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 explore the genetic etiology of a pedigree with intellectual disability and explore its pathogenesis.Methods:A Chinese pedigree which had presented at the Henan Provincial People′s Hospital in March 2023 was selected as the study subject. Clinical data of the pedigree were collected, along with peripheral venous blood samples from its members. Whole exome sequencing (WES) was carried out, and candidate variants were verified by Sanger sequencing. Amniotic fluid was collected for prenatal diagnosis. This study was approved by the Medical Ethics Committee of the Henan Provincial People′s Hospital (No. 2019-134).Results:Both the proband (a 6-year-old male) and his mother (30 years old) had various degrees of intellectual and motor impairment. WES revealed that the proband has harbored a de novo heterozygous c. 2563_2567dup (p.Lys856fs) variant of the UBE3A gene, while his mother, maternal grandmother and fetus had all harbored a novel heterozygous c. 409+ 1G>A variant of the RNF13 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PVS1+ PS1+ PM2_Supporting; PVS1+ PM2_Supporting+ PP3). Conclusion:Based on the clinical manifestations and the result of genetic testing, the heterozygous c.2563_2567dup (p.Lys856fs) variant of the UBE3A gene probably underlay the intellectual disability and developmental delay in the proband, whilst the heterozygous c. 409+ 1G>A variant of the RNF13 gene may underlie the intellectual disability in the proband′s mother and grandmother. Above results have enabled genetic counseling and prenatal diagnosis for this pedigree.

Objective:To explore the clinical characteristics of neonatal ureaplasma meningitis.Methods:A retrospective analysis was conducted on the clinical manifestations, diagnosis, treatment, and follow-up of a case of ureaplasma parvum (UP) meningitis in a neonate with persistent cerebrospinal fluid (CSF) abnormalities, admitted to the Neonatology Department of the Children's Hospital of Chongqing Medical University on September 2021. Literature was searched using the keywords "neonate", "ureaplasma", and "meningitis" in databases including CNKI, Wanfang Medical Database, Yiigle, VIP Database, SinoMed, and Chinese Medical Care Repository, as well as PubMed, Embase, and Web of Science, from their inception to December 2023. The clinical characteristics of the cases obtained were analyzed in conjunction with the present case. Descriptive statistical analysis and Chi-square test (or Fisher's exact test) were used for data analysis. Results:(1) Case report: The patient was a female neonate, born at 30 +2 gestational weeks, who experienced severe asphyxia at birth and was transferred to the neonatal intensive care unit of our hospital after resuscitation involving mechanical ventilation and chest compressions at an external hospital. On the 7th day of birth, the patient developed seizures, and CSF examination indicated meningitis. Blood and CSF cultures were negative, and empirical anti-infective treatment for one month showed no significant improvement. On the 39th day of birth, metagenomics next generation sequencing (mNGS) of the CSF indicated UP positivity, confirming UP meningitis. The patient received ten weeks of quinolone antibiotics. During hospitalization, a ventriculoperitoneal shunt was performed due to hydrocephalus, and the patient was discharged after improvement. At 2 years and 1 month of follow-up, the patient had cerebral palsy (hemiplegic type) and was undergoing rehabilitation therapy. (2) Literature review: A total of 31 articles were retrieved, encompassing 46 cases, plus the present case, making a total of 47 cases. Among these, 57% (27/47) were preterm infants, 54% (22/41) were low birth weight infants (some articles did not report this item, hence the denominator is less than 47), and 76% (28/37) were born via vaginal delivery. Cases who developed symptoms within the first week accounted for 71% (24/34), and 74% (26/35) had mothers with ureaplasma infection or high-risk factors during pregnancy. The main clinical manifestations included fever [63% (20/32)], seizures or apnea/respiratory distress [each 44% (14/32)]. CSF examination mainly showed significantly elevated white blood cells [287×10 6/L (69×10 6/L-1 176×10 6/L)], decreased glucose [0.79 mmol/L (0.10-1.17 mmol/L)], and elevated protein [3.01 g/L (1.80-8.14 g/L)], with negative general bacterial cultures. CSF mNGS [30% (14/47)], CSF polymerase chain reaction [17% (8/47)], and CSF culture [66% (31/47)] were the main methods for detecting ureaplasma. Treatment primarily involved macrolide antibiotics alone [46% (16/35)] or in combination with other antibiotics [29% (10/35)]. The duration of anti-ureaplasma treatment ranged from 2 to 10 weeks. Intracranial hemorrhage and hydrocephalus were the most common neurological complications [66% (25/38) and 61% (23/38), respectively]. Among the 47 cases, 31 were infected with ureaplasma urealyticum (UU) and 15 with UP (one case was not typed). There were no significant differences in epidemiology, clinical manifestations, neurological complications, and prognosis between UP and UU meningitis. Compared to UU meningitis, a higher proportion of UP meningitis cases were treated with macrolide antibiotics [13/15 vs. 52% (14/27), χ2=5.09, P=0.024]. Among the 43 reported cases of ureaplasma meningitis with outcomes, 44% (19/43) experienced developmental delays or death. The case fatality rate of UU meningitis was higher than that of UP meningitis [39% (11/28) vs. 0/14, Fisher's exact test, P=0.007]. Conclusions:Neonatal ureaplasma meningitis lacks specific clinical manifestations and has a variable prognosis. When empirical anti-infective treatment is ineffective in infants with purulent changes in CSF, intracranial ureaplasma infection should be considered. Macrolide antibiotics alone or in combination with other antibiotics can be the first-choice treatment for ureaplasma infection.

