Cardiac fibrosis is characterized by an elevated amount of extracellular matrix (ECM) within the heart. However, the persistence of cardiac fibrosis ultimately diminishes contractility and precipitates cardiac dysfunction. Circular RNAs (circRNAs) are emerging as important regulators of cardiac fibrosis. Here, we elucidate the functional role of a specific circular RNA CELF1 in cardiac fibrosis and delineate a novel feedback loop mechanism. Functionally, circ-CELF1 was involved in enhancing fibrosis-related markers' expression and promoting the proliferation of cardiac fibroblasts (CFs), thereby exacerbating cardiac fibrosis. Mechanistically, circ-CELF1 reduced the ubiquitination-degradation rate of BRPF3, leading to an elevation of BRPF3 protein levels. Additionally, BRPF3 acted as a modular scaffold for the recruitment of histone acetyltransferase KAT7 to facilitate the induction of H3K14 acetylation within the promoters of the Celf1 gene. Thus, the transcription of Celf1 was dramatically activated, thereby inhibiting the subsequent response of their downstream target gene Smad7 expression to promote cardiac fibrosis. Moreover, Celf1 further promoted Celf1 pre-mRNA transcription and back-splicing, thereby establishing a feedback loop for circ-CELF1 production. Consequently, a novel feedback loop involving CELF1/circ-CELF1/BRPF3/KAT7 was established, suggesting that circ-CELF1 may serve as a potential novel therapeutic target for cardiac fibrosis.

Objective:To investigate possible neuromodulatory mechanisms involved in the involvement of parvalbu-min(PV)expression in the basal ganglia output nuclei,entopeduncular nucleus(EPN)and substantia nigra pars etic-ulata(SNr),in exercise-induced chronic fatigue impairs working memory capacity.Methods:Male SD rats were divid-ed into control group and Fatigue group by random number method,and a three-stage incremental load treadmill training program was selected to establish a chronic exhaustion exercise-induced fatigue rat model.The working memory ability of rats was assessed by the Y-maze autonomous alternation experiment.Immunohistochemical staining was used to ob-serve the expression of parvalbumin(PV)positive neurons and cysteine aspartate-specific protease-3(caspase-3)in EPN and SNr of rats.Results:The accuracy of voluntary alternation in the fatigue group was obviously lower than that in control group(P＜0.05).The results of immunohistochemical staining showed that the density of PV positive neu-rons and the degree of positive fiber staining in EPN and SNr in the fatigue group were obviously lower than those in the control group(P＜0.05,P＜0.01).The number of caspase-3 positive cells per unit area of EPN and SNr in the fa-tigue group was obviously higher than that in the control group(P＜0.05,P＜0.01).Conclusion:The mechanism of impairing working memory in rats caused by exercise-induced chronic fatigue may be related to the apoptosis of PV posi-tive neurons in EPN and SNr.

The cartilage-protective effect of ginkgolide C(GC)on the two modeling modalities was investigated based on joint pain,degree of cartilage pathology,ECM degradation process,and level of inflammatory mediator production in rats.Twenty-five SD rats were selected and randomly di-vided into five groups:the control group(Control group),model 1 group(ACLT group),adminis-tration 1 group(ACLT+GC group),model 2 group(MIA group),and administration 2 group(MIA+GC group.)The rats were euthanized after 4 weeks of the test.Femur,tibia and blood samples were collected from the right hind limb of rats.The degree of pathology in the femur and tibia of rats was assessed by saffron O solid green staining and OARSI score.Immunohistochemis-try was used to detect the expression levels of collagen Ⅱ and MMP-13 in cartilage.ELISA was used to detect the changes in the levels of MMP-3,MMP-13,CTX-Ⅱ,COMP,COX-2,INOS,IL-1β,and TNF-α in the serum of rats.Cold sensitivity test and knee extension vocalization test were conducted to detect the degree of joint pain in rats.ACLT could cause more severe structural dam-age to articular cartilage compared with the MIA group.The OARSI scores and the expression of MMP-13 in femur and tibia,and the serum levels of MMP-13,MMP-3,CTX-Ⅱ,and COMP were higher in the ACLT group than those in the MIA group.However,the levels of inflammatory me-diators COX-2,IL-1β,and TNF-α were significantly lower in the ACLT group than in the MIA group(P＜0.0l).GC intervention reduced the OARSI score(P＜0.05 or P＜0.01)and pain scores,inhibited the ECM matrix degrading enzymes(MMP-13,MMP-3),cartilage metabolism markers(CTX-11,COMP),and inflammatory mediators(COX-2,INOS,IL-1β and TNF-α)ex-pression,and promoted collagen Ⅱ synthesis.Both modeling methods resulted in cartilage damage.In particular,the OA model constructed by ACLT+PMMx method in rats had obvious joint dam-age,which was favorable to investigate the degree of cartilage structural damage.GC attenuated cartilage pathological changes,pain severity and inflammatory response in the rat OA model in both groups,thus exerting a cartilage-protective effect.

