Pulmonary arterial hypertension (PAH) is a clinical hemodynamic syndrome characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance leading to right heart failure and death. Vascular remodeling is the most prominent histopathological feature of PAH, which is regulated by many factors. Endoplasmic reticulum stress, calcium disorder and mitochondrial dysfunction are involved in the vascular cell proliferation and apoptosis by regulating intracellular calcium homeostasis and cellular metabolism. Epigenetic phenomenon such as DNA damage and abnormal expression of miRNA are also involved in the regulation of abnormal proliferation of vascular cells. Vascular cell phenotype switching including endothelial-mesenchymal transition and smooth muscle cell phenotype switching play an important role in abnormal proliferation of vascular cells. Vascular remodeling is produced by a variety of cells and molecular pathways, and aiming at multiple targets which is expected to find a new breakthroug
To explore the expression, localization and regulatory effect on mitochondrial calcium signaling of Rictor in embryonic stem cell-derived cardiomyocytes (ESC-CMs). Classical embryonic stem cell cardiomyogenesis model was used for differentiation of mouse embryonic stem cells into cardiomyocytes. The location of Rictor in ESC-CMs was investigated by immunofluorescence and Western blot. The expression of Rictor in mouse embryonic stem cells was interfered with lentiviral technology, then the superposition of mitochondria and endoplasmic reticulum (ER) in ESC-CMs was detected with immunofluorescence method; the cellular ultrastructure of ESC-CMs was observed by transmission electron microscope; the mitochondrial calcium transients of ESC-CMs was detected by living cell workstation;immunoprecipitation was used to detect the interaction between 1,5,5-trisphosphate receptor (IP3 receptor, IP3R), glucose-regulated protein 75 (Grp75) and voltage-dependent anion channel 1 (VDAC1) in mitochondrial outer membrane; the e
To investigate the developmental characteristics of resilience in children aged 3-5, and to explore the relationship between temperament, parenting style and resilience. A total of 570 preschoolers aged 3-5 years in Hangzhou participated in this study. The children's teachers completed the assessment of the resilience scale of DECA-P2 (Devereux Early Childhood Assessment for Preschoolers Second Edition); the children's parents completed assessment of temperament questionnaire CBQ (Children's Behavior Questionnaire) and parenting style questionnaire PSDQ (Parenting Styles and Dimensions Questionnaire). Totally 432 valid questionnaires were retrieved with a recovery rate of 75.79%. The levels of initiative and self-regulation of 5-y children were higher than those of children aged 3 or 4 (all <0.01); the level of attachment/relationship of 5-y children was higher than that of children aged 4 ( <0.01); the levels of initiative and self-regulation of girls were higher than those of boys ( <0.05 or <0.01). The neg
To construct a three-dimensional structural model for the selectivity filter in the transient receptor pontential melastatin 8 (TRPM8) ion channel. In the Rosetta computational structural biology suite, multiple rounds of modeling with the kinematic loop closure algorithm were performed. After nine rounds of computational modeling, we obtained the models of the selectivity filter within the TRPM8 channel with the lowest energy and high convergence. The model showed that the sidechain of D918 points were away from the central ion permeation pathway, while the sidechains of Q914, D920 and T923 pointed towards it. The glycosylation site N934 was located outside the pore region and its side chain directed to the extracellular water environment. A three-dimensional structural model for the selectivity filter in the TRPM8 ion channel was constructed, which provides reliable structural information for exploring the mechanism of ion selectivity.
To explore the effects of intrauterine infection on early growth and neurobehavioral development in neonatal rats. (E. coli) was inoculated into uterine cervix of pregnant rats with gestation of 15 d to establish the intrauterine infection model, and the effect on the delivery of pregnant rats was observed. The neonatal rat brain tissue was stained with Hematoxylin-Eosin and the cerebral white matter damage was assessed. Immunohistochemical staining and Western blot analysis were performed to evaluate the expression of glial fibrillary acidic protein (GFAP), 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and neurofilament (NF) in pup brains. Birth weight and early growth development indices were monitored,and neurobehavioral tests were performed to access the change of neurobehavioral development in neonatal rats. The white blood cell count increased significantly in the uterus and placenta of the pregnant rats after intrauterine E. coli infection and no significant impact was observed on the delivery
As a non-invasive approach, sonogenetics is applied to control neuronal activity. The mechanosensitive channel(MSC), which has low threshold of responding to ultrasound, may be the alternative solution. Sonogenetics is the technique that activates the MSC expressed in targeted neurons by low intensity ultrasound, thus achieve the neuromodulation. In this review, we introduce the mechanosensitive channel of large conductance, transient receptor potential, channels of the two-pore-domain potassium family, Piezo and the recent progress on their application in sonogenetics.
