Effects of Bisphenol A and Its Substitute, Bisphenol F, on the Gut Microbiota in Mice.

Objective: The aim of this study was to assess the impact of bisphenol A (BPA) and its substitute, bisphenol F (BPF), on the colonic fecal community structure and function of mice. Methods: We exposed 6-8-week-old male C57BL/6 mice to 5 mg/(kg∙day) and 50 µg/(kg∙day) of BPA or BPF for 14 days. Fecal samples from the colon were analyzed using 16S rRNA sequencing. Results: Gut microbiome community richness and diversity, species composition, and function were significantly altered in mice exposed to BPA or BPF. This change was characterized by elevated levels of Ruminococcaceae UCG-010 and Oscillibacter and decreased levels of Prevotella 9 and Streptococcus. Additionally, pathways related to carbohydrate and amino acid metabolism showed substantial enrichment. Conclusion: Mice exposed to different BP analogs exhibited distinct gut bacterial community richness, composition, and related metabolic pathways. Considering the essential role of gut bacteria in maintaining intestinal homeostasis, our study highlights the intestinal toxicity of BPs in vertebrates.

Development of a prognostic risk marker of colon adenocarcinoma based on a weighted gene co-expression network and its clinical significance / 中国比较医学杂志

Objective Because of the poor prognosis of colon adenocarcinoma(COAD),it is necessary to screen prognosis-related genes in COAD patients and establish a new prognostic risk assessment model.Methods COAD-related data from the cancer genome atlas(TCGA)and gene expression omnibus(GEO)were used as training and validation sets,respectively.Weighted gene co-expression network analysis(WGCNA),a Cox regression model and least absolute selection and shrinkage operator(LASSO)regression analysis were used to screen prognosis-related genes of COAD and establish a prognostic model.A receiver operating characteristic(ROC)curve was combined with a survival curve to verify the model accuracy,and a nomogram was constructed.Patients were divided into two groups by the median risk score.The immune cell proportion score(IPS)was used to evaluate the immunotherapy response of the two groups.Results A total of 15 feature genes were screened.The area under the ROC curve in the predictive model of COAD patients was＞0.6,and the survival rate of the high-risk group was significantly lower than that of the low-risk group(P＜0.05),suggesting a good distinguishing ability for high-and low-risk COAD patients.Patients in the low-risk group had a higher IPS(P=0.026),indicating a better response to immunotherapy.Conclusions The model developed for COAD in this study has a good ability to predict the survival of patients at high and low risk of COAD.

Comparison of postoperative visual acuity between two TECNIS multifocal intraocular lenses with different collocations / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To investigate the effect of different lens combinations on visual acuity, visual quality and patient satisfaction by comparing mixed implantation of Tecnis Symfony ZXR00(ZXR00)and Tecnis ZMB00(ZMB00)lenses, bilateral implantation of ZMB00 lenses, and bilateral implantation of ZXR00 lenses.METHODS:This retrospective case-control study included 117 patients with cataracts(234 eyes)who underwent phacoemulsification combined with intraocular lens(IOLs)implantation from August 2020 to December 2021. The 3 groups included 36 patients(72 eyes)who underwent bilateral implantation of ZXR00(RR group), 37 patients(74 eyes)who underwent bilateral implantation of ZMB00(MM group), and 44 patients(88 eyes)who underwent implantation with a combination of ZXR00 and ZMB00(MR group). The uncorrected distance visual acuity(UDVA, 5 m), uncorrected intermediate visual acuity(UIVA, 80 cm), uncorrected near visual acuity(UNVA, 40 cm), corrected distance visual acuity(CDVA), defocus curve, stereopsis and VF-14 and QoV visual quality scale of the patients in the three groups were assessed at 3-month follow-up.RESULTS:Bilateral UNVA in the MM and MR group were significantly better than that in the RR group(P<0.05). Bilateral UIVA was the best in the RR group. There were no significant differences in bilateral UDVA, CDVA and stereopsis among the groups(P>0.05). Values for near-stereoscopic acuity at 40 cm were 107.27±80.53, 105.67±83.79, and 108.69±97.66(20-400)arcsec in the MR, MM, and RR groups, respectively(P>0.05). Satisfaction rates exceeded 90% in all groups.CONCLUSION:All groups achieved good distance, intermediate, and near visual acuity and near-stereoscopic vision postoperatively. Mixed implantation with ZXR00 and ZMB00 lenses achieved excellent full-range vision and resulted in high satisfaction. These results may aid in developing individualized clinical treatment plans.

