[Study of the types of mutations of Thalassemia in Shanghai area].

OBJECTIVE: To analyze the mutations of globin genes among patients suspected for thalassemia from the Shanghai area. METHODS: A total of 4 644 patients diagnosed at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine between June 2016 and December 2019 were selected as the study subjects. The patients were tested for common mutations associated with thalassemia gene by Gap-PCR and reverse dot blotting (RDB). Patients were suspected to harbor rare mutations based on the inconsistency between hematological phenotypes and results of common mutation detection, and were further analyzed by Gap-PCR and Sanger sequencing. RESULTS: Among the 4 644 patients, 2 194 (47.24%) were found to carry common thalassemia mutations, among which 701 (15.09%) were α-thalassemia, 1 448 (31.18%) were ß-thalassemia, and 45 (0.97%) were both α- and ß-thalassemia. Forty six samples were found to harbor rare mutations, which included 17 α-globin gene and 29 ß-globin gene mutations. CD77(CCC>ACC) (HBA2: c.232C>A) of the α-globin gene, NG_000007.3: g.70567_71015del449, codon 102(-A) (HBB: c.308_308delA) and IVS-Ⅱ-636 (A>G) (HBB: c.316-215A>G) of the ß-globin gene were previously unreported new types of globin gene mutations. CONCLUSION: Among the 4 644 patients, the detection rate for common thalassemia mutations was 47.24%, whilst 46 samples were detected with rare gene mutations. The type of gene mutation types were diverse in the Shanghai area. The study has provided more accurate results for genetic diagnosis and counseling.

Investigation analysis of the acute asthma risk factor and phenotype based on relational analysis with outdoor air pollutants in Xi'an, China.

Asthma is a common chronic heterogeneous disease. Outdoor air pollutants are an important cause of acute asthma. Until now, the association between the risk of acute asthma and outdoor air pollutants is unclear. And the relationship between the different phenotypes of asthma and outdoor air pollutants has not been reported. Thus, an analysis of the association between outdoor air pollutants and daily acute asthma inpatient and outpatient visits in Xi'an, China, from January 1 to December 31, 2018, was conducted. A total of 3395 people were included in the study. The statistical analysis and relational analysis based on the logistic regression were used for illustrating the relatedness of the acute asthma risk factor and phenotype with outdoor air pollutants, while the age, gender, pollen peak and non-pollen peak periods, high type 2 (T2) asthma and non-high T2 asthma were also stratified. Results showed that particulate matter with particle size below 10 µm and 2.5 µm (PM10 and PM2.5), sulfur dioxide(SO2), nitrogen dioxide(NO2), and carbon monoxide(CO) increase the risk of acute asthma and that air pollutants have a lagged effect on asthma patients. PM10, NO2, CO, and Ozone (O3) are associated with an increased risk of acute attacks of high T2 asthma. PM10, PM2.5, SO2, NO2 and CO are associated with an increased risk of acute asthma in males of 0-16 years old. PM10 and PM2.5 are more harmful to asthma patients with abnormal lung function.

Idiopathic Spontaneous Intra-Abdominal Hemorrhage or Abdominal Apoplexy: A Rare Cause of Abdominal Pain.

Idiopathic spontaneous intra-abdominal hemorrhage (ISIH) is a rare condition that can be catastrophic if not diagnosed and treated promptly. Herein, we report a case of ISIH due to suspected hemorrhage of the proximal branch of the superior mesenteric artery, which caused epigastric pain.

Clinical characterization and genomic landscape of gynecological cancers among patients attending a Chinese hospital.

