THE ROLE OF THE TRANSCRIPTION FACTOR PU.l IN REGULATION OF SELF-RENEWAL IN ACUTE MYELOID LEUKEMIA

Acute Myeloid Leukemia (AML) is associated with reduced levels or activity of the transcription factor PU.l in mice and humans. However, little is known about how reduced levels of this essential regulator of hematopoiesis causes AML. We hypothesize that reduced levels of PU.l cause AML by promoting self-renewal of myeloid progenitors through cell-cycle deregulation. Using mice homozygous for an allele of PU.l (encoded by Sfpil) which expresses PU.l at -20% of normal levels (Sfpilm/m), we show that these mice are runted and display an abnormal skeletal phenotype. This is due to an absence of TRAP+osteoclasts and a failure to upregulate p57kip2in chrondrocytes. In addition to the skeletal phenotype, a large expansion of immature myeloid cells occurs in the spleen of newborn SfpilBWm mice suggesting unregulated cell cycle in vivo. SfpilBN/BNmyeloid precursors had indefinite colony formation ability when grown in differentiating media, which suggests self-renewal. Next, restoration of PU.l using a retroviral vector opposed self-renewal and promoted differentiation in vitro seen by an increase in CDlib and a decrease in c-Kit levels. We have identified E2fl as a target gene of PU. 1, which regulates cell cycle progression. This model system will allow us to further understand the mechanisms behind hematopoiesis and leukemia. Manipulation of PU.l levels might be used as a treatment to promote myeloid differentiation and cell cycle arrest

Deletion of genes encoding PU.1 and Spi-B in B cells impairs differentiation and induces pre-B cell acute lymphoblastic leukemia

The E26 transformation-specific (Ets) transcription factor PU.1 is required to generate lymphoid progenitor cells from hematopoietic stem cells, but it is not required to generate B cells from committed B-cell lineage progenitors.We hypothesized that PU.1 function in B-cell differentiation is complemented by the related Ets transcription factor Spi-B. To test this hypothesis, mice were generated lacking both PU.1 and Spi-B in the B-cell lineage. Unlike mice lacking PU.1 or Spi-B, mice deficient in both PU.1 and Spi-B in the B-cell lineage had reduced frequencies of B cells as well as impaired B-cell differentiation. Strikingly, all PU.1 and Spi-B-deficient mice developed pre-B cell acute lymphoblastic leukemia before 30 weeks of age. Pre-B cells accumulated in the thymus resulting in massive thymic enlargement and dyspnea. These findings demonstrate that PU.1 and Spi-B are essential transcriptional regulators of B-cell differentiation as well as novel tumor suppressors in the B-cell lineage. © 2011 by The American Society of Hematology

Towards a new image processing system at Wendelstein 7-X: From spatial calibration to characterization of thermal events

Wendelstein 7-X (W7-X) is the most advanced fusion experiment in the stellarator line and is aimed at proving that the stellarator concept is suitable for a fusion reactor. One of the most important issues for fusion reactors is the monitoring of plasma facing components when exposed to very high heat loads, through the use of visible and infrared (IR) cameras. In this paper, a new image processing system for the analysis of the strike lines on the inboard limiters from the first W7-X experimental campaign is presented. This system builds a model of the IR cameras through the use of spatial calibration techniques, helping to characterize the strike lines by using the information given by real spatial coordinates of each pixel. The characterization of the strike lines is made in terms of position, size, and shape, after projecting the camera image in a 2D grid which tries to preserve the curvilinear surface distances between points. The description of the strike-line shape is made by means of the Fourier Descriptors

Forward modeling of collective Thomson scattering for Wendelstein 7-X plasmas: Electrostatic approximation