Family analysis of primary microcephaly caused by complex heterozygous variants of the RTTN gene and literature review / 中国儿童保健杂志

【Objective】 To analyze the genetic variation characteristics and clinical phenotypes of a family with primary microcephaly (MCPH) caused by RTTN gene variation, and to provide reference for genetic counseling and prenatal diagnosis. 【Methods】 Clinical data of the three patients (including 2 fetuses and 2-year-old proband,and one fetus with clinical diagnosis) and their parents were collected and analyzed. Two of the children and their parents were tested by trio whole exome sequencing (trio-WES), sanger sequencing validation sites, and the hazard of their compound heterozygous variants was predicted. Literature review was conducted through domestic and international databases to collect reported RTTN gene mutation cases. 【Results】 Three patients in this family had anomalies of the septum pellucidum, hypoplasia of the corpus callosum and other brain malformations during fetal period. The proband (G2) and fetus (G3) showed intrauterine growth retardation and MCPH in late pregnancy; besides, G2 was born with global developmental delay. Trio-WES detected a c.2101(exon16)C>T(p.Arg701Ter,1526) nonsense and a c.2863(exon22)G>A(p.Glu955Lys)missense in the RTTN gene of G2 and G3, which were inherited from their father and mother, forming a compound heterozygous variant. According to the American College of Medical Genetics and Genomics (ACMG) variant classification guidelines, two variants were likely to be pathogenic (LP) and uncertain significance (VUS). Among them, c.2863(exon22)G>A was a newly discovered missense, which was predicted by the software to be harmful to the gene product. 【Conclusions】 Complex heterozygous variations of RTTN gene (c.2101C>T and c.2863G>A) are the genetic cause of MCPH in this family. This report has enriched the variation spectrum of RTTN gene, provided guidance for prenatal diagnosis and reproduction of this family, as well as material and reference for further understanding of the diseases caused by this gene mutation.

Expression of leptin and its receptor correlates with hypoxia-inducible factor-1α in infants with cyanotic congenital heart disease / 基础医学与临床

Objective To investigate the correlation between serum leptin level and body mass index(BMI)in in-fants with cyanosis congenital heart disease,and the relationship between leptin and Ob gene receptor(Ob-R)and hypoxia-inducible factor 1α(HIF-1α)in myocardium.Methods A total of 52 children under 6 months of age with congenital heart disease who underwent surgical treatment in the Department of Congenital Heart Surgery,Fuwai Hospital from January 2019 to October 2020 were included in this study.According to the arterial partial pressure of oxygen(PaO2)of 90 mmHg,they were divided into cyanotic group(n=30)and acyanotic group(n=22).Their height and weight were collected to calculate BMI.The serum leptin level was measured by ELISA.The ex-pressions of HIF-1α and Ob-R in myocardial tissue were detected by RT-PCR and Western blot.In animal mod-el,SD rats were divided into normoxia group and hypoxia intervention group,which were subjected to continuous hypoxia(10％ O2)for 4 weeks.The hypoxia intervention group received intraperitoneal injection of HIF-1α in-hibitor digoxin(2 mg/kg)daily from the 14 th to 21st day of hypoxia,respectively.The body weight of rats was recorded,and the expressions of HIF-1α and Ob-R were detected by RT-qPCR and Western blot.Results Com-pared with the acyanosis group,the cyanosis group had a significantly lower BMI(P<0.05)and a lower leptin/BMI ratio(leptin/BMI)(P<0.05).Spearman correlation analysis confirmed that serum leptin in the circulatory system was positively correlated with BMI(P<0.05).In the cyanosis group,the expression of Ob-R increased with the upregulation of HIF-1α,showing a positive correlation.In animal model,with the down-regulation of HIF-1α expression in digoxin injection,the Ob-R level was significantly lower than that in the control group(P<0.05),the trend of weight loss was significantly inhibited(P<0.05).The right ventricular hypertrophy in-dex was significantly lower than that in the control group(P<0.05).Conclusions HIF-1α regulates the expres-sion of Ob-R in myocardial tissue,and the mechanism of its association with leptin and Ob-R may help to find new therapeutic target for improving the prognosis of infants with congenital heart disease.