Objective:To evaluate the optimization effect of transcutaneous electrical acupoint stimulation (TEAS) combined with moderate sedation with propofol (TEAS-propofol balanced anesthesia) for gastrointestinal endoscopy.Methods:This was a single-blind randomized controlled trial. American Society of Anesthesiologists Physical Status classification Ⅰ-Ⅲ patients, aged 18-64 yr, undergoing elective gastrointestinal endoscopy at the Endoscopic Diagnosis and Treatment Center of the Affiliated Hospital of Qingdao University from May to August 2022, were divided into 2 groups using the block random allocation method: conventional anesthesia group (group C) and TEAS-propofol balanced anesthesia group (group TPB). Patients received moderate sedation with propofol plus routine anesthesia with fentanyl 50 μg in group C. In TPB group, TEAS was performed at bilateral Neiguan, Hegu and Zusanli acupoints before surgery until the end of surgery, and patients received propofol for moderate sedation (Modified Observer′s Assessment of Alertness/Sedation scale score was 3). The efficacy and safety of anesthesia and parameters related to outcomes were observed and recorded.Results:In this study, 66 patients were recruited, with 33 in each group, the failure rate of anesthesia in both groups was 3%, and no reflux or aspiration was found. Compared with group C, no significant changes were found in the patients′ satisfaction on the same day, intraoperative pain response score, incidence of intraoperative adverse reactions (tachycardia, hypertension, bucking and body movement), awake time, consumption of propofol, rate of intraoperative awareness and rate of patients hoping to receive the same anesthesia method again postoperatively ( P>0.05), the patients′ satisfaction was significantly increased on the next day ( P<0.05), the incidence of intraoperative respiratory depression, physician satisfaction, and degree of postoperative dizziness and nausea were significantly reduced ( P<0.05), and the discharge time and time to the complete recovery of normal behavior function was significantly shortened in group TPB ( P<0.05). Conclusions:The combination of TEAS at bilateral Neiguan, Hegu and Zusanli acupoints with moderate sedation using propofol for gastrointestinal endoscopy is not only safe and effective, but also beneficial to the postoperative outcome of patients, and the effect is better than that of conventional anesthesia with propofol and fentanyl.

AIM:To explore the intensity-dependent effects of exercises to alleviate fear memory generaliza-tion in post-traumatic stress disorder(PTSD)and the underlying mechanism.METHODS:Male C57 BL/6J mice were randomly divided into the control group,PTSD group,high-intensity exercise(PTSD-High)group,and low-intensity exer-cise(PTSD-Low)group.PTSD model were created via using a combination of conditioned foot shock(CF)and single-pro-longed stress(SPS).The contextual fear test was used to test the mice's ability to discriminate safety situations from fear condition.Immunofluorescence observed and quantified the newborn immature neurons in the DG area of the mice's hippo-campus.ELISA was used to determine the secretion level of serum tissue adiponectin.RESULTS:(1)The immobility times for the PTSD-High and Control groups were significantly lower than those of the PTSD group.(2)Immunofluores-cence analysis showed that the cell density,dendritic branching points and length of newborn immature neurons were ele-vated in High and Low groups compared to the PTSD group.(3)Adiponectin levels in the serum of the control and PTSD-High group were significantly higher than those in the PTSD group and PTSD-Low group.CONCLUSION:Fear memory establishment in PTSD mice is associated with decreased hippocampal neurogenesis.High-intensity exercise ameliorated fear memory by enhancing adiponectin secretion and promoting hippocampal neurogenesis.High-intensity exercise exerted better improvement of brain functions to PTSD model.

