Coagulation factor XIa (FXIa) plays a crucial role in thrombus formation; therefore, the development of potent and safe FXIa inhibitors is of great significance. In this study, compound F22, previously discovered by our group, was selected as the lead compound. Based on the principles of bioisosterism and fragment-based drug design, four series comprising 14 novel Asundexian derivatives not previously reported in the literature were designed and synthesized. The structures of the target compounds were confirmed by 1H NMR and HRMS, and their inhibitory activities against FXIa were evaluated using chromogenic substrate assay. Results showed that compound FD-1 exhibited the most potent activity, with an IC50 value of 2.8 nmol/L, which was superior to that of the lead compound F22 (IC50 = 4.5 nmol/L) and the reference drug Asundexian (IC50 = 5.0 nmol/L). Furthermore, in the activated partial thromboplastin time (aPTT) assay, compound FD-1 demonstrated excellent anticoagulant activity, outperforming Asundexian, showing no significant effect on prothrombin time (PT). These findings provide valuable insights for further structural optimization and rational design of small-molecule FXIa inhibitors.

Objective:To investigate the effect of continuous renal replacement therapy (CRRT) on energy metabolism and thermal balance in ICU patients with acute kidney injury (AKI).Methods:This study was a prospective observational study, which included AKI patients who underwent CRRT in ICU of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine from May 2020 to December 2023. The patients' general clinical characteristics, comorbidities, body temperature, disease severity score, CRRT treatment time and filter lifespan were recorded. The concentrations of glucose and lactate in blood and ultrafiltrate, and the citrate level in the ultrafiltrate when regional citrate anticoagulation adopted were analyzed regularly. Subgroup analysis was carried out according to different anticoagulation modes and whether the patients with diabetes or shock. The changes of energy metabolism and thermal balance corresponding to the changes in glucose, lactate, citrate and body temperature induced by CRRT were calculated daily.Results:This study included 420 AKI patients undergoing CRRT. When the blood lactate was between 14-18 mmol/L, there was a loss of approximately 200-250 kcal of energy per day, while the blood lactate was between 6.5-11.5 mmol/L, the daily corresponding energy loss was about 100-150 kcal. During CRRT on the first day, the patients with diabetes or shock had a mild decrease of blood glucose, while patients without diabetes and shock had mild increase of blood glucose. When the target of blood glucose was gradually achieved, the mean daily increase of energy corresponding to blood glucose intake was about 100-130 kcal in patients undergoing CRRT. The mean daily increase of energy corresponding to citrate intake was approximately 330 kcal, when the patient was undertaken by CRRT with regional citrate anticoagulation. For every 1℃ decrease in body temperature, the mean daily heat loss caused by extracorporeal thermal radiation during CRRT was about 200 kcal.Conclusions:When conducting nutritional assessment and prescription for AKI patients supported by CRRT in the ICU, it is essential to fully consider the impact of CRRT on the patient's energy metabolism and heat balance. This includes the clearance of lactate, the balance of blood glucose, the intake of citrate, and the reduction in body temperature. Additionally, the type and stage of the disease, as well as individual differences, must be taken into account to achieve personalized nutritional assessment and precise implementation.

In the past decades, significant progress has been achived in cartilage regeneration. The traditional techniques for constructing tissue engineering cartilage scaffold mainly include pore agent method (or template method), phase separation method, gas foaming method, freeze-drying method, electrospinning method, etc. Cartilage is heterogeneous, and it is difficult for traditional scaffolds to simulate the high anisotropy of cartilage. Therefore, functional regeneration of cartilage is challenging. With the progress of three-dimensional(3D) printing technology, it is possible to prepare functional bionic scaffolds with fine structure and gradient changes through co-deposition of biomaterials, cells and active biomolecules, so as to achieve functional cartilage regeneration. This article reviewed 3D printing technology of cartilage tissue engineering, and the application of 3D printing technology in cartilage regeneration at different anatomical positions (articular cartilage, auricle cartilage, nasal cartilage). In addition, the importance of preparing bionic constructs with regional structure gradient and regional composition gradient was discussed. 3D bioprinting technology, 4D printing techniques, smart biomaterials brought hope for the construction of bionic tissues and organs.