Effects of Bisphenol A and Its Substitute, Bisphenol F, on the Gut Microbiota in Mice / 生物医学与环境科学（英文）

OBJECTIVE@#The aim of this study was to assess the impact of bisphenol A (BPA) and its substitute, bisphenol F (BPF), on the colonic fecal community structure and function of mice.@*METHODS@#We exposed 6-8-week-old male C57BL/6 mice to 5 mg/(kg∙day) and 50 μg/(kg∙day) of BPA or BPF for 14 days. Fecal samples from the colon were analyzed using 16S rRNA sequencing.@*RESULTS@#Gut microbiome community richness and diversity, species composition, and function were significantly altered in mice exposed to BPA or BPF. This change was characterized by elevated levels of Ruminococcaceae UCG-010 and Oscillibacter and decreased levels of Prevotella 9 and Streptococcus. Additionally, pathways related to carbohydrate and amino acid metabolism showed substantial enrichment.@*CONCLUSION@#Mice exposed to different BP analogs exhibited distinct gut bacterial community richness, composition, and related metabolic pathways. Considering the essential role of gut bacteria in maintaining intestinal homeostasis, our study highlights the intestinal toxicity of BPs in vertebrates.

Visualizing the dynamic mechanical power and time burden of mechanical ventilation patients: an analysis of the MIMIC-IV database.

BACKGROUND: Limiting driving pressure and mechanical power is associated with reduced mortality risk in both patients with and without acute respiratory distress syndrome. However, it is still poorly understood how the intensity of mechanical ventilation and its corresponding duration impact the risk of mortality. METHODS: Critically ill patients who received mechanical ventilation were identified from the Medical Information Mart for Intensive Care (MIMIC)-IV database. A visualization method was developed by calculating the odds ratio of survival for all combinations of ventilation duration and intensity to assess the relationship between the intensity and duration of mechanical ventilation and the mortality risk. RESULTS: A total of 6251 patients were included. The color-coded plot demonstrates the intuitive concept that episodes of higher dynamic mechanical power can only be tolerated for shorter durations. The three fitting contour lines represent 0%, 10%, and 20% increments in the mortality risk, respectively, and exhibit an exponential pattern: higher dynamic mechanical power is associated with an increased mortality risk with shorter exposure durations. CONCLUSIONS: Cumulative exposure to higher intensities and/or longer duration of mechanical ventilation is associated with worse outcomes. Considering both the intensity and duration of mechanical ventilation may help evaluate patient outcomes and guide adjustments in mechanical ventilation to minimize harmful exposure.

METTL3 Promotes the Growth and Invasion of Melanoma Cells by Regulating the lncRNA SNHG3/miR-330-5p Axis.

Accumulating evidence indicates that m6A methyltransferase 3 (METTL3) plays a pivotal role in different malignancies including melanoma. However, the function and underlying mechanisms by which METTL3 contributes to the tumorigenesis of melanoma remain undocumented. The association of METTL3 and long noncoding RNA (lncRNA) small nucleolar RNA host gene 3 (SNHG3) with clinicopathological characteristics and prognosis in patients with melanoma was analyzed by real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting, and The Cancer Genome Atlas data sets. The role of METTL3 in melanoma cells was assessed by in vitro and in vivo experiments. The m6A dot blot, methylated RNA immunoprecipitation (MeRIP), and RT-qPCR were used to verify METTL3-mediated m6A modification of lncRNA SNHG3. The effect of METTL3 on lncRNA SNHG3 was determined by luciferase gene reporter assay, RT-qPCR, and Western blotting. We found that METTL3 was upregulated in melanoma tissue samples and associated with poor survival in patients with melanoma. Knockdown of METTL3 suppressed the growth and invasion of melanoma cells in vitro and in vivo, whereas restored expression of METTL3 promoted these effects. Mechanistic investigations showed that knockdown of METTL3 reduced SNHG3 m6A levels and its messenger ribonucleic acid (mRNA) expression levels. SNHG3 could act as a sponge of microRNA (miR)-330-5p to upregulate the expression of CCHC-type zinc finger nucleic acid binding protein (CNBP). SNHG3 overexpression reversed METTL3-knockdown-caused antitumor effects, miR-330-5p upregulation and CNBP downregulation. SNHG3 had a positive correlation with METTL3 expression but a negative correlation with miR-330-5p expression in melanoma tissue samples. In conclusion, our findings demonstrated that METTL3-mediated m6A modification of lncRNA SNHG3 promoted the growth and invasion of melanoma cells by regulating the miR-330-5p/CNBP axis.

