Renewal of stem cells differs from cancer cell growth in self-controlled cell division. The mir-302 microRNA (miRNA) family (mir-302s) is expressed most abundantly in slow-growing human embryonic stem (ES) cells, and quickly decreases after cell differentiation and proliferation. Therefore, mir-302s was investigated as one of the key factors essential for maintenance of ES cell renewal and pluripotency in this study. The Pol-II-based intronic miRNA expression system was used to transgenically transfect the mir-302s into several human cancer cell lines. The mir-302 -transfected cells, namely, miRNA-induced pluripotent stem (mirPS) cells, not only expressed many key ES cell markers, such as Oct3/4, SSEA-3, SSEA-4 ,Sox2, and Nanog, but also had a highly demethylated genome similar to a reprogrammed zygotic genome. Microarray analyses further revealed that genomewide gene expression patterns between the mirPS and human ES H1 and H9 cells shared over 86% similarity. Using molecular guidance in vitro, these mirPS cells could differentiate into distinct tissue cell types, such as neuron-, chondrocyte-, fibroblast-, and spermatogonia-like primordial cells. Based on these findings, we conclude that mir-302s not only function to reprogram cancer cells into an ES-like pluripotent state but also to maintain this state under a feeder-free cultural condition, which may offer a great opportunity for therapeutic intervention.
Global demethylation is required for early zygote development to establish stem cell pluripotency, yet our findings reiterate this epigenetic reprogramming event in somatic cells through ectopic introduction of mir-302 function. Here, we report that induced mir-302 expression beyond 1.3-fold of the concentration in human embryonic stem (hES) H1 and H9 cells led to reprogramming of human hair follicle cells (hHFCs) to induced pluripotent stem (iPS) cells. This reprogramming mechanism functioned through mir-302-targeted co-suppression of four epigenetic regulators, AOF2 (also known as KDM1 or LSD1), AOF1, MECP1-p66 and MECP2. Silencing AOF2 also caused DNMT1 deficiency and further enhanced global demethylation during somatic cell reprogramming (SCR) of hHFCs. Re-supplementing AOF2 in iPS cells disrupted such global demethylation and induced cell differentiation. Given that both hES and iPS cells highly express mir-302, our findings suggest a novel link between zygotic reprogramming and SCR, providing a regulatory mechanism responsible for global demethylation in both events. As the mechanism of conventional iPS cell induction methods remains largely unknown, understanding this microRNA (miRNA)-mediated SCR mechanism may shed light on the improvements of iPS cell generation.
Recurrent somatic mutation of SRSF2, one of the RNA splicing machinery genes, has been identified in a substantial proportion of patients with myelodysplastic syndrome (MDS). However, the clinical and biologic characteristics of MDS with this mutation remain to be addressed. In this study, 34 (14.6%) of the 233 MDS patients were found to have SRSF2 mutation. SRSF2 mutation was closely associated with male sex (P ؍ .001) and older age (P < .001). It occurred concurrently with at least 1 additional mutation in 29 patients (85.3%) and was closely associated with RUNX1, IDH2, and ASXL1 mutations (P ؍ .004, P < .001, and P < .001, respectively). Patients with SRSF2 mutation had an inferior overall survival (P ؍ .010), especially in the lower risk patients. Further exploration showed that the prognostic impact of SRSF2 mutation might be attributed to its close association with old age. Sequential analyses in 173 samples from 66 patients showed that all SRSF2-mutated patients retained their original mutations, whereas none of the SRSF2-wild patients acquired a novel mutation during disease evolution. IntroductionPre-mRNA needs splicing process to become mature mRNA for further translation into proteins. The splicing of pre-mRNA, a highly regulated cascade of processes, is important for gene expression and genetic diversity; more than 90% of human genes undergo alternative splicing to make various protein isoforms for different biologic functions. 1,2 SRSF2, located at 17q25.1, encodes serine/arginine-rich splicing factor 2 that belongs to the serine/ arginine-rich protein family, important for splice-site selection, spliceosome assembly, and both constitutive and alternative splicing. 