Arginine methylation is a critical post-translational modification that plays multifaceted biological functions. However, the manipulation of protein arginine methylation largely depends on genetic or pharmaceutic inhibition of the regulatory enzymes, protein arginine methyltransferases (PRMTs), or non-methylation substitution of corresponding arginine residue to lysine or alanine of protein of interest (POI), which inevitably affects other substrates, or disrupts the structure of POI. Thus, it urges an approach to specifically modulate the arginine methylation of a POI under physiological conditions. To this end, we report the discovery of a methylation tagging system (MeTAG), that enables targeted modification of protein arginine methylation. Through bridging the methyltransferase PRMT5 proximity to a POI, MeTAG facilitates the arginine methylation of POIs, including known arginine methylated proteins, androgen receptor (AR) and protein kinase B (AKT), as well as a neo-substrate E1A binding protein (p300), in a reversible and PRMT5-dependent manner. Moreover, MeTAG can regulate downstream signaling in a methylation dependent manner, leading to downregulation of PSMA mRNA level and activation of AKT. Therefore, MeTAG represents a feasible approach to modulate protein methylation and thereby perturbs protein function in biological and therapeutic contexts.

Background::We previously reported that activation of the cell cycle in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) enhances their remuscularization capacity after human cardiac muscle patch transplantation in infarcted mouse hearts. Herein, we sought to identify the effect of magnesium lithospermate B (MLB) on hiPSC-CMs during myocardial repair using a myocardial infarction (MI) mouse model.Methods::In C57BL/6 mice, MI was surgically induced by ligating the left anterior descending coronary artery. The mice were randomly divided into five groups ( n = 10 per group); a MI group (treated with phosphate-buffered saline only), a hiPSC-CMs group, a MLB group, a hiPSC-CMs + MLB group, and a Sham operation group. Cardiac function and MLB therapeutic efficacy were evaluated by echocardiography and histochemical staining 4 weeks after surgery. To identify the associated mechanism, nuclear factor (NF)-κB p65 and intercellular cell adhesion molecule-1 (ICAM1) signals, cell adhesion ability, generation of reactive oxygen species, and rates of apoptosis were detected in human umbilical vein endothelial cells (HUVECs) and hiPSC-CMs. Results::After 4 weeks of transplantation, the number of cells that engrafted in the hiPSC-CMs + MLB group was about five times higher than those in the hiPSC-CMs group. Additionally, MLB treatment significantly reduced tohoku hospital pediatrics-1 (THP-1) cell adhesion, ICAM1 expression, NF-κB nuclear translocation, reactive oxygen species production, NF-κB p65 phosphorylation, and cell apoptosis in HUVECs cultured under hypoxia. Similarly, treatment with MLB significantly inhibited the apoptosis of hiPSC-CMs via enhancing signal transducer and activator of transcription 3 (STAT3) phosphorylation and B-cell lymphoma-2 (BCL2) expression, promoting STAT3 nuclear translocation, and downregulating BCL2-Associated X, dual specificity phosphatase 2 (DUSP2), and cleaved-caspase-3 expression under hypoxia. Furthermore, MLB significantly suppressed the production of malondialdehyde and lactate dehydrogenase and the reduction in glutathione content induced by hypoxia in both HUVECs and hiPSC-CMs in vitro. Conclusions::MLB significantly enhanced the potential of hiPSC-CMs in repairing injured myocardium by improving endothelial cell function via the NF-κB/ICAM1 pathway and inhibiting hiPSC-CMs apoptosis via the DUSP2/STAT3 pathway.