Fabrication of a novel antioxidant emulsifier through tuning the molecular interaction between soy protein isolates and young apple polyphenols.

Soy protein isolates (SPI) exhibit weaker emulsifying properties than those of animal proteins, thereby limiting their wide applicability. In this study, a novel plant-based antioxidant emulsifier was developed using SPI and young apple polyphenols (YAP), and its underlying interaction mechanisms were discovered using multispectral technology and molecular docking. YAP physically bound to SPI through hydrogen bonds and hydrophobic interactions, which significantly enhanced the free radicals scavenging, reducing, and metal ion chelating abilities of SPI by introducing free hydroxyl groups. Moreover, SPI modified by YAP exerted better emulsifying performance owing to a looser protein structure, reflected by a higher random coil and a lower α-helix content. In addition, YAP may bridge adjacent SPI molecules, promoting the adsorption and anchoring of SPI at the oil-water interface. SPI-YAP complexes are promising antioxidant emulsifiers that can be used to nano-deliver functional oils and nutrients, thereby broadening SPI and YAP applications in the food industry.

The magnitude, but not the duration of elevated central venous pressure is associated with mortality in sepsis patients: An analysis of the MIMIC-IV database.

BACKGROUND: It is unclear whether the magnitude and duration of elevated central venous pressure (ECVP) greater than ten mmHg has the same impact on mortality in sepsis patients. METHODS: Critically ill patients with sepsis were identified from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The duration and the magnitude of ECVP were calculated. Normalized ECVP load was defined as the ECVP load (the sum of ECVP value times its duration) divided by the total duration of ECVP. The primary endpoint was 28-day mortality. Kaplan-Meier survival analysis was used to compare survival between patients with high or low normalized ECVP load. RESULTS: A total of 1071 sepsis patients were included. Higher normalized ECVP load was associated with higher mortality rate; in contrast, the duration of ECVP was not associated with mortality. A linear relationship between normalized ECVP load and mortality was identified. Patients with higher normalized ECVP load had less urine output and more positive fluid balance. CONCLUSION: The magnitude, but not the duration of ECVP, is associated with mortality in sepsis patients. ECVP should be considered as a valuable and easily accessible safety parameter during fluid resuscitation.

Effects of moderate-intensity aerobic exercise combined with acupuncture on attention function of mentally-retarded adolescents: a randomised controlled trial.

OBJECTIVE: To detect the impact of moderate-intensity aerobic exercise combined with acupuncture on the attention function of mentally-retarded adolescents from the three dimensions of attention concentration, attention transfer and attention span. METHODS: A total of 48 adolescents with mild to moderate mental disabilities were recruited. The participants were randomly divided into four groups: control group (C), Traditional Chinese Medicine acupuncture group (M), moderate-intensity aerobic exercise group (E) and exercise and acupuncture combined intervention group (J). Before and after the experimental intervention, the participant's height, weight and attention ability were measured. RESULTS: The improved range of attention total duration of the J group after the intervention was significantly higher than that of the E and M groups (0.05), whereas that of the latter groups was significantly higher compared to that of the C group ( 0.05). The J group showed significantly higher ( 0.05) attention span values after the intervention compared to the E, M and C groups. The C group did not show a significant difference in attention transfer at 12 weeks compared to before intervention (0.05), whereas the E, M and J groups increased significantly ( 0.05) after intervention than the C group. CONCLUSIONS: Moderate-intensity aerobic exercise combined with acupuncture can more effectively improve the attention concentration and attention span of mentally-retarded adolescents than aerobic exercise or acupuncture alone.

Prevalence and risk factors of stroke in China: a national serial cross-sectional study from 2003 to 2018.

