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.

BACKGROUND:Studies have shown that both Panax notoginseng saponins and concentrated growth factor can promote fracture healing,but there are few studies addressing their combined effects on fracture healing.Panax notoginseng saponins may accelerate fracture healing by promoting the release of concentrated growth factor-related factors over a certain period of time. OBJECTIVE:To study the effect of Panax notoginseng saponins on concentrated growth factor release and fracture healing in rats. METHODS:Eighteen 8-week-old Sprague-Dawley rats were numbered and randomly divided into three groups:Panax notoginseng saponins group,model control group and blank group.Panax notoginseng saponins group was fed with Panax notoginseng saponins for 2 weeks.Model control group was given 2 mL of normal saline for 2 weeks and blank group was fed normally.Concentrated growth factor was obtained by the centrifugation method both from the Panax notoginseng saponins group and model control group.After 1 week of normal feeding,all animals underwent modeling for femoral fracture.The Panax notoginseng saponins group and the model control group were implanted with autologous concentrated growth factor,and then the release concentration of growth factors at different time points(1 hour,1,3,5,7,9 and 11 days)were measured by ELISA.Fracture healing was assessed based on postoperative X-ray and hematoxylin-eosin staining of bone tissues. RESULTS AND CONCLUSION:Compared with the model control group,the Panax notoginseng saponins group had higher release concentrations of vascular endothelial growth factor A and transforming growth factor β at 7,9,and 11 days,Platelet-derived growth factor BB at 5,9,and 11 days,and basic fibroblast growth factor at 1-11 days(P<0.01).X-ray examinations indicated that fracture healing in the Panax notoginseng saponins group was better than that in the model control group,and fracture healing in these two groups was better than that in the blank group at 2 months after surgery.Hematoxylin-eosin staining results found that the constituent osteocyte density in the Panax notoginseng saponins group was greater than that in the model control group,and the constituent osteocyte density in these two groups was better than that in the blank group.These findings indicate that Panax notoginseng saponins can increase the concentration of concentrated growth factor-related factors.After intervention with Panax notoginseng saponins,concentrated growth factors are more advantageous in promoting fracture healing in rats.

The correct working posture of dentists is not only the premise of clinical diagnosis, treatment quality and safety but also an important guarantee for the occupational health of dentists. Presently, research on the working posture of dental professionals and related influencing factors is relatively mature internationally. Still, the dental curriculums in our country have not systematically introduced theoretical knowledge and standards related to working posture. This review analyzes and summarizes previous literature on the importance of dental working posture, criteria, assessment methods, and influencing factors, in hopes of providing references and theoretical supports for future guidelines and standards.

Objective:To investigate the prognosis of childhood adrenoleukodystrophy (ALD) with cognitive disorder after haploidentical allogenic hematopoietic stem cell transplantation (haplo-HSCT), and to identify risk factors affecting the prognosis.Methods:It was a single-center retrospective study involving 31 ALD children receiving haplo-HSCT in Peking University People′s Hospital from January 2014 to October 2022.Survival analysis was performed by Kaplan-Meier method. Cox regression analysis was performed to identify risk factors for the prognosis of childhood ALD following haplo-HSCT. Results:Among the 31 children with ALD, 1 case died of cardiogenic shock during the transplantation, and the remaining had a successful haplo-HSCT.Ten children with ALD had cognitive disorder before haplo-HSCT, including 3 cases with the minimal LOES score ≥10 points and 8 cases with the Neurologic Function Score (NFS)>0 point before haplo-HSCT.Six children had major functional disability (MFD) and 2 cases died due to progression of ALD after haplo-HSCT.Twenty children did not have cognitive disorder before haplo-HSCT, of whom 3 cases had the LOES score≥10 points and 6 cases had NFS>0 before haplo-HSCT.Four children had MFD and 2 cases died due to progression of ALD after haplo-HSCT.For ALD patients without cognitive disorder after haplo-HSCT, the 3-year and 5-year survival rate were 100.0% and 72.9%, respectively, and the 5-year MFD-free survival was 61.6%.For ALD patients with cognitive disorder after haplo-HSCT, the 3-year survival rate was 83.3%.Compared with ALD patients with the LOES score<10 points before haplo-HSCT, those with the LOES score≥10 points had 9.243 times the risk of developing MFD after haplo-HSCT ( P=0.024, 95% CI: 1.332-64.127). Compared with ALD patients without cognitive disorder before haplo-HSCT, ALD patients with cognitive disorder had 9.749 times the risk of developing MFD after haplo-HSCT ( P=0.023, 95% CI: 1.358-66.148). Conclusions:Cognitive disorder and LOES score≥10 points before haplo-HSCT are risk factors for developing MFD in children with ALD following haplo-HSCT.

