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 investigate the fatigue and workload status among medical students,and to explore the latent profiles of fatigue and workload and their effects on sleep and emotion.Methods A cross-sectional study design with convenience sampling was employed to distribute a comprehensive survey via mixed online and offline modes,and medical college students were enrolled as the subjects for this investigation.The general demographic data,depression,anxiety and stress scale,Pittsburgh sleep quality index,Epworth sleepiness scale,insomnia severity index,National Aeronautics and Space Administration task load index(NASA-TLX)and fatigue scale-14(FS-14)were used to investigate the basic information of the medical students,their emotions(depression,anxiety and stress),sleep(sleep quality,sleepiness and insomnia),workload and fatigue status.Based on latent profile analysis,the types of workload-fatigue profiles and differences in sleep and emotion were analyzed.Results A total of 485 medical students were enrolled,with an average age of(22.07±2.42)years.The total score of the NASA-TLX was 64.44±12.50,and the total score of the FS-14 was 7.90±3.63.Latent profile analysis identified 3 distinct workload-fatigue profiles:low workload-medium fatigue group(12.8％),medium workload-low fatigue group(32.8％),and high workload-high fatigue group(54.4％).Among these,the medium workload-low fatigue group exhibited the highest performance level(all P＜0.05),while the low workload-medium fatigue group showed the lowest effort level and performance level(all P＜0.05).The high workload-high fatigue group showed the highest task-related demand and frustration level(all P＜0.05).Regarding sleep and emotional status,the medium workload-low fatigue group had significantly better outcomes compared to the high workload-high fatigue group and the low workload-medium fatigue group(all P＜0.05).Conclusion Medical students experience a heavy workload and subjective fatigue.It is essential to appropriately adjust their workload,prioritize sleep and emotional well-being,and alleviate fatigue levels,so as to sustain personal physical and mental health.

Objective To compare the application effects of plankton multiplex polymerase chain reac-tion-capillary electrophoresis(PCR-CE),SYBR Green Ⅰ real-time quantitative PCR(qPCR)and microwave digestion-vacuum filtration-automated scanning electron microscopy(MD-VF-Auto SEM)in the diagnosis of drowning.Methods Lung,liver and kidney tissues from 212 drowned corpses and 30 non-drowned corpses were examined respectively by the three drowning-related plankton testing methods,and the detection rates of plankton in each tissue by three methods were compared.Results In drowned corpses,the total detection rates of PCR-CE,qPCR,and MD-VF-Auto SEM were 93.9%,96.2%,and 95.3%,respectively,with no statistically significant difference(P>0.05).The detection rate of lung tissue by MD-VF-Auto SEM(100%)was higher than those of PCR-CE and qPCR(P<0.05),and there was no significant difference in the detection rates of the three methods in liver or kidney tissues(P>0.05).In non-drowning corpses,a small number of diatoms(less than 10 cells/10 g)were detected by MD-VF-Auto SEM method,only in liver and kidney tissues,while the other two methods yielded negative results for all tissues.Conclusion All three methods have good efficacy in the examination of drowned corpses.The MD-VF-Auto SEM method directly observes diatom morpho-logical characteristics through scanning electron microscopy,and the qualitative and quantitative analy-ses are intuitive and accurate.It has great advantages in the examination of difficult degradation samples.The PCR-CE method and qPCR method have a low sample demand(0.5 g),are easy to operate and have short detection time(4-7 h).They are easy to be applied in the grassroots depart-ments and are suitable for the rapid determination of drowned corpses in routin cases.The combina-tion of the two DNA methods with the MD-VF-Auto SEM method can increase the detection rate of plankton,ensuring the reliability of examination results.This combined use is of significant importance in the application of drowning diagnosis.

Objective To investigate the effect of dihydromyricetin(DMY)on myocardial oxidative damage in exhaustive exercise mice.Methods C57BL/6 mice were divided into control group,model group,positive control group and low,medium and high dose experimental groups and with 10 mice in each group.Mice in control group and model group were intragastricated with distilled water;20,40 and 80 mg·kg-1 dihydromyricetin were given by gavage in low,medium and high dose experimental groups,while mice in positive control group were intragastricated with 100 mg·kg-1 Vitamin C once a day for 4 weeks.After administration,superoxide dismutase(SOD),malondialdehyde(MDA)and lactate dehydrogenase(LDH)were detected by the kit.The expression of nuclear factor E2-related factor 2(Nrf2)and heme oxygenase-1(HO-1)protein were detected by Western blot.Results SOD levels in control group,model group and low,medium,high dose experimental groups and positive control group were(57.81±6.92),(26.85±2.74),(33.68±4.52),(39.74±3.95),(48.97±4.26)and(39.22±3.54)U·mg-1;MDA were(4.72±0.36),(10.48±1.68),(8.75±0.82),(6.43±0.71),(5.11±0.48)and(6.36±0.64)nmol·mg-1;LDH were(268.71±23.94),(726.58±81.26),(621.32±47.59),(479.12±50.24),(337.91±34.99)and(486.15±50.98)U·L-1;Nrf2 protein expression were 0.75±0.06,0.19±0.02,0.30±0.04,0.47±0.05,0.63±0.06 and 0.49±0.06;the protein expression of HO-1 were 0.83±0.08,0.27±0.05,0.39±0.04,0.52±0.03,0.77±0.07 and 0.55±0.06,respectively.There were statistically significant differences between control group and model group(all P＜0.05);there were statistically significant differences in the above indexes between model group and positive control group,low dose experimental group,medium dose experimental group,high dose experimental group(all P＜0.05).Conclusion Dihydromyricetin can delay myocardial oxidative injury in exhaustive exercise mice,which may be related to Nrf2/HO-1 pathway.

