Glioma represents the most prevalent malignant tumor of the central nervous system, with chemotherapy serving as an essential adjunctive treatment. However, most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier (BBB). This study introduced a novel dual-targeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles (C8Pt-Ls). Specifically, nanobodies (Nbs) with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls, resulting in the generation of Nb-C8Pt-Ls. Within the bloodstream, Nb-C8Pt-Ls could bound more fibrinogen, forming the protein corona that specifically interacted with LRP-1, a receptor highly expressed on the BBB. This interaction enabled a "Hitchhiking Effect" mechanism, facilitating efficient trans-BBB transport and promoting effective brain targeting. Additionally, the protein corona interacted with LRP-1, which is also overexpressed in glioma cells, achieving precise tumor targeting. Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1) complex, confirming its binding specificity and stability. Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors, induced apoptosis in glioma cells, and improved therapeutic efficacy. This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.

General anesthesia, pivotal for surgical procedures, requires precise depth monitoring to mitigate risks ranging from intraoperative awareness to postoperative cognitive impairments. Traditional assessment methods, relying on physiological indicators or behavioral responses, fall short of accurately capturing the nuanced states of unconsciousness. This study introduces a machine learning-based approach to decode anesthesia depth, leveraging EEG data across different anesthesia states induced by propofol and esketamine in rats. Our findings demonstrate the model's robust predictive accuracy, underscored by a novel intra-subject dataset partitioning and a 5-fold cross-validation method. The research diverges from conventional monitoring by utilizing anesthetic infusion rates as objective indicators of anesthesia states, highlighting distinct EEG patterns and enhancing prediction accuracy. Moreover, the model's ability to generalize across individuals suggests its potential for broad clinical application, distinguishing between anesthetic agents and their depths. Despite relying on rat EEG data, which poses questions about real-world applicability, our approach marks a significant advance in anesthesia monitoring.
Animals ; Machine Learning ; Electroencephalography/methods* ; Ketamine/administration & dosage* ; Rats ; Male ; Propofol/administration & dosage* ; Rats, Sprague-Dawley ; Anesthesia, General/methods* ; Brain/physiology* ; Intraoperative Neurophysiological Monitoring/methods*

Peptides are a particular molecule class with inherent attributes of some small-molecule drugs and macromolecular biologics, thereby inspiring continuous searches for peptides with therapeutic and/or agrochemical potentials. However, the success rate is decreasing, presumably because many interesting but less-abundant peptides are so scarce or labile that they are likely 'overlooked' during the characterization effort. Here, we present the biochemical characterization and druggability improvement of an unprecedented minor fungal RiPP (ribosomally synthesized and post-translationally modified peptide), named acalitide, by taking the relevant advantages of metabolomics approach and disulfide-bridged substructure which is more frequently imprinted in the marketed peptide drug molecules. Acalitide is biosynthetically unique in the macrotricyclization via two disulfide bridges and a protease (AcaB)-catalyzed lactamization of AcaA, an unprecedented precursor peptide. Such a biosynthetic logic was successfully re-edited for its sample supply renewal to facilitate the identification of the in vitro and in vivo antiparkinsonian efficacy of acalitide which was further confirmed safe and rendered brain-targetable by the liposome encapsulation strategy. Taken together, the work updates the mining strategy and biosynthetic complexity of RiPPs to unravel an antiparkinsonian drug candidate valuable for combating Parkinson's disease that is globally prevailing in an alarming manner.