Objective To explore the effects and influencing factors of traditional occupational health training on occupational health literacy (OHL) of employees in micro-, small- and medium-sized enterprises. Methods A total of 540 employees from 154 micro-, small- and medium-sized enterprises, who participated (347 employees) and not-participated (193 employees) in traditional occupational health training, and 171 community residents/students (not-participated in occupational health training) were selected as the research subjects using the convenient sampling method. The OHL level was investigated using Occupational Health Literacy Questionnaire of National Key Populations. Results The overall OHL level of employees was 43.3% (234/540). Among them, the overall OHL level of untrained and trained employees was 38.9% and 45.8%, respectively, and the overall OHL level of community residents/students was 43.3%. The results of multivariate logistic regression analysis showed that the higher the educational level, the higher the OHL level (all P<0.01). The OHL level of untrained and trained employees was higher than that of untrained community residents/students (all P<0.05). The interaction of education level and training status had no statistical difference on the OHL level of the research subjects (P>0.05). The results of factorial design analysis of variance showed that the overall OHL score rate of untrained employees and trained employees was higher than that of untrained community residents/students (all P<0.05). However, there was no significant difference in overall OHL score rate between untrained and trained employees (P>0.05). Conclusion The role of traditional occupational health training in improving the OHL level of employees in micro-, small- and medium-sized enterprises needs to be improved. The responsibility of enterprise occupational health training should be implemented, and multiple measures should be taken to enrich the ways and approaches of occupational health education for enterprise employees, to effectively improve the OHL of workers.

Abstract： Objective　To elucidate the antigenic antibody reaction of recombinant expression of non-structural protein 1 (NS1) of Japanese encephalitis (JE) virus with various mosquito-borne flaviviruses, including JE virus, and the antigenic antibody reaction of serum samples of patients infected with JE virus in acute stage. Methods　In this study, Escherichia coli prokaryotic expression vector (pET) system was used to recombinant express Japanese encephalitis virus NS1 gene. Western Blot assay was performed to detect the antibody responses of the recombinantly expressed protein against a variety of mosquito-transmitted flaviviruses, including JE virus, as well as antigen-antibody reactions of serum from patients with acute JE virus infection. Results　The NS1 gene expression product of JE virus (P3 strain) was in the form of an inclusion body, and the denatured and renatured expression product was displayed as a single band in the denatured gel (polyacrylamide gel electrophoresis, PAGE), with a molecular weight of about 45 000. The results of further antigen-antibody analysis showed that the antigen/antibody hybridization reaction of the expression product with polyclonal or monoclonal antibody of JE virus (mosquito isolates, encephalitis isolates) and serum samples of patients with acute JE virus infection could be completely consistent. The recombinant product showed negative antigen/antibody hybridization reactions with mosquito-transmitted flaviviruses, such as dengue virus and yellow fever virus polyclonal antibodies, but positive reactions with polyclonal antibodies to West Nile virus and Murray Valley encephalitis virus. Conclusions　In this study, the recombinant expression of the NS1 protein of JE virus was successfully obtained, and the antigen/antibody reaction between the recombinant protein and samples of patients infected with mosquito-borne flavivirus and JE virus was analyzed. The study results provide important basic data for elucidating the antigen-antibody reaction between the NS1 protein of JE virus and mosquito-borne flavivirus. The recombinant expression protein obtained in this study provides an important material basis for further research on the function of JE virus NS1 protein.