Objective: To explore the association of milk tea consumption with comorbid of overweight/obesity and depressive symptoms among college students, so as to provide a reference for promoting the physical and mental health of college students. Methods: A questionnaire survey was conducted from August to October 2023 using convenience sampling among 13 920 students from nine universities in Shanghai, Jiangxi, and Hubei provinces (municipality directly under the central government). Information on college students demographic characteristics, milk tea consumption, overweight/obesity status, and depressive symptoms was collected. Chi square tests were used to compare the association between different demographic characteristics and milk tea consumption with comorbid overweight/obesity and depressive symptoms. Multivariate Logistic regression analysis was performed to infer the strength of the association. Results: The detection rate of comorbidity of overweight/obesity and depressive symptoms was 5.8% among college students. The univariate analysis revealed statistically significant differences in the detection rate of comorbidity of overweight/obesity and depressive symptoms among various groups, including gender, grade, parents education level, only child status, family economic status, meeting moderate to high levels of physical activity standards, sleep quality, and frequent fast food consumption ( χ 2= 82.10, 23.07, 8.91, 10.87 , 4.56, 47.60, 17.60, 386.74, 96.61, P <0.05). There were also statistically significant differences between groups based on milk tea consumption frequency and quantity ( χ 2=42.12, 38.76, P <0.01). Compared with the group of without consuming milk tea, Logistic regression analysis showed that college students who consumed milk tea 4-5 times and ≥6 times had higher risk of comorbid overweight/obesity and depressive symptoms ( OR =1.98, 2.46), and college students who consumed 1-1 500 mL and ≥3 000 mL of milk tea also had higher comorbidity risk ( OR =1.52, 1.22) ( P <0.05). Conclusions Frequent and excessive milk tea consumption among college students may increase the risk of comorbid of overweight/obesity and depressive symptoms. It is recommended to reduce the frequency and quantity of milk tea consumption to improve college students physical and mental health.

This article reviews the concept, evaluation tools, current situation, influencing factors and promotion strategies of nurses′ remote health care readiness, in an effort to provide reference for nursing managers to construct intervention programs to improve the level of nurses′ remote health care readiness, to promote the successful development of remote healthcare and the sinking of high-quality nursing resources.

Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease (MAFLD). However, there are few reported lipotoxicity inhibitors. Here, we identified a natural anti-lipotoxicity candidate, HN-001, from the marine fungus Aspergillus sp. C1. HN-001 dose- and time- dependently reversed palmitic acid (PA)-induced hepatocyte death. This protection was associated with IRE-1α-mediated XBP-1 splicing inhibition, which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation. Knockdown of XBP-1s attenuated lipotoxicity, but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes. Notably, the ER stress and lipotoxicity amelioration was associated with PLA2. Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity, reduced lysophosphatidylcholine (LPC) level, subsequently ameliorated lipotoxicity. In contrast, overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001. Additionally, HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway. In vivo, chronic administration of HN-001 (i.p.) in mice alleviated all manifestations of MAFLD, including hepatic steatosis, liver injury, inflammation, and fibrogenesis. These effects were correlated with PLA2/IRE-1α/XBP-1s axis and JNK signaling suppression. These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity, and provide a natural structural basis for developing anti-MAFLD candidates.

