Background::Intrauterine growth restriction (IUGR) is associated with adverse metabolic outcomes during adulthood. Histone modifications and changes in DNA methylation-affected genes are important for fetal development. This study aimed to investigate the epigenetic mechanisms in IUGR.Methods::IUGR models were established in Sprague–Dawley rats using a maternal nutritional restriction approach during pregnancy. The abundance of insulin-like growth factor 2 (IGF2), phosphoinositide 3-kinase (PI3K), AKT serine/threonine kinase 2 (AKT2), and peroxisome proliferators-activated receptor gamma coactivator 1 alpha (PGC-1α) was examined by real-time polymerase chain reaction (RT-PCR) and Western blotting analysis. Chromatin immunoprecipitation RT-PCR was employed to analyze histone modification in CCCTC-binding factor (CTCF) 1–4 binding sites of the Igf2/H19 imprinting control region (ICR). The methylation states of CTCF1–4 binding sites were studied by pyrosequencing. Results::The IUGR models were constructed successfully. Igf2 mRNA abundance in the placenta, fetal liver, and newborn liver was decreased in the IUGR group ( P <0.01). Meanwhile, as compared with the control group, the expression levels of AKT2, PI3K, and PGC-1α were lower in newborn and 8-week-old livers in the IUGR group ( P <0.05). In addition, knocking down Igf2 reduced the protein expression levels of AKT2-phosphorylation and PGC-1α ( P <0.05). In CTCF binding sites 1-4 of the Igf2/ H19 ICR, acetylated histones H3 (AcH3) enrichment was significantly lower in CTCF1-3 in newborn and 8-week-old IUGR rats. Histone H3 tri-methylated lysine 4 (H3K4me3) enrichment was significantly lower in the CTCF1–4 of newborn and 8-week-old IUGR groups ( P <0.01). H3K9me2 enrichment was significantly higher in the IUGR group ( P <0.01). The CpG dinucleotide methylation levels of CTCF1 and CTCF3, but not those of CTCF2 and CTCF4 binding sites in IUGR rat fetal, 4-week old, and 8-week-old livers decreased significantly ( P <0.05). Conclusion::The methylation status and histone modification in the Igf2/H19 ICR are related to growth and lipid metabolism via the PGC-1α/PI3K/AKT2 pathway in IUGR rats.

Biomanufacturing is an advanced manufacturing method that integrates biology, chemistry, and engineering. It utilizes renewable biomass and biological organisms as production media to scale up the production of target products through fermentation. Compared with petrochemical routes, biomanufacturing offers significant advantages in reducing CO₂ emissions, lowering energy consumption, and cutting costs. With the development of systems biology and synthetic biology and the accumulation of bioinformatics data, the integration of information technologies such as artificial intelligence, large models, and high-performance computing with biotechnology is propelling biomanufacturing into a data-driven era. This paper reviews the latest research progress on databases, knowledge bases, and large language models for biomanufacturing. It explores the development directions, challenges, and emerging technical methods in this field, aiming to provide guidance and inspiration for scientific research in related areas.
Biotechnology/methods* ; Knowledge Bases ; Synthetic Biology ; Databases, Factual ; Artificial Intelligence ; Systems Biology ; Computational Biology ; Fermentation

With the rapid advancement of synthetic biology, CRISPR-Cas systems have emerged as a powerful tool for gene editing, demonstrating significant potential in various fields, including medicine, agriculture, and industrial biotechnology. This review comprehensively summarizes the significant progress in applying artificial intelligence (AI) technologies to the design, mining, and modification of CRISPR-Cas systems. AI technologies, especially machine learning, have revolutionized sgRNA design by analyzing high-throughput sequencing data, thereby improving the editing efficiency and predicting off-target effects with high accuracy. Furthermore, this paper explores the role of AI in sgRNA design and evaluation, highlighting its contributions to the annotation and mining of CRISPR arrays and Cas proteins, as well as its potential for modifying key proteins involved in gene editing. These advancements have not only improved the efficiency and precision of gene editing but also expanded the horizons of genome engineering, paving the way for intelligent and precise genome editing.
CRISPR-Cas Systems/genetics* ; Artificial Intelligence ; Gene Editing/methods* ; RNA, Guide, CRISPR-Cas Systems/genetics* ; Machine Learning ; Humans ; Genetic Engineering/methods* ; Synthetic Biology

