Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

By consulting the ancient and modern literature， the name， origin， quality evaluation， harvesting and processing methods of Curculiginis Rhizoma（CR） were systematically combed and verified， in order to provide a basis for the development and utilization of famous classical formulas containing CR. The results of herbal textual research showed that the name Xianmao was first recorded in Leigong Paozhilun， the name of CR was used in all dynasties and this name came from its efficacy and morphological characteristics， the mainstream source for CR of the past dynasties was the rhizome of Curculigo orchioides or C. capitulata， since modern times， C. orchioides has been the main source of commodities. In ancient times， most of the places of origin of the description were the western regions and southwest China， while in modern times， Sichuan and Guizhou were regarded as genuine places. Since modern times， its quality has been summarized as the best with thick roots， firm texture and black-brown surface， the harvesting and processing methods recorded in the past dynasties are mainly sun drying after harvest in the second， eighth and ninth months of the lunar calendar， and most of them are harvested in autumn and winter in modern times. In ancient times， there were many processing methods of CR， mainly in processing with rice swill， while in modern times， stir-frying with wine was the main processing method. The nature， taste， meridian tropism， functions and indications of CR are basically consistent from ancient to modern times， the taboos for taking are to avoid iron， cow's milk， and beef. Although there are some differences in the understanding of the toxicity of CR in the past dynasties， most of the materia medica are clear that it has a certain toxicity. Based on the research conclusion， it is suggested that the rhizome of C. orchioides of Lycoris family should be used as its source in the famous classical formulas， and the corresponding processing method should be selected according to the processing requirements in the formulas， while the raw products is recommended to be selected as medicine if the processing requirement is not specified.

Objective:To investigate the effect of low density lipoprotein cholesterol (LDL-C) on the progression of retinal arteriosclerosis by using a deep learning model.Methods:A cohort study was performed.Data of 1 928 individuals who underwent the medical examination at Beijing Yijiandian Clinic between January 2016 and August 2023 were reviewed, including baseline demographics, physical examination, serological test and fundus photography.Retinal arteriosclerosis was identified using a deep learning model.Five groups were divided according to LDL-C levels, including 389 subjects in group 1 (0.64-1.90 mmol/L), 387 subjects in group 2 (1.91-2.26 mmol/L), 384 subjects in group 3 (2.27-2.57 mmol/L), 385 subjects in group 4 (2.58-2.95 mmol/L), and 383 subjects in group 5 (2.96-6.06 mmol/L).The association between LDL-C levels and progression of retinal arteriosclerosis and the dose-response relationship were analyzed by logistic regression analysis and restricted cubic spline (RCS) regression model.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Peking University People's Hospital (No.2021PHB058-001).Written informed consent was obtained from each subject.Results:The incidence of retinal arteriosclerosis progression was 22.10% (426/1 928) during the mean follow-up (66.84±6.58) months.The proportions of fundus progression in groups 1, 2, 3, 4, and 5 were 15.68%(61/389), 21.71%(84/387), 21.35%(82/384), 25.71%(99/385), and 26.11%(100/383), respectively, with statistical significant differences among them ( χ2=15.97, P=0.003).Using group 1 as a reference, LDL-C 2.58-2.95 mmol/L was an independent risk factor for progression of retinal arteriosclerosis ( OR=1.52, 95% CI: 1.04-2.22), and RCS analysis showed an " L" shaped association.The effect of LDL-C on retinal arteriosclerosis showed a threshold effect, with the risk of retinal arteriosclerosis progression increasing with increasing LDL-C when LDL-C was <2.34 mmol/L ( OR=1.97, 95% CI: 1.10-3.62), and stabilizing when LDL-C was ≥2.34 mmol/L. Conclusions:LDL-C has a threshold effect on the impact of retinal arteriosclerosis progression, and the threshold is 2.34 mmol/L.