Objective: To synthesis a Gd-labeled molecular probe capable of responding to fibroblast activation protein(FAP) highly expressed in tumor-associated fibroblasts for magnetic resonance imaging studies of pancreatic cancer. Methods: The chemical structure of Z-Gly-Pro-Cys-Lys(Gd-DOTA)-CBT(contrast agent 1) was characterized through mass spectrometry analysis.High-performance liquid chromatography(HPLC) was used to verify the contrast agent 1 formed a dimer under the cleavage of fibroblast activation protease(FAP) in vitro,and further self-assembled to form Gd-nanoparticles.The cell counting Kit-8(CCK-8) assay was used for biological safety analysis.BxPc-3 tumor-bearing mice were established and randomly divided into three groups,3 mice intravenously(i.v.) injected with 0.08 mmol/kg contrast agent 1 through tail vein were designated as the experimental group,3mice i.v.injected with 0.08 mmol/kg Gd-DTPA were designated as the control group,and 3 mice i.v.injected with normal saline were designated as the blank control group(n=3).Dynamic MR scanning from 0 to 3 hours was performed for them,respectively.The enhancement effects of T1-and T2-weighted imaging were observed and the rate of change in the tumor-to-muscle ratio(T/M) over time was analyzed. Results: Contrast agent 1 efficiently responded to FAP in vitro,forming dimers under the action of FAP,and further self-assembled to form nanoparticle structures.Contrast agent 1 has good biocompatibility.The BxPc-3 tumor-bearing mice showed that the T1-weighted contrast of the tumor reached its highest level at 2 h post injection of contrast agent 1 or Gd-DTPA.In T1-weighted imaging,the T/M at 2 h in the experimental group was 135.20%±0.06% of 0 h,the T/M at 2 h in the Gd-DTPA group was 115.70%±0.05% of 0 h and the T/M at 2 h in the saline group was 113.5%±0.02% of 0h.Compared with Gd-DTPA control group,the experimental group had significantly enhanced T1-weighted MR contrast,and the difference was statistically significant(P<0.01).In tumor T2-weighted imaging,the T/M quantitative analysis showed that the tumor T2-weighted contrast enhancement of the three groups was relatively small,and the T/M of the experimental group and the control group at 0.5 h was 94.60±0.03% and 106.30±0.04% of the 0 h,respectively.In the normal saline group,T/M at 0.5 h was 102.20±0.002% of that at 0 h,and no significant enhancement of the T2-weighted MR contrast of tumor was observed. Conclusion Successfully construct a FAP-responsive molecular probe which can self-assemble to form a Gd-nanoparticle structure in tumor cells under the cleavage of FAP,effectively improving the enrichment of Gd in the target region,and enhancing T1-weighted magnetic resonance imaging of pancreatic cancer,which has potential clinical application value.

Objective:To explore the impact of whole blood organophosphate esters (OPEs) flame retardant exposure on thyroid function-related hormones in healthy older adults.Methods:In this panel study, five repeated population-based epidemiological surveys and biological sample collection were conducted from September 2018 to January 2019, with 76 healthy older adults aged 60-69 years in the Dianliu Community of Jinan, Shandong Province. Information on the sociodemographic characteristics, diet, and health status of the respondents was systematically gathered through questionnaires and physical examinations. Fasting venous blood was collected to determine the levels of OPEs, thyroid-stimulating hormone (TSH), triiodothyronine (T 3), and thyroxine (T 4). A linear mixed-effects model was used to analyze the impact of OPEs exposure on thyroid function-related hormones in healthy older adults. Results:Each of the 76 subjects participated in at least two follow-up visits, resulting in a total of 350 person visits. The age of the study participants was (65.07±2.76) years, with 38 participants of both sexes. A total of eight OPEs were included with a detection rate exceeding 50%, and the M ( Q 1, Q3) for ∑OPEs was 3.85 (2.33, 5.74) ng/ml, with alkyl-OPEs being the major type of OPEs with an M ( Q 1, Q3) of 1.27 (0.64, 2.50) ng/ml. The M ( Q 1, Q3) for TSH, T 3, and T 4 was 3.74 (2.55, 5.69) μIU/ml, 1.32 (1.10, 1.60) ng/ml, and 45.04 (36.96, 53.27) ng/ml, respectively. Linear mixed-effects model showed that TSH was significantly decreased by 9.93% (95% CI:-15.17%, -4.36%) and 11.14% (95% CI:-15.94%, -6.06%) in older adults for each quartile level increase in TnBP and TEHP exposures, respectively. Gender-stratified analysis indicated that TEHP exposure was negatively associated with TSH levels in male older adults, whereas a decrease in TSH levels among female older adults was associated with TnBP exposure. Conclusion:Exposure to whole blood OPEs is associated with decreased TSH levels among healthy older adults, with notable gender differences.

