Integrated Approaches to Testing and Assessment(IATA)is a toxicological assessment decision-making method that integrates existing information from various sources,including physical and chemical properties,animal testing,and non-animal testing.Through the evaluation and analysis of a series of iterative strategies,it ultimately obtains risk assessment conclusions,thereby providing a basis for risk management decisions regarding chemical substances.The use of IATA is becoming increasingly prevalent in such areas as ocular irritation and genotoxicity.This paper introduces the conceptual connotation of IATA,sorts out the framework elements and sequential processes,explains the commonly used framework construction methods,shares cases of application in various exposure scenarios,and finally envisions future research directions in order to provide better methodological support for the risk assessment of chemical substances.

We designed and synthesized eighteen lycorine derivatives with five different structural types, and evaluated their antiviral activities on a HCoV-OC43-infected H460 cell model. Structure-activity relationships suggested that the introduction of appropriate substituents on the 6N atom of lycorine was beneficial to activity. Compound 6a gave a good activity with the half effective concentration (EC₅₀) and selectivity index (SI) values of 2.36 μmol·L^-1 and 16.52, respectively. Surface plasmon resonance (SPR) result indicated that 6a might target the non-structural protein 12 (NSP12) subunit in RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 with the dissociation constant (K_D) value of 1.36 μmol·L^-1. Molecular docking indicated that 6a might act on nidovirus RdRp-associated nucleotidyltransferase (NiRAN) catalytic center of NSP12, distinct from the mechanism of nucleoside-like drugs such as remdesivir. This study provides scientific data for the development of lycorine derivatives into a new class of anti-SARS-CoV-2 small molecule inhibitors.

In this study, we designed and synthesized 12 novel aloperine derivatives with different core structures. Among them, compound 3 with a ten-membered ring core was obtained through a special ring expansion reaction after γ-H Huffman elimination of quaternary ammonium salt, and the structure was verified by X-single crystal diffraction. Furthermore, their antiviral activity against human β-coronavirus HCoV-OC43 was evaluated by CCK-8 assay. Quaternary ammonium salt 2a and 3 had a good inhibitory effect against HCoV-OC43, and 2a had the highest anti-HCoV-OC43 activity with an EC₅₀ values of 3.77 μmol·L^-1 and a SI value of over 53.1. Schrӧdinger molecular docking results showed that both 2a and 3 might display their anti-HCoV-OC43 activity by directly acting on host TMPRSS2 and SR-B1. The results expanded the structural types of endocyclic aloperine and the function against coronavirus, and provided useful scientific data for the development of pharmaceutical applications of these compounds.

Objective To explore the predictive value of immune inflammation combined with liver function hematological indicators for the metastasis of colorectal cancer.Methods A retrospective analysis of clinical data of 133 patients with colorectal cancer was conducted.The patients were divided into three groups based on disease progression after 24 months of postoperative follow-up:non-metastasis group(n=38),liver metastasis group(n=43),and non-liver distant metastasis group(n=52).The immune inflammatory markers and liver function hematological indicators of progression-free survival were analyzed.Nomogram prediction models were constructed using univariate and multivariate logistic regression analyses to identify risk factors for metastasis of colorectal cancer.The accuracy of the nomogram was validated using receiver operating characteristic(ROC)curve and calibration curve,and the clinical predictive efficacy was evaluated through decision curve and clinical impact curve.Results Univariate and multivariate logistic regression analyses showed that pan-immune-inflammatory value(PIV),prognostic nutritional index(PNI),and bile acid(BA)were independent predictors of colorectal cancer metastasis.The area under the ROC curve of the combined prediction of metastasis was 0.84;neutrophil/lymphocyte ratio(NLR)and BA were independent predictors of liver metastasis from colorectal cancer.The area under the ROC curve of the combined prediction of liver metastasis was 0.83;PIV and PNI were independent predictive factors for the occurrence of non-liver distant metastasis from colorectal cancer.The area under the ROC curve for the combined prediction of non-liver distant metastasis was 0.83.The calibration curve,decision curve,and clinical impact curve showed that the three models had good accuracy and net benefit value.Conclusion The nomogram constructed based on immune inflammation and liver function hematological indicators can predict the metastasis of patients with colorectal cancer and has high predictive efficacy and clinical application prospects.

