zDHHC20-driven S-palmitoylation of CD80 is required for its costimulatory function.

CD80 is a transmembrane glycoprotein belonging to the B7 family, which has emerged as a crucial molecule in T cell modulation via the CD28 or CTLA4 axes. CD80-involved regulation of immune balance is a finely tuned process and it is important to elucidate the underlying mechanism for regulating CD80 function. In this study we investigated the post-translational modification of CD80 and its biological relevance. By using a metabolic labeling strategy, we found that CD80 was S-palmitoylated on multiple cysteine residues (Cys261/262/266/271) in both the transmembrane and the cytoplasmic regions. We further identified zDHHC20 as a bona fide palmitoyl-transferase determining the S-palmitoylation level of CD80. We demonstrated that S-palmitoylation protected CD80 protein from ubiquitination degradation, regulating the protein stability, and ensured its accurate plasma membrane localization. The palmitoylation-deficient mutant (4CS) CD80 disrupted these functions, ultimately resulting in the loss of its costimulatory function upon T cell activation. Taken together, our results describe a new post-translational modification of CD80 by S-palmitoylation as a novel mechanism for the regulation of CD80 upon T cell activation.

Prevalence, risk factors, and prediction of inappropriate use of non-vitamin K antagonist oral anticoagulants in elderly Chinese patients with atrial fibrillation: A study protocol.

Background: Atrial fibrillation (AF) is an arrhythmia that is prevalent globally, and its incidence grows exponentially with aging. Non-vitamin K antagonist oral anticoagulants (NOACs) have been developed in recent years, and it challenges the supremacy of warfarin for thromboembolism prophylaxis in AF. Nevertheless, there are limited data specifically evaluating the real-life use of NOACs in elderly patients with AF in China. Methods: This is a national, multicenter, non-interventional, cross-sectional study that enrolls patients with AF aged 75 years and above from 31 institutions across China. Data were collected using the Hospital Information System. The primary outcomes include (1) profiles of NOAC use in the elderly; (2) frequency of inappropriate NOAC use based on guidelines and approved labeling recommendations; (3) exploring potential risk factors related to NOACs inappropriate use; and (4) creating a prediction tool for inappropriate NOACs use. Conclusion: The results of this study reveal the prevalence, risk factors, and corresponding prediction tool of inappropriate NOACs use in older patients with AF in China, as well as provide valuable insights into the clinical application of NOACs in high-risk populations in the real-world setting. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT05361889.

Cardiac Fibroblast-Specific Activating Transcription Factor 3 Promotes Myocardial Repair after Myocardial Infarction.

BACKGROUND: Myocardial ischemia injury is one of the leading causes of death and disability worldwide. Cardiac fibroblasts (CFs) have central roles in modulating cardiac function under pathophysiological conditions. Activating transcription factor 3 (ATF3) plays a self-protective role in counteracting CF dysfunction. However, the precise function of CF-specific ATF3 during myocardial infarction (MI) injury/repair remains incompletely understood. The aim of this study was to determine whether CF-specific ATF3 affected cardiac repair after MI. METHODS: Fifteen male C57BL/6 wild-type mice were performed with MI operation to observe the expression of ATF3 at 0, 0.5, 1.0, 3.0, and 7.0 days postoperation. Model for MI was constructed in ATF3TGfl/flCol1a2-Cre+ (CF-specific ATF3 overexpression group, n = 5) and ATF3TGfl/flCol1a2-Cre- male mice (without CF-specific ATF3 overexpression group, n = 5). In addition, five mice of ATF3TGfl/flCol1a2-Cre+ and ATF3TGfl/flCol1a2-Cre- were subjected to sham MI operation. Heart function was detected by ultrasound and left ventricular remodeling was observed by Masson staining (myocardial fibrosis area was detected by blue collagen deposition area) at the 28th day after MI surgery in ATF3TGfl/flCol1a2-Cre+ and ATF3TGfl/flCol1a2-Cre- mice received sham or MI operation. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect cell proliferation/cell cycle-related gene expression in cardiac tissue. BrdU staining was used to detect fibroblast proliferation. RESULTS: After establishment of an MI model, we found that ATF3 proteins were increased in the heart of mice after MI surgery and dominantly expressed in CFs. Genetic overexpression of ATF3 in CFs (ATF3TGfl/flCol1a2-Cre+ group) resulted in an improvement in the heart function as indicated by increased cardiac ejection fraction (41.0% vs. 30.5%, t = 8.610, P = 0.001) and increased fractional shortening (26.8% vs. 18.1%, t = 7.173, P = 0.002), which was accompanied by a decrease in cardiac scar area (23.1% vs. 11.0%, t = 8.610, P = 0.001). qRT-PCR analysis of CFs isolated from ATF3TGfl/flCol1a2-Cre+ and ATF3TGfl/flCol1a2-Cre- ischemic hearts revealed a distinct transcriptional profile in ATF3-overexpressing CFs, displaying pro-proliferation properties. BrdU-positive cells significantly increased in ATF3-overexpressing CFs than control CFs under angiotensin II stimuli (11.5% vs. 6.8%, t = 31.599, P = 0.001) or serum stimuli (31.6% vs. 20.1%, t = 31.599, P = 0.001). The 5(6)-carboxyfluorescein N-hydroxysuccinimidyl ester assay showed that the cell numbers of the P2 and P3 generations were higher in the ATF3-overexpressing CFs at 24 h (P2: 91.6% vs. 71.8%, t = 8.465, P = 0.015) and 48 h (P3: 81.6% vs. 51.1%, t = 9.029, P = 0.012) after serum stimulation. Notably, ATF3 overexpression-induced CF proliferation was clearly increased in the heart after MI injury. CONCLUSIONS: We identify that CF-specific ATF3 might contribute to be MI repair through upregulating the expression of cell cycle/proliferation-related genes and enhancing cell proliferation.