Background: Gynecological cancers are the most lethal malignancies among females, most of which are associated with gene mutations. Few studies have compared the differences in the genomic landscape among various types of gynecological cancers. In this study, we evaluated the diversity of mutations in different gynecological cancers. Methods: A total of 184 patients with gynecological cancer, including ovarian, cervical, fallopian tube, and endometrial cancer, were included. Next-generation sequencing was performed to detect the mutations and tumor mutational burden (TMB). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were also conducted. Results: We found that 94.57% of patients had at least one mutation, among which single nucleotide variants, insertions and InDels were in the majority. TP53, PIK3CA, PTEN, KRAS, BRCA1, BRCA2, ARID1A, KMT2C, FGFR2, and FGFR3 were the top 10 most frequently mutated genes. Patients with ovarian cancer tended to have higher frequencies of BRCA1 and BRCA2 mutations, and the frequency of germline BRCA1 mutations (18/24, 75.00%) was higher than that of BRCA2 (11/19, 57.89%). A new mutation hotspot in BRCA2 (I770) was firstly discovered among Chinese patients with gynecological cancer. Patients with TP53, PIK3CA, PTEN, and FGFR3 mutations had significantly higher TMB values than those with wild-type genes. A significant cross was discovered between the enriched KEGG pathways of gynecological and breast cancers. GO enrichment revealed that the mutated genes were crucial for the cell cycle, neuronal apoptosis, and DNA repair. Conclusion: Various gynecological cancer types share similarities and differences both in clinical characterization and genomic mutations. Taken together with the results of TMB and enriched pathways, this study provided useful information on the molecular mechanism underlying gynecological cancers and the development of targeted drugs and precision medicine.

Protective Effects of Resveratrol Against Adenomyosis in a Mouse Model.

Adenomyosis is a uterine condition in which endometrial glands and stroma are commonly pathologically observed in the myometrium. In this study, we sought to determine the effect of resveratrol on the progression of adenomyosis. Adenomyosis was induced in mice given tamoxifen neonatally. All mice were subjected to body weight measurement and hotplate testing every four weeks beginning four weeks after birth. All mice with adenomyosis were randomly separated into 3 groups at 16 weeks: untreated, low-dose resveratrol (25 mg/kg), and high-dose resveratrol (50 mg/kg). After 3 weeks of treatment, final hotplate test and body weight measurement were performed, and the uterine horn blood samples were collected. Adenomyosis in mice caused body weight loss and uterine weight gain, reduced hotplate latency, and progression of endometrial fibrosis. The underlying biological process could be coupled with the overexpression of many cells' proliferation and immune-regulation-related genes. Resveratrol treatment could slow the progression of adenomyosis by enhancing hotplate latency, lowering endometrial fibrosis, and restoring cell proliferation- and immune-regulation-associated gene expression levels in endometrium and plasma. However, resveratrol treatment also reduced the body weight and uterine weight. In conclusion, Resveratrol might be a potential compound for treating patients with adenomyosis.

Preparation of 2D Materials and Their Application in Oil-Water Separation.

The problems of environmental pollution are increasingly severe. Among them, industrial wastewater is one of the primary sources of pollution, so it is essential to deal with wastewater, especially oil and water mixtures. At present, biomimetic materials with special wettability have been proven to be effective in oil-water separation. Compared with three-dimensional (3D) materials, two-dimensional (2D) materials show unique advantages in the preparation of special wettable materials due to their high specific surface area, high porosity, controlled structure, and rich functional group rich on the surface. In this review, we first introduce oil-water mixtures and the common oil-water separation mechanism. Then, the research progress of 2D materials in oil-water separation is presented, including but not limited to their structure, types, preparation principles, and methods. In addition, it is still impossible to prepare 2D materials with large sizes because they are powder-like, which greatly limits the application in oil-water separation. Therefore, we provide here a review of several ways to transform 2D materials into 3D materials. In the end, the challenges encountered by 2D materials in separating oil-water are also clarified to promote future applications.

PDMS/PVDF Electrospinning Membranes for Water-in-Oil Emulsion Separation and UV Protection.