Objective This study aimed to investigate the effect of stage Ⅰ comprehensive cardiac rehabili-tation in patients with acute ST elevation myocardial infarction(STEMI)after emergency percutaneous coronary intervention(PCI).Methods A total of 72 patients with acute ST-segment elevation myocardial infarction combined with PCI admitted to the Department of Cardiovascular Medicine of Beijing Electric Power Hospital of State Grid Corporation from June 2021 to June 2022,which were selected as the research objectsand divided into control group and observation group randomly(36 cases in each group).The control group was treated with routine nursing and health education,and the observation group with stage Ⅰ comprehensive cardiac rehabilitation,including initial assessment(cardiovascular comprehensive assessment),exercise training(exercise training and breathing train-ing),daily activity suggestions and health education,discharge assessment(six-minute walking test and Barthel index assessment).The score of Barthel index(BI)at discharge,the 6-minute walking test distance(6MWD)at discharge,the incidence of major adverse cardiovascular event(MACE)during hospitalization and within one month of discharge,and the length of stay were compared between the two groups.Results After intervention,the six-minute walking test distance(6MWD)and Barthel index(BI)score in the observation group were better than those in the control group,the difference was statistically significant(P<0.05).The incidence of major adverse cardiovascular events(MACE)during hospitalization and one month after discharge was lower in the observation group than in the control group,and the difference was statistically significant(P<0.05).The length of hospital-ization in observation group was lower than that in control groupbut there was no statistical difference(P>0.05).Conclusion The application of phase Ⅰ comprehensive cardiac rehabilitation training in patients with acute ST-segment elevation myocardial infarction combined with emergency PCI could improve the patients'exercise ability,improve their ability of daily activity,reduce the incidence of major adverse cardiovascular events(MACE)in the early stage of the disease,facilitate the patients to return to their families and society as soon as possible,and improve their quality of life.It has high clinical application value.

OBJECTIVE: To summarize the gene therapy strategies for neurofibromatosis type 1 (NF1) and related research progress. METHODS: The recent literature on gene therapy for NF1 at home and abroad was reviewed. The structure and function of the NF1 gene and its mutations were analyzed, and the current status as well as future prospects of the transgenic therapy and gene editing strategies were summarized. RESULTS: NF1 is an autosomal dominantly inherited tumor predisposition syndrome caused by mutations in the NF1 tumor suppressor gene, which impair the function of the neurofibromin and lead to the disease. It has complex clinical manifestations and is not yet curable. Gene therapy strategies for NF1 are still in the research and development stage. Existing studies on the transgenic therapy for NF1 have mainly focused on the construction and expression of the GTPase-activating protein-related domain in cells that lack of functional neurofibromin, confirming the feasibility of the transgenic therapy for NF1. Future research may focus on split adeno-associated virus (AAV) gene delivery, oversized AAV gene delivery, and the development of new vectors for targeted delivery of full-length NF1 cDNA. In addition, the gene editing tools of the new generation have great potential to treat monogenic genetic diseases such as NF1, but need to be further validated in terms of efficiency and safety. CONCLUSION Gene therapy, including both the transgenic therapy and gene editing, is expected to become an important new therapeutic approach for NF1 patients.
Humans ; Neurofibromatosis 1/pathology* ; Neurofibromin 1/metabolism* ; GTPase-Activating Proteins ; Mutation ; Genetic Predisposition to Disease ; Genetic Therapy

Objective To compare strain and gender differences between ICR and C57BL/6J mouse chronic fatigue syndrome models and provide experimental evidence for the selection of model animals for chronic fatigue syndrome.Methods ICR and C57BL/6J mice(half male and half female)were injected intraperitoneally with polyinosinic-polycytidylic acid(Poly I∶C)every three days and forced to swim daily.The modeling was performed for 15 consecutive days,during which the weight and food intake of the mice were measured,and fatigue scores were assessed.After the modeling was completed,behavioral tests were carried out,including exhaustive swimming,tail suspension,mechanical pain threshold,and elevated plus maze.Results Compared with the control group,both strains of model mice had significantly decreased exhaustion times in the exhaustive swimming test(P＜0.05,P＜0.01),significantly increased immobility time in the tail suspension test(P＜0.05,P＜0.01),and a significantly decreased mechanical pain threshold(P＜0.05,P＜0.01),and male model mice had significantly decreased open arm entry time and frequency in the elevated plus maze(P＜0.05,P＜0.01).The weight of model male C57BL/6J mice significantly decreased(P＜0.05,P＜0.01).The weight of model female ICR mice increased after a significant reduction(P＜0.05).The exhaustion time of control C57BL/6J mice was significantly lower than that of control ICR mice(P＜0.01).The immobility time of model C57BL/6J mice was significantly greater than that of model ICR mice(P＜0.01).Conclusions There were differences between the two strains of mice in terms of weight change,fatigue level,and depression.Within the same strain,there were differences between males and females,and the anxiety level of males was higher than that of females.

