Fear memories are temporarily suppressed after repeated retrieval, a phenomenon known as memory extinction.How to reduce or even eliminate fear memory is the key to the treatment of fear related diseases such as post-traumatic stress disorder(PTSD). A single extinction training based on Pavlov's fear regulation task could only inhibit the expression of conditioned fear memory traces, but it could not eliminate the acquired conditioned fear memory. However, according to the reconsolidation theory based on memory, the retrieval-extinction paradigm has a more lasting effect on the erasure and rewriting of fear memory, and can effectively prevent the return of fear memory. Studies have shown that extraction-regression is closely related to a variety of neurotransmitter receptors such as glutamate receptor(GluR), dopamine receptor(DAR), L-type voltage-gated calcium channels(LVGCs) and cannabinoid. Moreover, its effect is closely related with factors such as retrieval-extinction memory stage. At present, most of the researches on extracted boundary conditions only stay at the level of behavior, with little understanding and exploration on the level of molecular mechanism. From the perspective of molecular neurobiology, with different stages of memory and different types of receptors and molecular mechanisms, this research reviewed the mechanisms of retrieval-extinction in recent years.It provided valuable signaling pathways, molecular targets and research directions for the treatment of fear-related diseases such as PTSD.

Objective: To analyze the using of pre-hospital emergency resources and treatment characteristics of acute alcoholism patients in Guangzhou. Methods: The pre-hospital emergency data of the emergency department of the Second Affiliated Hospital of Guangzhou Medical University from January 1st in 2009 to December 31st in 2018 were obtained from the database of the Guangzhou Emergency Medical Command Center. The related data of patients with acute alcoholism were collected, including gender, age, poisoning severity, treatment results, caller type, number of empty vehicles (empty vehicle was defined as the empty vehicle return caused by the ambulance who did not receive or refused to come to the hospital after the ambulance leaved), departure time (from the ambulance to the completion time), on-site time (from the ambulance to the patient boarding time) and the distribution of pre-hospital emergency time in 24 hours on weekdays and weekends. The relationship between acute alcoholism patients and the peak of in-hospital emergency treatment was analyzed. Results: A total of 2 408 acute alcoholism patients were recorded, among whom 2 109 patients (87.58%) with acute alcoholism, 126 (5.23%) with drug poisoning, 67 (2.78%) with chemical poisoning, 3 (0.13%) with pesticide poisoning, and 103 (4.28%) with other poisoning. Acute alcoholism patients were mainly male, with a total of 1 862 cases (88.29%), and the ratio between males and females was 7.54∶1. In 2 109 patients with acute alcoholism, 93.41% were in the age range of 18-59 years old. The number of mild patients was 1 717 (81.41%), 1 178 (55.86%) needed further treatment, and no patient died. For the occupation of pre-hospital emergency resources, 43.24% (912/2 109) of acute alcoholism called 120 through 110 with empty vehicles of 36.79% (776/2 109), which were significantly higher than the acute cerebrovascular disease [3.83% (362/9 461), 5.80% (549/9 461), both P < 0.01], acute trauma [24.29% (1 708/7 033), 7.96% (560/7 033), both P < 0.01], acute circulation system disease [2.44% (90/3 694), 2.87% (106/3 694), both P < 0.01], and acute respiratory system disease [0.86% (31/3 606), 1.58% (57/3 606), both P < 0.01]. Furthermore, empty vehicles were more likely to happen through 110 with empty vehicles rate of 51.75% (472/912), which was significantly higher than that through the witness [40.82% (60/147), P < 0.01] and relatives and friends [23.24% (244/1 050), P < 0.01]. The driving time and on-site time of acute alcoholism were significantly shorter than those of acute cerebrovascular disease, acute circulation system disease, and acute respiratory system disease [driving time (minutes): 26 (20, 34) vs. 34 (26, 45), 38 (29, 49), 38 (29, 50); on-site time (minutes): 6 (4, 10) vs. 10 (7, 14), 10 (7, 15), 10 (8, 15), all P < 0.01], but there was no statistical difference as compared with acute trauma [driving time (minutes): 26 (20, 34) vs. 29 (20, 42), on-site time (minutes): 6 (4, 10) vs. 7 (4, 11), both P > 0.05]. The regularity of variation in number of critically acute alcoholism patients was distinctive, which peaked in the period of 21:00-00:00 and bottomed out in the period of 09:00-13:00, which overlapped with the peak flow in the hospital emergency department (17:00-22:00). Conclusions Acute alcoholism patients occupy excessive pre-hospital emergency resources, and overlap with the hospital emergency treatment peak. It is necessary to strengthen the public propaganda and education on the rational usage of 120 emergency resources and reduce waste.