Objectives:To compare the diagnostic efficacy of non-ST-segment elevation myocardial infarction (NSTEMI) and the predictive value for major adverse cardiovascular events (MACE) of the 0/3-hour algorithm for high-sensitivity cardiac troponin (hs-cTn) recommended by the 2015 European Society of Cardiology (ESC) guidelines for the management of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and the 2021 "Chinese Expert Consensus on Laboratory Testing and Clinical Application of Cardiac Troponin" in suspected acute coronary syndrome (ACS) patients in the Chinese population. Methods:This is a multicenter prospective observational study,including 1527 patients with suspected ACS from three clinical centers from January 2017 to September 2020.Plasma hs-cTnI levels were measured using the ARCHITECT assay at the time of presentation and 3 hours later in patients with suspected ACS (test determination).Clinical judgment (independent clinical judgment by cardiac experts,independent of the test results) was used as the gold standard to compare the sensitivity,specificity,and consistency of the two diagnostic algorithms,and to analyze their predictive value for MACE at 30 days and 180 days.MACE in this study was defined as a composite event of cardiovascular death,myocardial infarction,and unplanned coronary revascularization. Results:According to clinical judgment,there were 400 patients with NSTEMI and 1127 patients without NSTEMI.The 0/3-hour algorithm recommended by the 2021 Chinese Expert Consensus showed higher sensitivity in diagnosing NSTEMI than the 2015 ESC guidelines (91.50％[95％ CI:88.32％-94.04％]vs.87.75％[95％ CI:84.13％-90.80％]),but slightly lower specificity (93.88％[95％ CI:92.32％-95.21％]vs.95.56％[95％ CI:94.19％-96.69％]),with both differences being statistically significant (both P<0.001).In the follow-up at 30 days and 180 days,the incidence of MACE in patients diagnosed with NSTEMI by both algorithms was higher than in those without NSTEMI (P<0.001).The incidence of MACE at 30 days and 180 days for the group excluded from the diagnosis of NSTEMI by 2015 ESC guidelines was 0.19％ and 1.120％,respectively,and for the NSTEMI group was 2.89％ and 3.68％,respectively;for the group excluded from NSTEMI by the 2021 Chinese Expert Consensus,the incidence was 0.096％ and 0.770％,respectively,and for the NSTEMI group was 2.91％ and 4.36％,respectively.Cox analysis showed that the HR ratio for MACE at 180 days in the NSTEMI group diagnosed by both algorithms was 3.418 and 5.892,respectively,significantly higher than the group excluded from NSTEMI. Conclusions:The 0/3-hour algorithm recommended by the 2021 Chinese Expert Consensus has superior diagnostic sensitivity compared to the 2015 ESC NSTE-ACS guidelines,at the cost of slightly lower specificity.Both algorithms can effectively predict MACE within 180 days,but based on the data from this study,the algorithm recommended by the 2021 Chinese Expert Consensus is more sensitive in predicting the risk of MACE,and patients excluded from the diagnosis of NSTEMI by this method have a lower incidence of MACE,suggesting that its application in clinical practice may be more helpful in terms of long-term safe management of patients.

Objective:Exploring the role and clinical value of tRNA methyltransferase 61A(TRMT61A)expression in head and neck squam-ous cell carcinoma(HNSCC).Methods:This study analyzed the expression levels of TRMT61A across various cancer tissues and specifically in HNSCC tissues compared to normal head and neck tissues using the Cancer Genome Atlas(TCGA)database.The expression level and pro-gnostic characteristics of TRMT61A in patients with HNSCC were investigated.Furthermore,the proliferation and colony-formation ability of an HNSCC cell line following TRMT61A knockdown was assessed using Western blot,cell counting kit-8(CCK-8),and colony-formation assays.Results:TRMT61A was highly expressed in HNSCC tissues,and its elevated expression significantly correlated with reduced overall survival(OS),progression-free survival(PFS),and disease-specific survival(DSS)in patients.In vitro experiments demonstrated that knocking down TRMT61A suppressed proliferation and the colony-forming ability of HNSCC cells.Conclusions:TRMT61A plays an important role in tumor progression in HNSCC.Targeting TRMT61A expression is a promising approach to affect tumor cell proliferation in HNSCC and is expected to become an effective prognostic indicator for patients with HNSCC.Thus,TRMT61A is a potential therapeutic target for the treatment of HNSCC.