Objective:To determine the effects of early enteral nutrition (EEN) on the short-term prognosis of patients receiving veno-arterial extracorporeal membrane oxygenation (VA-ECMO).Methods:61 patients admitted to the Coronary Care Unit (CCU) of Henan Provincial Peoples' Hospital from February 2022 to March 2023 to receive VA-ECMO treatment were selected as the study objects according a retrospective survey. The patients were divided into an achievement group ( n=34) and a non-achievement group ( n=27) based on whether the feeding amount reached 70% or over of the target calories (25kcal/kg.d) on the 7th day of ECMO treatment. The general characteristics, disease information, complications, and prognosis between the two groups after ICU admission were recorded and compared. A multivariable Cox proportional hazards model was used to evaluate the impact of various factors on clinical outcomes. Kaplan-Meier analysis was used to draw survival curves for the two groups, and the predictive value of the ratio of actual EN intake to target energy was calculated by plotting the ROC curve. Results:A total of 61 patients were included, with an overall in-hospital mortality rate of 50.82% (31/61), with 32.35% (11/34) in the achievement group, and 70.37% (19/27) in the non-achievement group. Cox regression analysis revealed that the occurrence of hypoxic-ischemic encephalopathy (HR=0.341, 95% CI:0.119-0.975), ECOM weaning failure ( HR=0.269, 95% CI:0.111-0.651), and achieving EN targets on the 7th day of VA-ECMO treatment ( HR=10.891, 95% CI:1.178-100.718) were independent factors for patient mortality during hospitalization. The ROC curve for the percentage of EN achievement on the 7th day of VA-ECMO treatment and in-hospital mortality showed an area under the curve of 0.755, with a cutoff value of 0.73. Conclusion:The presence of ischemic hypoxic encephalopathy, ECOM weaning failure, and whether achieving EN targets or not is closely related to the prognosis of VA-ECMO patients. Patients who achieving EN targets of over 73% had the lowest in-hospital mortality rate. Therefore, more attention should be paid to the energy intake of VA-ECMO patients to reduce their risk of mortality.

Objective To provide foundational data for exploring the association between KIR genes and diseases by an-alyzing the frequency and polymorphism of killer-cell immunoglobulin-like receptor(KIR)genes in Han,Manchu and Kore-an populations in Jilin Province.Methods KIR gene typing was performed on 129 Manchu,198 Korean and 201 Han indi-viduals from Jilin using the polymerase chain reaction-sequence specific primers(PCR-SSP)technique.Results KIR3DL2,KIR3DL3,KIR3DP1 and KIR2DL4 were detected in all subjects.KIR2DL1,KIR2DL3,KIR2DS4,KIR3DL1 and KIR2DP1 genes had high detection frequencies,ranging from 93％to 98％across the three ethnic groups.In contrast,the detection rates of KIR2DL2,KIR2DL5,KIR3DS1,KIR2DS1,KIR2DS2,KIR2DS3 and KIR2DS5 were lower,ranging from 13％to 45％.Notably,the detection frequencies of KIR2DL5(17.83％)and KIR2DS1(17.83％)in the Manchu population were significantly lower than those in the Korean(42.93％,47.47％)and Han(33.83％,33.33％)populations in Jilin.The detection frequencies of KIR2DL5(42.93％)and KIR2DS1(47.47％)were significantly higher in the Korean popula-tion compared to the Han(33.83％,33.33％)and Manchu(17.83％,17.83％)population.The frequency of the KIRAA hap-lotype in the Han population was the highest among the three ethnic groups in Jilin at 61.19％,significantly higher than that in the Korean population(42.93％).Differences between the three groups were statistically significant(P＜0.05),and remained significant after Bonferroni correction(Pc＜0.05).Conclusion The distribution of KIR genes in the Korean,Manchu and Han population in Jilin reflects the polymorphism of KIR genes in the Chinese population and also showcases unique ethnic genetic and regional characteristics.