Objective:To explore the impact of whole blood organophosphate esters (OPEs) flame retardant exposure on thyroid function-related hormones in healthy older adults.Methods:In this panel study, five repeated population-based epidemiological surveys and biological sample collection were conducted from September 2018 to January 2019, with 76 healthy older adults aged 60-69 years in the Dianliu Community of Jinan, Shandong Province. Information on the sociodemographic characteristics, diet, and health status of the respondents was systematically gathered through questionnaires and physical examinations. Fasting venous blood was collected to determine the levels of OPEs, thyroid-stimulating hormone (TSH), triiodothyronine (T 3), and thyroxine (T 4). A linear mixed-effects model was used to analyze the impact of OPEs exposure on thyroid function-related hormones in healthy older adults. Results:Each of the 76 subjects participated in at least two follow-up visits, resulting in a total of 350 person visits. The age of the study participants was (65.07±2.76) years, with 38 participants of both sexes. A total of eight OPEs were included with a detection rate exceeding 50%, and the M ( Q 1, Q3) for ∑OPEs was 3.85 (2.33, 5.74) ng/ml, with alkyl-OPEs being the major type of OPEs with an M ( Q 1, Q3) of 1.27 (0.64, 2.50) ng/ml. The M ( Q 1, Q3) for TSH, T 3, and T 4 was 3.74 (2.55, 5.69) μIU/ml, 1.32 (1.10, 1.60) ng/ml, and 45.04 (36.96, 53.27) ng/ml, respectively. Linear mixed-effects model showed that TSH was significantly decreased by 9.93% (95% CI:-15.17%, -4.36%) and 11.14% (95% CI:-15.94%, -6.06%) in older adults for each quartile level increase in TnBP and TEHP exposures, respectively. Gender-stratified analysis indicated that TEHP exposure was negatively associated with TSH levels in male older adults, whereas a decrease in TSH levels among female older adults was associated with TnBP exposure. Conclusion:Exposure to whole blood OPEs is associated with decreased TSH levels among healthy older adults, with notable gender differences.

This study explores the histological features and Bmp4 expression patterns in the replaced tooth germ of Xenopus laevis. Tooth germ formation starts from the dental placode through epithelial-mesenchymal interactions, involving various signaling pathways such as Fgf, Shh, Bmp, and Wnt. In mice, Bmp4 expression in the dental placode inhibits Pax9 expression in the dental mesenchyme. Although absent in the presumptive dental lamina of birds and toothless mammals, Bmp4 remains conserved in reptiles and fish owing to gene duplication. However, its expression in amphibian tooth germs is poorly understood. Three-month-old X. laevis were employed in this study. Initially, samples underwent paraffin embedding and were sectioned into 5 or 12 μm ribbons for H&E staining and in situ hybridization, respectively. Results revealed teeth appearing in two maxillary rows: the labial side, with prefunctional and functional teeth, and the lingual side, with replaced tooth germs behind functional teeth. Enameloid was observed between the inner dental epithelium and dental mesenchyme at the cap or early bell stages, whereas enamel and dentin formed during the late bell or mineralization stages from the replaced tooth germ. Bmp4 expression was evident in the inner dental epithelium (ameloblasts), dental papilla (odontoblasts), stellate reticulum, and Hertwig’s epithelial root sheath.Overall, these findings highlight the conservation of Bmp4 expression in X. laevis tooth development.

This study explores the histological features and Bmp4 expression patterns in the replaced tooth germ of Xenopus laevis. Tooth germ formation starts from the dental placode through epithelial-mesenchymal interactions, involving various signaling pathways such as Fgf, Shh, Bmp, and Wnt. In mice, Bmp4 expression in the dental placode inhibits Pax9 expression in the dental mesenchyme. Although absent in the presumptive dental lamina of birds and toothless mammals, Bmp4 remains conserved in reptiles and fish owing to gene duplication. However, its expression in amphibian tooth germs is poorly understood. Three-month-old X. laevis were employed in this study. Initially, samples underwent paraffin embedding and were sectioned into 5 or 12 μm ribbons for H&E staining and in situ hybridization, respectively. Results revealed teeth appearing in two maxillary rows: the labial side, with prefunctional and functional teeth, and the lingual side, with replaced tooth germs behind functional teeth. Enameloid was observed between the inner dental epithelium and dental mesenchyme at the cap or early bell stages, whereas enamel and dentin formed during the late bell or mineralization stages from the replaced tooth germ. Bmp4 expression was evident in the inner dental epithelium (ameloblasts), dental papilla (odontoblasts), stellate reticulum, and Hertwig’s epithelial root sheath.Overall, these findings highlight the conservation of Bmp4 expression in X. laevis tooth development.

