Distinct from the complementary inhibition mechanism through binding to the target with three-dimensional conformation of small molecule inhibitors, targeted protein degradation technology takes tremendous advantage of endogenous protein degradation pathway inside cells to degrade plenty of “undruggable” target proteins, which provides a novel route for the treatment of many serious diseases, mainly including proteolysis-targeting chimeras, lysosome-targeting chimeras, autophagy-targeting chimeras, antibody-based proteolysis-targeting chimeras, etc. Unlike proteolysis-targeting chimeras first found in 2001, which rely on ubiquitin-proteasome system to mainly degrade intracellular proteins of interest, lysosome-targeting chimeras identified in 2020, which was act as the fastly developing technology, utilize cellular lysosomal pathway through endocytosis mediated by lysosome-targeting receptor to degrade both extracellular and membrane proteins. As an emerging biomedical technology, nucleic acid-driven lysosome-targeting chimeras utilize nucleic acids as certain components of chimera molecule to replace with ligand to lysosome-targeting receptor or protein of interest, exhibiting broad application prospects and potential clinical value in disease treatment and drug development. This review mainly introduced present progress of nucleic acid-driven lysosome-targeting chimeras technology, including its basic composition, its advantages compared with antibody or glycopeptide-based lysosome-targeting chimeras, and focused on its chief application, in terms of the type of lysosome-targeting receptors. Most research about the development of nucleic acid-driven lysosome-targeting chimeras focused on those which utilized cation-independent mannose-6-phosphonate receptor as the lysosome-targeting receptor. Both mannose-6-phosphonate-modified glycopeptide and nucleic aptamer targeting cation-independent mannose-6-phosphonate receptor, even double-stranded DNA molecule moiety can be taken advantage as the ligand to lysosome-targeting receptor. The same as classical lysosome-targeting chimeras, asialoglycoprotein receptor can also be used for advance of nucleic acid-driven lysosome-targeting chimeras. Another new-found lysosome-targeting receptor, scavenger receptor, can bind dendritic DNA molecules to mediate cellular internalization of complex and lysosomal degradation of target protein, suggesting the successful application of scavenger receptor-mediated nucleic acid-driven lysosome-targeting chimeras. In addition, this review briefly overviewed the history of lysosome-targeting chimeras, including first-generation and second-generation lysosome-targeting chimeras through cation-independent mannose-6-phosphonate receptor-mediated and asialoglycoprotein receptor-mediated endocytosis respectively, so that a clear timeline can be presented for the advance of chimera technique. Meantime, current deficiency and challenge of lysosome-targeting chimeras was also mentioned to give some direction for deep progress of lysosome-targeting chimeras. Finally, according to faulty lysosomal degradation efficiency, more cellular mechanism where lysosome-targeting chimeras perform degradation of protein of interest need to be deeply explored. In view of current progress and direction of nucleic acid-driven lysosome-targeting chimeras, we discussed its current challenges and development direction in the future. Stability of natural nucleic acid molecule and optimized chimera construction have a great influence on the biological function of lysosome-targeting chimeras. Discovery of novel lysosome-targeting receptors and nucleic aptamer with higher affinity to the target will greatly facilitate profound advance of chimera technique. In summary, nucleic acid-driven lysosome-targeting chimeras have many superiorities, such as lower immunogenicity, expedient synthesis of chimera molecules and so on, in contrast to classical lysosome-targeting chimeras, making it more valuable. Also, the chimera technology provides new ideas and methods for biomedical research, drug development and clinical treatment, and can be used more widely through further research and optimization.