Objective To investigate the efficacy and safety of programmed death receptor-1 (PD-1) inhibitor combined with transarterial chemoembolization (TACE) and anti-angiogenic drug tyrosine kinase inhibitor (TKI) versus TACE combined with TKI in the treatment of advanced hepatocellular carcinoma (HCC) and related influencing factors for prognosis. Methods An analysis was performed for all patients who received TACE+TKI+PD-1 inhibitor and some patients who received TACE+TKI in The First Affiliated Hospital of Air Force Medical University from June 2018 to July 2021. Related clinical data were collected, and propensity score matching (PSM) was used to balance the baseline characteristics between groups. The chi-square test was used for comparison of categorical data between two groups; the Wilcoxon rank-sum test was used for comparison of the number of TACE procedures between two groups; the Kaplan-Meier method was used to analyze overall survival (OS), and univariate and multivariate Cox regression models were used to analyze the influencing factors for prognosis. Results A total of 181 patients with advanced HCC were screened out, among whom 50 patients were treated with TACE+TKI+PD-1 inhibitor; after PSM, 40 patients treated with TACE+TKI+PD-1 inhibitor were enrolled as observation group and 40 patients treated with TACE+TKI were enrolled as control group. At the end of follow-up, the median follow-up time was 28.6 (95% confidence interval [ CI ]: 22.1-35.1) months, and the median OS was 15.9 (95% CI : 7.5-24.2) months in the observation group and 11.2 (95% CI : 5.0-17.5) months in the control group. The Cox regression analysis showed that the application of PD-1 inhibitor (hazard ratio [ HR ]=0.42, 95% CI : 0.23-0.80, P =0.008), the number of TACE procedures ( HR =0.67, 95% CI : 0.46-0.99, P =0.043), Child-Pugh class ( HR =2.40, 95% CI : 1.15-5.00, P =0.019), and vascular invasion ( HR =3.42, 95% CI : 1.11-9.42, P =0.031) were independent influencing factors for prognosis. The incidence rate of grade > 2 adverse events was 40% for both the observation group and the control group, and there was no significant difference between the two groups ( P =0.818). Conclusion Compared with TACE+TKI, TACE+TKI+PD-1 inhibitor can significantly prolong the OS of patients in advanced HCC, with relatively controllable adverse events.

Genome-wide association studies (GWASs) are the most widely used method to identify genetic risk loci associated with orofacial clefts (OFC). However, despite the increasing size of cohort, GWASs are still insufficient to detect all the heritability, suggesting there are more associations under the current stringent statistical threshold. In this study, we obtained an integrated epigenomic dataset based on the chromatin conformation of a human oral epithelial cell line (HIOEC) using RNA-seq, ATAC-seq, H3K27ac ChIP-seq, and DLO Hi-C. Presumably, this epigenomic dataset could reveal the missing functional variants located in the oral epithelial cell active enhancers/promoters along with their risk target genes, despite relatively less-stringent statistical association with OFC. Taken a non-syndromic cleft palate only (NSCPO) GWAS data of the Chinese Han population as an example, 3664 SNPs that cannot reach the strict significance threshold were subjected to this functional identification pipeline. In total, 254 potential risk SNPs residing in active cis-regulatory elements interacting with 1 718 promoters of oral epithelium-expressed genes were screened. Gapped k-mer machine learning based on enhancers interacting with epithelium-expressed genes along with in vivo and in vitro reporter assays were employed as functional validation. Among all the potential SNPs, we chose and confirmed that the risk alleles of rs560789 and rs174570 reduced the epithelial-specific enhancer activity by preventing the binding of transcription factors related to epithelial development. In summary, we established chromatin conformation datasets of human oral epithelial cells and provided a framework for testing and understanding how regulatory variants impart risk for clefts.
Chromatin ; Cleft Lip/genetics* ; Cleft Palate/genetics* ; Epithelium ; Genome-Wide Association Study ; Humans