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

OBJECTIVE To prepare C-phycocyanin nanoparticles （CPC-NPs） and evaluate the in vitro mechanism of CPC- NPs on acute lung injury induced by lipopolysaccharide （LPS） combined with seawater. METHODS Ion crosslinking method was used to prepare CPC-NPs using CPC as the drug， carboxymethyl chitosan （CMCS） as the carrier， and CaCl2 as the crosslinking agent. The basic characterization of CPC-NPs was carried out. Mouse alveolar type Ⅱ epithelial cells MLE-12 and macrophages RAW264.7 were divided into 7 groups： normal group （Con group）， model group （Mod group）， blank NPs group， CPC-NPs 30， 60， 120 and 240 μg/mL groups. Except for the Con group， all other groups were treated with a combination of 10 μg/mL LPS and 25% seawater for 6 hours. After modeling， each treatment group was treated with corresponding drugs for 24 hours. The levels of malondialdehyde （MDA）， total antioxidant capacity （T-AOC）， superoxide dismutase （SOD）， catalase （CAT）， and glutathione peroxidase （GSH-Px） in MLE-12 cells， as well as the expression levels of B-cell lymphoma-2 （Bcl-2）， Bcl-2 associated X protein （Bax）， caspase-3 protein and mRNA， CAT and glutathione S-transferase （GST） mRNA were determined. The levels of interleukin- 1β （IL-1β）， tumor necrosis factor-α （TNF-α） and IL-6 in RAW264.7 cells， as well as the expression levels of NOD-like receptor thermal protein domain associated protein 3 （NLRP3）， cleaved caspase-1 protein， and mRNA expressions of IL-1β，TNF-α， IL-6 and inducible nitric oxide synthase （iNOS） were all detected. RESULTS The prepared CPC-NPs had particle size of （675.69±64.58） nm， Zeta potential of （－20.11± E-mail：zhangleifang1986@163.com 0.98） mV， polydispersity coefficient of 0.455±0.010 （n＝3）；entrapment efficiency of 35.60%， and drug loading of 16.13%；CPC-NPs had regular spherical shapes， where the drug could be sustainably released for more than 30 hours. Compared with Mod group， the levels of T-AOC， SOD， CAT （excluding the 30 μg/mL group of CPC-NPs） and GSH-Px， mRNA expressions of CAT and GST， as well as the Bcl-2/Bax protein ratio and mRNA ratio were significantly increased in MLE-12 cells of different concentration groups of CPC-NPs， while MDA levels and caspase-3 protein and mRNA expression were significantly reduced （P＜0.01 or P＜0.05）. Compared with Mod group， the levels of IL-1β， TNF-α and IL-6， NLRP3 and cleaved-caspase-1 protein expressions， as well as the mRNA expressions of IL-1β， TNF-α， IL-6 and iNOS in RAW264.7 cells of different concentration groups of CPC-NPs were significantly reduced （P＜0.01 or P＜0.05）. CONCLUSIONS CPC-NPs with lung targeting and sustained release property were prepared successfully， which can alleviate acute lung injury induced by LPS combined with seawater through antioxidant stress， inhibiting cell apoptosis and inflammatory response.

Objective To investigate the efficacy and safety of Xihuang capsules as an adjuvant treatment for metastatic colorectal cancer and their impact on immune function. Methods A retrospective analysis was conducted on clinical data from 112 patients diagnosed with metastatic colorectal cancer. The patients were categorized into two groups: a control group (n=56) that did not take Xihuang capsules and an observation group (n=56) that did. The efficacy, improvement of quality of life, toxic and side effects and immune function of the two groups were analyzed and compared. Results After treatment, the disease control rate (DCR) and the rate of improvement in quality of life were significantly higher in the observation group compared to the control group. Additionally, levels of carcinoembryonic antigen (CEA) and the incidence of adverse reactions, including bone marrow suppression and liver and kidney function damage, were significantly lower in the observation group. Furthermore, the percentages of CD4⁺ and CD8⁺ T cells, the CD8⁺/CD4⁺ T cells ratio, as well as serum levels of high mobility group box-1 (HMGB1) and interleukin 2 (IL-2) in observation group were significantly elevated compared to pre-treatment levels. Subgroup analysis revealed that patients with a Karnofsky Performance Status (KPS) score ≤80, a high CD8⁺/CD4⁺ T cells ratio, and elevated HMGB1 levels experienced a significantly higher objective response rate (ORR) in the observation group. Conversely, patients with stage IVB disease, who had KPS score ≤80, a low CD8⁺/CD4⁺ T cells ratio and high CEA and IL-2 levels demonstrated a more pronounced DCR in the observation group. Conclusion Xihuang capsules exhibit promising clinical efficacy as an adjuvant treatment for advanced colorectal cancer. They not only enhance patients' quality of life and reduce the toxic and adverse effects of chemotherapy, but also improve immune function. These benefits are particularly significant in patients with a high tumor burden, indicating that Xihuang capsules are worthy of clinical application.
Humans ; Colorectal Neoplasms/immunology* ; Male ; Female ; Middle Aged ; Drugs, Chinese Herbal/adverse effects* ; Capsules ; Aged ; Carcinoembryonic Antigen/blood* ; Retrospective Studies ; Quality of Life ; Adult ; Neoplasm Metastasis ; Interleukin-2/blood* ; HMGB1 Protein/blood* ; Chemotherapy, Adjuvant

Cognitive function has become a hot spot in the field of epilepsy. However,the relationship between cognitive function and epilepsy has not been clearly demonstrated. Clinical trials have showed that epi-lepsy and epileptic relevant factors are both associated with cognitive function in children. Children with cogni-tive impairment are often caused by those two factors. This article focuses on cognitive function in children with epilepsy age below 6 years,and mainly reviews the characteristics of cognitive function in these children with epilepsy.

AIM:To develop the quality standard for Capsicum Rheumatism Gel(Fructus Capsici extract,menthol,borneol). METHODS:HPLC was used to determine capsaicin in Capsaicum Rheumatism Gel.The se-(paration) was performed on zorbax C_(18) column with methanol-water-phosphoric acid (70∶30∶0.085) as a mobile phase.The flow rate was 0.8 mL/min,and the detection wavelength was at 280 nm.Menthol and borneol contents in Capsaicum Rheumatiosm Gel were determined by GC and naphthalene was adopted as internal standard substance. RESULTS:There was a good linear relationship for capsaicin at a range of 0.082 65-0.578 55 ?g and the average revovery was 97.86% with RSD=1.28%.There were good liner relationships for menthol and borneol at a range of 0.081 0-1.053 ?g,0.080 8-1.050 4 ?g and the average revovery was 98.668%,97.536%. CONCLUSION:The method proves to be simple,precise and reproducible and is suitable for quantitative control of Capsicum Rheumatism Gel.