The circadian clock plays a critical role in regulating various physiological processes, including gene expression, metabolic regulation, immune response, and the sleep-wake cycle in living organisms. Post-translational modifications (PTMs) are crucial regulatory mechanisms to maintain the precise oscillation of the circadian clock. By modulating the stability, activity, cell localization and protein-protein interactions of core clock proteins, PTMs enable these proteins to respond dynamically to environmental and intracellular changes, thereby sustaining the periodic oscillations of the circadian clock. Different types of PTMs exert their effects through distincting molecular mechanisms, collectively ensuring the proper function of the circadian system. This review systematically summarized several major types of PTMs, including phosphorylation, acetylation, ubiquitination, SUMOylation and oxidative modification, and overviewed their roles in regulating the core clock proteins and the associated pathways, with the goals of providing a theoretical foundation for the deeper understanding of clock mechanisms and the treatment of diseases associated with circadian disruption.
Protein Processing, Post-Translational/physiology* ; Circadian Rhythm/physiology* ; Humans ; Animals ; CLOCK Proteins/physiology* ; Circadian Clocks/physiology* ; Phosphorylation ; Acetylation ; Ubiquitination ; Sumoylation

Objective To investigate the effect of programmed death-1(PD-1)on cell infiltration in muscle tissue and immune response types in mice infected with Trichinella spiralis.Methods C57BL/6J wild-type(WT)and PD-1 deficient(PD-1-/-)mice were infected with T.spiralis(400 muscle larvae per mouse),and samples were collected on day 35 after infection.The proportions of infiltrating inflammatory cells and fibroblasts around encapsulated larvae were assessed by immunohistochemistry.The expression levels of interferon-γ(IFN-γ),interleukin(IL)-4,IL-5,IL-13,and eotaxin in muscle tissue were measured using enzyme-linked immunosorbent assay.Peripheral blood and spleen were collected at different time points after infection.The percentages of CD4+IFN-γ+Th1 and CD4+IL-4+Th2 within CD4+T cells population in peripheral blood and spleen of mice were analyzed using flow cytometry.Results The proportions of eosinophils and fibroblasts among total infiltrating cells around the encapsulated larvae in the muscle of PD-1-/-mice were significantly lower than those in WT mice after T.spiralis infection(P＜0.01).The infected PD-1-/-mice exhibited higher proportions of macrophages,T cells and B cells in total infiltrating cells than the infected WT mice(P＜0.01).The levels of IL-4,IL-5,IL-13,and eotaxin in the muscle tissue of infected PD-1-/-mice were significantly lower than those in infected WT mice(P＜0.05).However,IFN-γ levels were not significantly different between the infected WT and PD-1-/-mice.The proportions of Th2 cells in CD4+T cells from peripheral blood and spleen of infected PD-1-/-mice were significantly lower than those in infected WT mice,whereas the proportion of Th1 cells showed no difference among the infected groups.Conclusions PD-1 deletion results in decreased expression of key chemokines of eosinophils and key cytokines of fibroblast formation,and a corresponding decrease in inflammatory cells in muscle in T.spiralis-infected mice.This effect may be associated with a diminished Th2 immune response caused by PD-1 deletion.

The study explored the therapeutic effect and mechanism of the compound composed of tangerine peel,plum,agrimony and hawthorn on Eimeria tenella in chicks.In the experiment,144 chicks were divided into six groups:the blank group,the model group,the diclazuril group,and the high-dose,medium-dose and low-dose traditional Chinese medicine compound groups.The 14-day-old chickens were infected,the body weight and mortality were recorded,and the samples were dis-sected at 21 days of age.The anticoccidial effect of Chenpi compound at different doses was evalua-ted by calculating anticoccidial index,feed conversion rate and detecting serum cytokine levels and related mRNA expression levels.The results showed that the anticoccidial index of the middle dose group was 172.86,and the anticoccidial index of the low dose group was 158.98.In the middle and low dose groups,the levels of IL-1β,IL-6 and MDA in serum decreased significantly,while the levels of IL-4,IL10,T-AOC,SOD,CAT and GSH-Px increased significantly,and the mRNA ex-pression levels of related inflammation and antioxidant pathways changed.Further studies found that the medium-dose compound can regulate the ChTLR15/ChMyD88/ChNF-κB/ChNLRP3/Caspase-1 inflammatory signaling pathway,activate the Nrf2/Keap1/HO-1 antioxidant signaling pathway,and enhance the body's anti-inflammatory and antioxidant capacity;at the same time,it can increase the expression of intestinal tight junction ZO-1 and Occludin,repair the damaged in-testinal barrier,and play an anticoccidial role.The results showed that the middle dose of tangerine peel compound had a good effect in the treatment of coccidiosis,and its mechanism involved the regulation of anti-inflammatory and antioxidant pathways.