BACKGROUND:Transcranial magneto-acoustic-electrical stimulation is a novel non-invasive neural regulation technique that utilizes the induced electric field generated by the coupling effect of ultrasound and static magnetic field to regulate the discharge activity of the nervous system.However,the mechanism by which it affects synaptic plasticity in the brain is still not enough. OBJECTIVE:To explore the effect of transcranial magneto-acoustic-electrical stimulation intensity on synaptic plasticity of the prefrontal cortex neural network in mice. METHODS:(1)Animal experiment:Twenty-four C57 mice were equally and randomly divided into four groups:the control group receiving pseudo-stimulation,the 6.35 W/cm2 stimulation group receiving coupled stimulation of 0.3 T,6.35 W/cm2,the 17.36 W/cm2 stimulation group receiving coupled stimulation of 0.3 T,17.36 W/cm2,and the 56.25 W/cm2 stimulation group receiving coupled stimulation of 0.3 T,56.25 W/cm2.The local field potential signals and behavioral correctness were recorded during the execution of T-maze in mice.(2)Modeling and simulation experiments:A neural network model of the prefrontal cortex in mice stimulated by transcranial magneto-acoustic-electrical stimulation was constructed to compare the structural connectivity characteristics of the neural network under different stimulation intensities. RESULTS AND CONCLUSION:Transcranial magneto-acoustic-electrical stimulation could effectively shorten the behavior learning time,improve the working memory ability of mice(P＜0.05),and continue to stimulate the frontal lobe of mice after learning behavior.There was no significant difference in the accuracy of the T-maze behavioral experiment among the experimental groups(P＞0.1).Analysis of local field potential signals in the frontal lobe of mice revealed that transcranial magneto-acoustic-electrical stimulation promoted energy enhancement of β and γ rhythms.As the stimulation intensity increased,there was an asynchronous decrease in β and γ rhythms.Through β-γ phase amplitude coupling,it was found that stimuli could enhance the neural network's ability to adapt to new information and task requirements.Modeling and simulation experiments found that stimulation could enhance the discharge level of the neural network,increase the long-term synaptic weight level,and decrease the short-term synaptic weight level only when the stimulation intensity was high.To conclude,there is a complex nonlinear relationship between different stimulus intensities and the functional structure of neural networks.This neural regulation technique may provide new possibilities for the treatment of related neurological diseases such as synaptic dysfunction and neural network abnormalities.

Small interfering RNA (siRNA) has a promising future in the treatment of ocular diseases due to its high efficiency, specificity, and low toxicity in inhibiting the expression of target genes and proteins. However, due to the unique anatomical structure of the eye and various barriers, delivering nucleic acids to the retina remains a significant challenge. In this study, we rationally design PACD, an A-B-C type non-viral vector copolymer composed of a hydrophilic PEG block (A), a siRNA binding block (B) and a pH-responsive block (C). PACDs can self-assemble into nanosized polymeric micelles that compact siRNAs into polyplexes through simple mixing. By evaluating its pH-responsive activity, gene silencing efficiency in retinal cells, intraocular distribution, and anti-angiogenesis therapy in a mouse model of hypoxia-induced angiogenesis, we demonstrate the efficiency and safety of PACD in delivering siRNA in the retina. We are surprised to discover that, the PACD/siRNA polyplexes exhibit remarkable intracellular endosomal escape efficiency, excellent gene silencing, and inhibit retinal angiogenesis. Our study provides design guidance for developing efficient nonviral ocular nucleic acid delivery systems.

