Objective: To analyze the differences in bile acid profiles during different pregnancy durations of patients with intrahepatic cholestasis of pregnancy (ICP), so as to provide a reference for early prevention and treatment of ICP and optimization of maternal-infant health outcomes. Methods: Pregnant women who underwent routine prenatal examinations and delivered at Hangzhou Obstetrics and Gynecology Hospital from 2021 to 2023 were selected as study subjects. According to the ICP guidelines (2020), pregnant women were categorized into normal group, mild ICP group, and moderate/severe ICP group. Age, parity, and gravidity were collected through the obstetric electronic medical record system, liver function indicators and seven bile acid levels were collected through the hospital's laboratory information system. Differences in bile acid profiles across pregnancy durations among the three groups were compared. Results: A total of 238 pregnant women were enrolled, including 57 cases (23.95%) in the normal group, 136 cases (57.14%) in the mild ICP group, and 45 cases (18.91%) in the moderate/severe ICP group. There were statistically significant differences between the three groups in total bile acid (TBA), cholic acid (CA), chenodeoxycholic acid (CDCA), glycochenodeoxycholic acid (GCDCA), glycocholic acid (GCA), taurocholic acid (TCA) levels (all P<0.05). Compared with the normal group, CA, GCDCA and GCA, and TCA were higher in the mild and moderate/severe ICP groups; compared with the mild ICP group, GCA was higher in the moderate/severe ICP group (all P<0.05). Significant differences were observed in the levels of GCDCA, GCA, and TCA among three groups pregnant women in the early, mid, and late pregnancy (all P<0.05). Compared with the normal group, mild ICP group had higher GCDCA and GCA in the early and mid pregnancy; moderate/severe ICP group had higher TCA in the early pregnancy and higher GCDCA and GCA in the late pregnancy. Compared with the mild ICP group, mild ICP group had higher TCA in the early pregnancy and the moderate/severe ICP group had higher GCA in the late pregnancy. Conclusions GCDCA, GCA, and TCA levels remain higher in ICP patients than in normal pregnant women across all pregnancy durations. Personalized perinatal management plans can be developed based on bile acid profile dynamics to optimize maternal-fetal outcomes.

Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the Aβ-Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how Aβ mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric Aβ (o-Aβ) bound to microglial Kv2.1 and promoted Kv2.1-dependent potassium efflux to activate NLRP3 inflammasome resulting in neuronal tauopathy by using Kv2.1 inhibitor drofenine (Dfe) as a probe. The underlying mechanism has been intensively investigated by assays with Kv2.1 knockdown in vitro (si-Kv2.1) and in vivo (AAV-ePHP-si-Kv2.1). Dfe deprived o-Aβ of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-κB pathway while improving the cognitive impairment of 5×FAD-AD model mice. Our results have highly addressed that the Kv2.1 channel is required for o-Aβ-driven microglial NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Dfe as a Kv2.1 inhibitor shows potential in the treatment of AD.

Obesity usually exacerbates the immunosuppressive tumor microenvironment (ITME), hindering CD8⁺ T cell infiltration and function, which further represents a significant barrier to the efficacy of immunotherapy. Herein, a multifunctional liposomal system (CR-Lip) for encapsulating celastrol (CEL) was utilized to remodel obesity-related ITME and improve cancer immunotherapy, wherein Ginsenoside Rg3 (Rg3) was detected interspersed in the phospholipid bilayer and its glycosyl exposed on the surface of the liposome. CR-Lip had a relatively uniform size (116.5 nm), facilitating favorable tumor tissue accumulation through the interaction between Rg3 and glucose transporter 1 overexpressed in obese tumor cells. Upon reaching the tumor region, CR-Lip was found to induce the immunogenic cell death (ICD) of HFD tumor cells. Notably, the level of PHD3 in HFD tumor cells was effectively boosted by CR-Lip to effectively block metabolic reprogramming and increase the availability of major free fatty acids fuel sources. In vivo, experiments studies revealed that the easy-obtained nano platform stimulated enhanced the production of various cytokines in tumor tissues, DC maturation, CD8⁺ T-cell infiltration, and synergistic anticancer therapeutic potency with aPD-1 (tumor inhibition rate = 82.1%) towards obesity-related melanoma. Consequently, this study presented an efficacious approach to tumor immunotherapy in obese mice by encompassing tumor eradication, inducing ICD, and reprogramming metabolism. Furthermore, it offered a unique insight into a valuable attempt at the immunotherapy of obesity-associated related tumors.