In the past decades, significant progress has been achived in cartilage regeneration. The traditional techniques for constructing tissue engineering cartilage scaffold mainly include pore agent method (or template method), phase separation method, gas foaming method, freeze-drying method, electrospinning method, etc. Cartilage is heterogeneous, and it is difficult for traditional scaffolds to simulate the high anisotropy of cartilage. Therefore, functional regeneration of cartilage is challenging. With the progress of three-dimensional(3D) printing technology, it is possible to prepare functional bionic scaffolds with fine structure and gradient changes through co-deposition of biomaterials, cells and active biomolecules, so as to achieve functional cartilage regeneration. This article reviewed 3D printing technology of cartilage tissue engineering, and the application of 3D printing technology in cartilage regeneration at different anatomical positions (articular cartilage, auricle cartilage, nasal cartilage). In addition, the importance of preparing bionic constructs with regional structure gradient and regional composition gradient was discussed. 3D bioprinting technology, 4D printing techniques, smart biomaterials brought hope for the construction of bionic tissues and organs.

Objective:To investigate the effect of N-acetylserotonin (NAS) on the retinal microglia polarization in retinal ischemia-reperfusion injury (RIRI) rats and explore its mechanism via nucleotide-bound oligomeric domain 1 (NOD1)/receptor interacting protein 2 (Rip2) pathway.Methods:Healthy male Sprague Dawley rats were randomly divided into Sham ( n=21), RIRI ( n=21) and NAS (injected intraperitoneally 30 min before and after modeling with NAS, 10 mg/kg, n=18) groups, using random number table. And the right eye was used experimental eye. The RIRI model of rats in RIRI group and NAS group was established by anterior chamber high intraocular pressure method. Rats in NAS group were intraperitoneally injected with 10 mg/kg NAS before and 30 min after modeling, respectively. The retinal morphology and the number of retinal ganglion cell (RGC) in each group were detected by hematoxylin-eosin staining and immunohistochemical staining. The effect of NAS on polarization of retinal microglia was detected by immunofluorescence staining. Transcriptome sequencing technology was used to screen out the differentially expressed genes between Sham and RIRI groups. Western blot and real-time quantitative polymerase chain reaction (RT-PCR) were used to examine the differentially expressed genes. Immunohistochemical staining, Western blot and RT-PCR were used to investigate the effect of NAS on the expression of NOD1 and Rip2 protein and mRNA in retinal tissue and microglia of rats. General linear regression analysis was performed to determine the correlation between the number difference of NOD1 + cells and the number difference of M1 and M2 microglia in retinal tissues of rats in NAS group and RIRI group. Results:A large number of RGC were observed in the retina of rats in Sham group. 24 h after modeling, compared with Sham group, the inner retinal thickness of rats in RIRI group was significantly increased and the number of RGC was significantly decreased. The thickness of inner retina in NAS group was significantly thinner and the number of RGC was significantly increased. Compared with Sham group, the number of retinal microglia of M1 and M2 in RIRI group was significantly increased. Compared with RIRI group, the number of M1 microglia decreased significantly and the number of M2 microglia increased significantly in NAS group. There was statistical significance in the number of M1 and M2 microglia in the retina of the three groups ( P<0.05). Transcriptome sequencing results showed that retinal NOD1 and Rip2 were important differential genes 24 h after modeling. The mRNA and protein relative expressions of NOD1 and Rip2 in retina of RIRI group were significantly higher than those of Sham group, with statistical significance ( P<0.05). The number of NOD1 + and Rip2 + cells and the relative expression of mRNA and protein in retinal microglia in RIRI group were significantly higher than those in Sham group, and NAS group was also significantly higher than that in Sham group, but lower than that in RIRI group, with statistical significance ( P<0.05). The number of Iba-1 +/NOD1 + and Iba-1 +/Rip2 + cells in retinal microglia in RIRI group was significantly increased compared with that in Sham group, and the number of Iba-1 +/Rip2 + cells in NAS group was significantly decreased compared with that in RIRI group, but still significantly higher than that in Sham group, with statistical significance ( P<0.05). Correlation analysis results showed that the difference of retinal NOD1 + and Rip2 + cells in NAS group and RIRI group was positively correlated with that of M1 microglia ( r=0.851, 0.895), and negatively correlated with that of M2 microglia ( r=-0.797, -0.819). The differences were statistically significant ( P<0.05). Conclusion:NAS can regulate the microglial polarization from M1 to M2 phenotype, the mechanism is correlated with the NOD1/Rip2 pathway.

Immunoparalysis is the main cause of death in patients with intermediate and terminal sepsis. The correction of immunoparalysis is an important direction of sepsis treatment. In the pathological process of sepsis, a variety of factors contribute to the imbalanced secretion of cytokines, weakened function of antigen-presenting cells, apoptosis and depletion of lymphocytes, and ultimately lead to immunoparalysis, secondary infection, and even patient deaths. Cytokines such as GM-CSF, IFN-γ, IL-7, and IL-15, immune checkpoint-related therapies such as PD-1/PD-L1 antibodies, CTLA-4 antibodies, TIM-3 antibodies, and LAG-3 antibodies, and immunoreactive substances such as thymosin α1 and immunoglobulin might be beneficial to correct the immune paralysis of patients. the progress of immunotherapy to correct immune paralysis in sepsis were reviewed in this article.