Herpes simplex virus (HSV), including HSV-1 and HSV-2, is an important pathogen that can cause many diseases. Usually these diseases are recurrent and incurable. After lytic infection on the surface of peripheral mucosa, HSV can enter sensory neurons and establish latent infection during which viral replication ceases. Moreover, latent virus can re-enter the replication cycle by reactivation and return to peripheral tissues to start recurrent infection. This ability to escape host immune surveillance during latent infection and to spread during reactivation is a viral survival strategy and the fundamental reason why no drug can completely eradicate the virus at present. Although there are many studies on latency and reactivation of HSV, and much progress has been made, many specific mechanisms of the process remain obscure or even controversial due to the complexity of this process and the limitations of research models. This paper reviews the major results of research on HSV latency and reactivation, and dis
Ion channels mediate ion transport across membranes, and play vital roles in processes of matter exchange, energy transfer and signal transduction in living organisms. Recently, structural studies of ion channels have greatly advanced our understanding of their ion selectivity and gating mechanisms. Structural studies of voltage-gated potassium channels elucidate the structural basis for potassium selectivity and voltage-gating mechanism; structural studies of voltage-gated sodium channels reveal their slow and fast inactivation mechanisms; and structural studies of transient receptor potential (TRP) channels provide complex and diverse structures of TRP channels, and their ligand gating mechanisms. In the article we summarize recent progress on ion channel structural biology, and outlook the prospect of ion channel structural biology in the future.
To investigate the expression of Wilms'tumor 1 ( ) gene in patients with acute myeloid leukemia (AML), and to explore its application in predicting prognosis of AML in patients with wild or mutated nucleophosmin 1( ) and Fms-like tyrosine kinase 3-internal tandem duplication ( ). One hundred and sixty-seven newly diagnosed AML patients(exclued M3 type) were enrolled in this study. The survival of patients were analyzed with Kaplan-Meier method. The clinical data, laboratory findings and the survival of patients were analyzed and compared between patients with high expression (high- group) and those with low expression (low- group), as well as among the patients with or wild type and mutants. The overall response rates (ORR) in high- and low- groups were 65.9% (83/126) and 95.1% (39/41), respectively ( <0.01). Compared with the low- group, the high- group had lower 2-y overall survival (OS) rate (46.1% vs. 75.2%, <0.05) and 2-y disease free survival (DFS) rate (43.5% vs. 68.5%, <0.05). After induction chemothe
To investigate risk factors of death in newborns with congenital diaphragmatic hernia (CDH). A total of 126 newborns with CDH from June 2012 to September 2018 were enrolled. Concomitant malformations were recorded by descriptive analysis. Newborns received surgical treatment ( =120) for CDH were divided into survival group and fatal group. The risk factors of death were analyzed by univariate and multivariate logistic regression and the ROC curve with generated with relevant variables. There were 55 CDH newborns with concomitant malformations (43.7%), including 20 cases (15.9%) with multi-malformation. Logistic regression analysis showed that premature rupture of membranes (PROM), postoperative atelectasis, long duration of postoperative mechanical ventilation, postoperative high oxygenation index (OI) were related to death (all <0.05), and the delayed surgery was a protective factor ( <0.05). In ROC analysis of postoperative OI in predicting death, the area under the curve (AUC) was 0.841, with the cutoff va
Rifamycins, a group of bacterial RNA polymerase inhibitors, are the firstline antimicrobial drugs to treat tuberculosis. In light of the emergence of rifamycinresistant bacteria, development of new RNA polymerase inhibitors that kill rifamycinresistant bacteria with high bioavailability is urgent. Structural analysis of bacterial RNA polymerase in complex with inhibitors by crystallography and cryo-EM indicates that RNA polymerase inhibitors function through five distinct molecular mechanisms:inhibition of the extension of short RNA; competition with substrates; inhibition of the conformational change of the'bridge helix'; inhibition of clamp opening;inhibition of clamp closure. This article reviews the research progress of these five groups of RNA polymerase inhibitors to provide references for the modification of existing RNA polymerase inhibitors and the discovery of new RNA polymerase inhibitors.
Chemotherapy resistance is one of the biggest challenges in treatment of ovarian cancer. Mounting evidence shows that the exosomes shedding from tumor cells are considered to be involved in chemotherapy resistance of ovarian cancer by enhanced exosomal export of drugs, transferring RNAs or proteins and interfering with the bioactivity of therapeutic anti-tumor antibodies. In this review, we display the correlation between exosomes and chemotherapy resistance of ovarian cancer, the mechanism of exosomes involved in chemotherapy resistance of ovarian cancer, and discuss the potential clinical values of exosomes in chemotherapy resistance of ovarian cancer.