Stroke imposes a substantial burden worldwide. With the rapid economic and lifestyle transition in China, trends of the prevalence of stroke across different geographic regions in China remain largely unknown. Capitalizing on the data in the National Health Services Surveys (NHSS), we assessed the prevalence and risk factors of stroke in China from 2003 to 2018. In this study, data from 2003, 2008, 2013, and 2018 NHSS were collected. Stroke cases were based on participants' self-report of a previous diagnosis by clinicians. We estimated the trends of stroke prevalence for the overall population and subgroups by age, sex, and socioeconomic factors, then compared across different geographic regions. We applied multivariable logistic regression to assess associations between stroke and risk factors. The number of participants aged 15 years or older were 154,077, 146,231, 230,067, and 212,318 in 2003, 2008, 2013, and 2018, respectively, among whom, 1435, 1996, 3781, and 6069 were stroke patients. The age and sex standardized prevalence per 100,000 individuals was 879 in 2003, 1100 in 2008, 1098 in 2013, and 1613 in 2018. Prevalence per 100,000 individuals in rural areas increased from 669 in 2003 to 1898 in 2018, while urban areas had a stable trend from 1261 in 2003 to 1365 in 2018. Across geographic regions, the central region consistently had the highest prevalence, but the western region has an alarmingly increasing trend from 623/100,000 in 2003 to 1898/100,000 in 2018 (P trend<0.001), surpassing the eastern region in 2013. Advanced age, male sex, rural area, central region, hypertension, diabetes, depression, low education and income level, retirement or unemployment, excessive physical activity, and unimproved sanitation facilities were significantly associated with stroke. In conclusion, the increasing prevalence of stroke in China was primarily driven by economically underdeveloped regions. It is important to develop targeted prevention programs in underdeveloped regions. Besides traditional risk factors, more attention should be paid to nontraditional risk factors to improve the prevention of stroke.

Two new antimicrobial monoterpenoid indole alkaloids from the roots of Rauvolfia yunnanensis.

Two new monoterpenoid indole alkaloids 3-hydroxylochnerine (1) and 10-hydroxyvinorine (2) were isolated from the roots of Rauvolfia yunnanensis. Their structures were elucidated based on the analysis of spectroscopic data and ECD calculation. Both compounds exhibited potent antimicrobial activity against Bacillus subtilis and Escherichia coli, and their activities were comparable to the well-known antibacterial drug berberine.

RNF43 inhibits PD-L1 expression via β-catenin in melanoma cells and promotes CD8 + T cell-mediated anti-tumor immune reaction / 国际肿瘤学杂志