Abstract: Objective To express Mycobacterium tuberculosis Rv2626c protein in Escherichia coli (E. coli) and study the antigenicity of the purified recombinant Rv2626c protein. Methods The amino acid sequence of Rv2626c protein from Mycobacterium tuberculosis H37Rv strain (accession number: CCP45424.1) in GenBank was retrieved and converted into the corresponding DNA sequence according to the codon preference of E. coli. This DNA sequence was synthesized and cloned into pET24a(+) plasmid to construct pET24a(+)-Rv2626c recombinant plasmid. This plasmid was transformed into E. coli BL21(DE3) cells, and the expression of Rv2626c protein was induced under various conditions of isopropyl β-D-thiogalactopyranoside (IPTG) concentrations, temperature, and period. The recombinant Rv2626c protein was identified by SDS-PAGE and Western Blot. The recombinant Rv2626c protein was purified by nickel chelate affinity chromatography and used to immunize violet blue rabbits to prepare anti-Rv2626c anti-serum. The specificity and titer of the serum were respectively detected by Western Blot and enzyme-linked immunosorbent assay (ELISA). Results The recombinant plasmid pET24a(+)-Rv2626c was successfully constructed. SDS-PAGE analysis showed that recombinant Rv2626c was expressed in the recombinant plasmid transformed E. coli with IPTG induction, with a molecular weight of about 14 500, and the size was consistent with the expectation. The optimal expression condition for recombinant Rv2626c protein was at 31 ℃ with 1.0 mmol/L IPTG for 6 hours. The target protein was mainly present in a soluble form, which was consistent with the results of Western blot. The hyperimmunized serum with recombinant Rv2626c protein vaccination showed good specificity, with a titer of 1∶ 256 000 detected by ELISA. Conclusions Mycobacterium tuberculosis Rv2626c protein is successfully expressed in E. coli, and the purified protein has good purity and antigenic activity, laying the foundation for further reveals of its biological functions.

A 2-year-old boy was admitted to Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine in Nov 30^th, 2018, due to polydipsia, polyphagia, polyuria accompanied with increased glucose levels for more than 2 weeks. He presented with symmetrical short stature [height 81 cm (－2.2 SD), weight 9.8 kg (－2.1 SD), body mass index 14.94 kg/m² (P₁₀-P₁₅)], and with no special facial or physical features. Laboratory results showed that the glycated hemoglobin A1c was 14%, the fasting C-peptide was 0.3 ng/mL, and the islet autoantibodies were all negative. Oral glucose tolerance test showed significant increases in both fasting and postprandial glucose, but partial islet functions remained (post-load C-peptide increased 1.43 times compared to baseline). A heterozygous variant c.1366C>T (p.R456C) was detected in GATA6 gene, thereby the boy was diagnosed with a specific type of diabetes mellitus. The boy had congenital heart disease and suffered from transient hyperosmolar hyperglycemia after a patent ductus arteriosus surgery at 11 months of age. Insulin replacement therapy was prescribed, but without regular follow-up thereafter. The latest follow-up was about 3.5 years after the diagnosis of diabetes when the child was 5 years and 11 months old, with the fasting blood glucose of 6.0-10.0 mmol/L, and the 2 h postprandial glucose of 17.0-20.0 mmol/L.
Male ; Child ; Humans ; Child, Preschool ; Infant ; Diabetes Mellitus, Type 2/complications* ; Mutation, Missense ; C-Peptide/genetics* ; China ; Insulin/genetics* ; Glucose ; Blood Glucose ; GATA6 Transcription Factor/genetics*