This study explores the histological features and Bmp4 expression patterns in the replaced tooth germ of Xenopus laevis. Tooth germ formation starts from the dental placode through epithelial-mesenchymal interactions, involving various signaling pathways such as Fgf, Shh, Bmp, and Wnt. In mice, Bmp4 expression in the dental placode inhibits Pax9 expression in the dental mesenchyme. Although absent in the presumptive dental lamina of birds and toothless mammals, Bmp4 remains conserved in reptiles and fish owing to gene duplication. However, its expression in amphibian tooth germs is poorly understood. Three-month-old X. laevis were employed in this study. Initially, samples underwent paraffin embedding and were sectioned into 5 or 12 μm ribbons for H&E staining and in situ hybridization, respectively. Results revealed teeth appearing in two maxillary rows: the labial side, with prefunctional and functional teeth, and the lingual side, with replaced tooth germs behind functional teeth. Enameloid was observed between the inner dental epithelium and dental mesenchyme at the cap or early bell stages, whereas enamel and dentin formed during the late bell or mineralization stages from the replaced tooth germ. Bmp4 expression was evident in the inner dental epithelium (ameloblasts), dental papilla (odontoblasts), stellate reticulum, and Hertwig’s epithelial root sheath.Overall, these findings highlight the conservation of Bmp4 expression in X. laevis tooth development.

Objective:To analyze the research status and hotspots of post-stroke cognitive impairment management, so as to provide basis for post-stroke cognitive impairment management.Methods:The articles on the post-stroke cognitive impairment management in the Web of Science from November 1, 2011 to November 1, 2021 were retrieved systematically. The bibliometric analysis was carried out from the aspects of year, journal and country. The Latent Dirichlet Allocation (LDA) topic model was used to mine potential topics and determine topic keywords.Results:A total of 1 815 articles were included. The overall number of the article showed a steady growth trend, with a total of 394 source publications, and the journal with the largest number of articles was Stroke (61 articles) . The United States was the main country for research in this field, with 34.93% (634/1 815) of the articles issued. Six topics were identified through the LDA topic model, including functional impairment and mental health in various fields of patients with post-stroke cognitive impairment, neuropsychological screening and evaluation tools, rehabilitation training and effect evaluation, support and health promotion of family caregivers, epidemiological characteristics and risk factors of post-stroke cognitive impairment. Conclusions:The research on the post-stroke cognitive impairment management is generally on the rise. The topic mining and analysis of the research is conducive to further providing the development direction and information support for the post-stroke cognitive impairment management.

Objective: To establish an experimental model of Turner′s tooth caused by trauma in SD rats and observe its surface by scanning electronic microscopes(SEM) and energy dispersive spectrometry(EDS) was performed. Methods: 40 SD rats aged one day were randomly divided into four groups(n=10). The control group did nothing, The experimental group was exerted different perpendicular forces(per 5 mm2) on the mandibular anterior alveolar process, which was divided into 5 N force group, 10 N force group and 15 N force group. The SD rats were killed at 30 days old to observe the enamel development of their mandibular central incisors. Meanwhile, SEM and EDS were used to observe normal enamel area and enamel hypoplasia area. Results: The control group: all teeth erupted; all enamels developed well. 5 N force group: all teeth erupted; the occurrence rate of enamel hypoplasia was 10%(2 teeth had enamel discoloration). 10 N force group: 1 tooth unerupted; the occurrence rate of enamel hypoplasia was 80%(12 teeth had enamel discoloration and 4 had enamel defects). 15 N force group: 7 teeth unerupted, the occurrence rate of enamel hypoplasia was 60%(3 teeth had enamel discoloration and 9 had enamel defects). There was a statistic difference in the number of unerupted teeth between group 10 N force group and 15 N force group(P<0.05). Under SEM, cracks and rough appeared on the surface of enamel. EDS showed that the Ca and P content in enamel hypoplasia was lower than that in the normal enamel area(P<0.05). Conclusion Tooth trauma can lead to enamel hypoplasia and unerupted teeth. The force of 10 N per 5 mm2is better to establish an experimental model of Turner′s tooth caused by trauma in SD rats. The surface enamel of Turner′s tooth caused by trauma is rough, uneven and the content of calcium and phosphorus decreases.