With industry development, the separation of oily wastewater is becoming more critical. Inspired by organisms such as lotus leaves, biomimetic superhydrophobic surfaces with micro-nano structures have shown great potential in this regard. In this work, PDMS/PVDF oil-water separation membranes with designed microstructures were prepared by electrospinning technology. The membrane-forming effect of electrospinning with different ratios of PDMS and PVDF was studied. The study found that membranes with high PDMS content were more likely to form microspheres, and PDMS tended to concentrate on the microspheres. The results also showed that the microspheres would bring better hydrophobicity to the membrane. When the ratio of PDMS to PVDF is 1:2, the membrane has a water contact angle of up to 150° and an oil contact angle of 0°. At this ratio, the separation efficiency of the membrane for the water-in-oil emulsion is 98.7%, and it can still maintain more than 98% after ten separation cycles, which is a good candidate for oil-water separation. Furthermore, microspheres enable the membrane to achieve macroscopic uniformity and microscopic phase separation so that the membranes have both good elongation and fracture strength. In addition, the PDMS/PVDF membranes also exhibit excellent UV resistance, and their UV protection factor is greater than 185, making them a potential UV protective material.

Understanding Temporal Relations in Mandarin Chinese: An ERP Investigation.

Temporal connectives play a crucial role in marking the sequence of events during language comprehension. Although existing studies have shown that sentence comprehension can be modulated by temporal connectives, they have mainly focused on languages with grammatical tense such as English. It thus remains unclear how temporal information is processed in tenseless languages. The present study used event-related potentials (ERPs) to examine how world knowledge is retrieved and integrated in sentences linked by zhiqian (before) and zhihou (after) in Mandarin Chinese (e.g., After/Before going to the countryside, Grandpa went to the city because the air there was fresh and pure). The critical words (e.g., fresh) were either congruent or incongruent with world knowledge. Relative to the after-congruent sentences, the after-incongruent sentences evoked a P600 on critical words and a negativity on sentence-final words, whereas relative to before-congruent sentences, before-incongruent sentences showed no significant difference on critical words but a sustained negativity on sentence-final words. Additionally, before-congruent sentences elicited a larger sustained positivity (P600) than after-congruent sentences. The results suggest that before is more difficult to process than after in Mandarin Chinese, supporting the iconicity account of temporal relations.

Berberine attenuates hyperalgesia in mice with adenomyosis.

PURPOSE: Adenomyosis is a common gynecological disease, but its pathogenesis and treatment options are not yet completely clear. This study aimed to investigate the analgesic effect of berberine on tamoxifen-induced neonatal mouse adenomyosis and its curative effects on the disease. METHODS: The mouse adenomyosis model was established in neonatal female mice via oral administration of tamoxifen suspended solution. Adenomyosis mice were given berberine by intraperitoneal injection with the dosage of 5, 10, and 20 mg/kg body weight, respectively, at 17 weeks after birth. The pain sensation of the mice was evaluated by hotplate and tail-flick tests. The mRNA levels of gene expression were detected by RT-qPCR. The protein expression was analyzed by ELISA and Western blot. RESULTS: Berberine reduced the uterine weight, suppressed the myometrial infiltration of ectopic endometrium, improved the hotplate and tail-flick latency of the adenomyosis mice. Mechanistically, berberine downregulated the expression of genes related to pain and inflammation, such as TRPV1, COX-2, VEGF and OTR, impaired the inflammatory response at the DRG site, and inhibited the expression of TLR4 in DRG and uterine tissues. CONCLUSIONS: Berberine attenuates hyperalgesia and exhibits analgesic and therapeutic effects on adenomyosis mice.

Notch1 contributes to TNF-α-induced proliferation and migration of airway smooth muscle cells through regulation of the Hes1/PTEN axis.