Objective:To investigate the regulatory effects of ring finger protein 43 (RNF43) on CD8 + T cell-mediated anti-tumor immune reaction in melanoma. Methods:RNF43 gene was over-expressed and knockdown in mouse melanoma cells line B16-OVA by lentivirus infection; In vivo proliferation of mouse melanoma cells line B16-OVA in the Lv-Ctrl-OE, Lv-RNF43-OE, Lv-Ctrl-KD and Lv-RNF43-KD groups was detected by subcutaneous tumorigenesis assay in mice, and the expression levels of CD8 + T cells perforin and interferon γ (IFN-γ) in tumor immune microenvironment of melanoma were detected by flow cytometry; The expression levels of β-catenin and programmed death-ligand 1 (PD-L1) mRNA in cells were detected by quantitative real-time PCR assay; The effect of RNF43 on the transcriptional regulation of PD-L1 was detected by dual-luciferase reporter gene assay. Results:Stable RNF43 over-expressing and RNF43 knockdown mouse melanoma cells lines Lv-RNF43-OE and Lv-RNF43-KD were successfully constructed. The results of subcutaneous tumorigenesis experiment in mice showed that the tumor mass of the Lv-RNF43-OE group was (0.08±0.06) g, which was significantly smaller than that of the Lv-Ctrl-OE group [ (1.04±0.52) g], with a statistically significant difference ( t=3.71, P=0.032) ; The tumor mass of Lv-RNF43-KD group was (1.94±0.29) g, with no statistically significant difference ( t=-1.70, P=0.164) compared with that of the Lv-Ctrl-KD group (1.15±0.74) g. The flow cytometry results showed that the fluorescence intensity of CD8 + T cell perforin in the Lv-RNF43-OE group was 9 034 ± 2 628, which was significantly higher than that in the Lv-Ctrl-OE group (3 847 ±1 637), with a statistically significant difference ( t=-3.35, P=0.015) ; The fluorescence intensity of CD8 + T cell perforin in the Lv-RNF43-KD group was 966±247, which was significantly lower than that in the Lv-Ctrl-KD group (2 226±646), with a statistically significant difference ( t=3.16, P=0.034) ; The fluorescence intensity of IFN-γ of CD8 + T cell in the Lv-RNF43-OE group was 2 422±429, which was significantly higher than that of 1 688±324 in the Lv-Ctrl-OE group, with a statistically significant difference ( t=-2.73, P=0.034) ; The fluorescence intensity of IFN-γ of CD8 + T cell in the Lv-RNF43-KD group was 614 (454, 863), with a statistically significant difference ( Z=-1.96, P=0.050) compared with 1 159 (1 152, 2 068) in the Lv-Ctrl-KD group. The results of quantitative real-time PCR showed that the relative expression level of β-catenin mRNA in the Lv-RNF43-OE group was 0.67±0.16, which was significantly lower than that of 1.00±0.11 in the Lv-Ctrl-OE group, with a statistically significant difference ( t=2.98, P=0.041) ; The relative expression level of PD-L1 mRNA in the Lv-RNF43-OE group was 0.32±0.09, which was significantly lower than that of 1.00±0.09 in the Lv-Ctrl-OE group, with a statistically significant difference ( t=9.13, P=0.001). The results of the dual-luciferase reporter gene assay showed that the PD-L1 promoter luciferase activity in the pCMV6-NC, RNF43, RNF43+β-catenin and β-catenin groups were 1.00±0.00, 0.84±0.00, 1.49±0.00 and 1.57±0.03 ( F=2 218.33, P<0.001). Further pairwise comparison showed that compared with the pCMV6-NC group, PD-L1 promoter luciferase activity was significantly lower in the RNF43 group ( P<0.001) and significantly higher in the RNF43+β-catenin and β-catenin groups ( P<0.001; P=0.003) ; compared with the RNF43 group, PD-L1 promoter luciferase activity was significantly higher in the RNF43+β-catenin group ( P<0.001) . Conclusion:RNF43 may reduce the expression of PD-L1 mRNA in melanoma by inhibiting the expression of β-catenin and promote CD8 + T cell-mediated anti-tumor immune reaction.

Bisphenol A induces testicular oxidative stress in mice leading to ferroptosis / 亚洲男科学杂志(英文版)

Bisphenol A is a common environmental factor and endocrine disruptor that exerts a negative impact on male reproductive ability. By exploring bisphenol A-induced testicular cell death using the Institute of Cancer Research (ICR) mouse model, we found that a ferroptosis phenomenon may exist. Mice were divided into six groups and administered different doses of bisphenol A via intragastric gavage once daily for 45 consecutive days. Serum was then collected to determine the levels of superoxide dismutase and malondialdehyde. Epididymal sperm was also collected for semen analysis, and testicular tissue was collected for ferritin content determination, electron microscope observation of mitochondrial morphology, immunohistochemistry, real-time quantitative polymerase chain reaction, and western blot analysis. Exposure to bisphenol A was found to decrease sperm quality and cause oxidative damage, iron accumulation, and mitochondrial damage in the testes of mice. In addition, bisphenol A was confirmed to affect the expression of the ferroptosis-related genes, glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), cyclooxygenase 2 (COX2), and acyl-CoA synthetase 4 (ACSL4) in mouse testicular tissues. Accordingly, we speculate that bisphenol A induces oxidative stress, which leads to the ferroptosis of testicular cells. Overall, the inhibition of ferroptosis may be a potential strategy to reduce male reproductive toxicity caused by bisphenol A.