Objective To report a case of synovial sarcoma of the liver and review the literature for improving the understanding of the disease.Methods The clinical data of a patient with liver synovial sarcoma admitted to the First Affiliated Hospital of Henan University were analyzed retrospectively.The imaging,pathological features,treatment and prognosis of this disease were summarized by searching the database(CNKI,Wanfang Data,PubMed,untill July 2022)and the literature results analyzed comprehensively.Results The patient was a 71-year-old female who was admitted to the hospital due to abdominal pain.Computed tomography(CT)scan showed a mass with mixed density in the right lobe and caudate lobe of the liver.The large cross section size was about 115 mm×87 mm and the mass showed continuous heterogeneous enhancement,being considered as malignant hepatic tumors with multiple metastasis of the liver and lung.Ultrasound-guided needle biopsy was performed,and microscopy showed the tumor cells were obvious atypical,and some were spindle-shaped.Immunohistochemistry showed that the patient was positive for vimentin(VIM),epithelial membrane antigen(EMA),methylation of histone at lysine 27(H3K27Me3),and negative for pan cytokeratin(CK-pan)and S-100,and pathological diagnosis of synovial sarcoma was made.The patient did not undergo subsequent treatment and was lost to follow-up after discharge.A total of 12 cases of hepatic synovial sarcoma were reported after searching the database.The clinical manifestations were abdominal pain or distention.The lesions were mostly located in the right lobe of the liver,usually large,heterogeneous density,and heterogeneous enhancement on enhanced CT or magnetic resonance imaging(MRI).Spindle-shaped cells were found at histopathologic examination.Immunohistochemistry showed the patient was positive for VIM,EMA,H3K27Me,B-cell leukemia/lymphoma-2(BCL-2)and transducer-like enhancer of split 1(TLE1).SS18-SSX fusion gene or SS18 gene isolation were detected.Eleven patients received surgical treatment,5 received adjuvant chemotherapy,and 4 had recurrence or metastasis during the follow-up period.Conclusions Synovial sarcoma of the liver is a rare malignant tumor of the liver.The clinical and imaging features are not specific.The diagnosis depends on pathology.At present,the main treatment is surgery,and comprehensive treatment such as adjuvant chemotherapy can be performed.The prognosis of the patient is poor.

Refeeding syndrome(RFS)has a high incidence among critically ill patients and significantly impacts the re-covery and prognosis of the patients.In this paper,we reviewed the literature on the risk factors and risk prediction models for RFS,finding the risk factors of RFS included patient-related,treatment-related factors and disease-related factors and the risk prediction models encompassed risk stratification model,risk score models and the Logistic regression models.It was concluded from the review that early assessment was crucial to preventing the occurrence of RFS.However,there was still a lack of reliable RFS risk prediction models with good predictive performance.It was found as well that it was crucial for the prevention of RFS to attach importance to nutritional and serological indicators and other factors.It was expected to be a necessity to conduct prospec-tive and multicenter studies to develop a risk prediction model for predicting RFS for ICU patients.Our review provides a refer-ence for early assessment and intervention for critically ill patients with RFS.

Objective To evaluate the efficacy of vitamin C intravenous injection in the treatment of patients with sepsis.Methods PubMed,Embase,Scopus,Cochrane Library,and Clinical Trial databases were retrieved,with a retrieval period from database establishment to December 2022.English literatures on randomized controlled trial(RCT)of vitamin C intravenous injection for the treatment of sepsis or septic shock were collected.Meta-analysis was conducted using RevMan 5.3 software and Stata 15.0 software after literature screening,extraction,and evalua-tion of the bias risk included in the studies by two researchers independently.Results A total of 16 RCT studies involving 3 301 patients were included in the analysis.In terms of main outcomes,the 28-day mortality of patients in the vitamin C treatment group was slightly lower than that of the control group,but the difference was not statis-tically significant(RR=0.86,95％CI[0.72-1.03],P=0.10;I2=44％,P=0.10).In terms of secondary out-comes,vitamin C intravenous injection can reduce the duration of vasoactive drug usage time(MD=-23.44,95％CI[-30.53--16.35],P＜0.01;I2=0,P=0.97),but has no significant effect on the 90-day mortality,inten-sive care unit mortality,hospital mortality,duration of mechanical ventilation,difference in estimated sequential organ failure assessment score at 72 hour,length of stay in ICU,and total length of hospital stay of patients(P＞0.05).Conclusion Intravenous vitamin C injection can significantly reduce vasoactive drug usage time,but the available evidence is insufficient to support that intravenous vitamin C can improve the prognosis of patients with sepsis or septic shock.More high-quality,multicenter randomized controlled trial is needed to provide more substantial evidence about the efficacy of vitamin C in treating sepsis or septic shock.