Objective:To investigate the effect of Early infarct growth rate(EIGR) on the prognosis of patients with acute large vessel occlusive ischemic stroke.Methods:A total of 164 patients with acute large vessel occlusive ischemic stroke were enrolled in the emergency department of the First Affiliated Hospital of Nanjing Medical University from January 1, 2020 to December 31, 2022.According to the change of the National Institutes of Health Stroke Scale (NIHSS) score at admission and 72 h after treatment, the patients were divided into good prognosis group and poor prognosis group. The basic clinical data of the two groups were observed and compared. The risk factors of poor prognosis were analyzed by univariate regression. The effect of EIGR on prognosis after age stratification was further analyzed.Results:Comparing the clinical data of the two groups, there was no difference in EIGR (mL/h) (7.67 vs. 8.24, P=0.211) between the two groups. The product between EIGR and age was included as the interaction term, and the result of the interaction term in the model was statistically significant ( OR=1.002, 95% CI: 1.000-1.003, P=0.032) .Moreover, the result was still statistically significant after adjusting for relevant variables (gender, history of hypertension, history of atrial fibrillation, history of diabetes, history of coronary heart disease, and history of stroke) ( OR=1.002, 95% CI:1.000-1.003, P=0.027). Subgroup analysis was performed according to the median age (71 years). In the elderly group, the proportion of poor prognosis was higher with fast core infarction growth rate defined by 25 mL/h and 15 mL/h ( P < 0.05).In the younger age group, there was no significant difference in the proportion of poor prognosis in the fast core infarction growth rate compared with the slow type ( P > 0.05). Conclusions:EIGR can predict the early clinical outcome early in elderly patients with large vessel occlusive ischemic stroke.

Objective:To investigate the iodine nutritional status of pregnant women in Qingdao and the effect of prevention and treatment of iodine deficiency disorders (IDD), so as to provide a basis for residents to supplement iodine scientifically, and take targeted prevention measures and adjust intervention strategies.Methods:In accordance with the requirements of the "National Iodine Deficiency Disorders Surveillance Program (2016 edition)" and "Shandong Iodine Deficiency Disorders Surveillance Program", the cluster sampling method was adopted to select pregnant women from 10 districts (cities) in Qingdao from 2018 to 2020, to investigate their basic information and thyroid disease history. Meanwhile, household edible salt samples and random urine samples were collected to detect iodine content.Results:A total of 3 000 pregnant women were monitored from 2018 to 2020, the median age was 31 years, and the median gestational age was 18 weeks. There were significant differences in the distribution of age, gestational age, whether senile puerpera, and pregnancy in different years ( H/χ 2 = 29.35, 81.03, 65.62, 77.34, P < 0.001). The median salt iodine of edible salt ( n = 3 000) and iodized salt ( n = 2 700) in pregnant women's homes were 23.02 and 23.70 mg/kg, respectively. The qualified rate of iodized salt, the coverage rate of iodized salt and the consumption rate of qualified iodized salt were 89.59% (2 419/2 700), 90.00% (2 700/3 000) and 80.63% (2 419/3 000). The comparison of qualified rate of iodized salt, coverage rate of iodized salt and consumption rate of qualified iodized salt among different years was statistically significant (χ 2 = 48.09, 36.62, 61.08, P < 0.001), the coverage rate of iodized salt and the consumption rate of qualified iodized salt showed a downward trend year by year (χ 2trent = 35.54, 29.50, P < 0.001). A total of 3 000 urine samples were collected from pregnant women and the median urinary iodine of pregnant women was 147.85 μg/L. The urinary iodine level in the third trimester was lower than that in the first and second trimesters ( P < 0.001). The urinary iodine level in the non elderly group was higher than that in the elderly group ( Z = - 6.66, P < 0.001). The urinary iodine level in the group without thyroid disease was higher than that in the group with thyroid disease ( Z = - 1.99, P = 0.047). The urinary iodine level in iodized salt group was higher than that in non-iodized salt group ( Z = - 2.42, P = 0.015). Conclusions:The iodine nutrition of pregnant women in Qingdao is generally at an insufficient level, and the risk of iodine deficiency is high, which needs attention. In recent years, the coverage rate of iodized salt and the consumption rate of qualified iodized salt in Qingdao have shown a downward trend, and have failed to meet the requirements of national standards. In the future, we should strengthen the monitoring and health education of IDD in pregnant women.