Lipopolysaccharides (LPS) are major outer membrane components of Gram-negative bacteria. Unlike most Gram-negative bacteria, Acinetobacter baumannii can still survive and acquire polymyxin resistance after complete loss of LPS. Previous studies of LPS-deficient Acinetobacter baumannii mostly focused on LPS-deficient strains induced by polymyxin, whose background was complex and unstable. To investigate LPS loss-mediated polymyxin resistant-Acinetobacter baumannii, this study constructed a stable and clear background LPS-deficient strain by knocking out lpxC gene in Acinetobacter baumannii ATCC 19606 with CIRSPR/Cas9, and then studied the phenotypic changes of the lpxC-deficient strain including morphology, growth rate, antibiotic susceptibility, virulence, membrane permeability, and membrane potential. Animal experiments were approved by the Animal Care and Welfare Committee Institute of Medicinal Biotechnology, CAMS and PUMC (approval number: IMB-20240119D₉). The results indicated that the lpxC gene of Acinetobacter baumannii ATCC 19606 was successfully knocked out. After losing the lpxC, the strain underwent the morphological change from rod-shaped to spherical. Furthermore, it leads to reduced growth rate, enhanced membrane permeability, decreased membrane potential, lower virulence, and increased antibiotic susceptibility to β-lactams, quinolones, aminoglycosides, macrolides, glycopeptides. The lpxC deletion results in significant changes in membrane homeostasis and adaptability of Acinetobacter baumannii. Understanding the phenotypic changes of colistin-resistant Acinetobacter baumannii mediated by LPS loss is useful for exploring the resistance mechanism of Acinetobacter baumannii and developing new therapeutic strategies.

ObjectiveTo investigate the genetic polymorphism and structure of 47 autosomal microhaplotypes in the Han population in Changshu City, Jiangsu Province, and to evaluate the forensic efficiencies and forensic parameters. MethodsThe DNA library of unrelated individual samples was prepared according to MHSeqTyper47 kit manual and sequenced on the MiSeq FGx platform. Microhaplotype genotyping and sequencing depth statistics were processed using MHTyper. The genetic information of samples was then evaluated. The fixation index and genetic distance between the Jiangsu Changshu population and the reference populations in the 1000 Genomes Project phase 3 (1KG) were calculated, and forensic parameters were evaluated. ResultsThe fixation index and genetic distance between the Han population in Changshu, Jiangsu, and the CHB (Han Chinese in Beijing, China) reference population in 1KG were the lowest. The effective allele number (A_e) of each locus is also the closest between the two populations. The combined matching probability (CMP) of the Changshu Han population is close to the 5 populations of the East Asian reference super-population in 1KG, which is 1.25×10^-36, and the combined probability of exclusion reached 0.999 999 999 964 1. ConclusionThis study reported the genetic polymorphism and allele frequency of 47 microhaplotypes in a Han population in Changshu City, Jiangsu Province. This information provides a data basis for 47 microhaplotypes in forensic applications. In addition, the polymorphism differences between the 1KG reference population and the Han population in Changshu, Jiangsu were compared, and the genetic structure of 47 microhaplotypes in the Han population in Changshu, Jiangsu was revealed. In general, the reference data of the East Asian super-population in 1KG is more in line with the genetic characteristics of Han population in Changshu, Jiangsu.

【Objective】 To explore the application of machine learning in scientific and rational blood preparation and predictive analysis for surgical blood usage before liver transplantation surgery. 【Methods】 Clinical basic information including gender, age, clinical diagnosis and surgical methods of 356 liver transplantation patients were collected. The duration (Time) and preoperative laboratory test results of hemoglobin (Hb), hematocrit (Hct), platelet count (Plt), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), total bilirubin (TBIL), albumin (ALB), creatinine (Crea) and total protein (TP), as well as the amount of intraoperative blood transfusion were collected. A machine learning model capable of predicting the risk of massive blood transfusion during liver transplantation surgery was established by Python, and was evaluated to select the optimal predictive model. 【Results】 Among the 7 machine learning models constructed, the logistic regression model performed the best (AUROC: 0.90, F1 score: 0.82), with an accuracy of 79.44% and precision of 79.69%, followed by the random forest classifier (AUROC: 0.87, F1 score: 0.83), with an accuracy of 79.44% and precision of 77.94%. 【Conclusion】 Establishing a machine learning prediction model by Python is of significant clinical importance for scientific blood preparation, predicting the risk of massive blood transfusion and ensuring the safety of blood use in liver transplantation surgery.