Notch1 has been implicated in asthma pathogenesis. However, the function of Notch1 in regulating airway smooth muscle (ASM) cell proliferation and migration during airway remodeling of asthma remains unknown. Using an in vitro model induced by tumor necrosis factor (TNF)-α, we reported in this study that Notch1 participated in TNF-α-induced proliferation and migration of ASM cells. Our results demonstrated that Notch1 expression was significantly upregulated in ASM cells exposed to TNF-α. Notch1 inhibition significantly repressed TNF-α-induced ASM cell proliferation and migration, while Notch1 overexpression promoted the opposite effect. Moreover, Notch1 inhibition downregulated the expression of Notch-1 intracellular domain (NICD) and Hes1, while upregulated PTEN expression in TNF-α-exposed cells. Notably, Hes1 overexpression partially reversed the Notch1-inhibition-mediated inhibitory effect on TNF-α-induced ASM cell proliferation and migration. In addition, the promoting effect of Notch1 inhibition on PTEN expression was markedly abrogated by Hes1 overexpression. Overall, these findings demonstrated that Notch1 inhibition repressed TNF-α-induced ASM cell proliferation and migration by modulating the Hes1/PTEN signaling axis, a finding that highlights the involvement of Notch1/Hes1/PTEN in regulating airway remodeling of asthma.

PTEN participates in airway remodeling of asthma by regulating CD38/Ca2+/CREB signaling.

Both phosphatase and tensin homologue deleted on chromosome ten (PTEN) and cluster of differentiation 38 (CD38) have been suggested to be key regulators of the pathogenesis of asthma. However, the precise role and molecular mechanisms by which PTEN and CD38 are involved in airway remodeling throughout asthma pathogenesis remains poorly understood. This study aimed to elucidate the role of PTEN and CD38 in airway remodeling of asthma. Exposure to tumor necrosis factor-α (TNF-α) in airway smooth muscle (ASM) cells markedly decreased PTEN expression, and increased expression of CD38. Overexpression of PTEN suppressed the expression of CD38 and downregulated proliferation and migration induced by TNF-α stimulation, which was partially reversed by CD38 overexpression. PTEN/CD38 axis regulated Ca2+ levels and cyclic AMP response-element binding protein (CREB) phosphorylation in TNF-α-stimulated ASM cells. The in vitro knockdown of CD38 or overexpression of PTEN remarkably restricted airway remodeling and decreased Ca2+ concentrations and CREB phosphorylation in asthmatic mice. CD38 overexpression abolished the inhibitory effects of PTEN overexpression on airway remodeling. These findings demonstrate that PTEN inhibits airway remodeling of asthma through the downregulation of CD38-mediated Ca2+/CREB signaling, highlighting a key role of PTEN/CD38/Ca2+/CREB signaling in the molecular pathogenesis of asthma.

SETD7 promotes TNF-α-induced proliferation and migration of airway smooth muscle cells in vitro through enhancing NF-κB/CD38 signaling.

The inflammation-induced the excessive proliferation and migration of airway smooth muscle (ASM) cells in the airway wall contribute to airway remodeling in asthma pathogenesis. SET domain-containing lysine methyltransferase 7 (SETD7) has emerged as one of the key regulators of inflammation. Yet, the function of SETD7 in regulating inflammation-induced ASM cell proliferation and invasion remains unclear. In the present study, we aimed to investigate the function of SETD7 in regulating ASM cell proliferation and invasion induced by tumor necrosis factor (TNF)-α in vitro. Our results showed that SETD7 expression was upregulated in ASM cells stimulated with TNF-α. Silencing SETD7 significantly decreased TNF-α-induced ASM cell proliferation and migration, while SETD7 overexpression exhibited the opposite effect. Notably, silencing SETD7 decreased the activation of nuclear factor (NF)-κB and reduced the expression of CD38 induced by TNF-α. Blocking NF-κB activation significantly abrogated the promotional effect of SETD7 overexpression on CD38 expression. Moreover, overexpression of CD38 partially reversed the inhibitory effect of SETD7 silencing on TNF-α-induced ASM cell proliferation and migration. Overall, these results demonstrate that SETD7 regulates TNF-α-induced ASM cell proliferation and migration through modulation of NF-κB/CD38 signaling, suggesting a potential role of SETD7 in asthma airway remodeling.

Degradation of endogenous proteins and generation of a null-like phenotype in zebrafish using Trim-Away technology.