3 Recently, through next-generation whole exome sequencing, recurrent somatic mutations involving the RNA splicing machinery were identified in a substantial proportion of patients with myelodysplastic syndrome (MDS), 4-7 a myeloid hematopoietic disorder characterized by ineffective hematopoiesis, cytopenias, and risk of transformation to acute leukemia. 8,9 Among these mutations, the clinical relevance of 2 prevalent mutations, U2AF35 4,6,10 and SF3B1, 4,5,7,[11][12][13][14] have been explored. Mutations in SRSF2 also have been reported in MDS patients, 4,7,10,15,16 but studies concerning the clinical correlations of the mutations are limited. In addition, the interaction of SRSF2 mutation with other genetic alternations in MDS patients and its stability during disease progression remain to be determined.The pathogenesis of MDS has not been clearly identified; genomic damage with accumulation of genetic aberrations, 8,17 deregulated or autoreactive immune responses, 18,19 and abnormal bone marrow (BM) microenvironment 20,21 might all contribute to the development and progression of this preleukemic disease. Because the regulation of RNA splicing is important for normal cell function, genetic alternation in SRSF2 may play an important role in the pathogenesis of MDS. 4 Here, we aimed to define the clinical correlations of SRSF2 mut...
We report the crystal structures of the ligand-binding domain (LBD) of a rat inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) in its apo and InsP3-bound conformations. Comparison of these two conformations reveals that LBD's first β-trefoil fold (β-TF1) and armadillo repeat fold (ARF) move together as a unit relative to its second β-trefoil fold (β-TF2). Whereas apo-LBD may spontaneously transition between gating conformations, InsP3 binding shifts this equilibrium towards the active state.
Summary To date, the vast majority of the research on aggression has been conducted on Western samples. This research expands the culture‐bound understanding of aggression by examining universal and culture‐specific dimensions that underlie the psychological structure of aggression. Drawing on cultural logics of honor, dignity, and face, we examine the construal of aggression across Pakistan, Israel, Japan, and the United States. Multidimensional scaling analyses revealed potentially universal dimensions of aggression. In all four nations, dimensions of damage to self‐worth and direct versus indirect aggression emerged, and a physical versus verbal aggression emerged in Pakistan, Israel, and Japan. In addition, an infringement to personal resources dimension emerged in the United States and Israel, and a degree of threat dimension emerged in Pakistan. Further, results demonstrated cultural specificity in terms of (i) where aggressive behaviors fell along each dimension and (ii) meanings that defined each dimension across cultures. These findings have implications for the prevention and attenuation of intercultural conflicts as well as the advancement of the cross‐cultural psychology and the aggression literatures. Copyright © 2013 John Wiley & Sons, Ltd.
We aimed to analyze clinical impacts of the U2AF1 mutation on patients with myelodysplastic syndrome (MDS) and its stability during disease progression. We checked mutation status of the U2AF1 by direct sequencing in 478 de novo MDS patients and correlated with the clinical characteristics and outcomes. We also sequentially analyzed the U2AF1 mutation in 421 samples from 142 patients to determine its stability during the disease courses. Thirty-six patients (7.5%) were found to have U2AF1 mutations, which occurred more frequently in younger patients (P 5 0.033). U2AF1 mutation was an independent poor-risk factor for overall survival (OS) in all patients (P 5 0.030) and younger patients (P 5 0.041). U2AF1 mutation could also predict shorter time-to-leukemia transformation (TTL) in younger patients (P 5 0.020). In addition, U2AF1 mutation was associated with shorter TTL in lower-risk MDS patients. Sequential analyses showed all original U2AF1 mutations in U2AF1-mutated patients were retained during follow-ups unless complete remission was achieved, whereas none of the U2AF1-wild patients acquired a novel mutation during disease evolution. U2AF1 mutation is more prevalent in younger MDS patients and associated with inferior outcomes although it is stable during the clinical course. The mutation may be used as a biomarker for risk stratification. Am. J. Hematol. 88:E277-E282,
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