Natural components serve the survival instincts of cells that are obtained through long-term evolution, while they often fail to meet the demands of engineered cells for efficiently performing biological functions in special industrial environments. Enzymes, as biological catalysts, play a key role in biosynthetic pathways, significantly enhancing the rate and selectivity of biochemical reactions. However, the catalytic efficiency, stability, substrate specificity, and tolerance of natural enzymes often fall short of industrial production requirements. Therefore, exploring and modifying enzymes to suit specific biomanufacturing processes has become crucial. In recent years, artificial intelligence (AI) has played an increasingly important role in the discovery, evaluation, engineering, and de novo design of proteins. AI can accelerate the discovery and optimization of proteins by analyzing large amounts of bioinformatics data and predicting protein functions and characteristics by machine learning and deep learning algorithms. Moreover, AI can assist researchers in designing new protein structures by simulating and predicting their performance under different conditions, providing guidance for protein design. This paper reviews the latest research advances in protein discovery, evaluation, engineering, and de novo design for biomanufacturing and explores the hot topics, challenges, and emerging technical methods in this field, aiming to provide guidance and inspiration for researchers in related fields.
Protein Engineering/methods* ; Artificial Intelligence ; Proteins/genetics* ; Computational Biology ; Machine Learning ; Data Mining ; Algorithms ; Deep Learning

BACKGROUND:Early exercise treatment is the main prevention way for traumatic joint contracture and is also a research focus.Swimming may be a potential intervention for joint contracture due to the special physical properties of water. OBJECTIVE:To explore the effects of swimming on the development of joint contracture in a rat model and study its mechanisms. METHODS:Twenty-four Sprague-Dawley rats were randomly divided into a blank control group(n=8)and a joint contracture group(n=16).After the surgical operation of knee joint contracture rat models,the joint contracture group was randomly subdivided into a surgical control group(n=8)and a swimming treatment group(n=8).Swimming started in the swimming treatment group in the second week after surgery and lasted for a total of 5 weeks.At the 6th week after surgery,the body mass,knee joint range of motion,and quadriceps diameter were tested,and the diameter/body mass index was calculated.Hematoxylin-eosin staining was performed to detect the pathological changes in the knee joint capsule and quadriceps muscle,and Masson staining was used to observe fibrotic changes in the knee joint capsule.Furthermore,the protein expression of transforming growth factor β1 and type I collagen in the knee joint capsule was quantified by immunohistochemical assay and western blot was performed to detect the protein expression of MuRF1 in the quadriceps femoris. RESULTS AND CONCLUSION:Compared with the blank control group,the knee range of motion decreased in the surgical control and swimming treatment groups(P<0.01),and knee extension deficit and arthrogenic extension deficit were significantly increased(P<0.01),the diameter of the quadriceps muscle was decreased(P<0.01),the joint capsule showed significant fibrosis,the quadriceps muscle was atrophied,and the diameter/body mass index was decreased(P<0.01).Compared with the surgical control group,the swimming treatment group showed a significant increase in knee joint range of motion and quadriceps diameter(P<0.01),and significant improvement in joint capsule fibrosis and quadriceps atrophy.Compared with the blank control group,collagen fiber content and expression of transforming growth factor β1 and type I collagen were increased in the joint capsule of rats in both the surgical control group and the swimming treatment group(P<0.01).Compared with the surgical control group,collagen fiber content and expression of transforming growth factor β1 and type I collagen protein in the joint capsule were decreased in the swimming treatment group.Compared with the blank control group,the expression of MuRF1 protein in the quadriceps muscle of rats in the surgical control group and the swimming treatment group was increased(P<0.05).Compared with the surgical control group,the expression of MuRF1 protein in the quadriceps muscle of rats in the swimming treatment group was decreased(P<0.05).To conclude,early swimming intervention reduces transforming growth factor β1 and type I collagen expression in the joint capsule of traumatic joint contracture rats,decreases MuRF1 expression in the quadriceps muscle,and increases joint range of motion and quadriceps diameter,thereby inhibiting the development of joint contracture.

Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

Background/Aims: Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated. Methods: TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection. Results: TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy. Conclusions Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

Body weight abnormalities, including overweight, obesity, and underweight, have become a dual public health challenge in Chinese adults: overweight and obesity lead to a variety of chronic complications, while underweight increases the risks of malnutrition, sarcopenia, and organ dysfunction. To systematically address these issues, multidisciplinary experts in endocrinology, sports science, nutrition, and psychiatry from various regions have held multiple weight management seminars. Based on the latest epidemiological data and clinical evidence, they expanded the guideline to include assessment and intervention strategies for underweight, in addition to the core content of obesity management. This guideline outlines the etiological mechanisms, evaluation methods, and multidimensional management strategies for overweight and obesity, covering key areas such as diagnosis and assessment, medical nutrition therapy, exercise prescription, pharmacological intervention, and psychological support. It is intended to provide a scientific and standardized approach to weight management across the adult population, aiming to curb the rising prevalence of obesity, mitigate complications associated with abnormal body weight, and improve nutritional status and overall quality of life.

Objective:To report the nationwide surveillance results of pathogenic profiles and antimicrobial resistance patterns of Gram-positive bloodstream infections in China in 2023.Methods:The clinical isolates of Gram-posttive bacteria from blood cultures were collected in member hospitals of National Bloodstream Infection Bacterial Resistant Investigation Collaborative System（BRICS）during January to December 2023. Antimicrobial susceptibility testing was performed using the dilution method recommended by the Clinical and Laboratory Standards Institute（CLSI）. Statistical analyses were conducted using WHONET 5.6 and SPSS 25.0 software.Results:A total of 4 385 Gram-positive bacterial isolates were obtained from 60 participating center. The top five pathogens were Staphylococcus aureus（ n=1 544，35.2%），coagulase-negative Staphylococci（ n=1 441，32.9%）， Enterococcus faecium（ n=574，13.1%）， Enterococcus faecalis（ n=385，8.8%），and α-hemolytic Streptococci（ n=187，4.3%）. The prevalence of methicillin-resistant Staphylococcus aureus（MRSA）and methicillin-resistant coagulase-negative Staphylococci（MRCNS）was 26.2%（405/1 544）and 69.8%（1 006/1 441），respectively. Notably，all Staphylococci remained susceptible to glycopeptide or daptomycin. Staphylococcus aureus demonstrated excellent susceptibility（>97.0%）to cephalobiol，rifampicin，trimethoprim-sulfamethoxazole，linezolid，minocycline，tigecycline，and eravacycline. No Enterococcus exhibiting resistance to linezolid were detected. Glycopeptide resistance was uncommon but more frequent in Enterococcus faecium（resistance to vancomycin and teicoplanin：both 1.7%）compared to Enterococcus faecalis（both 0.3%）. The detection rates of MRSA and MRCNS exhibited significant regional variations across the country（ χ2=17.674 and 148.650，respectively，both P<0.001）. No vancomycin-resistant Enterococci were detected in central China. Institutional comparison demonstrated higher prevalence of MRSA（ χ2=14.111， P<0.001）and MRCNS（ χ2=4.828， P=0.028）in provincial hospitals than that in municipal hospitals. Socioeconomic analysis identified elevated detection rates of both MRSA（ χ2=18.986， P<0.001）and MRCNS（ χ2=4.477， P=0.034）in less developed regions（per capita GDP