Trim-Away is a recent technique to rapidly deplete a protein from any cell type. Guided by antibodies, TRIM21 selects proteins for destruction. However, the applicability of this method in model organisms has not been investigated. Here, we show that Trim-Away can degrade proteins in zebrafish embryos. Trim-Away depletes proteins faster than morpholinos, which enables analysis of protein function during early embryogenesis. Furthermore, Trim-Away can be applied to evaluate the role of maternally contributed proteins in zebrafish embryos. Our findings indicate that Trim-Away is a powerful tool to perform functional analysis of proteins during zebrafish development.

The signaling pathways that mediate the anti-cancer effects of caloric restriction.

Caloric restriction (CR) has been shown to promote longevity and ameliorate aging-associated diseases, including cancer. Extensive research over recent decades has revealed that CR reduces IGF-1/PI3K/AKT signaling and increases sirtuin signaling. We recently found that CR also enhances ALDOA/DNA-PK/p53 signaling. In the present review, we summarize the molecular mechanisms underlying the modulation of the IGF-1/PI3K/AKT pathway, sirtuin signaling, and the ALDOA/DNA-PK/p53 pathway by CR. We also summarize the evidence concerning the roles of these signaling pathways in carcinogenesis, and discuss how they are regulated by CR. Finally, we discuss the crosstalk between these signaling pathways.

HPV16 E7-induced upregulation of KDM2A promotes cervical cancer progression by regulating miR-132-radixin pathway.

BACKGROUND: Human papillomavirus (HPV) infection and viral proteins expression cause a number of epigenetic alterations leading to cervical carcinogenesis. The recent discovery of a large amount of histone methylation modifiers reveals important roles of these enzymes in regulating tumor progression. METHODS: The changes in expression of 48 histone methylation modifiers were assessed following knockdown of HPV16 E7 in CaSki cells. Lysine-specific demethylase 2A (KDM2A)-regulated microRNAs (miRNAs) in cervical cancer pathogenesis were disclosed using quantitative real-time polymerase chain reaction. The function of KDM2A-miRNAs on cervical cancer was investigated in vitro and in vivo. RESULTS: Upregulation of KDM2A induced by HPV16 E7 promotes cervical cancer cell proliferation and invasion and is correlated with poor prognosis in patients with cervical cancer. KDM2A physically interacts with the promoter of miR-132 and suppresses its expression by removing the mono or dimethyl group from H3K36 at the miR-132 locus. Functionally, miR-132 represses cancer cell proliferation and invasion by inhibiting radixin (RDX). Upregulated KDM2A promotes cervical cancer progression by repressing miR-132, which results in a derepression of RDX. Therefore, KDM2A functions as a tumor activator in cervical cancer pathogenesis by binding miR-132 promoter and abrogating its tumor suppressive function. CONCLUSION: Our results suggest a function for KDM2A in cervical cancer progression and suggest its candidacy as a new prognostic biomarker and target for clinical management of cervical cancer.

Retracted Article: The nuclear export of TR3 mediated gambogic acid-induced apoptosis in cervical cancer cells through mitochondrial dysfunction.

At present, chemotherapy is still the main treatment for cervical cancer. However, the drug resistance of chemotherapy drugs seriously restricts its use, so it is urgent to develop new drugs for cervical cancer. Some studies have shown that gambogic acid has a strong anti-tumor effect, while the anti-tumor effect and molecular mechanism of gambogic acid on cervical cancer need to be studied. Our study confirms that the cytotoxic effect of gambogic acid on cervical cancer cells depends on the expression of TR3 protein. Moreover, gambogic acid-induced apoptosis requires TR3 expression. In the mechanism, gambogic acid promoted nuclear export of TR3, resulting in up-regulation of p53, which leads to the decrease of mitochondrial membrane potential, eventually inducing apoptosis. These results suggest that the nuclear export of TR3 mediated gambogic acid-induced apoptosis through a p53-dependent apoptosis pathway.

MicroRNA-218-5p inhibits cell growth and metastasis in cervical cancer via LYN/NF-κB signaling pathway.