The optimal anticoagulant therapy for mechanical heart valves in a gallbladder cancer patient with hepatic metastases: A case report.

RATIONALE: Developing an optimal anticoagulant strategy poses a challenging task in patients with mechanical heart valves (MHVs) throughout their lifetime. We report an optimal anticoagulant therapy in a cancer patient with hepatic metastases after MHV replacement. PATIENT CONCERNS: A 68-year-old female with MHVs suffered from gallbladder cancer with hepatic metastases. Her international normalized ratio (INR) fluctuated owing to the declined hepatic function. DIAGNOSES: Gallbladder cancer and hepatic metastases, with a history of mechanic aortic valve replacement and mitral valve replacement. INTERVENTIONS: Warfarin was discontinued and Vitamin K1 was immediately administrated via intravenous infusion. low-molecular-weight heparin (LMWH) was regarded as a preferable option, and nadroparin at the dosage of 4100IU daily was administered. OUTCOMES: No adverse event occurred during the patient's hospitalization and two-week follow up after discharge. LESSONS: LMWH may represent a reasonable alternative regarding the inhibition of thrombus and bleeding in MHVs carriers with cancer and hepatic metastases.

[Efficacy of sublingual immunotherapy with dermatophagoides farinae drops in monosensitized and polysensitized patients with allergic rhinitis].

OBJECTIVE: To compare the efficacy of sublingual immunotherapy (SLIT) with standardized Dermatophagoides farinae drops in monosensitized and polysensitized patients with allergic rhinitis. METHODS: The efficacy of SLIT in 69 patients who were sensitized to house dust mites and treated with Dermatophagoides farinae drops for 1.5-2.0 year with complete clinical data were analyzed retrospectively. These patients had been divided into the monoallergen sensitized group and polyallergen sensitized group according to the results of skin prick tests. The total medication score (TMS) and the total nasal symptoms score (TNSS) were evaluated before and half an year, 1.0 year and 1.5-2.0 years after SLIT treatment. RESULTS: After SLIT treatment for half an year, the TNSS in the monoallergen sensitized group (2.00 [1.00; 3.00]) was significantly lower than that in the polyallergen sensitized group (3.00 [2.00; 4.00], Z = -2.851, P < 0.05), this significant difference of TNSS between the two groups was also found after SLIT treatment for 1.0 year (0.00 [0.00; 1.00], 2.00 [0.00; 3.00], Z = -2.590, P < 0.05). Whereas, there was no significant difference between the two groups after 1.5-2.0 years treatment refer to the TNSS (0.00 [0.00; 1.00], 0.00 [0. 00; 2.00], Z = -1.461, P > 0.05). Half an year, 1.0 year and 1.5-2.0 years after SLIT treatment, the TMS in both groups reduced significantly, with no significant difference between two groups (Z value was - 0.777, -0.944, -0.907, all P > 0. 05). CONCLUSIONS: SLIT with Dermatophagoides farinae drops is effective in monosensitized and polysensitized patients with allergic rhinitis. And equivalent efficacy could be achieved after 1.5-2.years.