Transcriptional and epigenetic mechanisms of the first cell fate decision and reprogramming

The placenta is a transient but vital organ mediating a myriad of interactions between maternal and embryonic tissues. The cells in the trophectoderm (TE) lineage are responsible for proper implantation, placentation, and immunological functions of the placenta. However, our understanding of molecular mechanisms underlying placentation and TE development is still rudimentary. Deciphering the mechanisms by which key TE-specific transcription factors (TFs) control the first cell fate decision, as well as the maintenance and differentiation of TE, is a prerequisite for understanding early embryonic development and ultimately improving healthy pregnancy. First, using a combination of functional genomics, bioinformatics, and mouse genetics, I revealed that Arid3a is a critical regulator for controlling the first cell fate decision and placental development. Ectopically expressed Arid3a induces TE-like gene expression programs in embryonic stem (ES) cells. Moreover, Arid3a is not only essential for maintaining self-renewing TS cells, but also for promoting further differentiation of trophoblastic lineages. Consistently, Arid3a-/- mice suffer from severely impaired post-implantation development, resulting in early embryonic lethality. I further showed that Arid3a directly activates TE-specific genes while repressing pluripotency genes by recruiting HDAC1. Second, I studied the mechanisms underlying TF-mediated conversion of ES to trophoblast stem (TS)-like cells. Upon overexpression of TS cell-specific TFs, Cdx2, Arid3a, and Gata3 (CAG factors) in ES cells, I performed time–course profiling of chromatin accessibility, transcriptomes, and occupancy of these reprogramming factors during reprogramming. Using an integrative analysis, I discovered that CAG factors orchestrate the conversion via a sequential two-step regulation in a timely, ordered manner, with repression of pluripotency genes by decommissioning active enhancers, followed by activation of TS cell-specific genes as pioneer factors that can access closed chromatin. Taken together, my studies unveiled that Arid3a functions as a pivotal regulator of TE and placental development by regulating the commitment to the first cell fate, as well as by executing TE lineage differentiation. I advanced our understanding of the mechanisms underlying TF-mediated reprogramming of ES to TS-like cells, in particular Arid3a-mediated transcriptional and epigenetic regulation. Thus, my studies will be beneficial for enhancing clinical applications such as disease modeling, drug screening, and regenerative therapies.Cellular and Molecular Biolog

Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations Associated with First-Line Stavudine-Containing Antiretroviral Therapy: Programmatic Implications for Countries Phasing Out Stavudine

Background The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. Methods We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. Results Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. Conclusions Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therap

Discutindo a educação ambiental no cotidiano escolar: desenvolvimento de projetos na escola formação inicial e continuada de professores

A presente pesquisa buscou discutir como a Educação Ambiental (EA) vem sendo trabalhada, no Ensino Fundamental e como os docentes desta escola compreendem e vem inserindo a EA no cotidiano escolar., em uma escola estadual do município de Tangará da Serra/MT, Brasil. Para tanto, realizou-se entrevistas com os professores que fazem parte de um projeto interdisciplinar de EA na escola pesquisada. Verificou-se que o projeto da escola não vem conseguindo alcançar os objetivos propostos por: desconhecimento do mesmo, pelos professores; formação deficiente dos professores, não entendimento da EA como processo de ensino-aprendizagem, falta de recursos didáticos, planejamento inadequado das atividades. A partir dessa constatação, procurou-se debater a impossibilidade de tratar do tema fora do trabalho interdisciplinar, bem como, e principalmente, a importância de um estudo mais aprofundado de EA, vinculando teoria e prática, tanto na formação docente, como em projetos escolares, a fim de fugir do tradicional vínculo “EA e ecologia, lixo e horta”.Facultad de Humanidades y Ciencias de la Educació

Nucleoside reverse transcriptase inhibitor resistance mutations associated with first-line stavudine-containing antiretroviral therapy: programmatic implications for countries phasing out stavudine.

International audienc

Correction: The 5th edition of The World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms (vol 36, pg 1720, 2022)

10.1038/s41375-023-01962-5LEUKEMIA3791944-195

J Exp Med

To investigate the role of Lyt-2 and Thy-1 in cytolysis, we have generated, by ethyl methanesulfonate mutagenesis and selection, variants of the cloned cytolytic T lymphocyte line L3 that specifically lack either Lyt-2 or Thy-1. An analysis of these variants indicates that neither Lyt-2 nor Lyt-3 is responsible for the lethal hit, but suggests that Lyt-2 and/or Lyt-3 are required for an antigen receptor functional in cytolysis. The data also suggest that the expression of Lyt-3 on the cell surface is not independent of the expression of Lyt-2. Finally the data indicate the Thy-1 plays no role in cytolysis.6788878PMC218609