Objective:To investigate the effect of Enolase inhibition (ENOblock) on autophagy- related protein expression and motor function promotion after spinal cord injury in rats.Methods:A total of 160 female SD rats were divided into sham-operation group, 3-methyladenine (3-MA) autophagy inhibitor treatment group (3-MA group), spinal cord injury group and ENOblock treatment group (ENOblock group) according to the random number table, with 40 rats per group. Back laminectomy without injury to the spinal cord was performed in sham-operation group. Spinal cord injury at T 8 was induced by using a modified Allen weight-drop apparatus to establish a spinal cord injury model in the rest three groups. 3-MA and ENOblock groups were injected 3-MA (2.5 mg/kg) and ENOblock (100 μg/kg) into the caudal vein immediately after injury, respectively. Sham-operation and spinal cord injury groups were injected same dose of isotonic sodium chloride solution into the caudal vein. At 1, 3, 7, 14 and 21 days after injury, BBB score was used to evaluate lower limb motor function. At day 3 after injury, the ratio of microtubule-associated protein 1 light chain 3 (LC3)-II to LC3-I and protein expressions of autophagy effector protein (Beclin-1) and polyubiq-uitinbinding protein (p62) were detected by Western blotting. At day 7 after injury, LC3-Ⅱ and Beclin-1 positive cells in the injured area of the spinal cord were determined by immunofluorescence staining. At day 3 after injury, the mRNA expressions of Beclin-1 and Enolase in the injured area of the spinal cord were detected by RT-PCR. Results:At 1, 3, 7, 14 and 21 days after injury, BBB score was lowered in 3-MA group [(1.4±1.1)points, (2.4±0.9)points, (3.8±1.8)points, (7.6±1.1)points, (9.0±2.1)points], spinal cord injury group [(0.8±0.5)points, (1.8±0.9)points, (3.6±0.9)points, (6.2±1.3)points, (8.0±0.7)points] and ENOblock group [(2.0±0.9)points, (2.2±0.8)points, (4.8±1.1)points, (10.6±1.5)points, (13.2±0.8)points] compared to sham-operation group [(21.0±0.0)points at all time points] (all P<0.05). Moreover, the score in ENOblock group was significantly higher than that in spinal cord injury group at 14, 21 days after injury, and the score in 3-MA group was significantly higher than that in spinal cord injury group at day 21 after injury (all P<0.05). At day 3 after injury, Western blotting showed that the ratio of LC3-II to LC3-I and protein expressions of Beclin-1 and p62 were 0.46±0.10, 0.41±0.03, 0.81±0.03 in sham-operation group, 0.66±0.06, 0.69±0.02, 0.59±0.05 in 3-MA group, 0.85±0.06, 1.07±0.03, 0.41±0.02 in spinal cord injury group and 0.68±0.06, 0.66±0.08, 0.55±0.02 in ENOblock group. By comparison, spinal cord injury group showed significantly higher ratio of LC3-II to LC3-I and protein expression of Beclin-1 and significantly lower protein expression of p62 than sham-operation group (all P<0.05); 3-MA and ENOblock groups showed significantly lower ratio of LC3-II to LC3-I and protein expression of Beclin-1 and significantly higher protein expression of p62 than spinal cord injury group (all P<0.05); there was no significant difference in the ratio of LC3-II to LC3-I and protein expressions of Beclin-1 and p62 between 3-MA and ENOblock groups (all P>0.05). At day 7 after injury, immunofluorescence staining showed that LC3-II and Beclin-1 positive cells in 3-MA and ENOblock groups were less than those in spinal cord injury group. At day 3 after injury, RT-PCR showed that mRNA expressions of Beclin-1 and Enolase in spinal cord injury group (1.08±0.16, 0.98±0.17) were higher than those in sham-operation group (0.25±0.06, 0.29±0.03). Moreover, mRNA expressions of Beclin-1 and Enolase in 3-MA group (0.77±0.11, 0.72±0.04) and ENOblock group (0.81±0.10, 0.64±0.09) were lower than those in spinal cord injury group (all P<0.05). There was no significant difference in mRNA expressions of Beclin-1 and Enolase between 3-MA and ENOblock groups (all P>0.05). Conclusions:Autophagy activity is significantly up-regulated after spinal cord injury in rats. ENOblock can inhibit autophagy and promote motor function recovery in rats by regulating the expression of autophagy-related proteins.

