Tat-interactive protein 60 (Tip60) is a member of the MYST family, proteins of which are related by an atypical histone acetyltransferase (HAT) domain. Although Tip60 has been implicated in cellular activities including DNA repair, apoptosis, and transcriptional regulation, its function during embryonic development is unknown. We ablated the Tip60 gene (Htatip) from the mouse by replacing exons 1-9 with a neomycin resistance cassette. Development and reproduction of wild-type and heterozygous animals were normal. However, homozygous ablation of the Tip60 gene caused embryolethality near the blastocyst stage of development, as evidenced by inability of cells in Tip60-null blastocysts to hatch and survive in culture. Monitoring cell proliferation and death by detecting EdU-substituted DNA and TUNEL labeling revealed suppression of cell proliferation concomitant with increased cell death as Tip60-null cells attempted to hatch from blastocysts. These findings indicate that Tip60 is essential for cellular survival during the blastocyst-gastrula transition of embryogenesis.

Acute myelogenous leukemia (AML) is a high-risk hematopoietic malignancy caused by a variety of mutations, including genes encoding the cohesin complex. Recent studies have demonstrated that reduction in cohesin complex levels leads to enhanced self-renewal in hematopoietic stem and progenitors (HSPCs). We sought to delineate the molecular mechanisms by which cohesin mutations promote enhanced HSPC self-renewal since this represents a critical initial step during leukemic transformation. We verified that RNAi against the cohesin subunit Rad21 causes enhanced self-renewal of HSPCs in vitro through derepression of Polycomb Repressive Complex 2 (PRC2) target genes, including Hoxa7 and Hoxa9. Importantly, knockdown of either Hoxa7 or Hoxa9 suppressed self-renewal, implying both are critical downstream effectors of reduced cohesin levels. We further demonstrate that the cohesin and PRC2 complexes interact and are bound in close proximity to Hoxa7 and Hoxa9. Rad21 depletion resulted in decreased levels of H3K27me3 at the Hoxa7 and Hoxa9 promoters, consistent with Rad21 being critical to proper gene silencing by recruiting the PRC2 complex. Our data demonstrates that the cohesin complex regulates PRC2 targeting to silence Hoxa7 and Hoxa9 and negatively regulate self-renewal. Our studies identify a novel epigenetic mechanism underlying leukemogenesis in AML patients with cohesin mutations.

Effects of a computerized professional development (PD) program for a concept teaching routine were investigated in two studies. For each, teachers were randomly assigned to either a virtual workshop group that used a multimedia software program for PD or an actual workshop group that participated in a live PD session. In Study 1, the teachers’ knowledge about the routine and planning for the routine significantly improved after completing either workshop; no significant differences were found between the groups. Both teacher groups were satisfied with the PD. In Study 2, the teachers’ performance of the routine in their classrooms improved, as did student performance on tests of concept knowledge. Students were satisfied with the instruction provided by both groups of teachers. No differences were found between the posttest scores earned by the teacher groups or by students of the teachers. Implications regarding computerized PD for teachers are discussed.

Protocols have been established that direct differentiation of human pluripotent stem cells into a variety of cell types, including the endoderm and its derivatives. This model of differentiation has been useful for investigating the molecular mechanisms that guide human developmental processes. Using a directed differentiation protocol combined with shRNA depletion we sought to understand the role of GATA6 in regulating the earliest switch from pluripotency to definitive endoderm. We reveal that GATA6 depletion during endoderm formation results in apoptosis of nascent endoderm cells, concomitant with a loss of endoderm gene expression. We show by chromatin immunoprecipitation followed by DNA sequencing that GATA6 directly binds to several genes encoding transcription factors that are necessary for endoderm differentiation. Our data support the view that GATA6 is a central regulator of the formation of human definitive endoderm from pluripotent stem cells by directly controlling endoderm gene expression.

Named entity recognition (NER) is one of the best studied tasks in natural language processing. However, most approaches are not capable of handling nested structures which are common in many applications. In this paper we introduce a novel neural network architecture that first merges tokens and/or entities into entities forming nested structures, and then labels each of them independently. Unlike previous work, our merge and label approach predicts real-valued instead of discrete segmentation structures, which allow it to combine word and nested entity embeddings while maintaining differentiability. We evaluate our approach using the ACE 2005 Corpus, where it achieves state-of-the-art F1 of 74.6, further improved with contextual embeddings (BERT) to 82.4, an overall improvement of close to 8 F1 points over previous approaches trained on the same data. Additionally we compare it against BiLSTM-CRFs, the dominant approach for flat NER structures, demonstrating that its ability to predict nested structures does not impact performance in simpler cases. 1