Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Background: Nasopharyngeal carcinoma (NPC) is characterized by high programmed death-ligand 1 (PD-L1) expression and abundant infiltration of non-malignant lymphocytes, which renders patients potentially suitable candidates for immune checkpoint blockade therapies. Palate, lung, and nasal epithelium clone (PLUNC) inhibit the growth of NPC cells and enhance cellular apoptosis and differentiation. Currently, the relationship between PLUNC (as a tumor-suppressor) and PD-L1 in NPC is unclear. Methods: We collected clinical samples of NPC to verify the relationship between PLUNC and PD-L1. PLUNC plasmid was transfected into NPC cells, and the variation of PD-L1 was verified by western blot and immunofluorescence. In NPC cells, we verified the relationship of PD-L1, activating transcription factor 3 (ATF3), and β-catenin by western blot and immunofluorescence. Later, we further verified that PLUNC regulates PD-L1 through β-catenin. Finally, the effect of PLUNC on β-catenin was verified by co-immunoprecipitation (Co-IP). Results: We found that PLUNC expression was lower in NPC tissues than in paracancer tissues. PD-L1 expression was opposite to that of PLUNC. Western blot and immunofluorescence showed that β-catenin could upregulate ATF3 and PD-L1, while PLUNC could downregulate ATF3/PD-L1 by inhibiting the expression of β-catenin. PLUNC inhibits the entry of β-catenin into the nucleus. Co-IP experiments demonstrated that PLUNC inhibited the interaction of DEAD-box helicase 17 (DDX17) and β-catenin. Conclusions PLUNC downregulates the expression of PD-L1 by inhibiting the interaction of DDX17/β-catenin in NPC.

The research on the cardiovascular toxicity of air pollutants is in urgent need of collaborative innovation across multiple models. This paper systematically reviewed the advantages and limitations of four principal research models of cardiotoxicity, including epidemiological model, mammalian model, zebrafish model, and in vitro model. Epidemiological models have been used to demonstrate a significant correlation between exposure to PM_2.5 and both the incidence and mortality of cardiovascular diseases within populations; however, these models face challenges in establishing causal inferences and interpreting individual mechanisms. Mammalian models have been applied to elucidate the pathogenic mechanisms of PM_2.5 at both the systemic and organ-specific levels, yet they encounter difficulties related to interspecies differences and throughput constraints. Zebrafish models, with their transparent embryos and observable development, offer a distinctive opportunity for high-throughput screening and mechanistic investigation of PM_2.5-induced cardiac developmental toxicity. Nonetheless, their cardiac physiological structure diverges from that of mammals, limiting their capacity to accurately model chronic conditions such as coronary heart disease. In vitro models, particularly human heart organoids and chip technologies, have provided profound insights into the direct toxic mechanisms of PM_2.5, including disruptions in calcium homeostasis, cellular senescence, and electrophysiological irregularities at the cellular and molecular levels. Despite these advancements, the complexity and developmental maturity of these models present challenges to their broader application. This paper proposed that the key to overcoming the bottlenecks of single models lies in the construction of an integrated evaluation system that combines “epidemiological studies, mammalian models, zebrafish models, and in vitro models”. By focusing on three aspects, namely model integration, technological convergence, and policy support, it is intended to collaboratively address issues such as standardization of multi-model data, simulation of complex exposure scenarios and susceptible life stages, and transformation pathways. This will provide innovative methodological support for the analysis of the cardiotoxic mechanisms of air pollutants, the assessment of environmental health impacts, and the formulation of precise prevention and control strategies.

Background and aims:Clinical data regarding patients with chronic hepatitis B(CHB)after Omicron BA.5 infection are currently limited.This study aimed to assess the clinical characteristics of patients with CHB and Omicron BA.5 infection in South China.Methods:This retrospective study was conducted from January to March 2023 in a cohort of 485 healthy individuals and 553 patients with CHB.Clinical features,encompassing COVID-19-related symptoms,levels of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)antibodies,vaccination status,liver functions,and virological markers of hepatitis B virus(HBV)infection were measured.Results:COVID-19-related symptom patterns were similar in both groups,except for fever,which was notably less prevalent(85.4％vs.90.4％,P=0.047)among patients with CHB who experienced a significantly shorter duration of fever(median 2.2(25th-75th percentile,1.0-3.0)days vs.2.3(1.0-3.0)days,P=0.048)and a shorter time for symptom relief(9.2(5.0-14.0)vs.11.1(5.0-14.0)days,P=0.015).The levels of SARS-CoV-2 antibodies were comparable between the two groups but increased after booster vaccinations.In patients with CHB,globulin(GLB)and hepatitis B envelope antibody levels were significantly increased after Omicron BA.5 infection,regardless of nucleos(t)ide analog regimens comparing entecavir(ETV)with tenofovir(TFV).Patients with CHB treated with TFV had significantly higher levels of SARS-CoV-2 antibodies than those treated with ETV(1065.1(346.9-1188.5)COI vs.765.5(24.5-1119.1)COI,P=0.025).Conclusions:No significant exacerbation of COVID-19 symptoms was observed in conjunction with the efficacy of COVID-19 booster vaccinations.There were no notable alterations in liver functions except for GLB.HBV reactivation,as evidenced by increased HBV DNA,was observed among patients with CHB after Omicron BA.5 infection.These changes were not affected by ETV versus TFV administration;however,TFV resulted in a significant increase in SARS-CoV-2 antibody levels.Further studies are required to improve care and therapeutics for patients with CHB who contracted COVID-19.