Objective To analyze the survival status, distribution characteristics and social security of newly diagnosed occupational pneumoconiosis patients in Guizhou Province from 2006 to 2021. Methods The newly diagnosed pneumoconiosis cases reported in Guizhou Province from 2006 to 2021 were collected from the “Occupational Diseases and Hazards Monitoring Information System” under “National Health Insurance Disease Prevention and Control Information System”. Telephone or face-to-face surveys were conducted to investigate these patients. Results A total of 12 413 newly diagnosed pneumoconiosis patients were reported in Guizhou Province from 2006 to 2021, with 11 192 cases included in the follow-up, and 10 631 cases were followed-up successfully. According to the follow-up study, 10 565 cases (accounting for 99.4%) were survived, and 66 cases (accounting for 0.6%) died. The number of pneumoconiosis showed an increasing trend followed by a sharp decline from 2006 to 2021, reaching its peak in 2016. The main industry of the newly pneumoconiosis cases was concentrated in the mining industry (accounting for 90.6%). The top three regions with surviving cases in the follow-up were Bijie City, Zunyi City, and Qiannan Prefecture, accounting for 34.0%, 25.4% and 12.0%, respectively. The main types of pneumoconiosis were coal workers' pneumoconiosis and silicosis, accounting for 67.1% and 30.8%, respectively. Most cases were in the age group of 50 to <60 years old, accounting for 59.1%, and the majority of the workers had worked in dusty environments for 5 to <25 years, accounting for 91.5%. In terms of social security, about 89.5% of cases were in the basic medical insurance for urban and rural residents which was the most popular social security. The employer's compensation rate was 67.7%, and the work-related injury insurance participation rate was 51.5%. Conclusion Pneumoconiosis cases in Guizhou Province exhibit significant regional disparities. It has a high concentration in the industry, a younger age profile, and limited social security coverage. It is necessary to strengthen the special management of dust and industry supervision in mining industry, intensify follow-up work for pneumoconiosis cases, reinforce the construction of pneumoconiosis rehabilitation station in key regions, and improve the quality of life of pneumoconiosis cases.

Abstract: Objective To investigate the molecular characteristics of the H9N2 avian influenza virus (AIV) causing human infection in Yunnan Province in 2019, and to provide the scientific basis for the prevention and control of avian influenza in Yunnan Province. Methods Influenza virus typing was performed by real-time RT-PCR in two influenza-like illness samples, and the Illumina Miseq high-throughput sequencer was used to determine the viral genome sequence. HA and NA gene sequence alignment and phylogenetic tree construction were performed using Mega7.0 software. Results Real-time RT-PCR results showed that two influenza-like illness samples were positive for H9N2 subtype. The full length of HA and NA were obtained by genomic sequencing. Sequence system evolution analysis showed that the HA and NA of the two AIVs in Yunnan Province were in the same evolutionary clade as A/Chicken/Zhejiang/HJ/2007 and belonged to the G57 type. The HA nucleotide and amino acid homology of the two AIVs were 93.92% and 95.00%, respectively, and the NA nucleotide and amino acid homology was 93.31% and 82.03%, respectively. The nucleotide (amino acid) homology of HA was 92.29%-96.94% (93.77%-98.43%) and 92.84%-94.92% (94.18%-96.23%), respectively, and NA nucleotide homology (amino acid) were 91.81%-97.60% (77.82%-94.83%), 94.38%-97.22% (85.47%-94.55%), respectively, compared with that of human infected H9N2 epidemic strains obtained in China from 2015 to 2020. Both AIVs HA protein cleavage site sequences were PSRSSR↓GLF, which was in line with the characteristics of low pathogenic influenza. The analysis of HA protein receptor binding site showed that amino acids at positions 109, 161, 163, 191, 202, 203 and 234 were consistent with the reference strains, while amino acids at position 198 were mutated to T. N166D and 168N mutations were also found in HA protein, and both AIVs had 7 potential glycosylation sites. Analysis of the erythrocyte binding site of NA gene found that there were amino acid mutations at positions 369, 402, 403, and 432, and amino acid deletion at positions 63-65 was found in the NA genes. There were 4 and 5 potential glycosylation sites in the two AIVs, respectively, and no drug resistance site mutations were found. Conclusions　The receptor binding sites, erythrocyte binding sites and glycosylation sites of HA and NA genes of H9N2 AIV in Yunnan Province have different degrees of variation, and monitoring and prevention and control should be strengthened.

