Requisite chromatin remodeling for myeloid and erythroid lineage differentiation from erythromyeloid progenitors

The mammalian SWitch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling BAF (BRG1/BRM-associated factor) complex plays an essential role in developmental and pathological processes. We show that the deletion of Baf155, which encodes a subunit of the BAF complex, in the Tie2(+) lineage (Baf155 (CKO) leads to defects in yolk sac myeloid and definitive erythroid (EryD) lineage differentiation from erythromyeloid progenitors (EMPs). The chromatin of myeloid gene loci in Baf155 CKO EMPs is mostly inaccessible and enriched mainly by the ETS binding motif. BAF155 interacts with PU.1 and is recruited to PU.1 target gene loci together with p300 and KDM6a. Treatment of Baf155 CKO embryos with GSK126, an H3K27me2/3 methyltransferase EZH2 inhibitor, rescues myeloid lineage gene expression. This study uncovers indispensable BAF-mediated chromatin remodeling of myeloid gene loci at the EMP stage. Future studies exploiting epigenetics in the generation and application of EMP derivatives for tissue repair, regeneration, and disease are warranted

Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing

Pancreatic adenocarcinoma (PAC) is among the most lethal malignancies. While research has implicated multiple genes in disease pathogenesis, identification of therapeutic leads has been difficult and the majority of currently available therapies provide only marginal benefit. To address this issue, our goal was to genomically characterize individual PAC patients to understand the range of aberrations that are occurring in each tumor. Because our understanding of PAC tumorigenesis is limited, evaluation of separate cases may reveal aberrations, that are less common but may provide relevant information on the disease, or that may represent viable therapeutic targets for the patient. We used next generation sequencing to assess global somatic events across 3 PAC patients to characterize each patient and to identify potential targets. This study is the first to report whole genome sequencing (WGS) findings in paired tumor/normal samples collected from 3 separate PAC patients. We generated on average 132 billion mappable bases across all patients using WGS, and identified 142 somatic coding events including point mutations, insertion/deletions, and chromosomal copy number variants. We did not identify any significant somatic translocation events. We also performed RNA sequencing on 2 of these patients' tumors for which tumor RNA was available to evaluate expression changes that may be associated with somatic events, and generated over 100 million mapped reads for each patient. We further performed pathway analysis of all sequencing data to identify processes that may be the most heavily impacted from somatic and expression alterations. As expected, the KRAS signaling pathway was the most heavily impacted pathway (P<0.05), along with tumor-stroma interactions and tumor suppressive pathways. While sequencing of more patients is needed, the high resolution genomic and transcriptomic information we have acquired here provides valuable information on the molecular composition of PAC and helps to establish a foundation for improved therapeutic selection

Down-Regulation of Yes Associated Protein 1 Expression Reduces Cell Proliferation and Clonogenicity of Pancreatic Cancer Cells

BACKGROUND: The Hippo pathway regulates organ size by inhibiting cell proliferation and promoting cell apoptosis upon its activation. The Yes Associated Protein 1 (YAP1) is a nuclear effector of the Hippo pathway that promotes cell growth as a transcription co-activator. In human cancer, the YAP1 gene was reported as amplified and over-expressed in several tumor types. METHODS: Immunohistochemical staining of YAP1 protein was used to assess the expression of YAP1 in pancreatic tumor tissues. siRNA oligonucleotides were used to knockdown the expression of YAP1 and their effects on pancreatic cancer cells were investigated using cell proliferation, apoptosis, and anchorage-independent growth assays. The Wilcoxon signed-rank, Pearson correlation coefficient, Kendall's Tau, Spearman's Rho, and an independent two-sample t (two-tailed) test were used to determine the statistical significance of the data. RESULTS: Immunohistochemistry studies in pancreatic tumor tissues revealed YAP1 staining intensities were moderate to strong in the nucleus and cytoplasm of the tumor cells, whereas the adjacent normal epithelial showed negative to weak staining. In cultured cells, YAP1 expression and localization was modulated by cell density. YAP1 total protein expression increased in the nuclear fractions in BxPC-3 and PANC-1, while it declined in HPDE6 as cell density increased. Additionally, treatment of pancreatic cancer cell lines, BxPC-3 and PANC-1, with YAP1-targeting siRNA oligonucleotides significantly reduced their proliferation in vitro. Furthermore, treatment with YAP1 siRNA oligonucleotides diminished the anchorage-independent growth on soft agar of pancreatic cancer cells, suggesting a role of YAP1 in pancreatic cancer tumorigenesis. CONCLUSIONS: YAP1 is overexpressed in pancreatic cancer tissues and potentially plays an important role in the clonogenicity and growth of pancreatic cancer cells

The Factuality Status of Chinese Necessity Modals. Exploring the Distribution Via Corpus-Based Approach

This paper is intended to test the deontic vs anankastic hypothesis outlined by Sparvoli 2012. The stipulation is that, in past contexts, deontic modals trigger a counterfactual inference, while anankastic modals (here called ‘goal-oriented modals’) either trigger an actuality entailment effects (‘only possibility’ modals) or a generic non-factual reading (‘mere necessity’ modals). The result of this corpus-based study conducted in a Chinese-English parallel corpus confirms the crucial role played by the deontic vs goal oriented contrast in the marking of factuality in Chinese and shows that the factuality value decreases across a cline from goal-oriented to deontic modals

In vitro inhibition of pathogenic Verticillium dahliae, causal agent of potato wilt disease in China by Trichoderma isolates

Twenty (20) of Verticillium dahliae were isolated from wilted potato specimens collected from six districts in Guizhou, China. All the isolates were evaluated for pathogenicity on two potato cultivars, Favorita (susceptible) and Hui-2 (resistant) using the root dip inoculation (RDI) and microsclerotia inoculation (MI). All of the V. dahliae isolates appeared to be pathogenic on both cultivars but VGZ-HZ-4 isolate gave the highest wilt incidence comparing to the others, seconded by VGZ-SC-1 and VGZ-XW-1. Combined analysis of wilt incidence resulting from using two inoculation methods for VGZ-HZ-4 and VGZ-XW-1 isolates on the two potato cultivars showed that the MI gave a higher wilt incidence than that of the RDI and cultivar Favorita had a higher wilt incidence than that of Hui-2. These two V. dahliae isolates were further used as representative isolates for mycelial inhibition (MyI) test with 33 Trichoderma isolates under a dual culture condition on potato dextrose agar plate. The 33 Trichoderma isolates consisting of 21 isolates isolated from potato soils from seven districts of Guizhou, 11 isolates from single spore isolates of the TGZ-150 isolate preserved at Guizhou Institute of Plant Protection (GZIPP) and one isolate TGZ-OLD-81 also preserved at the GZIPP. Most of the single spore isolates and TGZ-SC-4 were found to have higher MyI efficiency than that of the rest. The results indicate that the Trichoderma isolates in this study have initial modes of action of biological control to protect potato crop against V. dahlia.Keywords: Trichoderma, potato wilt disease, growth inhibition, Verticillium dahliae, antagonistic fungi.African Journal of Biotechnology, Vol 13(31) 3402-341