BACKGROUND: We are committed to investigate miR-218-5 effects on the progression of cervical cancer (CC) cell and find out the molecular mechanism. METHODS: GSE9750 was obtained from GEO database and R Limma package was applied to filter out dysregulated genes. The pathways were enriched by GSEA software, ClusterProfiler and enrichplot packages to predict the function of DEGs. The binding sites of LYN were detected by miRanda and TargetScan. The miR2Disease database was used to find miRNAs related with CC. The expression of miR-218-5p and LYN were quantified by qRT-PCR and that of LYN protein was measured by western blot. The targeted relationships between miR-218-5p and LYN were verified by dual-luciferase reporter assay. Colony formation assays, wound healing, transwell invasion assay and flow cytometer analysis were performed to investigate the roles that miR-218-5p and LYN played in migration, invasion and death of cervical carcinoma. Xenografts established in nude mice were used to assess tumor growth in vivo. RESULTS: The highly expressed mRNA LYN was selected by microarray analysis in GSE9750. NF-κB signaling pathway was enriched base on GSEA results. The expression of miR-218-5p was lower but LYN was higher in CC primary tumors compared with normal control. In addition, miR-218-5p could regulate the expression of LYN in HeLa cells negatively. Overexpression of LYN could promote cell migration and invasion, but inhibit cell death in vitro, and also promote tumor formation in vivo via activating NF-κB signaling pathway which could be reversed by miR-218-5p. CONCLUSIONS: MiR-218-5p suppressed the progression of CC via LYN/NF-κB signaling pathway.

miR-133a acts as a tumor suppressor in colorectal cancer by targeting eIF4A1.

Emerging evidence indicates that microRNAs play critical roles in carcinogenesis and cancer progression. In this study, miR-133a was found to be significantly downregulated in colon tumor tissues. We aimed to determine its biological function, molecular mechanisms, and direct target genes in colorectal cancer. From these results, we found that miR-133a was significantly downregulated in primary tumor tissues and colon cancer cell lines. Ectopic expression of miR-133a in colon cancer cell lines significantly suppressed cell growth, as evidenced by cell viability and colony formation assays, as well as reduced xenograft tumor growth in nude mice. However, the effect of miR-133a was abolished by the overexpression of eIF4A1. Moreover, miR-133a inhibited cellular migration and invasiveness. A luciferase activity assay revealed oncogene eukaryotic translation initiation factor 4A1 as a direct target gene of miR-133a, whose expression was inversely correlated with that of miR-133a. Our results demonstrate that miR-133a plays a pivotal role in colorectal cancer by inhibiting cell proliferation, invasion, and migration by targeting oncogenic eukaryotic translation initiation factor 4A1, which acts as a tumor suppressor and may provide a new potential therapeutic target in colorectal cancer.

In vitro and in vivo comparison of binary Mg alloys and pure Mg.

Biodegradable materials are under investigation due to their promising properties for biomedical applications as implant material. In the present study, two binary magnesium (Mg) alloys (Mg2Ag and Mg10Gd) and pure Mg (99.99%) were used in order to compare the degradation performance of the materials in in vitro to in vivo conditions. In vitro analysis of cell distribution and viability was performed on discs of pure Mg, Mg2Ag and Mg10Gd. The results verified viable pre-osteoblast cells on all three alloys and no obvious toxic effect within the first two weeks. The degradation rates in in vitro and in vivo conditions (Sprague-Dawley® rats) showed that the degradation rates differ especially in the 1st week of the experiments. While in vitro Mg2Ag displayed the fastest degradation rate, in vivo, Mg10Gd revealed the highest degradation rate. After four weeks of in vitro immersion tests, the degradation rate of Mg2Ag was significantly reduced and approached the values of pure Mg and Mg10Gd. Interestingly, after 4 weeks the estimated in vitro degradation rates approximate in vivo values. Our systematic experiment indicates that a correlation between in vitro and in vivo observations still has some limitations that have to be considered in order to perform representative in vitro experiments that display the in vivo situation.