Aim To investigate the changes in hepatic lactylation during liver regeneration and its impact on regeneration.Methods A partial hepatectomy(PHx)mouse model was used to study liver regenera-tion.Sodium oxamate was administered intraperitoneal-ly to inhibit lactate dehydrogenase,and blood and liver tissues were collected at different time points post-sur-gery.The histopathological status was observed using HE staining.Proliferating cell nuclear antigen(PC-NA)levels were detected by immunohistochemistry.Lactylation was assessed using immunofluorescence.Liver LDH enzyme activity,lactate levels and serum alanine aminotransferase(ALT)and aspartate trans-aminase(AST)levels were measured using assay kits.Results After PHx,the liver volume of mice gradual-ly increased,returning to preoperative size on day 7.PCNA levels peaked at 48 hours post-surgery.Liver tissue lactate levels increased to approximately 1.5 times the preoperative level at 12 hours post-surgery and remained elevated until day 7.The lactylation lev-el in hepatocytes peaked at 24 hours post-surgery,gradually declined after 48 hours,and returned to pre-operative levels on day 7.Compared to the PHx group,the sodium oxamate(750 mg·kg-1)+PHx group showed significantly reduced lactylation levels in hepa-tocytes and a smaller liver regeneration volume on day 7.Conclusion Lactylation regulates hepatocyte pro-liferation and promotes liver regeneration after PHx.

PURPOSE: To investigate the protective effect of sub-hypothermic mechanical perfusion combined with membrane lung oxygenation on ischemic hypoxic injury of yorkshire brain tissue caused by traumatic blood loss. METHODS: This article performed a random controlled trial. Brain tissue of 7 yorkshire was selected and divided into the sub-low temperature anterograde machine perfusion group (n = 4) and the blank control group (n = 3) using the random number table method. A yorkshire model of brain tissue injury induced by traumatic blood loss was established. Firstly, the perfusion temperature and blood oxygen saturation were monitored in real-time during the perfusion process. The number of red blood cells, hemoglobin content, NA⁺, K⁺, and Ca²⁺ ions concentrations and pH of the perfusate were detected. Following perfusion, we specifically examined the parietal lobe to assess its water content. The prefrontal cortex and hippocampus were then dissected for histological evaluation, allowing us to investigate potential regional differences in tissue injury. The blank control group was sampled directly before perfusion. All statistical analyses and graphs were performed using GraphPad Prism 8.0 Student t-test. All tests were two-sided, and p value of less than 0.05 was considered to indicate statistical significance. RESULTS: The contents of red blood cells and hemoglobin during perfusion were maintained at normal levels but more red blood cells were destroyed 3 h after the perfusion. The blood oxygen saturation of the perfusion group was maintained at 95% - 98%. NA⁺ and K⁺ concentrations were normal most of the time during perfusion but increased significantly at about 4 h. The Ca²⁺ concentration remained within the normal range at each period. Glucose levels were slightly higher than the baseline level. The pH of the perfusion solution was slightly lower at the beginning of perfusion, and then gradually increased to the normal level. The water content of brain tissue in the sub-low and docile perfusion group was 78.95% ± 0.39%, which was significantly higher than that in the control group (75.27% ± 0.55%, t = 10.49, p < 0.001), and the difference was statistically significant. Compared with the blank control group, the structure and morphology of pyramidal neurons in the prefrontal cortex and CA1 region of the hippocampal gyrus were similar, and their integrity was better. The structural integrity of granulosa neurons was destroyed and cell edema increased in the perfusion group compared with the blank control group. Immunofluorescence staining for glail fibrillary acidic protein and Iba1, markers of glial cells, revealed well-preserved cell structures in the perfusion group. While there were indications of abnormal cellular activity, the analysis showed no significant difference in axon thickness or integrity compared to the 1-h blank control group. CONCLUSIONS Mild hypothermic machine perfusion can improve ischemia and hypoxia injury of yorkshire brain tissue caused by traumatic blood loss and delay the necrosis and apoptosis of yorkshire brain tissue by continuous oxygen supply, maintaining ion homeostasis and reducing tissue metabolism level.
Animals ; Perfusion/methods* ; Disease Models, Animal ; Brain Injuries/etiology* ; Swine ; Male ; Hypothermia, Induced/methods*