To investigate the mechanism of congenital paramyotonia caused by human skeletal muscle voltage-gated sodium channel hNav1.4 mutant I1363T. The conservation of the mutant site were detecled by using amino acid sequence alignment; the C-terminal mCherry fusion hNav1.4 was constructed, and the expression and distribution of wild type and hNav1.4 mutant I1363T were determined by confocal microscopy; the steady-state activation, fast inactivation and window current of wild type and hNav1.4 mutant I1363T were examined by whole-cell patch clamp. Alignment of the amino acid sequences revealed that Ile1363 is highly conserved in human sodium channels. There was no significant difference in expression level and distribution between wild type and I1363T. Although no significant differences were observed between I1363T mutant and wild type in the activation upon channel gating, the of voltage-dependence of fast inactivation of I1363T mutant[(-59.01±0.26) mV] shifted 9 mV towards depolarization as compared with wild type
G protein-coupled receptors(GPCRs)represent the largest class of cell surface receptors,mediating wide range of cellular and physiological processes through their transducers,G proteins and the-arrestins participate in almost all pathological processes. Recent technological advances are revolutionizing the utility of cryo-electron microscopy(cryo-EM),leading to a tremendous progress in the structural studies of biological macromolecules and cryo-EM has played a leading role in the structural biology of GPCR signaling complex. New discoveries of high-resolution threedimensional structures of GPCR signaling complexes based on cryo-EM have emerged vigorously,which depict the common structural characteristics of intermolecular interaction between GPCR and G protein complex-the conformational changes of the transmembrane helix 6 of receptors,and also demonstrate the structural basis of G protein subtype selectivity. Single-particle cryo-EM becomes an efficient tool for identifying the molecular mechanism of recept
Cellular senescence is a key factor driving age-related diseases. Recent studies have revealed that senescence-associated secretory phenotype, telomere attrition, epigenetic changes, and mitochondrial autophagy damage may mediate the pathogenesis of senescence-related idiopathic pulmonary fibrosis (IPF). Reducing the level of cellular senescence or clearing senescent cells can down-regulate the expression of fibrosis factors and alleviate the symptoms of IPF. In this review, we outlined the role and mechanism of cellular senescence in IPF.
To develop methods of extraction and purification of Cterminal NUDT9 homology domain of human transient receptor potential melastatin 2 (TRPM2) channel. After sonication and centrifuge of strain Rosetta (DE3) which was induced by isopropylthio-β-D-galactoside, GST-NUDT9-H was collected after the binding of supernatant with GST beads and eluted with reduced glutathione. Then the elution buffer containing fusion protein was purified by size exclusion chromatography after concentration and centrifuge. Finally, with the cleavage of thrombin and binding with the GST beads, NUDT9-H with high purity in supernatant was collected. The GST-NUDT9-H fusion protein was stabilized with lysis buffer containing 0.5% n-dodecyl -β-d-maltoside (DDM), and wash buffer containing 0.025% DDM in size-exclusion chromatography system, and finally the NUDT9-H with high purity was obtained after cleaved by thrombin (1 U/2 mg fusion protein) for 24 h. Due to the poor stability of NUDT9-H, it is necessary to add DDM in extraction and puri
To evaluate the efficacy and safety of digestive tract stent implantation under direct visual endoscopy without X-ray monitoring in the treatment of digestive tract stricture. The clinical data of patients undergoing digestive tract stent placement under direct visual endoscopy without X-ray monitoring in the First Affiliated Hospital of Zhejiang University School of Medicine from March 2003 to November 2017 were retrospectively analyzed. The process of procedures, the postoperative complications and the postoperative follow-up data were documented. The survival time of patients with malignant gastrointestinal stricture was compared between those with and without stent implantation. Among 562 patients, there were 310 cases of esophagus and cardia stricture, 40 cases of gastroduodenus stricture, 212 cases of colorectum stricture, and 63 cases with esophagus-tracheal fistula,esophagus-mediastinal fistula or anastomotic fistula. The stents were implanted successfully in 560 cases (99.64%) and the symptoms were a
To evaluate the long-term efficacy of percutaneous mechanical thrombectomy (PMT) combined with stent implantation in treatment of acute iliofemoral vein thrombosis. Seventy patients with acute iliac vein thrombosis were treated with PMT combined stent implantation in Ningbo No.2 Hospital from November 2015 to November 2017. During the follow-up, the improvement of blood flow was evaluated, the occurrence of post-thrombotic syndrome was assessed by the Villalta rating scale, and the stent patency was examined with lower extremity ultrasound or angiography. The blood flow was significantly improved after procedure in all 70 patients, including 62 cases (88.6%) of grade Ⅲ clearance, 5 cases (7.1%) of grade Ⅱ clearance, and 3 cases (4.3%) of grade Ⅰ clearance. No significant complications occurred during the treatment. The patients were followed up for (15.0±2.5) months. During the follow-up, 64 patients (91.4%) had unobstructed stents, and 9 patients (12.8%) had post-thrombotic syndrome. PMT combined with stent
To investigate the metabolic profiles of urine from mice with early-stage Alzheimer's disease (AD). Urine samples were collected from 13 mice of 16 weeks and 15 wild-type mice. H-NMR spectroscopy was acquired with a one-dimensional NOESY pulse sequence, and the integral values were imported to SIMCA-P+12.0 software for analysis. The metabonomic analysis showed that the metabolic profiles of the mice were significantly different from that of age-matched wild-type mice. The levels of 3-hydroxybutyrate, 2-hydroxybutyrate, succinic acid, 2-ketoglutaric acid, citric acid, cis-aconitic acid, fumaric acid decreased, and those of acetic acid, trimethylamine, taurine, creatinine, hippuric acid, formic acid, trigonelline, urea increased (all <0.05). Metabolic pathways including glucose metabolism and methylamine metabolism may be involved in the pathogenesis of early AD.