BACKGROUND: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. METHODS: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. RESULTS: In vitro , blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg -1 ·day -1 ) and Rapamycin (0.1 mg·kg -1 ·day -1 ) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. CONCLUSIONS Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
Animals ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Interferon Regulatory Factors/metabolism* ; Heart Transplantation/methods* ; T-Lymphocytes/immunology* ; Sirolimus/therapeutic use* ; Pyridones/therapeutic use* ; Graft Survival/drug effects* ; Pyrimidinones/therapeutic use* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Male ; Signal Transduction/drug effects*

Fatigue-related traffic accidents and fatalities have been extensively studied by scholars globally.Specialized vehicles,due to their unique mission profiles,are more likely to cause driving-related fatigue and serious consequences.This paper reviews the current research of fatigue driving by using an inductive analysis method to summarize the mechanisms,risk factors,and monitoring methods.This paper also offers a vision of priorities and methodologies for research in the future.It is recommended that the mechanisms of driving fatigue be explored at the molecular biological level and that fatigue monitoring systems be made more feasible via the combined application of non-intrusive monitoring in order to reduce the toll on life and property taken by driving fatigue.

To apply electrical impedance tomography (EIT) technology to assess the lung regional ventilation distribution in patients admitted to the intensive care unit (ICU) after a cardiac surgery, and to analyze its value of predicting patients' short-term prognosis.

Objective To assess the value of cardiac magnetic resonance(CMR)imaging for predicting adverse left ventricular remodeling in patients with ST-segment elevation myocardial infarction(STEMI).Methods We retrospectively analyzed the clinical data and serial CMR(cine and LGE sequences)images of 86 STEMI patients within 1 week and 5 months after percutaneous coronary intervention(PCI),including 25 patients with adverse LV remodeling and 61 without adverse LV remodeling,defined as an increase of left ventricular end-systolic volume(LVESV)over 15%at the second CMR compared to the initial CMR.The CMR images were analyzed for LV volume,infarct characteristics,and global and infarct zone myocardial function.The independent predictors of adverse LV remodeling following STEMI were analyzed using univariate and multivariate Logistic regression methods.Results The initial CMR showed no significant differences in LV volume or LV ejection fraction(LVEF)between the two groups,but the infarct mass and microvascular obstructive(MVO)mass were significantly greater in adverse LV remodeling group(P<0.05).Myocardial injury and cardiac function of the patients recovered over time in both groups.At the second CMR,the patients with adverse LV remodeling showed a significantly lower LVEF,a larger left ventricular end-systolic volume index(LVESVI)and a greater extent of infarct mass(P<0.001)with lower global peak strains and strain rates in the radial,circumferential,and longitudinal directions(P<0.05),infarct zone peak strains in the 3 directions,and infarct zone peak radial and circumferential strain rates(P<0.05).The independent predictors for adverse LV remodeling following STEMI included the extent of infarct mass(AUC=0.793,95%CI:0.693-0.873;cut-off value:30.67%),radial diastolic peak strain rate(AUC=0.645,95%CI:0.534-0.745;cut-off value:0.58%),and RAAS inhibitor(AUC= 0.699,95%CI:0.590-0.793).Conclusion The extent of infarct mass,peak radial diastolic strain rate,and RAAS inhibitor are independent predictors of adverse LV remodeling following STEMI.

Background::Homoharringtonine (HHT) is an effective anti-inflammatory, anti-viral, and anti-tumor protein synthesis inhibitor that has been applied clinically. Here, we explored the therapeutic effects of HHT in a mouse heart transplant model.Methods::Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver, kidney, and hematology. A mouse heart transplantation model was constructed, and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan–Meier analysis, immunostaining, and bulk RNA sequencing analysis. The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells (Tregs) differentiation. Results::HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo. Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days ( P <0.001) without non-immune toxicity. The allografts had long-term survival after continuous HHT treatment for 28 days. HHT significantly reduced lymphocyte infiltration in the graft, and interferon-γ-secreting CD4 + and CD8 + T cells in the spleen ( P <0.01). HHT significantly increased the number of peripheral Tregs (about 20%, P <0.001) and serum interleukin (IL)-10 levels. HHT downregulated the expression of T cell receptor (TCR) signaling pathway-related genes ( CD4, H2-Eb1, TRAT1, and CD74) and upregulated the expression of IL-10 and transforming growth factor (TGF) -β pathway-related genes and Treg signature genes ( CTLA4, Foxp3, CD74, and ICOS). HHT increased CD4 + Foxp3 + cells and Foxp3 expression ex vivo, and it enhanced the inhibitory function of inducible Tregs. Conclusions::HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels, thereby promoting mouse heart allograft acceptance. These findings may have therapeutic implications for organ transplant recipients, particularly those with viral infections and malignancies, which require a more suitable anti-rejection medication.