Objective:To understand the viral spectrum changes of respiratory tract infections in Kunming city from 2018 to 2021.Methods:Throat swab samples were collected from influenza-like cases in 2 general hospitals and 1 children’s hospital in Kunming city from 2018 to 2021. Real-time RT-PCR was used to detect 14 common respiratory viruses (including influenza virus, human adenovirus, human respiratory syncytial virus, human rhinovirus, human bocavirus, human metapneumovirus, human parainfluenza virus, human coronavirus), and the detection data before and during the epidemic were analyzed.Results:From 2018 to 2021, a total of 12 302 specimens were collected and tested, and 2 600 positive specimens were detected, with a total positive rate of 21.13%. The positive detection rate before the epidemic was 25.91%, which was significantly higher than 16.18% during the epidemic ( χ2=174.35, P<0.05), and the detection rates of Flu and HAdV decreased by 75.36% and 45.31% respectively, while the detection rates of HRV and 229E increased by 72.22% and 350% respectively. During the epidemic, the total virus detection rate of male and female cases and all age groups under 50 years old were lower than before the epidemic. Conclusions:The epidemic of SARS-CoV-2 and the implementation of corresponding prevention and control measures have an impact on the epidemic trend of common respiratory viruses in Kunming, and the monitoring of multiple respiratory viruses is of great significance.

OBJE CTIVE To inv estigate the antibiotic use and rationality for children in community health service institutions from Beijing ，and to provide reference for promoting rational use of antibiotics in primary healthcare institutions. METHODS All the prescriptions for children from primary healthcare institutions in 2019 were extracted from prescription review system of community health service institutions in Beijing. The use of antibiotics was described according to the related indicators of the World Health Organization/International Network for Rational Use of Drug （WHO/INRUD）. The structure of antibiotics use was analyzed according to the anatomical therapeutic chemical （ATC）classification as well as the WHO AWaRe classification and diagnosis. RESULTS A total of 288 primary healthcare institutions and 10 422 prescriptions for children were included. The number of institutions in high-income areas ，middle-income areas and low-income areas were 119，80 and 89 respectively，and the number of prescriptions involved were 2 430，2 163 and 5 829 respectively，including 1 447 prescriptions involving antibiotics （13.9％）. Among 1 447 prescriptions，the rate of prescriptions involving combined use of antibiotics was 1.4％（20 pieces）；the rate of prescriptions involving antibiotics injection was 9.7％（141 pieces）；4.8％ antibiotics prescriptions were rated as unreasonable （69 pieces）. The three most commonly used antibiotics were the macrolides （40.2％），the second-generation cephalosporins （26.5％） and the third-generati on cephalosporins （23.4％）. The proportion of antibioti cs prescriptions from groups of access ，caution， reserve and not recommended were 9.1％，92.1％，0.3％，and 0， respectively. The rate of antibiotics prescriptions fortonsillitis was the highest （31.9％ ）. Among 69 irrationalantibiotics prescriptions ，main of them were irrational drug use （56 pieces，81.2％）. CONCLUSIONS The rate of antibiotics prescriptions for children in primary healthcare institutions from Beijing is lower than the standard of WHO antibiotics prescription rate （20.0％-26.8％），but the use rate of antibiotics at caution grade is too high.