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::Findings on the association of genetic factors and colorectal cancer (CRC) survival are limited and inconsistent, and revealing the mechanism underlying their prognostic roles is of great importance. This study aimed to explore the relationship between functional genetic variations and the prognosis of CRC and further reveal the possible mechanism.Methods::We first systematically performed expression quantitative trait locus (eQTL) analysis using The Cancer Genome Atlas (TCGA) dataset. Then, the Kaplan-Meier analysis was used to filter out the survival-related eQTL target genes of CRC patients in two public datasets (TCGA and GSE39582 dataset from the Gene Expression Omnibus database). The seven most potentially functional eQTL single nucleotide polymorphisms (SNPs) associated with six survival-related eQTL target genes were genotyped in 907 Chinese CRC patients with clinical prognosis data. The regulatory mechanism of the survival-related SNP was further confirmed by functional experiments.Results::The rs71630754 regulating the expression of endoplasmic reticulum aminopeptidase 1 ( ERAP1) was significantly associated with the prognosis of CRC (additive model, hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.08-1.88, P = 0.012). The results of dual-luciferase reporter assay and electrophoretic mobility shift assay showed that the A allele of the rs71630754 could increase the binding of transcription factor 3 (TCF3) and subsequently reduce the expression of ERAP1. The results of bioinformatic analysis showed that lower expression of ERAP1 could affect the tumor immune microenvironment and was significantly associated with severe survival outcomes. Conclusion::The rs71630754 could influence the prognosis of CRC patients by regulating the expression of the immune-related gene ERAP1. Trial Registration::No. NCT00454519 (https://clinicaltrials.gov/)

Hypoxia is the common characteristic of almost all solid tumors,which prevents therapeutic drugs from reaching the tumors.Therefore,the development of new targeted agents for the accurate diagnosis of hypoxia tumors is widely concerned.As carbonic anhydrase Ⅸ(CA Ⅸ)is abundantly distributed on the hypoxia tumor cells,it is considered as a potential tumor biomarker.4-(2-Aminoethyl)benzenesulfo-namide(ABS)as a CA Ⅸ inhibitor has inherent inhibitory activity and good targeting effect.In this study,Ag2S quantum dots(QDs)were used as the carrier to prepare a novel diagnostic and therapeutic bio-probe(Ag2S@polyethylene glycol(PEG)-ABS)through ligand exchange and amide condensation reaction.Ag2S@PEG-ABS can selectively target tumors by surface-modified ABS and achieve accurate tumor im-aging by the near infrared-Ⅱ(NIR-Ⅱ)fluorescence characteristics of Ag2S QDs.PEG modification of Ag2S QDs greatly improves its water solubility and stability,and therefore achieves high photothermal sta-bility and high photothermal conversion efficiency(PCE)of 45.17％.Under laser irradiation,Ag2S@PEG-ABS has powerful photothermal and inherent antitumor combinations on colon cancer cells(CT-26)in vitro.It also has been proved that Ag2S@PEG-ABS can realize the effective treatment of hypoxia tumors in vivo and show good biocompatibility.Therefore,it is a new efficient integrated platform for the diagnosis and treatment of hypoxia tumors.

Drastic surges in intracellular reactive oxygen species (ROS) induce cell apoptosis, while most chemotherapy drugs lead to the accumulation of ROS. Here, we constructed an organic compound, arsenical N-‍(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide (AAZ2), which could prompt the ROS to trigger mitochondrial-dependent apoptosis in gastric cancer (GC). Mechanistically, by targeting pyruvate dehydrogenase kinase 1 (PDK1), AAZ2 caused metabolism alteration and the imbalance of redox homeostasis, followed by the inhibition of phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and leading to the activation of B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax)/caspase-9 (Cas9)/Cas3 cascades. Importantly, our in vivo data demonstrated that AAZ2 could inhibit the growth of GC xenograft. Overall, our data suggested that AAZ2 could contribute to metabolic abnormalities, leading to mitochondrial-dependent apoptosis by targeting PDK1 in GC.
Humans ; Signal Transduction ; Stomach Neoplasms/drug therapy* ; Reactive Oxygen Species/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Apoptosis ; Proto-Oncogene Proteins c-bcl-2 ; Cell Line, Tumor