Poly(ADP-ribosyl)ation (PARylation) is a specific form of post-translational modification (PTM) predominantly triggered by the activation of poly-ADP-ribose polymerase 1 (PARP1). However, the role and mechanism of PARylation in the advancement of acute kidney injury (AKI) remain undetermined. Here, we demonstrated the significant upregulation of PARP1 and its associated PARylation in murine models of AKI, consistent with renal biopsy findings in patients with AKI. This elevation in PARP1 expression might be attributed to trimethylation of histone H3 lysine 4 (H3K4me3). Furthermore, a reduction in PARylation levels mitigated renal dysfunction in the AKI mouse models. Mechanistically, liquid chromatography-mass spectrometry indicated that PARylation mainly occurred in receptor for activated C kinase 1 (RACK1), thereby facilitating its subsequent phosphorylation. Moreover, the phosphorylation of RACK1 enhanced its dimerization and accelerated the ubiquitination-mediated hypoxia inducible factor-1α (HIF-1α) degradation, thereby exacerbating kidney injury. Additionally, we identified a PARP1 proteolysis-targeting chimera (PROTAC), A19, as a PARP1 degrader that demonstrated superior protective effects against renal injury compared with PJ34, a previously identified PARP1 inhibitor. Collectively, both genetic and drug-based inhibition of PARylation mitigated kidney injury, indicating that the PARylated RACK1/HIF-1α axis could be a promising therapeutic target for AKI treatment.

Liposomes serve as critical carriers for drugs and vaccines, with their biological effects influenced by their size. The microfluidic method, renowned for its precise control, reproducibility, and scalability, has been widely employed for liposome preparation. Although some studies have explored factors affecting liposomal size in microfluidic processes, most focus on small-sized liposomes, predominantly through experimental data analysis. However, the production of larger liposomes, which are equally significant, remains underexplored. In this work, we thoroughly investigate multiple variables influencing liposome size during microfluidic preparation and develop a machine learning (ML) model capable of accurately predicting liposomal size. Experimental validation was conducted using a staggered herringbone micromixer (SHM) chip. Our findings reveal that most investigated variables significantly influence liposomal size, often interrelating in complex ways. We evaluated the predictive performance of several widely-used ML algorithms, including ensemble methods, through cross-validation (CV) for both liposome size and polydispersity index (PDI). A standalone dataset was experimentally validated to assess the accuracy of the ML predictions, with results indicating that ensemble algorithms provided the most reliable predictions. Specifically, gradient boosting was selected for size prediction, while random forest was employed for PDI prediction. We successfully produced uniform large (600 nm) and small (100 nm) liposomes using the optimised experimental conditions derived from the ML models. In conclusion, this study presents a robust methodology that enables precise control over liposome size distribution, offering valuable insights for medicinal research applications.

Objective:To explore the prognostic value of peripheral blood lymphocyte subsets in lymphoma patients with different infection status of Epstein-Barr virus (EBV).Methods:A retrospective cohort study. A total of 333 lymphoma patients newly diagnosed from November 2012 to August 2023 in the Affiliated Hospital of Xuzhou Medical University were included in the study, including 185 patients with Diffuse Large B-cell Lymphoma (DLBCL), 100 patients with Natural Killer/T-cell Lymphoma (NKTCL), and 48 patients with Hodgkin Lymphoma (HL). Clinical data and laboratory indicators of patients were collected, including lymphocyte subset ratios detected by flow cytometry and EBV-DNA levels measured by real-time quantitative polymerase chain reaction. The survival status of patients was recorded through referring to medical records and telephone follow-up. The Kaplan-Meier method was used to plot survival curves and compare the survival rates among different groups. The Cox proportional hazards model was applied to analyze factors related to overall survival in lymphoma patients.Results:In the NKTCL group, 73.0% (73/100) were positive for EBV-DNA, which was higher than 43.8% (81/185) in the DLBCL group and 35.4% (17/48) in the HL group ( P<0.001). Kaplan-Meier survival curves showed that lower overall survival rates in the DLBCL group with abnormal levels of CD19 +B cells and CD16 +CD56 +NK cells (defined as either high or low referring to the reference intervals), with EBV-DNA negative and abnormal levels of CD19 +B cells, or with EBV-DNA positive and abnormal levels of CD16 +CD56 +NK cells, compared with the normal level group ( P<0.05). Multivariable analysis suggested that the abnormal level of CD19 +B cells was an independent adverse prognostic factor for DLBCL patients ( HR=2.098, 95% CI 1.181-3.727, P=0.011). EBV-DNA positivity ( HR=17.623, 95% CI 2.397-129.565, P=0.048) and Ann Arbor stage (Ⅲ/Ⅳ) ( HR=2.770, 95% CI 1.335-5.750, P=0.006) were adverse prognostic factors for NKTCL patients. Conclusion:There are differences in peripheral blood lymphocyte subsets among lymphoma patients with different EBV infection status, and CD19 +B cell levels may serve as an independent prognostic factor for DLBCL patients.