Anti-glioma mechanism of pterostilbene by regulating apoptosis and GSDME-mediated pyroptosis pathways: a study based on network pharmacology and experimental research / 中国中药杂志

This study aimed to explore the anti-glioma effect of natural compound pterostilbene(PTE) through regulating pyroptosis and apoptosis pathways, and to analyze the possible anti-glioma pathways and targets of PTE by network pharmacology and molecular docking. In this study, the action targets of PTE and the glioma targets were obtained by network pharmacology to construct a target network and a protein-protein interaction(PPI) network to predict the possible action targets of PTE against glioma. Molecular docking was performed on the core targets by AutoDock and the action pathways of PTE against glioma were predicted by enrichment analysis. In addition, the effect of PTE on the viability of U87MG and GL261 glioma cells was detected by CCK-8 assay. Clone formation assay and cell scratching assay were used to explore the effect of different concentrations of PTE on the proliferation and migration, respectively of glioma cells. Hoechst staining was used to observe PTE-induced apoptosis in glioma cells. The changes in mitochondrial membrane potential were detected by JC-1 staining. The pyroptosis-inducing effect of PTE on glioma cells was observed by inverted microscopy and lactate dehydrogenase(LDH) assay. Hoechst 33342/PI dual staining assay was performed to detect the integrity of glioma cell membranes. The expressions of pyroptosis and apoptosis-related proteins in glioma cells after PTE induction were determined by Western blot. In this study, 37 anti-glioma targets of PTE were obtained, and enrichment analysis suggested that PTE exerted anti-glioma effects through various signaling pathways including cancer pathway, proteoglycan in cancer, PI3K/AKT pathway, and apoptosis regulatory pathway. Molecular docking revealed that PTE had good binding activity with the main targets. Compared with the control group, PTE significantly reduced the viability as well as the proliferation, migration and adhesion abilities of U87MG and GL261 cells; it induced the apoptosis of the two glioma cells and the decrease of mitochondrial membrane potential in U87MG cells, and the effects increased with the increase of drug concentration. Compared with the conditions in the control group, glioma cells in the PTE group had increased pyroptosis-specific appearance and gradually increased LDH release; the number of PI positive cells was significantly elevated with the increase of PTE concentration as revealed by Hoechst 33342/PI staining; the expression levels of apoptosis-related factors cleaved PARP1 and B-cell lymphoma-2(Bcl-2) associated X(BAX) in the PTE group were markedly up-regulated, while the expression level of Bcl-2 was markedly down-regulated; the activation levels of pyroptosis-related proteins cleaved caspase-3 and gasdermin E-N(GSDME-N) had a remarkable rise in the PTE group, while no significant changes were found in the activation levels of gasdermin D-N(GSDMD-N) and cleaved caspase-1. In summary, PTE plays an anti-glioma role by inhibiting cell viability, proliferation, and migration and activating the caspase-3/GSDME-mediated pyroptosis pathway and mitochondrial apoptosis pathway.

Genetic analysis of a child with Complex cortical dysplasia with other brain malformations type 6 due to a p.M73V variant of TUBB gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child with multiple malformations.@*METHODS@#A child who had presented at Shanxi Provincial Children's Hospital in February 2021 was selected as the study subject. Clinical data of the patient was collected, and whole exome sequencing (WES) was carried out to screen pathogenic variants associated with the phenotype. Candidate variant was validated by Sanger sequencing of her family members.@*RESULTS@#The child had normal skin, but right ear defect, hemivertebral deformity, ventricular septal defect, arterial duct and patent foramen ovale, and separation of collecting system of the left kidney. Cranial MRI showed irregular enlargement of bilateral ventricles and widening of the distance between the cerebral cortex and temporal meninges. Genetic testing revealed that she has harbored a heterozygous variant of NM_178014.4: c.217A>G (p.Met73Val) in the TUBB gene, which was unreported previously and predicted to be likely pathogenic based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). The child was diagnosed with Complex cortical dysplasia with other brain malformations 6 (CDCBM6).@*CONCLUSION@#CDCBM is a rare and serious disease with great genetic heterogeneity, and CDCBM6 caused by mutations of the TUBB gene is even rarer. Above finding has enriched the variant and phenotypic spectrum of the TUBB gene, and provided important reference for summarizing the genotype-phenotype correlation of the CDCBM6.