Objective To investigate the effect of Sema6D knockdown on the proliferation, migration, invasion and angiogenesis-promoting ability of human osteosarcoma cell lines. Methods The expression of Sema6D in clinical tissues and cell lines of human osteosarcoma was detected. After the targeted siRNA transfection, the changes of proliferation, migration and invasion were measured by CCK-8, wound healing and Transwell experiments. HUVECs were co-cultured with tumor conditioned medium to detect their tube formation ability. And the expression of signal pathway proteins was detected by Western blot. Results Sema6D was highly expressed in human osteosarcoma tissues and cell lines(P < 0.05). After silencing Sema6D, the proliferation, migration and invasion of 143B and MG63 cells decreased significantly(P < 0.05), the angiogenesis ability of HUVECs decreased in vitro(P < 0.01), and the expression of PI3K/AKT/mTOR and ERK-related signal pathway proteins decreased(P < 0.05). Conclusion Sema6D is overexpressed in human osteosarcoma tissues and cell lines. Knockdown of Sema6D expression level could inhibit the proliferation, migration, invasion and angiogenesis-promoting ability of human osteosarcoma cells via reducing PI3K/AKT/mTOR and ERK signal pathway.

Objective:To analyze the clinical characteristics and short-term prognosis of patients with acute asthmatic attack and comorbid bronchiectasis.Methods:The data of patients hospitalized for acute asthmatic attack in the Department of Respiratory and Critical Care Medicine of Peking University Third Hospital from January 1, 2012 to December 31, 2021 were retrospectively collected and analyzed. According to whether or not co-existing with bronchiectasis, all the patients were divided into asthmatic with bronchiectasis group and asthmatic without bronchiectasis group. Then the general conditions, comorbidities, pulmonary function test, grades of asthma severity, laboratory examination and in-hospital short-term prognosis of two groups were analyzed.Results:A total of 580 hospitalized patients with acute asthma attack were included, of which 132 cases (22.76%) were classified into asthmatic with bronchiectasis group and 448 cases (77.24%) were classified into asthmatic without bronchiectasis group. Co-existing with obsolete pulmonary tuberculosis and anxiety/depression in asthmatic with bronchiectasis group were more common than that in asthmatic without bronchiectasis group (13.64% vs 5.36%; 7.58% vs 2.68%) (both P<0.05). The pre-bronchodilator forced vital capacity (FVC) and its percentage to the predicted value (FVC%pred), forced expiratory volume in 1 second (FEV 1) and its percentage to the predicted value (FEV 1%pred), FEV 1/FVC and post-bronchodilator FEV 1 in asthmatic with bronchiectasis group were lower than those in the asthmatic without bronchiectasis group [2.44 (1.90, 3.01) vs 2.69 (2.10, 3.68) L, 1.55 (1.13, 2.00) vs 1.78 (1.25, 2.52) L, 70.14% (67.39%, 85.92%) vs 79.63% (70.00%, 89.52%), 70.00% (54.38%, 78.11%) vs 70.00% (61.47%, 85.00%), 61.57% (56.29%, 73.03%) vs 66.67% (60.00%, 75.00%), 1.72 (1.21, 2.18) vs 1.89 (1.37, 2.55) L] (all P<0.05). In previous year, the proportion of patients receiving hospitalization due to acute asthmatic attack in asthmatic with bronchiectasis group was higher than that in asthmatic without bronchiectasis group (15.15% vs 8.93%) ( P<0.05). The peak months of hospitalization due to acute asthmatic attack in asthmatic with bronchiectasis group were April, July and October, and the peak months in asthmatic without bronchiectasis group were April and September. The length of hospital stay was longer and the proportion of patients receiving invasive ventilation was higher in asthmatic with bronchiectasis group than those in asthmatic without bronchiectasis group [10.06 (7.62, 13.94) vs 9.95 (7.15, 13.76) d; 5.30% vs 2.01%] (both P<0.05). The risk factors for invasive mechanical ventilation in asthmatic patients with acute attack during hospitalization were co-existing with bronchiectasis, smoking, high level of partial pressure of carbon dioxide in arterial blood, serum creatinine and creatine kinase. Conclusion:Asthma patients with comorbid bronchiectasis have more frequent acute attack, a longer hospitalization due to acute asthmatic attack and a higher probability of invasive ventilation during hospitalization.