Background/Aims: Metabolic syndrome is common in patients with acute pancreatitis and its components have been reported to be associated with infectious complications. In this post hoc analysis, we aimed to evaluate whether metabolic abnormalities impact the effect of immuneenhancing thymosin alpha-1 (Tα1) therapy in acute necrotizing pancreatitis (ANP) patients. Methods: All data were obtained from the database for a multicenter randomized clinical trial that evaluated the efficacy of Tα1 in ANP patients. Patients who discontinued the Tα1 treatment prematurely were excluded. The primary outcome was 90-day infected pancreatic necrosis (IPN) after randomization. Three post hoc subgroups were defined based on the presence of hyperglycemia, hypertriglyceridemia, or both at the time of randomization. In each subgroup, the correlation between Tα1 and 90-day IPN was assessed using the Cox proportional-hazards regression model. Multivariable propensity-score methods were used to control potential bias. Results: Overall, 502 participants were included in this post hoc analysis (248 received Tα1 treatment and 254 received matching placebo treatment). Among them, 271 (54.0%) had hyperglycemia, 371 (73.9%) had hypertriglyceridemia and 229 (45.6%) had both. Tα1 therapy was associated with reduced incidence of IPN among patients with hyperglycemia (18.8% vs 29.7%: hazard ratio, 0.80; 95% confidence interval, 0.37 to 0.97; p=0.03), but not in the other subgroups. Additional multivariate regression models using three propensity-score methods yielded similar results. Conclusions Among ANP patients with hyperglycemia, immune-enhancing Tα1 treatment was associated with a reduced risk of IPN (ClinicalTrials.gov, Registry number: NCT02473406).

