Genetics of primary ovarian insufficiency: new developments and opportunities

BACKGROUND Primary ovarian insufficiency (POI) is characterized by marked heterogeneity, but with a significant genetic contribution. Identifying exact causative genes has been challenging, with many discoveries not replicated. It is timely to take stock of the field, outlining the progress made, framing the controversies and anticipating future directions in elucidating the genetics of POI. METHODS A search for original articles published up to May 2015 was performed using PubMed and Google Scholar, identifying studies on the genetic etiology of POI. Studies were included if chromosomal analysis, candidate gene screening and a genome-wide study were conducted. articles identified were restricted to English language full-text papers. RESULTS Chromosomal abnormalities have long been recognized as a frequent cause of POI, with a currently estimated prevalence of 10?13%. Using the traditional karyotype methodology, monosomy X, mosaicism, X chromosome deletions and rearrangements, X-autosome translocations, and isochromosomes have been detected. Based on candidate gene studies, single gene perturbations unequivocally having a deleterious effect in at least one population include Bone morphogenetic protein 15 (BMP15), Progesterone receptor membrane component 1 (PGRMC1), and Fragile X mental retardation 1 (FMR1) premutation on the X chromosome; Growth differentiation factor 9 (GDF9), Folliculogenesis specific bHLH transcription factor (FIGLA), Newborn ovary homeobox gene (NOBOX), Nuclear receptor subfamily 5, group A, member 1 (NR5A1) and Nanos homolog 3 (NANOS3) seem likely as well, but mostly being found in no more than 1?2% of a single population studied. Whole genome approaches have utilized genome-wide association studies (GWAS) to reveal loci not predicted on the basis of a candidate gene, but it remains difficult to locate causative genes and susceptible loci were not always replicated. Cytogenomic methods (array CGH) have identified other regions of interest but studies have not shown consistent results, the resolution of arrays has varied and replication is uncommon. Whole-exome sequencing in non-syndromic POI kindreds has only recently begun, revealing mutations in the Stromal antigen 3 (STAG3), Synaptonemal complex central element 1 (SYCE1), minichromosome maintenance complex component 8 and 9 (MCM8, MCM9) and ATP-dependent DNA helicase homolog (HFM1) genes. Given the slow progress in candidate-gene analysis and relatively small sample sizes available for GWAS, family-based whole exome and whole genome sequencing appear to be the most promising approaches for detecting potential genes responsible for POI. CONCLUSION Taken together, the cytogenetic, cytogenomic (array CGH) and exome sequencing approaches have revealed a genetic causation in ?20?25% of POI cases. Uncovering the remainder of the causative genes will be facilitated not only by whole genome approaches involving larger cohorts in multiple populations but also incorporating environmental exposures and exploring signaling pathways in intragenic and intergenic regions that point to perturbations in regulatory genes and networks

Preparation of PVA-GO Composite Hydrogel and Effect of Ionic Coordination on Its Properties

This paper adopts a method combining hybrid self-assembly, cyclic freezing-thawing and annealing treatment to prepare polyvinyl alcohol (PVA) and graphene oxide (GO) composite hydrogel. Then, the PVA-GO composite hydrogels are re-swelled in different ionic solutions (NaCl, MgCl2, CaCl2 and AlCl3) to improve mechanical strength, toughness and wear resistance by the ionic coordination bonds. The microstructure and morphology are characterized by Fourier transforms infrared spectroscopy (FTIR), x-ray diffraction (XRD) and Scanning electron microscopy (SEM), finding that the internal structure is porous three-dimensional network. Mechanical experiments indicate that the composite hydrogel with GO content of 0.05 wt% immersed in MgCl2 solution displays the best mechanical properties overall. Its tensile strength can reach 11.10 MPa and the elastic modulus reaches 1.72 MPa, which is 175% and 85% higher than the pure PVA, respectively. Sliding friction experiments illustrate that the composite hydrogel immersed in AlCl3 solution exhibits the lowest friction coefficient, and the higher the valence state of metal cation is, the better the wear reduction effect is. We expect to enrich the development of PVA-GO hydrogels in tissue engineering through synergy of hydrogen bonds and ionic coordination bonds

Novel NR5A1 Missense Mutation in Premature Ovarian Failure: Detection in Han Chinese Indicates Causation in Different Ethnic Groups