【Objective】 To statistically analyze the characteristics of ambiguous results of HLA-DPB1 genotyping given by AllType NGS 11-loci sequencing reagent via two next generation sequencing platforms, i. e. Ion Torrent S5 and Illumina Miseq. 【Methods】 A total of 434 samples from patients or donors were genotyped for HLA-DPB1 locus using AllType NGS 11-loci sequencing reagent from One Lambda company; 336 samples of them were sequenced via the Ion Torrent S5 platform and other 98 samples were sequenced via the Illumina Miseq platform. All 434 samples were genotyped for HLA-DPB1 gene simultaneously using PCR-SSO flow fluorescent bead method. The ambiguous genotypes of HLA-DPB1^*13∶01∶01/107∶01 were distinguished by Sanger sequencing. The HLA-DPB1 genotype results by NGS method were assigned by TypeStream Visual professional software, and the ratio of ambiguous combination was calculated by direct count method. 【Results】 Ambiguous results were found in 357 out of 434 samples, accounting for 82.3% (357/434) when HLA-DPB1 allele was assigned to the third field using NGS method. Ambiguous results with 45 types were given in 275 out of 336 samples by the Ion Torrent S5 platform, accounting for 81.8% (275/336) and 82(with 27 types) out of 98 samples by the Illumina Miseq platform, accounting for 83.7% (82/98). All samples were re-genotyped for HLA-DPB1 gene by PCR-SSO, and none HLA-DPB1 allele had been missed by NGS. A total of 43 ambiguous alleles in HLA-DPB1^*13∶01∶01/107∶01 involving 41 samples were distinguished by Sanger sequencing; HLA-DPB1^*13∶01∶01 were detected in 25 (58.1%, 25/43) and HLA-DPB1^*107∶01 in 18 (41.9%, 18/43). 【Conclusion】 There were still a high proportion of HLA-DPB1 ambiguous combinations using the AllType NGS 11-loci sequencing reagent. Sequencing exon 1 of HLA-DPB1 gene by Sanger sequencing can resolve part of the ambiguous results in HLA-DPB1^*13∶01∶01/107∶01 alleles.

Objective:To investigate the characteristics of regional brain functional centrality(DC)in patients with levodopa-induced dyskinesia(LID)and to explore the pathogenesis of LID.Methods:A total of 33 PD patients with LID(PD-LID), 41 PD patients without LID(PD-nLID)and 37 healthy controls from the First Affiliated Hospital of Nanjing Medical University were enrolled in this study.Differences in DC among the three groups were compared and the correlation between Z-DC values of the brain regions with differences and the scores of the involuntary movement scale(items 1-7)was analyzed.Results:Compared with Controls, PD-LID patients showed increased DC in the right amygdala(extending to the right globus pallidus)(MNI: x=30, y=-3, z=-18, t=4.00, P<0.05 after AlphaSim correction)and in the right postcentral gyrus(MNI: x=57, y=-9, z=39, t=-3.59; MNI: x=42, y=-33, z=57, t=-4.23, P<0.05 after AlphaSim correction)and reduced DC in the right superior parietal lobule(MNI: x=24, y=-51, z=72, t=-3.95, P<0.05 after AlphaSim correction).Compared with the PD-nLID group, the PD-LID group showed increased DC in the right globus pallidus(MNI: x=30, y=-12, z=-3, t=3.09, P<0.05 after AlphaSim correction).DC changes in the right globus pallidus were positively correlated with AIMS score( r=0.482, P=0.004). Conclusions:The enhancement of DC function in the right globus pallidus may be closely related to the onset and severity of LID.

OBJECTIVE: To detect loss of heterozygosity (LOH) at human leukocyte antigen (HLA) loci in a Chinese patient with leukemia after haploidentical hematopoietic stem cell transplantation. METHODS: HLA genotyping was carried out on peripheral blood, hair follicle and buccal swab samples derived from the patient after the transplantation as well as peripheral blood samples from his parents by using PCR-sequence specific oligonucleotide probe method and PCR-sequence based typing method. Short tandem repeat (STR) loci were detected by using a 23 site STR assay kit and a self-developed 6 STR loci assay for the HLA regions. RESULTS: After the transplantation, the HLA genotype of the peripheral blood sample of the patient was identical to his father. The patient was HLA-A*02:01,24:02, C*03:03,03:04, B*13:01,15:01, DRB1*08:03,12:02, DQB1*03:01,06:01 for his hair follicle specimen. However, homozygosity of the HLA loci was found in his buccal swab sample. Only the HLA-A*24:02-C*03:03-B*15:01-DRB1*08:03-DQB1*06:01 haplotype from his father's was present, while the HLA-A*02:01-C*03:04-B*13:01-DRB1*12:02-DQB1*03:01 haplotype from his mother was lost. After the transplantation, the alleles of the 23 STR sites in the patient's peripheral blood sample were consistent to his father, with no allelic loss detected in his buccal swab sample. However, at least 4 STR loci in the HLA region were lost in his buccal swab sample. CONCLUSION LOH at the HLA loci has been detected in the buccal swab sample of a patient with leukemia who received haploidentical hematopoietic stem cell transplantation.
HLA Antigens/genetics* ; HLA-A Antigens/genetics* ; Histocompatibility Antigens Class I/genetics* ; Humans ; Leukemia/genetics* ; Loss of Heterozygosity