Background: Nasopharyngeal carcinoma (NPC) is characterized by high programmed death-ligand 1 (PD-L1) expression and abundant infiltration of non-malignant lymphocytes, which renders patients potentially suitable candidates for immune checkpoint blockade therapies. Palate, lung, and nasal epithelium clone (PLUNC) inhibit the growth of NPC cells and enhance cellular apoptosis and differentiation. Currently, the relationship between PLUNC (as a tumor-suppressor) and PD-L1 in NPC is unclear. Methods: We collected clinical samples of NPC to verify the relationship between PLUNC and PD-L1. PLUNC plasmid was transfected into NPC cells, and the variation of PD-L1 was verified by western blot and immunofluorescence. In NPC cells, we verified the relationship of PD-L1, activating transcription factor 3 (ATF3), and β-catenin by western blot and immunofluorescence. Later, we further verified that PLUNC regulates PD-L1 through β-catenin. Finally, the effect of PLUNC on β-catenin was verified by co-immunoprecipitation (Co-IP). Results: We found that PLUNC expression was lower in NPC tissues than in paracancer tissues. PD-L1 expression was opposite to that of PLUNC. Western blot and immunofluorescence showed that β-catenin could upregulate ATF3 and PD-L1, while PLUNC could downregulate ATF3/PD-L1 by inhibiting the expression of β-catenin. PLUNC inhibits the entry of β-catenin into the nucleus. Co-IP experiments demonstrated that PLUNC inhibited the interaction of DEAD-box helicase 17 (DDX17) and β-catenin. Conclusions PLUNC downregulates the expression of PD-L1 by inhibiting the interaction of DDX17/β-catenin in NPC.

Background: Nasopharyngeal carcinoma (NPC) is characterized by high programmed death-ligand 1 (PD-L1) expression and abundant infiltration of non-malignant lymphocytes, which renders patients potentially suitable candidates for immune checkpoint blockade therapies. Palate, lung, and nasal epithelium clone (PLUNC) inhibit the growth of NPC cells and enhance cellular apoptosis and differentiation. Currently, the relationship between PLUNC (as a tumor-suppressor) and PD-L1 in NPC is unclear. Methods: We collected clinical samples of NPC to verify the relationship between PLUNC and PD-L1. PLUNC plasmid was transfected into NPC cells, and the variation of PD-L1 was verified by western blot and immunofluorescence. In NPC cells, we verified the relationship of PD-L1, activating transcription factor 3 (ATF3), and β-catenin by western blot and immunofluorescence. Later, we further verified that PLUNC regulates PD-L1 through β-catenin. Finally, the effect of PLUNC on β-catenin was verified by co-immunoprecipitation (Co-IP). Results: We found that PLUNC expression was lower in NPC tissues than in paracancer tissues. PD-L1 expression was opposite to that of PLUNC. Western blot and immunofluorescence showed that β-catenin could upregulate ATF3 and PD-L1, while PLUNC could downregulate ATF3/PD-L1 by inhibiting the expression of β-catenin. PLUNC inhibits the entry of β-catenin into the nucleus. Co-IP experiments demonstrated that PLUNC inhibited the interaction of DEAD-box helicase 17 (DDX17) and β-catenin. Conclusions PLUNC downregulates the expression of PD-L1 by inhibiting the interaction of DDX17/β-catenin in NPC.