Objective:To evaluate the effect of invasive arterial blood pressure (IBP) monitoring on the prognosis of patients with sepsis.Methods:Patients with sepsis from the MIMIC-Ⅳ database were collected and divided into IBP and non-invasive blood pressure monitoring (NIBP) groups according to whether IBP monitoring was performed. Baseline variables that were considered clinically relevant or showed a univariate relationship with the outcome were entered into a multivariate logistic regression model as covariates.Propensity score matching(PSM) and inverse probability of treatment weighing(IPTW) were used to adjust confounders to ensure the robustness of findings.Subgroup analysis were conducted to evaluate the effect of differences in IBP onset and duration on outcome.Results:The 28-day mortality is lower in IBP group compared with NIBP group( OR=0.54, 95% CI 0.46-0.62, P<0.001), the conclusion maintain robust after PSM and IPTW.Then we conducted a series of logistic regression regarding to different initial IBP time(<24 h,24 h-48 h,>48 h) and the initial IBP time within 24 h showed the same results compared to primary outcoms( OR=0.42, 95% CI: 0.36-0.49, P<0.001). IBP duration varied (≤1day, ≤2days, ≤3days, ≤4days, >4days) all showed a statistically significant association with decreased 28-day mortality in the IBP group. Conclusions:IBP is associated with decreased 28-day mortality in patients with sepsis, and the optimal time of IBP is within 24 hours.

OBJECTIVE: To analyze the pathogenic variant of preaxial polydactyly in a Chinese Han pedigree and identify the cause of polydactyly. METHODS: The peripheral blood DNA of the proband and her parents was extracted. The polydactyly-related genes were detected by trio whole exome sequencing, and the suspected pathogenic gene was screened out. Sanger sequencing was applied to other members of the pedigree. RESULTS: The results of gene sequencing showed that the LMBR1 gene had a heterozygous variant of c.423+4909(IVS5)C>T in 6 patients of the pedigree. The same variant was not detected in family members with normal phenotype. Based on the ACMG guidelines, c.423+4909(IVS5)C>T of the LMBR1 gene was predicted to be pathogenic (PM1+PM2+PP1-S(PS)+PP4+PP5). CONCLUSION The heterozygous C>T variant at position 4909 of intron 5 of the LMBR1 gene probably underlies the disease in this pedigree.
China ; Female ; Humans ; Mutation ; Pedigree ; Polydactyly/genetics* ; Thumb ; Whole Exome Sequencing

BACKGROUND:There is no literature about the treatment according to the mechanism of cervical spine injury classification, especial y for the treatment of extension type cervical fracture/dislocation with merger cases of posterior composite structure damage, whether simple anterior approach can meet the needs of the treatment has no detailed elaboration. This article may analyze from the aspect of cervical spine injury mechanism. OBJECTIVE:To observe the short-term effect of anterior cervical Cage-assisted fusion combined with locking titanium plate internal fixation for the treatment of extension type cervical fracture. METHODS:A retrospective analysis was performed in 15 extension type cervical spine fracture dislocation patients treated with decompression anterior cervical intervertebral disc resection plus bone graft with cage-fusion locking titanium plate internal fixation from June 2006 to March 2011 in the Department of Orthopedics, Xianning Central Hospital, including 10 cases of single segment injury and treatment, and five cases of multiple segment injury and treatment. Japanese Orthopaedic Association score and the neck disability index were compared before and after treatment;the cervical flexion and height were measured according to the antersposterior X-ray film taken before fixation, 1 week after fixation and final fol ow-up.RESULTS AND CONCLUSION:The patients were fol owed-up for 8-37 months. One case had Cage mild sinking and shift, and there was no internal fixation breakage or loosening in al the patients. Transient pharyngeal discomfort was observed in 11 patients. Compared with the preoperation, the Japanese Orthopaedic Association score, neck dysfunction index, fusion segment cervical flexion and fusion segment intervertebral disc height were significantly improved at 1 week after fixation and final fol ow-up (P<0.05). There were no significant differences between 1 week after fixation and final fol ow-up (P>0.05). The short-term effect of decompression anterior cervical intervertebral disc resection plus bone graft with cage-fusion locking titanium plate internal fixation for the treatment of extension-type cervical fracture is good.

OBJECTIVETo investigate the effect of polyethylene oxide (PEO) on renal blood flow and its renoprotective effect in rabbits with endotoxin sepsis.