OBJECTIVE: To investigate the safety and efficacy of avatrombopag（AVA） combined with rhIL-11 in treating thrombocytopenia induced by chemotherapy in acute myeloid leukemia. METHODS: The clinical information of 8 patients in the real world who received avatrombopag combined with rhIL-11 in cancer treatment-induced thrombocytopenia(CTIT) after AML chemotherapy were retrospectively analyzed, and at the same time, 8 patients who received rhIL-11 only in CTIT after AML chemotherapy served as the control group, A preliminary observation was to summarize and compare the therapeutic efficacy and adverse effects between the two groups. RESULTS: D3 and D7 platelet counts were not significantly different between the observation group and the control group after treatment. The platelet counts in the observation group was significantly higher than those of the control group on the 10th day after treatment (P < 0.01). The adverse reactions, such as weakness, abdominal pain, fatigue, nausea and edema after treatment were mild in the observation group and the control group. Except for one patient in the observation group who had a history of cerebral infarction before the onset of the disease and was routinely taking antiplatelet drugs, no thrombosis events occurred in the patients in the observation and control groups during the period of administration of the drug, and the total incidence rate of adverse reactions was not significantly different between the two groups. CONCLUSION The combination of AVA and rhIL-11 can enhance platelet recovery in CTIT of AML patients after chemotherapy. Compared with the rhIL-11 alone group, the platelet recovery time in AVA+rhIL-11 group was significantly shorter, the platelet count on the 10th day after drug administration was significantly higher. No statistically significant difference in the total incidence rate of adverse reactions was observed between rhIL-11 alone group and AVA+rhIL-11 group.
Humans ; Leukemia, Myeloid, Acute/drug therapy* ; Thrombocytopenia/chemically induced* ; Interleukin-11/therapeutic use* ; Retrospective Studies ; Adult ; Thiophenes/therapeutic use* ; Platelet Count ; Female ; Male ; Middle Aged ; Thiazoles

Ultrasound technology has been applied in the biomedical field,particularly in drug delivery and cell processing.In this study,the effects of different ultrasound power levels(40 W to 100 W)and time durations(1 min,5 min,or 5 min discontinuously)on the morphology of human red blood cells(hRBCs)membranes were systematically investigated using cryo-electron tomography(Cryo-ET).The hRBCs membranes were firstly subjected to ultrasound at power levels of 40 W and 60 W for 5 min each.Cryo-ET observations revealed minimal morphological changes in the hRBCs membranes following the 40 W treatment,with the membrane structure remaining relatively intact and only minor undulations appearing on the membrane surface.These undulations might result from the mild mechanical stress induced by ultrasound,which was insufficient to disrupt the overall membrane structure.At power of 60 W,the hRBCs membranes largely preserved their structural integrity.When the ultrasonic power was increased to 80 W,the structural damage to the hRBCs membranes became more severe.Cryo-ET images showed irregular ruptures and larger pores on the membrane surface,indicating a significant compromise in membrane integrity.At ultrasound power of 100 W,the hRBCs membranes were completely disrupted,resulting in the formation of numerous membrane fragments,and a complete loss of membrane continuity.To further explore the effects of ultrasound duration on erythrocyte membrane morphology,the ultrasonic power was fixed at 100 W and the impacts of varying treatment durations(1 min,5 min,and intermittent ultrasound)on the membrane structure were systematically investigated.After 1 min of ultrasonic treatment,Cryo-ET images showed minimal changes in erythrocyte membrane morphology.Although some small pores and undulations appeared on the membrane surface,the overall structure remained relatively intact.As the ultrasound duration extended to 5 min,the degree of membrane damage increased significantly.Cryo-ET images revealed extensive rupture and detachment of the membrane,with continuity being severely compromised.As to treatment alternating 1 min of ultrasound with 1 min of rest,for a total of 5 min of ultrasound exposure,Cryo-ET observations showed the integrity of the membrane-cytoskeleton attachment remained.Under intermittent ultrasound treatment,although some pores and ruptures were observed on the membrane surface,the overall structure remained more intact compared to continuous ultrasonic treatment.This preservation might be due to the intermittent treatment providing buffer periods for the membrane,allowing partial recovery after mechanical stress,thereby reducing the cumulative damage caused by continuous ultrasound.This work provided experimental basis for further understanding of mechanism of ultrasound induced change of cell membrane and cytoskeleton.