The role of radiotherapy in activating antitumor immune responses has attracted growing attention. Proton beam therapy (PBT), owing to its unique physical and biological properties, holds great potential in cancer immunotherapy. PBT not only directly kills tumor cells but also induces immunogenic cell death, remodels the tumor microenvironment, and modulates immune cell functions. Moreover, PBT shows distinct advantages in inducing systemic immune responses and establishing immune memory. Recent studies have demonstrated that PBT offers unique benefits over conventional photon radiotherapy in activating antitumor immunity and exhibits marked synergistic effects when combined with immune checkpoint inhibitors (ICIs). This review systematically summarizes recent advances in understanding the role and mechanisms of PBT in tumor immune modulation, discusses the prospects of its combination with immunotherapy, and provides new insights and theoretical evidence for comprehensive cancer treatment.

Objective:To investigate the clinical characteristics and treatment of human immunodeficiency virus (HIV) negative adult disseminated Talaromyces marneffei (TSM) infection, so as to improve the diagnosis and treatment of this disease.Methods:While two HIV-negative adult patients with disseminated T. Marneffei infection were reported, papers published between 1970 and February 2024 were collected from CNKI, Wanfang and Chongqing Weipu databases, and patient data meeting diagnostic criteria were collected. A total of 34 HIV-negative adults with disseminated T. Marneffei infection were collected. The data of 34 patients with this disease were retrospectively analyzed, and the demographic distribution, systematic signs, examination results, complications, diagnosis and treatment plan and effect of this disease were summarized.Results:Among the 34 patients, the ratio of male to female patients was 21∶13. The median age of onset was 51 years, ranging from 24 to 70 years. The incidence area was more common in the south of China. The most common clinical manifestation was fever. 70.6%(24/34) of patients were misdiagnosed, most often with tuberculosis. The methods of diagnosis were as follows: 26 cases were diagnosed by fungal culture, 5 cases by high-throughput sequencing and 3 cases by direct microscopy. 32 patients received antifungal therapy, 9 were cured, 10 improved, 2 died, 4 relapsed, 4 patients were effective (but the outcome was unknown), 2 patients had poor effect, and 1 patient had unknown effect. Two patients died soon after admission due to rapid disease progression.Conclusions:The symptoms of HIV negative adults infected with T. Marneffei are varied and may involve multiple systems. Infection is often misdiagnosed. Early identification and fungal culture can improve the detection rate. High-throughput sequencing is a relatively mature diagnostic technology.

Objective:To investigate the clinical characteristics and treatment of human immunodeficiency virus (HIV) negative adult disseminated Talaromyces marneffei (TSM) infection, so as to improve the diagnosis and treatment of this disease.Methods:While two HIV-negative adult patients with disseminated T. Marneffei infection were reported, papers published between 1970 and February 2024 were collected from CNKI, Wanfang and Chongqing Weipu databases, and patient data meeting diagnostic criteria were collected. A total of 34 HIV-negative adults with disseminated T. Marneffei infection were collected. The data of 34 patients with this disease were retrospectively analyzed, and the demographic distribution, systematic signs, examination results, complications, diagnosis and treatment plan and effect of this disease were summarized.Results:Among the 34 patients, the ratio of male to female patients was 21∶13. The median age of onset was 51 years, ranging from 24 to 70 years. The incidence area was more common in the south of China. The most common clinical manifestation was fever. 70.6%(24/34) of patients were misdiagnosed, most often with tuberculosis. The methods of diagnosis were as follows: 26 cases were diagnosed by fungal culture, 5 cases by high-throughput sequencing and 3 cases by direct microscopy. 32 patients received antifungal therapy, 9 were cured, 10 improved, 2 died, 4 relapsed, 4 patients were effective (but the outcome was unknown), 2 patients had poor effect, and 1 patient had unknown effect. Two patients died soon after admission due to rapid disease progression.Conclusions:The symptoms of HIV negative adults infected with T. Marneffei are varied and may involve multiple systems. Infection is often misdiagnosed. Early identification and fungal culture can improve the detection rate. High-throughput sequencing is a relatively mature diagnostic technology.

The role of radiotherapy in activating antitumor immune responses has attracted growing attention. Proton beam therapy (PBT), owing to its unique physical and biological properties, holds great potential in cancer immunotherapy. PBT not only directly kills tumor cells but also induces immunogenic cell death, remodels the tumor microenvironment, and modulates immune cell functions. Moreover, PBT shows distinct advantages in inducing systemic immune responses and establishing immune memory. Recent studies have demonstrated that PBT offers unique benefits over conventional photon radiotherapy in activating antitumor immunity and exhibits marked synergistic effects when combined with immune checkpoint inhibitors (ICIs). This review systematically summarizes recent advances in understanding the role and mechanisms of PBT in tumor immune modulation, discusses the prospects of its combination with immunotherapy, and provides new insights and theoretical evidence for comprehensive cancer treatment.