Heterogeneous Nuclear Ribonucleoprotein L is required for the survival and functional integrity of murine hematopoietic stem cells

The proliferation and survival of hematopoietic stem cells (HSCs) has to be strictly coordinated to ensure the timely production of all blood cells. Here we report that the splice factor and RNA binding protein hnRNP L (heterogeneous nuclear ribonucleoprotein L) is required for hematopoiesis, since its genetic ablation in mice reduces almost all blood cell lineages and causes premature death of the animals. In agreement with this, we observed that hnRNP L deficient HSCs lack both the ability to self-renew and foster hematopoietic differentiation in transplanted hosts. They also display mitochondrial dysfunction, elevated levels of γH2AX, are Annexin V positive and incorporate propidium iodide indicating that they undergo cell death. Lin-c-Kit+ fetal liver cells from hnRNP L deficient mice show high p53 protein levels and up-regulation of p53 target genes. In addition, cells lacking hnRNP L up-regulated the expression of the death receptors TrailR2 and CD95/Fas and show Caspase-3, Caspase-8 and Parp cleavage. Treatment with the pan-caspase inhibitor Z-VAD-fmk, but not the deletion of p53, restored cell survival in hnRNP L deficient cells. Our data suggest that hnRNP L is critical for the survival and functional integrity of HSCs by restricting the activation of caspase-dependent death receptor pathways

Проектирование системы электроснабжения базы по обслуживанию нефтегазодобывающего месторождения

Выпускная квалификационная работа 136 с., 19 рис., 60 табл., 24 источника, 4 приложения. Объектом исследования является ремонтно-механический цех базы по обслуживанию нефтегазодобывающего месторождения. Цель работы: Проектирование системы электроснабжения базы по облуживанию нефтегазодобывающего месторождения. Экономическое обоснование принятых решений. В процессе исследования произведен расчет нагрузок ремонтно-механического цеха и базы в целом с применением различных методов, выбор метода расчета производился на основе исходных данных, а также осуществлен выборThis graduate qualification work includes 136 p., 19 fig., 60 tables, 24 ones in list of references and 4 transcripts. The subject of research is mechanical repair shop of upstream and gas production field operation base. Work objective is energy supply system designing of upstream and gas production field operation base and its business case. In the course of investigations there was estimated a load analysis of upstream and gas production field operation base and its mechanical repair shop by different methods, based on input data. Also there were steps of the equipment selection and its testing of several operations. As a result of investigation the model of such base was engineered, and there was shown its commercial importance and ecological security. Range of application: petro

GFI1 is required for RUNX1/ETO positive acute myeloid leukemia

Contains fulltext : 196389.pdf (publisher's version ) (Open Access

Growth factor independent 1b (Gfi1b) and a new splice variant of Gfi1b are highly expressed in patients with acute and chronic leukemia.

Item does not contain fulltextGfi1b is a transcriptional repressor that is essential for erythroid cells and megakaryocytes, but is also expressed in hematopoietic stem cells and early myeloid progenitors. The chromosomal localization of the Gfi1b gene at 9q34 and its functional homology with the proto-oncogene Gfi1 were suggestive for a role of Gfi1b in malignant transformation and myeloid leukemia. We show here that the expression of Gfi1b is strongly elevated in CML and AML patients compared to normal healthy controls and that imatinib, a drug widely used to treat CML, further enhances Gfi1b expression in patients even after remission. Our data suggest that Gfi1b may be an important factor to establish or maintain myeloid leukemia and myeloproliferative diseases and that, high expression levels of Gfi1b might be associated with the emergence of Philadelphia chromosome negative myeloid malignancies after imatinib withdrawal or after the development of imatinib resistance

Auxiliary splice factor U2AF26 and transcription factor Gfi1 cooperate directly in regulating CD45 alternative splicing.

Contains fulltext : 50839.pdf (publisher's version ) (Closed access)By alternative splicing, different isoforms of the transmembrane tyrosine phosphatase CD45 are generated that either enhance or limit T cell receptor signaling. We report here that CD45 alternative splicing is regulated by cooperative action of the splice factor U2AF26 and the transcription factor Gfi1. U2AF26 promoted formation of the less-active CD45RO by facilitating exon exclusion. Gfi1 antagonized that process by directly interacting with U2AF26, identifying a previously unknown link between a transcription factor and alternative splicing. The presence of Gfi1 led to formation of the more-active CD45RB, whereas loss of Gfi1 favored CD45RO production. We propose that the relative abundance of U2AF26 and Gfi1 determines the ratio of CD45 isoforms, thereby regulating T cell activation

Evidence that Growth factor independence 1b regulates dormancy and peripheral blood mobilization of hematopoietic stem cells

Donor-matched transplantation of hematopoietic stem cells (HSCs) is widely used to treat hematologic malignancies but is associated with high mortality. The expansion of HSC numbers and their mobilization into the bloodstream could significantly improve therapy. We report here that adult mice conditionally deficient for the transcription Growth factor independence 1b (Gfi1b) show a significant expansion of functional HSCs in the bone marrow and blood. Despite this expansion, Gfi1bko/ko HSCs retain their ability to self-renew and to initiate multilineage differentiation but are no longer quiescent and contain elevated levels of reactive oxygen species. Treatment of Gfi1bko/ko mice with N-acetyl-cystein significantly reduced HSC numbers indicating that increased reactive oxygen species levels are at least partially responsible for the expansion of Gfi1b-deficient HSCs. Moreover, Gfi1b−/− HSCs show decreased expression of CXCR4 and Vascular cell adhesion protein-1, which are required to retain dormant HSCs in the endosteal niche, suggesting that Gfi1b regulates HSC dormancy and pool size without affecting their function. Finally, the additional deletion of the related Gfi1 gene in Gfi1bko/ko HSCs is incompatible with the maintenance of HSCs, suggesting that Gfi1b and Gfi1 have partially overlapping functions but that at least one Gfi gene is essential for the generation of HSCs