.Under neutral and alkaline conditions,the microspheres showed aggregation and adhesion.Under acidic conditions,the microspheres gradually decomposed into irregular fragments.The high ionic strength further promoted the surface corrosion of the microspheres,especially under extreme pH conditions.Simultaneously,PLGA microspheres encapsulating coumarin were prepared to simulate the microsphere formulation.The release rate of coumarin after degradation of the microspheres under different conditions was observed by measuring the absorbance with ultraviolet-visible spectrophotometry.The results were consistent with those of the blank microspheres.This study revealed that the degradation of PLGA microspheres was significantly pH-dependent,temperature sensitive and ion strength responsive.These findings not only helped to understand and optimize the long-term stability and controlled release performance of drug-carrying microspheres,but also provided a theoretical basis for further improvement of PLGA-based drug carrier design.

Respiratory syncytial virus(RSV)is a major cause of severe lower respiratory disease and can infect all populations,posing a significant health threat to infants and the elderly.After more than 60 years of research,there are only 2 RSV vaccines and 2 preventive monoclonal antibodies be licensed,but the use of the population is severely limited,expensive and difficult to large-scale popularization.RSV vaccine development faces a number of obstacles,such as the lack of animal models,avoidance of RSV immunity,and short duration of immunity.Since the failure of formalin inactivated RSV vaccine trials,RSV vaccine development has become more cautious and difficult.This article briefly reviews the research status of RSV vaccines,and introduces several representative vaccines currently under development,in order to facilitate researchers to review the latest progress and contribute to promoting vaccine research.

Respiratory syncytial virus(RSV)is a major cause of severe lower respiratory disease and can infect all populations,posing a significant health threat to infants and the elderly.After more than 60 years of research,there are only 2 RSV vaccines and 2 preventive monoclonal antibodies be licensed,but the use of the population is severely limited,expensive and difficult to large-scale popularization.RSV vaccine development faces a number of obstacles,such as the lack of animal models,avoidance of RSV immunity,and short duration of immunity.Since the failure of formalin inactivated RSV vaccine trials,RSV vaccine development has become more cautious and difficult.This article briefly reviews the research status of RSV vaccines,and introduces several representative vaccines currently under development,in order to facilitate researchers to review the latest progress and contribute to promoting vaccine research.

BACKGROUND: Patients with atrial fibrillation (AF) and prior stroke history have a high risk of cardiovascular events despite anticoagulation therapy. It is unclear whether catheter ablation (CA) has further benefits in these patients. METHODS: AF patients with a previous history of stroke or systemic embolism (SE) from the prospective Chinese Atrial Fibrillation Registry study between August 2011 and December 2020 were included in the analysis. Patients were matched in a 1:1 ratio to CA or medical treatment (MT) based on propensity score. The primary outcome was a composite of all-cause death or ischemic stroke (IS)/SE. RESULTS: During a total of 4.1 ± 2.3 years of follow-up, the primary outcome occurred in 111 patients in the CA group (3.3 per 100 person-years) and in 229 patients in the MT group (5.7 per 100 person-years). The CA group had a lower risk of the primary outcome compared to the MT group [hazard ratio (HR) = 0.59, 95% CI: 0.47-0.74, P < 0.001]. There was a significant decreasing risk of all-cause mortality (HR = 0.43, 95% CI: 0.31-0.61, P < 0.001), IS/SE (HR = 0.73, 95% CI: 0.54-0.97, P = 0.033), cardiovascular mortality (HR = 0.32, 95% CI: 0.19-0.54, P < 0.001) and AF recurrence (HR = 0.33, 95% CI: 0.30-0.37, P < 0.001) in the CA group compared to that in the MT group. Sensitivity analysis generated consistent results when adjusting for time-dependent usage of anticoagulants. CONCLUSIONS In AF patients with a prior stroke history, CA was associated with a lower combined risk of all-cause death or IS/SE. Further clinical trials are warranted to confirm the benefits of CA in these patients.

Objective:To study the value of urine-based multi-dimensional bioinformatics evaluation model (utLIFE model) in early diagnosis and postoperative monitoring of upper urinary tract urothelial carcinoma (UTUC).Methods:Morning urine samples of patients clinically diagnosed with UTUC without bladder cancer from Peking University First Hospital from August 2022 to October 2022 were collected. Urine samples were collected before and after surgery, and DNA was extracted for gene sequencing. The utLIFE model previously constructed by our center was used to calculate the score, based on 155 gene mutation sites and copy number variation, and the score ≥60 was defined as utLIFE positive. The sensitivity of utLIFE model in diagnosis of UTUC was analyzed with postoperative pathology as the gold standard. The utLIFE scores before and after operation were also compared.Results:A total of 53 patients were included in this study, all of whom were confirmed as UTUC by postoperative pathology. The median age of patients was 66 (59, 72) years. Twenty-four cases (45.3%) of UTUC tumors were located in the renal pelvis, 26 cases (49.1%) were located in the ureter, and 2 cases (5.7%)involved both ureter and renal pelvis. There were 27 patients (50.9%) at T 1stage and 26 patients (49.1%) at ≥T 2 stage. Preoperative utLIFE score of 53 patients was 79 (70, 84). The sensitivity of preoperative utLIFE diagnosis of UTUC was 96.2% (51/53). utLIFE showed similar high sensitivity in T 1 stage and ≥T 2 stage [100.0% (27/27) vs. 92.3% (24/26), P=0.236], in N 0 and ≥N 1 stage [ 95.0% (38/40) vs. 100.0% (5/5), P=1.000]. In addition, the sensitivity of preoperative utLIFE was higher than that of urine cytology [ 95.2% (20/21) vs. 23.8% (5/21). P<0.001], fluorescence in situ hybridization (FISH) [ 92.6% (25/27) vs. 55.5% (15/27), P=0.004] and ureteroscopy [ 86.7% (13/15) vs. 60.0% (9/15), P=1.000]. A total of 45 patients postoperative utLIFE samples were collected, and the postoperative utLIFE score was significantly lower than that of preoperative [ 36 (18, 61) vs. 79 (70, 84), P<0.001]. Conclusions:utLIFE, as a non-invasive urine DNA bioinformatics assessment model, is significantly superior to cytology and FISH in early detection and has high sensitivity in diagnosis of UTUC, and can reflect perioperative minimal residual disease levels.