Curative effect analysis of transplantation in patients with myelodysplastic syndrome with ASXL1 gene mutation / 实用医学杂志

Objective To investigate the efficacy and influencing factors of allo-HSCT in the treatment of MDS patients with ASXL1+.Methods The second-generation sequencing technique was used to detect 22 gene mutations in 247 newly diagnosed MDS patients in our hospital.The patients were divided into chemotherapy group and transplant group according to treatment style.The differences of OS and PFS between the two groups were compared,and the influencing factors of prognosis of transplant patients were analyzed.Results ASXL1+ was detected in 75 patients(30.36%),with a median mutation ratio of 42.93(18.10,58.39)%,10 received supportive treatment,43 received demethylation therapy or demethylation combined with pre-excitation therapy,and 22 received allo-HSCT.2-year PFS rate and OS rate of transplantation group were significantly higher than that of chemotherapy group(P<0.05).The 2-year OS rate in the low ASXL1 mutation load group(VAF≤42.93%)was significantly higher than that in the high ASXL1 mutation load group(VAF>42.93%)(P<0.05).In the context of allo-HSCT in patients with ASXL1+,2-year OS and PFS rates were significantly reduced in patients with RUNX1+ or ASXL1+(P<0.05);Multivariate analysis showed that high mutation load of ASXL1 or U2AF1+ were independent risk factors for OS in transplant patient(P<0.05).U2AF1+ were the risk factors for PFS(P<0.05).Conclusion allo-HSCT significantly improved the prognosis of patients with ASXL1+ MDS.High ASXL1 mutation load or U2AF1+ were independent risk factors affecting the outcome of allo-HSCT.

Protective role for C3aR in experimental chronic pyelonephritis.

Emerging evidence suggest that C3aR plays important roles in homeostasis, host defense and disease. Although it is known that C3aR is protective in several models of acute bacterial infections, the role for C3aR in chronic infection is largely unknown. Here we show that C3aR is protective in experimental chronic pyelonephritis. Global C3aR deficient (C3ar-/- ) mice had higher renal bacterial load, more pronounced renal histological lesions, increased renal apoptotic cell accumulation, tissue inflammation and extracellular matrix deposition following renal infection with uropathogenic E. coli (UPEC) strain IH11128, compared to WT control mice. Myeloid C3aR deficient (Lyz2-C3ar-/- ) mice exhibited a similar disease phenotype to global C3ar-/- mice. Pharmacological treatment with a C3aR agonist reduced disease severity in experimental chronic pyelonephritis. Furthermore, macrophages of C3ar-/- mice exhibited impaired ability to phagocytose UPEC. Our data clearly demonstrate a protective role for C3aR against experimental chronic pyelonephritis, macrophage C3aR plays a major role in the protection, and C3aR is necessary for phagocytosis of UPEC by macrophages. Our observation that C3aR agonist curtailed the pathology suggests a therapeutic potential for activation of C3aR in chronic infection.

Cerebral venous sinus thrombosis caused by traumatic brain injury complicating thyroid storm: a case report and discussion.

INTRODUCTION: Cerebral venous sinus thrombosis (CVST) is an uncommon cerebrovascular disease with diverse predisposing factors. We report a case of CVST caused by a thyroid storm induced by traumatic brain injury. CASE PRESENTATION: A 29-year-old male patient with a history of Graves' disease with hyperthyroidism presented to our hospital with head trauma of cerebral contusion and laceration in both frontal lobes confirmed by admission CT scan. He received mannitol to lower intracranial pressure, haemostatic therapy, and antiepileptic treatment. Eight days later, he presented with signs of thyroid storms, such as tachycardia, hyperthermia, sweating and irritation, and his thyroid function tests revealed high levels of TPO-Ab, TR-Ab, TG-Ab, FT3 and FT4. Then, he entered a deep coma. His brain CT showed a thrombosis of multiple venous sinuses, along with the opening of peripheral collateral vessels, congestive infarction with haemorrhage and brain swelling. He regained consciousness after treatment with antithyroid drugs, anticoagulants, respiratory support and a regimen of sedation/analgesia. After a half-year follow-up, most of the patient's blocked cerebral venous sinuses had been recanalized, but there were still some sequelae, such as an impaired fine motor performance of the right hand and verbal expression defects. CONCLUSIONS: CVST can be induced by thyroid storms, and trauma-related thyroid storms can develop on the basis of hyperthyroidism. The purpose of this case report is to raise clinicians' awareness and improve their ability to diagnose CVST early in patients with traumatic brain injury complicating thyroid storms to improve the neurological prognosis among similar patients.