Sepsis is life-threatening with complex pathogenesis. It is a big problem in the medical field. Clinically, antibiotics, hormones and mechanical ventilation are the main treatments. There is a lack of specific therapeutic drugs. The treatment effect is not good. In recent years, more and more progress has been made in the treatment of sepsis with traditional Chinese medicine. This article reviews the etiology, pathogenesis and treatment strategies of sepsis. It focuses on four therapies, including clearing away heat and detoxification, clearing the interior, activating blood circulation and removing blood stasis, and strengthening the foundation. We further discuss the advantages and disadvantages of traditional Chinese medicine in the treatment of sepsis, in order to provide reference for the clinical treatment of sepsis.

In the past decades, great progress has been made in cartilage regeneration. The traditional techniques for constructing tissue engineering cartilage scaffold mainly include pore agent method (or template method ) , phase separation method, gas foaming method, freeze-drying method , electrospinning method, etc. Cartilage is heterogeneous, and it is difficult for traditional scaffolds to simulate the high anisotropy of cartilage. Therefore, functional regeneration of cartilage is challenging. With the progress of three-dimensional (3D) printing technology, it is possible to prepare functional bionic scaffolds with fine structure and gradient changes through co deposition of biomaterials, cells and active biomolecules, so as to achieve functional cartilage regeneration. This article reviews 3D printing technology of cartilage tissue engineering, and the application of 3D printing technology in cartilage regeneration at different anatomical positions (articular cartilage, auricle cartilage, nasal cartilage) . In addition, the importance of preparing bionic constructs with regional structure gradient and regional composition gradient was discussed. 3D bioprinting technology, 4 D printing techniques, smart biomaterials brought hope for the construction of bionic tissues and organs.

In the past decades, great progress has been made in cartilage regeneration. The traditional techniques for constructing tissue engineering cartilage scaffold mainly include pore agent method (or template method ) , phase separation method, gas foaming method, freeze-drying method , electrospinning method, etc. Cartilage is heterogeneous, and it is difficult for traditional scaffolds to simulate the high anisotropy of cartilage. Therefore, functional regeneration of cartilage is challenging. With the progress of three-dimensional (3D) printing technology, it is possible to prepare functional bionic scaffolds with fine structure and gradient changes through co deposition of biomaterials, cells and active biomolecules, so as to achieve functional cartilage regeneration. This article reviews 3D printing technology of cartilage tissue engineering, and the application of 3D printing technology in cartilage regeneration at different anatomical positions (articular cartilage, auricle cartilage, nasal cartilage) . In addition, the importance of preparing bionic constructs with regional structure gradient and regional composition gradient was discussed. 3D bioprinting technology, 4 D printing techniques, smart biomaterials brought hope for the construction of bionic tissues and organs.

Objective:To investigate the efficacy of flexion-lateral curvature-supination reduction combined with primary anterior surgery for the treatment of lower cervical dislocation with unilateral facet inter-locking.Methods:A retrospective analysis was performed in the 32 patients who had been admitted to Department of Spine Surgery, Honghui Hospital for lower cervical dislocation with unilateral facet interlocking from November 2015 to October 2018. According to their treatments, they were divided into 2 groups. In the emergency group treated by flexion-lateral curvature-supination reduction combined with primary anterior surgery, there were 13 males and 3 females, aged from 24 to 63 years. In the traction group treated by cranial traction reduction combined with secondary anterior surgery, there were 12 males and 4 females, aged from 20 to 64 years. The operation time, intraoperative blood loss, hospital stay, bone graft fusion, American Spinal Injury Association (ASIA) grade and Japanese Orthopaedic Association (JOA) score were compared between the 2 groups.Results:There was no significant difference in the preoperative general data between the 2 groups, showing they were comparable ( P<0.05). All patients were followed up from 26 to 40 months. The hospital stay for the emergency group [(7.2±1.2) d] was significantly shorter than that for the traction group[(10.9±1.2) d] ( P<0.05). There was no significant difference in the operation time, blood loss, ASIA grade or JOA score between the 2 groups ( P>0.05). All patients achieved osseous fusion of intervertebral space. Conclusion:Compared with traditional methods, flexion-lateral curvature-supination reduction combined with primay anterior surgery shows no significant difference in the recovery of neurological function but leads to a shorter hospital stay.