Background The etiology of most premature ovarian failure (POF) cases is usually elusive. Although genetic causes clearly exist and a likely susceptible region of 8q22.3 has been discovered, no predominant explanation exists for POF. More recently, evidences have indicated that mutations in NR5A1 gene could be causative for POF. We therefore screened for mutations in the NR5A1 gene in a large cohort of Chinese women with non-syndromic POF. Methods Mutation screening of NR5A1 gene was performed in 400 Han Chinese women with well-defined 46,XX idiopathic non-syndromic POF and 400 controls. Subsequently, functional characterization of the novel mutation identified was evaluated in vitro. Results A novel heterozygous missense mutation [c.13T\u3eG (p.Tyr5Asp)] in NR5A1 was identified in 1 of 384 patients (0.26%). This mutation impaired transcriptional activation on Amh, Inhibin-a, Cyp11a1and Cyp19a1 gene, as shown by transactivation assays. However, no dominant negative effect was observed, nor was there impact on protein expression and nuclear localization. Conclusions This novel mutation p.Tyr5Asp, in a novel non-domain region, is presumed to result in haploinsufficiency. Irrespectively, perturbation in NR5A1 is not a common explanation for POF in Chinese

Autophagy protects against palmitate-induced apoptosis in hepatocytes

BACKGROUND: Non-alcoholic fatty liver disease, one of the most common liver diseases, has obtained increasing attention. Palmitate (PA)-induced liver injury is considered a risk factor for the development of non-alcoholic fatty liver disease. Autophagy, a cellular degradative pathway, is an important self-defense mechanism in response to various stresses. In this study, we investigated whether autophagy plays a protective role in the progression of PA-induced hepatocytes injury. RESULTS: Annexin V-FITC/PI staining by FCM analysis, TUNEL assay and the detection of PARP and cleaved caspase3 expression levels demonstrated that PA treatment prominently induced the apoptosis of hepatocytes. Meanwhile, treatment of PA strongly induced the formation of GFP-LC3 dots, the conversion from LC3I to LC3II, the decrease of p62 protein levels and the increase of autophagosomes. These results indicated that PA also induced autophagy activation. Autophagy inhibition through chloroquine pretreatment or Atg5shRNA infection led to the increase of cell apoptosis after PA treatment. Moreover, induction of autophagy by pretreatment with rapamycin resulted in distinct decrease of PA-induced apoptosis. Therefore, autophagy can prevent hepatocytes from PA-induced apoptosis. In the further study, we explored pathway of autophagy activation in PA-treated hepatocytes. We found that PA activated PKCα in hepatocytes, and had no influence on mammalian target of rapamycin and endoplasmic reticulum stress pathways. CONCLUSIONS: These results demonstrated that autophagy plays a protective role in PA-induced hepatocytes apoptosis. And PA might induce autophagy through activating PKCα pathway in hepatocytes

MiR-455 targeting SOCS3 improve liver lipid disorders in diabetic mice

MiR-455 has been verified a key regulator of brown adipose tissue and adipose tissue-specific overexpression of miR-455 (ap2-miR-455) mice could combat high-fat-diet-induced obesity. This study is to verify overexpression of miR-455 could ameliorate the lipid accumulation and metabolism in the liver of db/db diabetic mice and explore the potential mechanisms. Diabetic mice (db/db) and control mice (db/m) were randomly divided into four groups. After overexpression of miR-455 in the liver of db/db mice, the triglycerides level in both serum and liver decreased, the lipid deposit in liver was improved, the expression of fatty acid synthase, stearoyl-CoA desaturase 1, sterol regulatory element binding protein 1c (SREBP-1c) and acetyl-CoA carboxylase (ACCα) was also significantly down-regulated. TargetScan indicated that suppressor of cytokine signalling 3 (SOCS3) is predicated to target miR-455 and the protein of SOCS3 in the liver of db/db mice after intervention was significantly decreased. The dual luciferase reporter assay showed that SOCS3 was target gene of miR-455. In vitro, in Palmitate (PA)-stimulated human normal liver (LO2) cells, transfected miR-455 mimic could significantly inhibit the expression of SOCS3, while transfected miR-455 inhibitor could up-regulate the expression of SOCS3. Transfecting LO2 cells with siRNA of SOCS3 could significantly down-regulate the protein expression of SREBP-1c and ACCα. Our study showed that overexpression of miR-455 in the liver could improve lipid metabolism in diabetic mice by down-regulating its target gene SOCS3

Pleurorhizoxylon yixingense gen. et sp. nov., a Euphyllophyte Axis with Anatomically Preserved Adventitious Roots from the Late Devonian of South China