Objective To assess the value of cardiac magnetic resonance(CMR)imaging for predicting adverse left ventricular remodeling in patients with ST-segment elevation myocardial infarction(STEMI).Methods We retrospectively analyzed the clinical data and serial CMR(cine and LGE sequences)images of 86 STEMI patients within 1 week and 5 months after percutaneous coronary intervention(PCI),including 25 patients with adverse LV remodeling and 61 without adverse LV remodeling,defined as an increase of left ventricular end-systolic volume(LVESV)over 15%at the second CMR compared to the initial CMR.The CMR images were analyzed for LV volume,infarct characteristics,and global and infarct zone myocardial function.The independent predictors of adverse LV remodeling following STEMI were analyzed using univariate and multivariate Logistic regression methods.Results The initial CMR showed no significant differences in LV volume or LV ejection fraction(LVEF)between the two groups,but the infarct mass and microvascular obstructive(MVO)mass were significantly greater in adverse LV remodeling group(P<0.05).Myocardial injury and cardiac function of the patients recovered over time in both groups.At the second CMR,the patients with adverse LV remodeling showed a significantly lower LVEF,a larger left ventricular end-systolic volume index(LVESVI)and a greater extent of infarct mass(P<0.001)with lower global peak strains and strain rates in the radial,circumferential,and longitudinal directions(P<0.05),infarct zone peak strains in the 3 directions,and infarct zone peak radial and circumferential strain rates(P<0.05).The independent predictors for adverse LV remodeling following STEMI included the extent of infarct mass(AUC=0.793,95%CI:0.693-0.873;cut-off value:30.67%),radial diastolic peak strain rate(AUC=0.645,95%CI:0.534-0.745;cut-off value:0.58%),and RAAS inhibitor(AUC= 0.699,95%CI:0.590-0.793).Conclusion The extent of infarct mass,peak radial diastolic strain rate,and RAAS inhibitor are independent predictors of adverse LV remodeling following STEMI.

Objective To explore the Helicobacter pylori (Hp) infection rate and antibody typing of 1111 physical examination people in plateau area, and to analyze the risk factors of Hp infection by logistics regression analysis. Methods 1111 healthy people with physical examination in plateau area from January 2022 to December 2022 were selected as the research subjects. The Hp infection rate and antibody typing were calculated, and the risk factors of Hp infection were analyzed by logistics regression analysis. Results The Hp infection rate of physical examination people in plateau area was 62.47% (694/1 111). The infection rate of type I HP in infected patients was higher than that of type Ⅱ HP(75.50% vs 24.50%) (χ²=361.141, P<0.001). The AUC of CagA in the diagnosis of Hp infection was higher than that of antibody VacA or Ure positive diagnosis alone (Z=6.740, 7.608, P<0.001). The proportions of people with male gender, often eating pickled or barbecued foods, history of chronic gastric disease and family members living together≥4 in infected group were higher than those in uninfected group (χ²=4.418, 8.708, 16.565, 32.583, P=0.036, 0.003, <0.001, <0.001) while the proportion of people with regular garlic consumption was lower than that in uninfected group (χ²=5.153, P=0.023). Often eating pickled or barbecued foods [OR (95%CI)=2.038 (1.049-3.961)], history of chronic gastric disease [OR(95%CI)=1.706 (1.132-2.569)] and family members living together≥4 [OR (95%CI)=1.857 (1.135-3.037)] were risk factors of Hp infection, and regular garlic consumption [OR (95%CI)=0.559 (0.346-0.903)] was a protective factor (P=0.036, 0.011, 0.014, 0.018). Conclusion The Hp infection rate and antibody Ure positive rate are higher in physical examination people in plateau area, and chronic gastric disease history and often eating pickled or barbecued foods are risk factors of Hp infection.

