Conformational States of Exchange Protein Directly Activated by cAMP (EPAC1) Revealed by Ensemble Modeling and Integrative Structural Biology.

Exchange proteins directly activated by cAMP (EPAC1 and EPAC2) are important allosteric regulators of cAMP-mediated signal transduction pathways. To understand the molecular mechanism of EPAC activation, we performed detailed Small-Angle X-ray Scattering (SAXS) analysis of EPAC1 in its apo (inactive), cAMP-bound, and effector (Rap1b)-bound states. Our study demonstrates that we can model the solution structures of EPAC1 in each state using ensemble analysis and homology models derived from the crystal structures of EPAC2.

High-Risk Human Papillomavirus E7 Maintains Stemness Via APH1B In Cervical Cancer Stem-Cell Like Cells.

Purpose: To determine whether early proteins from high-risk human papillomavirus (HPV) have the capacity to maintain cellular stemness.

Patients And Methods: First, we isolated cancer stem cell like cells from two cervical cancer cell lines, SiHa and CaSki, using non-adhesive culture with serum-free medium. Second, we knocked down HPV16 E7 in SiHa sphere cells and overexpressed HPV16 E7 in U2OS sphere cells.

Recent Advances in EPAC-Targeted Therapies: A Biophysical Perspective.

The universal second messenger cAMP regulates diverse intracellular processes by interacting with ubiquitously expressed proteins, such as Protein Kinase A (PKA) and the Exchange Protein directly Activated by cAMP (EPAC). EPAC is implicated in multiple pathologies, thus several EPAC-specific inhibitors have been identified in recent years. However, the mechanisms and molecular interactions underlying the EPAC inhibition elicited by such compounds are still poorly understood.

Crosstalk between Lys63- and Lys11-polyubiquitin signaling at DNA damage sites is driven by Cezanne.

The establishment of polyubiquitin conjugates with distinct linkages play important roles in the DNA damage response. Much remains unknown about the regulation of linkage-specific ubiquitin signaling at sites of DNA damage. Here we reveal that Cezanne (also known as Otud7B) deubiquitinating enzyme promotes the recruitment of Rap80/BRCA1-A complex by binding to Lys63-polyubiquitin and targeting Lys11-polyubiquitin.

Methamphetamine-Induced Cognitive Deficits and Psychiatric Symptoms Are Associated with Serum Markers of Liver Damage.

Cognitive deficits and psychiatric disorders have been regarded as the most common clinical symptoms of methamphetamine (MA) users. Accumulating evidence has shown that liver disease may be involved in cognitive deficits and psychiatric disorders. This study examines whether cognitive deficits and psychiatric symptoms are associated with serum levels of liver biomarkers in MA users.

Detection of DNA Modifications by Sequence-Specific Transcription Factors.

The establishment, detection, and alteration or elimination of epigenetic DNA modifications are essential to controlling gene expression ranging from bacteria to mammals. The DNA methylations occurring at cytosine and adenine are carried out by SAM-dependent methyltransferases. Successive oxidations of 5-methylcytosine (5mC) by Tet dioxygenases generate 5-hydroxymethyl (5hmC), 5-formyl (5fC), and 5-carboxyl (5caC) derivatives; thus, DNA elements with multiple methylation sites can have a wide range of modification states.

CircPLEKHM3 acts as a tumor suppressor through regulation of the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis in ovarian cancer.

Background: Emerging evidence has shown that circular RNAs (circRNAs) play essential roles in cancer biology and are potential biomarkers and targets for cancer therapy. However, the expression and function of circRNAs in ovarian carcinogenesis and its progression remain elusive.

Methods: RNA sequencing was performed to reveal circRNA expression profiles in ovarian cancerous and normal tissues.

The cell cycle-regulated DNA adenine methyltransferase CcrM opens a bubble at its DNA recognition site.

The Caulobacter crescentus cell cycle-regulated DNA methyltransferase (CcrM) methylates the adenine of hemimethylated GANTC after replication. Here we present the structure of CcrM in complex with double-stranded DNA containing the recognition sequence. CcrM contains an N-terminal methyltransferase domain and a C-terminal nonspecific DNA-binding domain.

Design, synthesis, and preliminary biological evaluation of catalpol propionates as antiaging drugs.

In this paper, catalpol propionylated analogs (CPs) were designed as drug ligands of glutathione peroxidase (GSH-Px) based on molecular docking (MD) using Surflex-Docking method. The calculated total scores (Total_score) and C log of CPs are higher than that of catalpol, which show that the CPs maybe served as potential lead compounds as new antiaging drugs. Furthermore, the maximum Total_score of isomers in one group CPs is often not that the molecule with minimum energy structure.

Finite element analysis of spiral plate and Herbert screw fixation for treatment of midshaft clavicle fractures.

Both spiral plate and Herbert screw fixations have been clinically adopted for treating midshaft displaced clavicle fractures. However, the biomechanical properties of the 2 implant fixations have not yet been thoroughly evaluated. Here we report the results of a finite element analysis of the biomechanical properties of midshaft clavicle fractures treated with Herbert screw and spiral plate fixation.

Structural basis for the target specificity of actin histidine methyltransferase SETD3.

SETD3 is an actin histidine-N methyltransferase, whereas other characterized SET-domain enzymes are protein lysine methyltransferases. We report that in a pre-reactive complex SETD3 binds the N-protonated form (N-H) of actin His73, and in a post-reactive product complex, SETD3 generates the methylated histidine in an N-protonated (N-H) and N-methylated form. During the reaction, the imidazole ring of His73 rotates ~105°, which shifts the proton from N to N, thus ensuring that the target atom N is deprotonated prior to the methyl transfer.