Poly(lactic-co-glycolide)(PLGA)is a key excipient in long-acting sustained-release preparations,and its degradation properties directly affect the drug release behavior.In this study,PLGA microspheres were prepared by microfluidic techniques,and the morphology changes of the microspheres were observed by scanning electron microscopy(SEM).In alkaline environment,due to the accelerated hydrolysis of ester bonds,the surface of the microspheres was rapidly dissolved and eroded,and the degradation rate was significantly higher than that in acidic environment.High temperature accelerated the degradation of PLGA microspheres.Under neutral and alkaline conditions,the microspheres showed aggregation and adhesion.Under acidic conditions,the microspheres gradually decomposed into irregular fragments.The high ionic strength further promoted the surface corrosion of the microspheres,especially under extreme pH conditions.Simultaneously,PLGA microspheres encapsulating coumarin were prepared to simulate the microsphere formulation.The release rate of coumarin after degradation of the microspheres under different conditions was observed by measuring the absorbance with ultraviolet-visible spectrophotometry.The results were consistent with those of the blank microspheres.This study revealed that the degradation of PLGA microspheres was significantly pH-dependent,temperature sensitive and ion strength responsive.These findings not only helped to understand and optimize the long-term stability and controlled release performance of drug-carrying microspheres,but also provided a theoretical basis for further improvement of PLGA-based drug carrier design.

Objective: To establish a machine learning-based precision blood donor recruitment model at the county level and assess its generalizability and applicability. Methods: A retrospective study was conducted using blood donation and SMS recruitment data from the Taicang Branch of the Suzhou Blood Center between 2019 and 2024. Multiple machine learning algorithms were employed, including extreme gradient boosting, support vector machine, k-nearest neighbor, logistic regression, decision tree, random forest, and multilayer perceptron. These were combined with techniques such as synthetic minority oversampling, undersampling, and cost-sensitive learning (using MFE and MSFE loss functions). Model parameters were optimized through grid search to identify the best-performing model. Results: In a prospective comparative study against conventional methods, the machine learning models increased the recruitment success rate among high-willingness donors by an average of 129.15%, and the recruitment efficiency per SMS improved by 125.02% compared with the traditional method. Under full-scale SMS sending, the recruitment rate per SMS increased by 42.61%, and SMS sending efficiency improved by 31.77%, significantly enhancing recruitment performance. Conclusion: This study represents the first application of a machine learning-based precision donor recruitment model at the county-level in China. The precise recruitment framework not only improves recruitment efficiency and reduces recruitment costs but also demonstrates strong scalability and generalizability. It provides a scientific and feasible intelligent pathway to ensure the safety and sustainability of the blood supply.

Aim To investigate the changes in hepatic lactylation during liver regeneration and its impact on regeneration.Methods A partial hepatectomy(PHx)mouse model was used to study liver regenera-tion.Sodium oxamate was administered intraperitoneal-ly to inhibit lactate dehydrogenase,and blood and liver tissues were collected at different time points post-sur-gery.The histopathological status was observed using HE staining.Proliferating cell nuclear antigen(PC-NA)levels were detected by immunohistochemistry.Lactylation was assessed using immunofluorescence.Liver LDH enzyme activity,lactate levels and serum alanine aminotransferase(ALT)and aspartate trans-aminase(AST)levels were measured using assay kits.Results After PHx,the liver volume of mice gradual-ly increased,returning to preoperative size on day 7.PCNA levels peaked at 48 hours post-surgery.Liver tissue lactate levels increased to approximately 1.5 times the preoperative level at 12 hours post-surgery and remained elevated until day 7.The lactylation lev-el in hepatocytes peaked at 24 hours post-surgery,gradually declined after 48 hours,and returned to pre-operative levels on day 7.Compared to the PHx group,the sodium oxamate(750 mg·kg-1)+PHx group showed significantly reduced lactylation levels in hepa-tocytes and a smaller liver regeneration volume on day 7.Conclusion Lactylation regulates hepatocyte pro-liferation and promotes liver regeneration after PHx.