Objective　To explore the applicability and best cut-off value of the Montreal Cognitive Assessment Scale Beijing Version (MoCA-BJ) for mild cognitive impairment (MCI) screening in Xian City.Methods　Community residents over 50 years old in Xiancheng District were enrolled as the research object,a random cluster sampling method was used to sample 1195 community elderly people in Xiancheng District.The subjects were tested for cognitive function with the Mini-mental State Examination (MMSE),and were divided into the normal group and the MCI group according to the diagnostic criteria,and the MoCA-BJ test was performed again.Groups were grouped according to education level,and the receiver operating curve (ROC) of each group was drawn to determine the MoCA-BJ cut-off value corresponding to the maximum Youden index.Results　MMSE and MoCA-BJ scores were significantly correlated,the correlation coefficient was 0.791 P<0.001;the best cut-off values of MoCA-BJ in each group were 19 (illiterate),21 (elementary school),and 25 (junior high school and above).The consistency test Kappa value is 0.686 P<0.001,and the consistency is good.Conclusion　MoCA-BJ can be effectively used in the screening of MCI population in this area.

Objective To investigate the biomechanical effects of femoral offset (FO) on total hip arthroplasty (THA) patients with developmental dysplasia of the hip (DDH). Methods Based on the musculoskeletal dynamic software AnyBody and the related data from a female patient with Crowe Ⅳ DDH, the corresponding patient-specific lower extremity musculoskeletal multi-body dynamic model was constructed to analyze both hip joint forces and abductor forces within ±20 mm variation of FOs. The dynamic finite element (FE) model of S-ROM stem with varying offsets was also established. The dynamic load during a whole walking gait cycle calculated by the multi-body musculoskeletal model was applied to this FE models, and the Von Mises stress, contact stress, and stem-sleeve micromotion were then analyzed. Results A variation of ±20 mm offset had small influences on peak forces of hip joints. However, the decrease in FO could lead to an obvious increase in peak abductor force, while the increase in FO could lead to an obvious increase in the maximum Von Mises stress, contact stress, and micromotion of S-ROM prosthesis stem. Conclusions The change in FO had an obvious influence on the abductor forces, the maximum Von Mises stress, the contact pressure and the consequent fretting wear of THA patients with DDH, which should be carefully considered by surgeons.

Small cell lung cancer (SCLC) is typified by early recurrence and metastasis associated with many genetic changes.The drug ROVA-T composed of the DLL3 antibody Rovalpituzumab and the cytotoxic drug Tesirine achieves the tumor-killing effect by releasing the Tesirine when bound to DLL3.Nfib promotes the SCLC metastasis by altering the structure of the chromosome.The PRAP,EZH2 and Weel inhibitors inhibit the DNA damage repair to improve the antitumor activity of chemotherapeutic drugs.Combination of Ipilimumab and Nivolumab can activate the human immune system to exert antitumor effect.

Objective To investigate SCCmec types in clinical isolates of methicillin-resistant Staphylococcus epidermidis (MRSE) carrying psm-mec.Methods We collected 165 strains of Staphylococcus epidermidis identified by automated microbiological identification system and screened MRSE by PCR amplification of esp and mecA gene.Strains with psm-mec were identified by amplification of psm-mec,fudoh and p221 DNA fragment;mec,ccr and SCCmec typing was conducted by multiplex PCR assay.Results Among 138 strains of MRSE,29 strains were identified as MRSE with psm-mec,and the carrying rate was 17.58%.Results of mec and ccr typing by multiple PCR showed that MRSE with psm-mec carried Class A mec,but the ccr type had obvious diversity.Results of SCCmec typing showed that all strains with psm-mec belonged to type Ⅱ and/or Ⅲ SCCmec.Conclusion Clinical isolates of MRSE with psm-mec carry homologous type Ⅱ and/or Ⅲ SCCmec harboring Class A mec.