In this paper, we present a method for numerical computation of collective Thomson scattering (CTS). We developed a forward model, eCTS, in the electrostatic approximation and benchmarked it against a full electromagnetic model. Differences between the electrostatic and the electromagnetic models are discussed. The sensitivity of the results to the ion temperature and the plasma composition is demonstrated. We integrated the model into the Bayesian data analysis framework Minerva and used it for the analysis of noisy synthetic data sets produced by a full electromagnetic model. It is shown that eCTS can be used for the inference of the bulk ion temperature. The model has been used to infer the bulk ion temperature from the first CTS measurements on Wendelstein 7-X

Magnetic configuration effects on the Wendelstein 7-X stellarator

The two leading concepts for confining high-temperature fusion plasmas are the tokamak and the stellarator. Tokamaks are rotationally symmetric and use a large plasma current to achieve confinement, whereas stellarators are non-axisymmetric and employ three-dimensionally shaped magnetic field coils to twist the field and confine the plasma. As a result, the magnetic field of a stellarator needs to be carefully designed to minimize the collisional transport arising from poorly confined particle orbits, which would otherwise cause excessive power losses at high plasma temperatures. In addition, this type of transport leads to the appearance of a net toroidal plasma current, the so-called bootstrap current. Here, we analyse results from the first experimental campaign of the Wendelstein 7-X stellarator, showing that its magnetic-field design allows good control of bootstrap currents and collisional transport. The energy confinement time is among the best ever achieved in stellarators, both in absolute figures (τE > 100 ms) and relative to the stellarator confinement scaling. The bootstrap current responds as predicted to changes in the magnetic mirror ratio. These initial experiments confirm several theoretically predicted properties of Wendelstein 7-X plasmas, and already indicate consistency with optimization measures

Major results from the first plasma campaign of the Wendelstein 7-X stellarator

After completing the main construction phase of Wendelstein 7-X (W7-X) and successfully commissioning the device, first plasma operation started at the end of 2015. Integral commissioning of plasma start-up and operation using electron cyclotron resonance heating (ECRH) and an extensive set of plasma diagnostics have been completed, allowing initial physics studies during the first operational campaign. Both in helium and hydrogen, plasma breakdown was easily achieved. Gaining experience with plasma vessel conditioning, discharge lengths could be extended gradually. Eventually, discharges lasted up to 6 s, reaching an injected energy of 4 MJ, which is twice the limit originally agreed for the limiter configuration employed during the first operational campaign. At power levels of 4 MW central electron densities reached 3  ×  1019 m−3, central electron temperatures reached values of 7 keV and ion temperatures reached just above 2 keV. Important physics studies during this first operational phase include a first assessment of power balance and energy confinement, ECRH power deposition experiments, 2nd harmonic O-mode ECRH using multi-pass absorption, and current drive experiments using electron cyclotron current drive. As in many plasma discharges the electron temperature exceeds the ion temperature significantly, these plasmas are governed by core electron root confinement showing a strong positive electric field in the plasma centre

Major results from the first plasma campaign of the Wendelstein 7-X stellarator

After completing the main construction phase of Wendelstein 7-X (W7-X) and successfully commissioning the device, first plasma operation started at the end of 2015. Integral commissioning of plasma start-up and operation using electron cyclotron resonance heating (ECRH) and an extensive set of plasma diagnostics have been completed, allowing initial physics studies during the first operational campaign. Both in helium and hydrogen, plasma breakdown was easily achieved. Gaining experience with plasma vessel conditioning, discharge lengths could be extended gradually. Eventually, discharges lasted up to 6 s, reaching an injected energy of 4 MJ, which is twice the limit originally agreed for the limiter configuration employed during the first operational campaign. At power levels of 4 MW central electron densities reached 3 1019 m-3, central electron temperatures reached values of 7 keV and ion temperatures reached just above 2 keV. Important physics studies during this first operational phase include a first assessment of power balance and energy confinement, ECRH power deposition experiments, 2nd harmonic O-mode ECRH using multi-pass absorption, and current drive experiments using electron cyclotron current drive. As in many plasma discharges the electron temperature exceeds the ion temperature significantly, these plasmas are governed by core electron root confinement showing a strong positive electric field in the plasma centre.Peer reviewe