Objective To explore the effect of virtual reality treadmill training on balance and gait in stroke patients. Methods From March,2022,to March,2023,40 stroke patients in Beijing Tiantan Hospital,Capital Medical University were randomly divided into control group(n = 20)and experimental group(n = 20).Both groups received rou-tine rehabilitation training.The control group received ordinary treadmill walking training,and the experimental group received treadmill walking training with virtual reality,for two weeks.They were assessed with Berg Bal-ance Scale(BBS)and Timed Up and Go Test(TUGT),and the envelope ellipse area,center of pressure(COP)av-erage speed of movement,step length,stride length and stride width were compared between two groups before and after treatment. Results After treatment,the scores of BBS and time of TUGT improved in both groups(|t|>3.508,P<0.01),and they were better in the experimental group than in the control group(|t|>3.019,P<0.01);there was no significant dif-ference in the envelope ellipse area,COP average speed,and stride width between two groups(P>0.05);howev-er,the step length and stride width improved in the experimental group(|t|>4.008,P<0.01). Conclusion Treadmill training with virtual reality can improve the balance and walking ability of stroke patients.

Trichinosis is a global food-borne zoonotic parasitic disease caused by Trichinella spiralis(T.spiralis),which causes serious harm to animal production,and the public health safety of humans and animals.T.spiralis has a complex devel-opment history,and its entire life cycle is completed in the same host.To coexist with the host,it has evolved various immune escape mechanisms for avoiding immune clearance by the host,thus establishing long-term chronic infection.In this study,to aid in understanding the pathogenic mechanism of T.spiralis,the immune escape mechanism of Trichinella is discussed from three aspects:the molecular role of antigens in various stages,the immune regulatory effect on the host,and the formation of cysts to generate immune isolation.

Objective:To investigate the correlation between the expression of GLI1 and im-mune invasion and clinical prognosis in gastric cancer.To study the effect of GLI1 expression on drug resistance in gastric cancer.Methods:The expression difference of GLI1 in gastric cancer and normal tissues was analyzed by using TCGA database,and the effect of clinical features and GLI1 gene ex-pression level on prognosis of patients with gastric cancer was analyzed.The correlation between GLI1 gene expression and tumor immune cell infiltration in gastric cancer tissues was analyzed to explore its influence on drug resistance of chemotherapy drugs and targeted drugs.Clinical samples were collect-ed to analyze the difference of GLI1 expression in gastric cancer and paracancer tissues.Results:The expression of GLI1 in gastric cancer tissues was 1.7 times that in normal tissues,and the overall sur-vival and disease-free survival of patients with high expression are shorter than those with low ex-pression(P＜0.05).The interstitial score,immune score and abundance of immunoinfiltrating cells were higher in the high expression of GLI1 in gastric cancer tissues.High expression of GLI1 reduces drug sensitivity and is positively correlated with the expression of immune checkpoint markers PDCD1(P＜0.05).GLI1 expression was significantly increased in patients with subdifferentiated gastric cancer.Conclusions:GLI1 expression is associated with the prognosis and immune infiltration of patients with gastric cancer,and it may lead to poor prognosis of patients by regulating chemotherapy resis-tance,which may be a potential therapeutic target and molecular marker for gastric cancer.

Objective To investigate the predictive values of interleukin(IL)-6 and IL-10 in the peripheral blood of donors of brain death for delayed graft function(DGF)in kidney transplant recipients.Methods The clinical data and blood samples of 21 donors of brain death and 42 kidney transplant recipients were retrospectively collected.The predictive values of IL-6 and IL-10 in the peripheral blood of donors for DGF were evaluated using the occurrence of DGF as a dependent variable.Results Among the 42 kidney transplant recipients,10 developed DGF.Univariate analysis showed that there were significant differences in the IL-6 and creatinine levels in the donors and cold ischemia time of donor kidney between DGF and non-DGF groups.The receiver operating characteristic curve showed that IL-6 and IL-10 in donor peripheral blood had certain predictive values for DGF in kidney transplant recipients(AUC=0.82,95%CI:0.64-0.99;AUC=0.73,95%CI:0.51-0.95).Despite adjusting for creatinine level and cold ischemia time,IL-6 still has a certain predictive value for DGF.Conclusion IL-6 in the peripheral blood of donors of brain death may be a predictor of DGF in kidney transplant recipients.