OBJECTIVE: To study the trend of surgical type, surgical procedure and etiological distribution of upper urinary tract repair in recent 10 years. METHODS: The preoperative and perioperative variables and follow-up data of upper urinary tract reconstruction surgery in RECUTTER (Reconstruction of Urinary Tract: Technology, Epidemiology and Result) database from 2010 to 2021 were searched, collected and analyzed. The surgical type, surgical procedure, duration of hospitalization, time of operation, incidence of short-term complications, and proportion of the patients undergoing reoperations were compared between the two groups of 2010-2017 period and 2018-2021 period. RESULTS: A total of 1 072 patients were included in the RECUTTER database. Congenital factors and iatrogenic injuries were the main causes of upper urinary tract repair. Among them, 129 (12.0%) patients had open operation, 403 (37.6%) patients had laparoscopic surgery, 322 (30.0%) patients had robot-assisted laparoscopic surgery and 218 (20.3%) patients had endourological procedure. In the last decade, the total number of surgeries showed a noticeable increasing annual trend and the proportion of robot-assisted laparoscopic surgery in 2018-2021 was significantly higher than that in 2010-2017 (P < 0.001). The 1 072 patients included 124 (11.6%) cases of ileal ureter replacements, 440 (41.1%) cases of pyeloplasty, 229 (21.4%) cases of balloon dilation, 109 (10.2%) cases of ureteral reimplantation, 49 (4.6%) cases of boari flap-Psoas hitch surgery, 60 (5.6%) cases of uretero-ureteral anastomosis, 61 (5.7%) cases of lingual mucosal onlay graft ureteroplasty or appendiceal onlay flap ureteroplasty. Pyeloplasty and balloon dilatation had been the main types of surgery, while the proportion of lingual mucosal onlay graft ureteroplasty plus appendiceal onlay flap ureteroplasty had increased significantly in recent years (P < 0.05). In addition, the time of operation was significantly increased (P < 0.05) after 2018, which was considered to be related to the sharp increase in the proportion of robot-assisted laparoscopic surgery. We found that minimally invasive surgery (endourological procedure and robot-assisted laparoscopic surgery) as an independent risk factor (P=0.050, OR=0.472) could reduce the incidence of short-term post-operative complications. CONCLUSION We have justified the value of the RECUTTER database, created by the Institute of Urology, Peking University in data support for clinical research work, and provided valuable experience for the construction of other multi-center databases at home and abroad. In recent 10 years, we have observed that, in upper urinary tract reconstruction surgery, the surgery type tends to be minimally invasive and the surgery procedure tends to be complicated, suggesting the superiority of robot-assisted laparoscopic surgery.
Humans ; Laparoscopy/methods* ; Retrospective Studies ; Robotic Surgical Procedures ; Treatment Outcome ; Ureter/surgery* ; Ureteral Obstruction/surgery* ; Urologic Surgical Procedures/methods*

OBJECTIVE: To develop a method for R-peak detection of ECG data from wearable devices to allow accurate estimation of the physiological parameters including heart rate and heart rate variability. METHODS: A fully convolutional neural network was applied to predict the R-peak heatmap of ECG data and locate the R-peak positions. The heartbeat-aware (HA) module was introduced to enable the model to learn to predict the heartbeat number and R-peak heatmap simultaneously, thereby improving the capability of the model for extraction of the global context. The R-R interval estimated by the predicted heartbeat number was adopted to calculate the minimum horizontal distance for peak positioning. To achieve real-time R-peak detection on mobile devices, the deep separable convolution was adopted to reduce the number of parameters and the computational complexity of the model. RESULTS: The proposed model was trained only with ECG data from wearable devices. At a tolerance window interval of 150 ms, the proposed method achieved R peak detection sensitivities of 100% for both wearable device ECG dataset and a public dataset (i.e. LUDB), and the true positivity rates exceeded 99.9%. As for the ECG signal of a 10 s duration, the CPU time of the proposed method for R-peak detection was about 23.2 ms. CONCLUSION The proposed method has good performance for R-peak detection of both wearable device ECG data and routine ECG data and also allows real-time R-peak detection of the ECG data.
Algorithms ; Electrocardiography ; Heart Rate ; Neural Networks, Computer ; Signal Processing, Computer-Assisted ; Wearable Electronic Devices