Astrocytes are increasingly recognized to play an active role in learning and memory, but whether neural inputs can trigger event-specific astrocytic Ca²⁺ dynamics in real time to participate in working memory remains unclear due to the difficulties in directly monitoring astrocytic Ca²⁺ dynamics in animals performing tasks. Here, using fiber photometry, we showed that population astrocytic Ca²⁺ dynamics in the hippocampus were gated by sensory inputs (centered at the turning point of the T-maze) and modified by the reward delivery during the encoding and retrieval phases. Notably, there was a strong inter-locked and antagonistic relationship between the astrocytic and neuronal Ca²⁺ dynamics with a 3-s phase difference. Furthermore, there was a robust synchronization of astrocytic Ca²⁺ at the population level among the hippocampus, medial prefrontal cortex, and striatum. The inter-locked, bidirectional communication between astrocytes and neurons at the population level may contribute to the modulation of information processing in working memory.
Animals ; Astrocytes ; Hippocampus/physiology* ; Humans ; Memory, Short-Term/physiology* ; Mice ; Neurons/physiology* ; Population Dynamics

Objective:To investigate a rapid protocol for the acquisition of a three-dimensional (3D) image of corneal nerve distribution and its various parameters.Methods:Four SPF female C57BL/6 mice were selected and four corneal samples with complete limbi were obtained using a dissecting microscope after the sacrifice of mice euthanized by ether.After conventional fixation, permeabilization, and immunostaining by an anti-β-Ⅲ tubulin fluorescent-conjugated antibody, a whole-nerve image of the whole-mount cornea was captured under a 60X oil lens using a scientific complementary metal-oxide-semiconductor detector and a high-resolution deconvolution microscope.The 3D image of the corneal nerve fiber was obtained after 3D deconvolution processing, Z-axis data projection, and automatic stitching using the self-contained image processing software of the microscope system.The corneal nerve density in different areas was analyzed using the automatic detection mode in the Filament Tracer module and the manual Autopath module of the interactive microscopic image analysis software Imaris.The use and care of animals complied with the statement of the Association for Research in Visual and Ophthalmology, and the study protocol was approved by an Experimental Animal Welfare Committee of Jinan University (No.JN-A-2002-01).Results:It was found that stromal nerve fibers in a dense network entered the Bowman membrane near the limbus, and branches of stromal nerve fibers formed subbasal nerve plexus, which stretched toward the center of the cornea to form a dense neural network-like structure and converged into a vortex-like structure at the apex of the cornea.Some subbasal nerves entered the epithelial layer vertically and some branches of nerve endings were found.Through the automatic detection mode of Imaris software, a gradual increase of the density from (2 488.88±282.84)μm/μm 2 at the limbus to (5 766.66±298.55)μm/μm 2 at the center of the cornea of the subbasal nerve branches, and a decrease of the density from (40.99±0.99)μm/μm 2 at the limbus to (34.57±1.28)μm/μm 2 at the center of the stromal nerves were found.It was also found that the stromal nerves at the limbus entered the Bowman membrane for about 151 μm and then began to branch to form subbasal nerves. Conclusions:The high-resolution deconvolution microscope system can be used to study the 3D distribution of the whole corneal nerve.Additionally, Imaris can be used for obtaining various parameters of the corneal nerves automatically and quickly.

Objective:To evaluate the correlation between elevated cTnI level and 28-day mortality after liver transplantation.Methods:A retrospective study was conducted in adult patients admitted to ICU after liver transplantation from Jun 2015 to March 2019 at Beijing Chao-Yang Hospital. The cardiac troponin Ⅰ levels within 48 h after surgery were examined. Patients outcome was followed up,the primary end point was mortality within 28-day. Univariate and multivariate logistic regression models were used to look for predictors of 28-day mortality.Results:Three hundred and eighteen patients were included in our analyses. Twenty-six patients died and 292 survived within 28 days after LT. Two hundred and forty-three of 318 (76.4%) cases presented elevated cTnI in the early stage after LT. Thirty-seven of 318 (11.6%) patients presented a moderate elevation of cTnI level (5-10 times over normal upper limit), 75 (23.6%) of them presented severe cTnI elevation (10 times over normal upper limit). Univariate and multivariate logistic regression model shows severe cTnI elevation was the independent prognostic factors associated with 28-day mortality [Odds Ratio (95% confidence interval)=3.151(1.218-8.150), P=0.018]. Conclusion:Early cTnI elevation is common after liver transplantation, and severe cTnI elevation is significantly associated with 28-day mortality.

Due to the limited self-repair ability of neurons after injury, there has been a lack of effective treatments for nerve injury in clinical practice. So, to find drugs that promote the repair after nerve injury has become a research hotspot. Schwann cells and neurons play an important role in regeneration of the peripheral nerves after injury. This review summarizes the classification of peripheral nerve injury, the signaling pathways related to peripheral nerve regeneration in Schwann cells and neurons as well as diseases related to peripheral nerve injury, and provides a basis for further exploration of the regeneration mechanism after peripheral nerve injury.