Objective:To explore the influence of deviation of the bolt in femoral neck system (FNS) on the short-term outcomes in young and middle-aged patients with displaced femoral neck fracture.Methods:A retrospective analysis was conducted of the 114 young and middle-aged patients with displaced femoral neck fracture who had been treated with FNS at Department of Orthopaedics, Suzhou Municipal Hospital from December 2019 to January 2023. Based on the postoperative measurements of the deviation of the bolt tip to the central axis of the femoral head and neck (W), the patients were divided into a central group (W≤20%) and a deviation group (W>20%). In the central group of 63 cases, there were 27 males and 36 females with a mean age of (46.4±8.0) years. In the deviation group of 51 cases, there were 20 males and 31 females with a mean age of (45.1±9.8) years. The 2 groups were compared in terms of weight-bearing time, fracture healing time, tip-apex distance, degree of femoral neck shortening, Harris Hip Score and EuroQol five-dimensional questionnaire-5L (EQ-5D-5L) utility value at the last follow-up, as well as complications and revision surgeries.Results:There was no statistically significant difference in the preoperative general information, auxiliary reduction or quality of fracture reduction between the 2 groups, showing comparability between groups ( P>0.05). There was no significant difference in the partial weight-bearing time between the 2 groups ( P>0.05). In the central group, the full weight-bearing time [15.0 (14.0, 16.0) weeks] and fracture healing time [14.0 (12.0, 15.0) weeks] were significantly shorter than those in the deviation group [16.0 (15.0, 19.0) weeks; 15.0 (13.0, 17.0) weeks], the tip-apex distance [(21.4±3.4) mm] was significantly shorter than that in the deviation group [(23.5±2.7) mm], the Harris Hip Score [(90.6±6.1) points] and EQ-5D-5L utility value [0.9 (0.8, 0.9)] at the last follow-up were significantly higher than those in the deviation group [(87.7±6.2) points; 0.9 (0.8, 0.9)], and the incidences of moderate and severe femoral neck shortening [25.4% (16/63)], avascular necrosis of the femoral head [0 (0/63)] and revision surgery [0 (0/63)] were significantly lower than those in the deviation group [66.7% (34/51), 7.8% (4/51), 9.8% (5/51)] (all P< 0.05). Conclusion:A closer positioning of the FNS bolt to the central axis of the femoral head and neck favors satisfactory short-term outcomes and a lower revision surgery rate in young and middle-aged patients with displaced femoral neck fracture.

Objective:To analyze the effect of panax notoginseng saponins(PNS)on mTORC1-HIF1α signaling pathway,and to explore its effect and mechanisms on the differentiation balance of Th17/Treg cells in CD4+T cells.Methods:Isolate the spleens of C57BL/6 mice,then select CD4+T cells by magnetic beads and cultured in vitro.The optimal concentration of PNS was screened by the CCK-8,and then these cells were divided into control group and PNS treatment group(5,10 and 20 μg/ml),each gives correspond-ing drug treatment after 48 h.Afterwards,flow cytometry was used to detect differentiation of Th17/Treg cells.Real-time quantitative fluorescent PCR was used to detect the expressions of RORγt,Foxp3,mTOR,Raptor,HIF1α mRNA.ELISA was used to detect the levels of IL-17A and IL-10 in the supernatant of cell culture.Western blot was used to detect the expressions and phosphorylation levels of 4EBP1,S6K and HIF1α proteins.Results:5,10,20 μg/ml PNS could significantly inhibit Th17 cells differentiation and promote Treg cells differentiation;5,10,20 μg/ml PNS could significantly reduce the expression of RORγt mRNA,and then reduce the level of IL-17A;20 μg/ml PNS could significantly promote the expression of Foxp3 mRNA and increase the level of IL-10;10,20 μg/ml PNS could significantly decrease the phosphorylation of 4EBP1 and S6K;5,10,20 μg/ml PNS could significantly reduce the expression of HIF1α mRNA and inhibit the expression of HIF1α protein.Conclusion:Certain concentrations of PNS can inhibit the differentiation of Th17 cells in CD4+T cells,and promote the differentiation of Treg cells,which is related with modulating mTORC1-HIF1α signaling pathway.