Reflection phase dispersion editing generates wideband invisible acoustic Huygens's metasurface.

Acoustic metasurfaces show non-traditional abilities in wave manipulation and provide alternate mechanisms for information communication and invisibility technology. However, most of the mechanisms remain narrow band (relative bandwidth ∼5%), and a wideband trait is essential for engineering applications. For example, controllable effective material properties-reflection or transmission phase-has barely been realized in wideband because the intrinsic dispersion relation is not always editable.

The value of hysteroscopy and transvaginal ultrasonography in the diagnosis of endometrial hyperplasia: a systematic review and meta-analysis.

Background: The systematic evaluation of the diagnostic value of hysteroscopy and transvaginal ultrasonography for endometrial hyperplasia.

Methods: A systematic search was performed using China Knowledge Network Database, Wanfang Chinese Database, China Biomedical Literature Database, China Science and Technology Journal Database, PubMed, Medline, The Cochrane Library, and web of science from their dates of inception to December 31, 2017, hysteroscopy and transvaginal ultrasonography were used for the diagnosis of endometrial lesions in those studies. Two researchers screened the literature, extracted data, and evaluated the methodological quality of the included studies independently based on the inclusion criteria.

[Preparation and chromatographic evaluation of zwitterionic stationary phases with controllable ratios of positively and negatively charged groups].

The present study focuses on the preparation and application of zwitterionic stationary phases with controllable ratios of positively charged amino groups and negatively charged phosphonic acid groups. Successful grafting was confirmed by elemental analysis and evaluation of pore structure characteristics. Additionally, the proportion of amino and phosphonic acid groups could be easily determined by the mass fractions of N and P.

Association of age and viral factors with high-risk HPV persistence: A retrospective follow-up study.

Objective: Cervical HR-HPV persistence is the main risk factor for cervical cancer. We aimed to investigate the association of age and viral factors with HR-HPV persistence.

Methods: From 2010 to 2017, 343,128 women underwent 390,411 tests performed by the Cervista HR-HPV assay (Data C3) and 157,123 women underwent 206,505 tests performed by the GenoArray HR-HPV assay (Data G14) in nine medical centers located in central and eastern China.

Structural basis of specific DNA binding by the transcription factor ZBTB24.

ZBTB24, encoding a protein of the ZBTB family of transcriptional regulators, is one of four known genes-the other three being DNMT3B, CDCA7 and HELLS-that are mutated in immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome, a genetic disorder characterized by DNA hypomethylation and antibody deficiency. The molecular mechanisms by which ZBTB24 regulates gene expression and the biological functions of ZBTB24 are poorly understood. Here, we identified a 12-bp consensus sequence [CT(G/T)CCAGGACCT] occupied by ZBTB24 in the mouse genome.

Prevalence and Characteristics of hrHPV Infection among 414,540 Women: A Multicenter Study in Central and Eastern China.

Understanding the prevalence and characteristics of high-risk human papillomavirus (hrHPV) with the large-scale multicenter data based on a US FDA-approved testing method is important to guide ongoing vaccination programs in China. We conducted a retrospective observational study based on data from 11 large hospitals in central and eastern China. From October 1st, 2012 to December 31st, 2016, a total of 480,034 cervical specimens were collected, and 414,540 eligible participants (14-80 years, mean age 39.

β-Cell-intrinsic β-arrestin 1 signaling enhances sulfonylurea-induced insulin secretion.

Beta-arrestin-1 and -2 (Barr1 and Barr2, respectively) are intracellular signaling molecules that regulate many important metabolic functions. We previously demonstrated that mice lacking Barr2 selectively in pancreatic beta-cells showed pronounced metabolic impairments. Here we investigated whether Barr1 plays a similar role in regulating beta-cell function and whole body glucose homeostasis.

Efficacy of hyperthermic intraperitoneal chemotherapy in patients with epithelial ovarian cancer: a meta-analysis.

The role of hyperthermic intraperitoneal chemotherapy (HIPEC) in epithelial ovarian cancer (EOC) is still controversial. Present analysis aims to evaluate the survival benefit of HIPEC in treatment of EOC patients. Articles related to 'HIPEC' and 'ovarian cancer' were comprehensively searched in four databases (PubMed, EMBASE, MEDLINE and Cochrane Library) up to 4 February 2018.

Synchronous occurrence of benign mesothelioma and adenomatoid tumor of uterus: A case report and review of literature.

Introduction: Synchronous occurrence of benign cystic mesothelioma and adenomatoid tumor of uterus (UAT) are very rare and few cases have been published in the English literature. They are easily misdiagnosed as malignant by clinicians, due to the lack of reports.

Patient Concerns: A case of benign mesothelial combined with uterus adenomatoid tumor (UAT) in a 48-year-old Chinese woman was reported.

Structural basis for preferential binding of human TCF4 to DNA containing 5-carboxylcytosine.

The psychiatric risk-associated transcription factor 4 (TCF4) is linked to schizophrenia. Rare TCF4 coding variants are found in individuals with Pitt-Hopkins syndrome-an intellectual disability and autism spectrum disorder. TCF4 contains a C-terminal basic-helix-loop-helix (bHLH) DNA binding domain which recognizes the enhancer-box (E-box) element 5'-CANNTG-3' (where N = any nucleotide).