Animals ; Macaca mulatta ; Optic Disk ; Glaucoma ; Craniocerebral Trauma ; Intraocular Pressure ; Low Tension Glaucoma

BACKGROUND:Ankylosing spondylitis is a chronic inflammatory disease with chronic rheumatic immunity.Soft tissue ossification and fusion and spinal stiffness can cause biomechanical changes. OBJECTIVE:To reconstruct the lumbar-sacral intervertebral disc in ankylosing spondylitis patients with lumbar kyphosis by finite element analysis,and to study the range of motion of each segment of T11-S1 and the biomechanical characteristics of annulus fibrosus and nucleus pulposus. METHODS:The imaging data were obtained from an ankylosing spondylitis patient with lumbar kyphosis.The original CT image data of continuously scanned spine were imported into Mimics 21.0 in DICOM format,and T11-S1 was reconstructed respectively.The established model was imported into 3-Matic software in the format of"Stl"to reconstruct the intervertebral disc,and the fibrous intervertebral disc model was obtained.The improved model was further imported into Hypermesh software,and the vertebra,nucleus pulposus,annulus fibrosus and ligament were mesh-divided.After the material properties were given,the model was imported into ABAQUS software to observe the range of motion of each vertebral body in seven different working conditions of T11-S1,and analyze the biomechanical characteristics of each segment of annulus fibrosus and nucleus pulposus. RESULTS AND CONCLUSION:(1)The range of motion of L1 vertebrae was higher than that of other vertebrae under six different working conditions:extension,forward flexion,rotation(left and right),and lateral flexion(left and right).The maximum range of motion was 2.18° during L1 vertebral flexion,and the minimum range of motion was 0.12° during L5 vertebral extension.(2)The annular fiber flexion at L2-L3 segments was greater than the extension(P<0.05),and the annular fiber flexion at L3-L4 and L4-L5 segments was less than the extension(P<0.05).The left rotation of L1-L2 annular fibers was greater than the right rotation(P<0.05).The left flexion of the annulus was greater than the right flexion in L1-L2,L2-L3,L3-L4,L4-L5 and L5-S1 segments(P<0.05).(3)The nucleus pulposus stresses of T11-L12,L1-L2,L2-L3,L3-L4 and L4-L5 segments in forward flexion were greater than in extension(P<0.05).The left rotation of T12-L1 and L3-L4 segments was smaller than the right rotation(P<0.05),and that of T11-T12,L1-L2,and L2-L3 segments was larger than the right rotation(P<0.05).The left flexion was larger than the right flexion in the T11-S1 segment.(4)It is concluded that in ankylosing spondylitis patients with lumbar kyphosis,the minimum range of motion of the vertebral body is located at the L5 vertebral body in extension.To prevent fractures,it is recommended to avoid exercise in the extension position.During the onset of lumbar kyphosis in patients with ankylosing spondylitis,the maximum stress of the annulus fibrosus and nucleus pulposus is located in the L1-L2 segment,which is fixed and will not alter with the change of body position.The late surgical treatment and correction of deformity should focus on releasing the pressure of the annulus fibrosus and nucleus pulposus in this segment to avoid the rupture of the annulus fibrosus and the injury of the nucleus pulposus.

BACKGROUND:Ankylosing spondylitis is a progressive inflammation of spinal stiffness deformity caused by tissue ossification and fibrosis.The posture of ankylosing spondylitis patients is abnormal and their activities are limited that minor injuries can lead to thoracolumbar fractures.Traditional medical image observation limits doctors'preoperative decision planning and postoperative disease prevention for ankylosing spondylitis treatment. OBJECTIVE:Based on the spinal model of ankylosing spondylitis patients before and after posterior spinal cancellous ossification osteotomy("Y"osteotomy for short),to explore the biomechanical changes of"Y"osteotomy and fixation in the treatment of ankylosing spondylitis. METHODS:Based on the preoperative and postoperative CT images of an ankylosing spondylitis patient who went to the Second Affiliated Hospital of Inner Mongolia Medical University,a three-dimensional spine model(T11-S1)before and after"Y"osteotomy(L3 osteotomy)was reconstructed in Mimics 19.0 software.A 7.5 Nm torque was applied to the top of T11 vertebral body to simulate the movement of the spine under six conditions:flexion,extension,left bending,right bending,left rotation and right rotation.Finally,the range of motion of each vertebral body,the stress of each intervertebral disc,and the stress of the screw rod system were simulated. RESULTS AND CONCLUSION:(1)After"Y"type osteotomy and posterior fixation,the range of motion of all vertebrae in the spine decreased,and the loss rate of upper vertebrae was large(L1:77.95%).(2)The maximum stress of the spinal intervertebral disc before operation occurred at the L1-L2 segment(0.55 MPa),and the maximum stress of the spinal intervertebral disc after operation occurred at the T11-T12 segment(0.50 MPa),and the stress of intervertebral disc below T12 was far less than that before operation.(3)The maximum stress of the screw rod system(166.67 MPa)occurred in the upper and middle segments of the rod body and the root of the pedicle screw.(4)In conclusion,the"Y"type posterior fixation operation enhances the stability of the spine and reduces the range of motion of the spine.The vertebral body decompression of the fixed segment is great and the stress-shielding phenomenon of the lower vertebral body is significant.The stiffness of the rod body and the stress concentration area of the pedicle screw should be strengthened to avoid the fracture of the rod caused by stress fatigue.