METHODSTwenty normal New Zealand white rabbits were randomly divided into normal saline (NS) group and PEO group (n=10), and endotoxin shock was induced by an intravenous injection of 0.6 mg/kg lipopolysaccharide. Resuscitation was performed when the blood pressure of the rabbits showed a 30% decline, using NS (in NS group) or the mixture of equal volumes of NS and 20 ng/g PEO (in PEO group) perfused at the rate of 5 ml/kg per hour. Before and during shock and at 1 h after resuscitation, the renal hemodynamics was monitored by ultrasound and the venous blood was extracted to examine the renal functions. The heart rate and arterial blood pressure were monitored throughout the experiment.

RESULTSThe rabbits in both groups showed a significantly lower renal artery blood flow velocity during the shock (P<0.05) with significantly increased pulsatility index (PI) and resistance index (RI) compared with those before the shock. One hour after resuscitation, the blood flow velocity in the renal arteries at all levels and the tertiary veins were reduced in NS group without obvious reduction of the PI and RI; in PEO group, the blood flow velocities in the renal arteries increased significantly compared to those before shock (P<0.05), and the PI and RI of the tertiary arteries were significantly lower than those in NS group (P<0.05). In both groups, BUN and Cr increased during endotoxin shock stage, and 1 h after resuscitation, PEO group showed significantly lower BUN and Cr levels than NS group (P<0.05).

CONCLUSIONA small dose of PEO can significantly promote renal perfusion in rabbits with septic shock, thus offering renoprotective effect against early damage in septicopyemia and septic shock.

Animals ; Hemodynamics ; Polyethylene Glycols ; pharmacology ; therapeutic use ; Rabbits ; Renal Circulation ; Shock, Septic ; drug therapy ; physiopathology

Objective To investigate the effects of hyperbaric oxygen (HBO) combined with neural stem cell (NSC) transplantation on functional recovery after spinal cord injury (SCI).Methods Forty healthy adult Sprague-Dawley rats were randomly divided into a sham group,an SCI group,an NSC group and an HBO+NSC group.In the latter three groups,complete spinal cord transection was performed at T10.The rats of the HBO+NSC group were treated with HBO therapy after NSC transplantation.Hindlimb motor function was assessed with the BassoBeattie-Bresnahan (BBB) scale and tilt table testing.Motor evoked potentials (MEPs) were measured to evaluate the rats'nerve conduction function.The amount of surviving transplanted NSCs at the injured site was counted using Hoechst dyeing.Results The average BBB scores and tilt table test results in the HBO+NSCs group were significantly better than in the SCI and NSC groups from the 2nd week post-SCI.By the 4th week the average latency period and MEP amplitude in the HBO+NSC group were significantly better than in the NSC group,while MEPs in the SCI group still had not re-appeared.The surviving amount of transplanted NSCs in the HBO+NSC group was also significantly greater than in the NSC group.Conclusion HBO combined with NSC transplantation has synergistic effects and can improve functional recovery after SCI.This may be explained by the important role of HBO in promoting the survival of transplanted NSCs.

Non-invasive blood glucose monitoring will be the development direction for detecting the blood glucose concentration of body in time. In this way, the concentration of the blood glucose can be controlled effectively, then the complicating diseases of diabetes can be reduced, so it is of great significance for diagnosis and treatment of diabetes. The recent developments of non-invasive blood glucose concentration monitoring technologies, including basic principles, results of verification test and instruments, are discussed, especially three methods with instruments facing market. The existing problems of these methods are also discussed. Finally, some difficult points of current non-invasive blood glucose monitoring methods are further discussed and the future trend of the technologies has been pointed out according to the above analysis.
Biosensing Techniques ; instrumentation ; methods ; Blood Glucose ; analysis ; Blood Glucose Self-Monitoring ; instrumentation ; methods ; Diabetes Mellitus ; blood ; Equipment Design ; Humans