Premise of research. Rooting structures were major contributors to Devonian global change, but anatomically preserved plant roots are rare from this period. We report a new type of plant axis from the Upper Devonian strata of South China that contains a protostele, relatively extensive secondary xylem, and adventitious root traces. Methodology. The original specimens were fragmentary coalified axes, most of which were embedded in Epon resin, sectioned transversely and longitudinally, and ground into thin sections. The sections were observed and imaged with a light microscope. A few were observed directly with a scanning electron microscope. Pivotal results. The axis of this new plant, named Pleurorhizoxylon gen. nov., consists of a three-ribbed protostele and thick secondary xylem; the primary xylem is of apparent mesarch maturation, with a single protoxylem lacuna near the end of each rib. The secondary xylem has variable rays composed of parenchyma cells and has scalariform to elliptical bordered pits on both radial and tangential walls of the tracheids. The adventitious root traces are located opposite each primary xylem rib going through the wood; they are accompanied by large rays and cause significant accommodation (knotting) in the wood. Extraxylary portions are poorly preserved, and no cambium or secondary phloem has been found. Conclusions. The new plant has a unique combination of characters and demonstrates the anatomical basis for adventitious root growth present in a Devonian moniliform plant, other than cladoxylopsids, for the first time

An analytical model of college students’ self-assessed satisfaction with the effectiveness of online learning: a structural equation model integrating LICE and S-O-R models

BackgroundNowadays, e-learning significantly affects college students’ academic life. This study aims to examine the factors that influence college students’ satisfaction with online learning outcomes.MethodThe study population consisted of undergraduate students from Dalian Medical University, with a total of 715 college students participating in the study. Out of these participants, 602 valid questionnaires were obtained. Demographic data was analyzed using SPSS.22, and the data was cleaned and prepared for testing the research hypotheses. The proposed research framework was examined using structural equation modeling (SEM) through Smart-PLS 3.0.ResultsThe results of the study showed that student satisfaction with learning outcomes was positively correlated with several factors: quality of teacher instruction (β = 0.100, p < 0.0001), quality of e-learning platforms (β = 0.059, p < 0.0001), individual learner factors such as learning motivation (β = 0.112, p < 0.001), and e-learning environment (β = 0.469, p < 0.001). Additionally, self-learning efficacy (β = 0.081, p < 0.0001), learning strategies (β = 0.031, p < 0.001), and learning motivation (β = 0.039, p < 0.001) were found to have mediating effects.ConclusionUnderstanding the satisfaction of college students with the effect of e-learning holds great significance in coping with teaching methods in unexpected situations. It enables adjustments to teaching strategies, improvements to learning platforms, and mobilization of students’ motivation. Thus, it serves as a valuable reference in addressing unexpected teaching scenarios

Experimental and computational study on anti-gastric cancer activity and mechanism of evodiamine derivatives

Introduction: Human topoisomerase 1 (TOP1) is an important target of various anticancer compounds. The design and discovery of inhibitors targeting TOP1 are of great significance for the development of anticancer drugs. Evodiamine and thieno [2,3-d] pyridine hybrids show potential antitumor activity. Herein, the anti-gastric cancer activities of these hybrids were investigated.Methods: The inhibitory effects of different concentrations of ten evodiamine derivatives on the gastric cancer cell line SGC-7901 were assessed using a methyl thiazolyl tetrazolium assay. Compounds EVO-1 and EVO-6 strongly inhibited gastric cancer cell proliferation, with inhibition rates of 81.17% ± 5.08% and 80.92% ± 2.75%, respectively. To discover the relationship between the structure and activity of these two derivatives, density functional theory was used to investigate their optimized geometries, natural population charges, frontier molecular orbitals, and molecular electrostatic potentials. To clarify their anti-gastric cancer mechanisms, molecular docking, molecular dynamics simulations, and binding free energy calculations were performed against TOP1.Results: The results demonstrated that these compounds could intercalate into the cleaved DNA-binding site to form a TOP1–DNA–ligand ternary complex, and the ligand remained secure at the cleaved DNA-binding site to form a stable ternary complex. As the binding free energy of compound EVO-1 with TOP1 (−38.33 kcal·mol−1) was lower than that of compound EVO-6 (−33.25 kcal·mol−1), compound EVO-1 could be a more potent anti-gastric cancer agent than compound EVO-6.Discussion: Thus, compound EVO-1 could be a promising anti-gastric cancer drug candidate. This study may facilitate the design and development of novel TOP1 inhibitors