Circadian rhythm is one of the biorhythms formed by organisms in the process of evolution to adapt to the rotation of the earth,which is manifested as a cyclical biorhythm of about 24 hours produced by the body under the control of the internal biological clock,coordinating sleep/wakefulness,body temperature regulation,endocrine time and other activities.Long-term circadian rhythm disorders can cause increased risk of metabolic disorders,gastrointestinal diseases,neurodegenerative diseasesand other illnesses.As a typical model animal,the aquatic organism zebrafish(Danio rerio)has been widely used in experimental studies of circadian rhythm.This paper introduces in detailthe operating mechanism of zebrafish circadian clock,the influencing factors of the input system,the genes and pathways of the circadian clock,and the physiological output,summarizes the application and advantages in circadian rhythm research,finally looks forward to future research and development,in order to provide theoretical support for circadian rhythm regulation mechanism research,related drug development and disease treatment strategies.

Chromatography is one of the most important separation and analytical techniques in production activity and academic research.With the growing demand for applications,the development of targeted separation devices is costly.However,the difficulty of constructing modeling makes it difficult to validate the theoretical studies of chromatography.Three dimensional(3D)printing,as a technology that can fabricate objects by depositing materials from the bottom to up,can custom print complex structures for specific needs,and shows many advantages such as low cost,low waste,high precision,high flexibility and parallel manufacturing,demonstrating great potential in the field of chromatography separations.In recent years,with the rapid development of 3D printing technology,the printing resolution and speed have progressively improved,and the range of printable materials has largely expanded.This has led to preliminary research and application of 3D printing technology in the field of chromatography separation,resulting in brand new discoveries and technological innovations.This article made a comprehensive overview of the latest advancements in research and application of 3D printing technology in separation science,including 3D printed columns,3D printed stationary phase,and 3D printed solid-phase extraction devices.Finally,The prospects and challenges of 3D printing technology in separation science were discussed.

OBJECTIVE: This study was aimed at investigating the carrier rate of, and molecular variation in, α- and β-globin gene mutations in Hunan Province. METHODS: We recruited 25,946 individuals attending premarital screening from 42 districts and counties in all 14 cities of Hunan Province. Hematological screening was performed, and molecular parameters were assessed. RESULTS: The overall carrier rate of thalassemia was 7.1%, including 4.83% for α-thalassemia, 2.15% for β-thalassemia, and 0.12% for both α- and β-thalassemia. The highest carrier rate of thalassemia was in Yongzhou (14.57%). The most abundant genotype of α-thalassemia and β-thalassemia was -α ^3.7/αα (50.23%) and β ^IVS-II-654/β ^N (28.23%), respectively. Four α-globin mutations [CD108 (ACC>AAC), CAP +29 (G>C), Hb Agrinio and Hb Cervantes] and six β-globin mutations [CAP +8 (C>T), IVS-II-848 (C>T), -56 (G>C), beta nt-77 (G>C), codon 20/21 (-TGGA) and Hb Knossos] had not previously been identified in China. Furthermore, this study provides the first report of the carrier rates of abnormal hemoglobin variants and α-globin triplication in Hunan Province, which were 0.49% and 1.99%, respectively. CONCLUSION Our study demonstrates the high complexity and diversity of thalassemia gene mutations in the Hunan population. The results should facilitate genetic counselling and the prevention of severe thalassemia in this region.
Humans ; beta-Thalassemia/genetics* ; alpha-Thalassemia/genetics* ; Hemoglobinopathies/genetics* ; China/epidemiology* ; High-Throughput Nucleotide Sequencing