Objective To explore the influencing factors of microcirculation dysfunction in patients with anterior wall acute myocardial infarction(AMI)and to establish a relevant prediction model.Methods A total of 130 patients with anterior wall AMI,whose microcirculation function was assessed by caIMR after receiving percutaneous coronary intervention(PCI)at Shanghai Sixth People's Hospital of China from January 2017 to September 2020,were enrolled in this study.The patients were divided into abnormal microcirculation resistance group(n=52)and normal microcirculation resistance group(n=78).The clinical data were compared between the two groups.The regression analysis was used to analyze the influencing factors of microcirculation dysfunction.Results In the abnormal microcirculation resistance group the contrast agent consumption,the onset-to-operation time,the Gensini total score and the LAD Gensini score were(121.92±31.37)mL,(10.51±5.12)min,(97.91±31.77)points and(69.36±13.15)points respectively,which were significantly higher than(109.03±28.2)mL,(4.94±2.94)min,(81.05±35.22)points and(54.45±23.48)points respectively in the normal microcirculation resistance group,the differences in the above indexes between the two groups were statistically significant(all P＜0.05).A prediction model covering interventional strategies was established,and its accuracy was higher than that of a conventional model,its AUC compared with the conventional model was 0.91 to 0.87,indicating that this model could well predict the risk of microcirculation dysfunction in patients with AMI after receiving PCI.Conclusion This prediction model can promptly identify high-risk microcirculation dysfunction patients with anterior wall AMI after receiving PCI.

Objective To investigate the clinical value of matrix-assisted laser desorption/ionization time of flight mass spectrometry(MALDI-TOF MS)in rapid detection of carbapenemase produced by Klebsiella pneumoniae and Pseudomonas aeruginosa.Methods A total of 60 strains of Klebsiella pneumoniae and 80 strains of Pseudomonas aeruginosa isolated from Pizhou People's Hospital affiliated to Xuzhou Medical University from January 2022 to October 2023 were collected,including 30 strains of carbapenem-resistant Klebsiella pneumoniae(CRKP),30 strains of carbapenem-sensitive Klebsiella pneumoniae(CSKP),50 strains of carbapenem-resistant Pseudo-monas aeruginosa(CRPA)and 30 strains of carbapenem-sensitive Pseudomonas aeruginosa(CSPA).Three detection methods were applied,i.e.,modified carbapenem inactivation method(mCIM),colloidal gold immunochromatography and Autof MS 1000 mass spectrometry identification system to evaluate the ability of Autof MS 1000 mass spectrometry identification system in detecting carbape-nase production of Klebsiella pneumoniae and Pseudomonas aeruginosa.Results The results of Autof MS 1000 mass spectrometry iden-tification system were consistent with those of both mCIM and colloidal gold immunochromatography.Carbapenemase was detected in 28 of the 30 CRKP strains,and it was negative in 2 CRKP strains.Carbapenamase was detected in 15 of the 50 CRPA strains and it was negative in 35 CRPA strains.Thirty strains of CSKP and 30 strains of CSPA were all Carbapenemase negative.The coincidence rate of the results of the three methods in the detection for carbapenase was 100％.Conclusion The result of Autof MS 1000 mass spectrome-try identification system has been consistent with those of mCIM and colloidal gold immunochromatography.It not only has the charac-teristics of cost-saving compare with of mCIM method,but also hold the advantages of fast speed and high accuracy of colloidal gold im-munochromatography method.Thus,Autof MS 1000 system can be used for the rapid identification of carbapenemase produced by Kleb-siella pneumoniae and Pseudomonas aeruginosa.