Cordyceps sinensis(C.sinensis)is a widely used and highly valuable traditional Chinese medicine.Several dipeptides have been detected in C.sinensis,but current scientific knowledge of its chemical makeup remains limited.In this study,an improved approach that integrates offline two-dimensional liquid chromatography(2D LC)separation,precursor ion list,library screening,and diagnostic ion filtering was established to systematically screen and characterize dipeptides in C.sinensis.Offline 2D LC integrating hydrophilic interaction LC and reverse phase separations was established to eliminate interference and identify the target dipeptides.A library containing the potential 400 dipeptides was created,and a precursor ion list with all theoretical precursor ions was adopted to trigger the MS/MS scan with high sensitivity.To identify dipeptides,the type and connection sequence of amino acids were determined according to the product ions.Ile and Leu residues were differentiated for the first time according to the characteristic ion at m/z 69.07.Ultimately,170 dipeptides were identified or tentatively characterized from C.sinensis,and most are reported for the first time in this species herein.In addition,the identified dipeptides were also applied for discrimination among the three Cordyceps species,and 11 markers were identified.The obtained results provide a deeper understanding of the chemical basis of C.sinensis.

Paraneoplastic neurological syndromes (PNS) are heterogeneous disorders caused by autoimmune responses of cancer, which can affect any part of the nervous system. Anti-amphiphysin antibody is one of the high-risk PNS antibodies, which is usually associated with small cell lung cancer and breast cancer. However, extrapulmonary neuroendocrine carcinoma is rare in patients with anti-amphiphysin antibody. A case of anti-amphiphysin-associated paraneoplastic brainstem encephalitis with esophageal neuroendocrine carcinoma is reported. The tumor was detected by fluorine 18 fluorodeoxyglucose positron emission tomography and pathologically confirmed by gastroscopic biopsy. The patient′s neurological symptoms were partially improved after treatment of intravenous immunoglobulin and glucocorticoids. However, the disease prognosis is closely related to the accompanying tumor.

Objective:To analyze the epidemiological characteristics of imported COVID-19 cases in early phase in Shanghai, introduce measures and provide reference for prevention and control of imported COVID-19 cases.Methods:Data of imported COVID-19 cases in Shanghai reported as of 30 March, 2020 were obtained from National Notifiable Disease Report System of China CDC and field epidemiological investigation reports by CDCs in Shanghai. The information about measures of prevention and control was collected from official websites and platforms of the governments. Data cleaning and statistical analysis were performed with softwares of EpiData 3.1, Excel 2019 and SAS 9.4.Results:A total of 171 imported COVID-19 cases had been reported as of 30 March, 2020 in Shanghai, including 170 confirmed cases and 1 asymptomatic infection case. Among them, cases of Chinese nationality accounted for 71.3% (122/171) and cases of foreign nationality accounted for 28.7% (49/171). The median age of the cases was 23 years ( P 25, P 75: 18, 35 years), and the male to female ratio of the cases was 1.3∶1. Students accounted for 56.6% (97/171). About 45.6% (78/171) of the cases fell ill before arriving in Shanghai. The cases with mild or common clinical manifestation accounted for 96.5% (165/171) and no significant difference in clinical type was observed between overseas Chinese cases and foreign cases. The epidemic curve by diagnosis date reached peak on March 24, and the number of the cases gradually declined due to the closed-loop management process of joint port prevention and control mechanism. The 171 imported COVID-19 cases were mainly from 24 countries and regions, including the United Kingdom (64 cases, 37.3%), the United States (32 cases, 18.6%), France (19 cases, 11.0%) and Italy (16 cases, 9.4%). About 40.4% of the cases (69/171) planned to continue travelling to 21 other provinces and municipalities in China. Customs quarantine and community observation/detection points identified 43.9% (75/171) cases and 31.0% (53/171) cases, respectively. Conclusions:The imported COVID-19 cases in early phase in Shanghai were mainly young population and students accounted for high proportion. The imported risk of COVID-19 was consistent with the severity of the epidemic in foreign countries. The closed-loop management model of the joint port prevention and control mechanism plays an important role in the identification and management of the imported COVID-19 cases.