Chromatin dynamics during differentiation of myeloid cells

Cellular commitment to differentiation requires a tightly synchronized, spatial-temporal interaction of regulatory proteins with the basic DNA and chromatin. A complex network of mechanisms, involving induction of lineage instructive transcription factors, installation or removal of histone modifications and changes in the DNA methylation pattern locally orchestrate the three dimensional chromatin structure and determine cell fate. Maturation of myeloid lineages from haematopoietic stem cells has emerged as a powerful model to study those principles of chromatin mechanisms in cellular differentiation and lineage fate selection. This review summarizes recent knowledge and puts forward novel ideas on how dynamics in the epigenetic landscape of myeloid cells shape the development, immune-activation and leukaemic transformation outcome

Associations between coronal mass ejections and interplanetary shocks

Nearly continuous complementary coronal observations and interplanetary plasma measurements for the years 1979-1982 are compared. It is shown that almost all low latitude high speed coronal mass ejections (CME's) were associated with shocks at HELIOS 1. Some suitably directed low speed CME's were clearly associated with shocks while others may have been associated with disturbed plasma (such as NCDE's) without shocks. A few opposite hemisphere CME's associated with great flares seem to be associated with shocks at HELIOS

Multiscale Modeling of Spheroid Tumors: Effect of Nutrient Availability on Tumor Evolution

Recent years have revealed a large number of complex mechanisms and interactions that drive the development of malignant tumors. Tumor evolution is a framework that explains tumor development as a process driven by survival of the fittest, with tumor cells of different properties competing for limited available resources. To predict the evolutionary trajectory of a tumor, knowledge of how cellular properties influence the fitness of a subpopulation in the context of the microenvironment is required and is often inaccessible. Computational multiscale-modeling of tissues enables the observation of the full trajectory of each cell within the tumor environment. Here, we model a 3D spheroid tumor with subcellular resolution. The fitness of individual cells and the evolutionary behavior of the tumor are quantified and linked to cellular and environmental parameters. The fitness of cells is solely influenced by their position in the tumor, which in turn is influenced by the two variable parameters of our model: cell–cell adhesion and cell motility. We observe the influence of nutrient independence and static and dynamically changing nutrient availability on the evolutionary trajectories of heterogeneous tumors in a high-resolution computational model. Regardless of nutrient availability, we find a fitness advantage of low-adhesion cells, which are favorable for tumor invasion. We find that the introduction of nutrient-dependent cell division and death accelerates the evolutionary speed. The evolutionary speed can be increased by fluctuations in nutrients. We identify a distinct frequency domain in which the evolutionary speed increases significantly over a tumor with constant nutrient supply. The findings suggest that an unstable supply of nutrients can accelerate tumor evolution and, thus, the transition to malignancy

Interpretation of the ion mass spectra in the mass range 25-35 obtained in the inner coma of Halley's comet by the HIS-sensor of the Giotto IMS Experiment

The IMS-HIS double-focussing mass spectrometer that flew on the Giotto spacecraft covered the mass per charge range from 12 to 56 (AMU/e). By comparing flight data, calibration data, and results of model calculations of the ion population in the inner coma, the absolute mass scale is established, and ions in the mass range 25 to 35 are identified. Ions resulting from protonation of molecules with high proton affinity are relatively abundant, enabling us to estimate relative source strengths for H2CO, CH3OH, HCN, and H2S, providing for the first time a positive in situ measurement of methanol. Also, upper limits for NO and some hydrocarbons are derived

Cross talk between Wnt/β-catenin and Irf8 in leukemia progression and drug resistance

Progression and disease relapse of chronic myeloid leukemia (CML) depends on leukemia-initiating cells (LIC) that resist treatment. Using mouse genetics and a BCR-ABL model of CML, we observed cross talk between Wnt/{beta}-catenin signaling and the interferon-regulatory factor 8 (Irf8). In normal hematopoiesis, activation of {beta}-catenin results in up-regulation of Irf8, which in turn limits oncogenic {beta}-catenin functions. Self-renewal and myeloproliferation become dependent on {beta}-catenin in Irf8-deficient animals that develop a CML-like disease. Combined Irf8 deletion and constitutive {beta}-catenin activation result in progression of CML into fatal blast crisis, elevated leukemic potential of BCR-ABL-induced LICs, and Imatinib resistance. Interestingly, activated {beta}-catenin enhances a preexisting Irf8-deficient gene signature, identifying {beta}-catenin as an amplifier of progression-specific gene regulation in the shift of CML to blast crisis. Collectively, our data uncover Irf8 as a roadblock for {beta}-catenin-driven leukemia and imply both factors as targets in combinatorial therapy

Observations of plasma dynamics in the coma of P/Halley by the Giotto Ion Mass Spectrometer

Observations in the coma of P/Halley by the Giotto Ion Mass Spectrometer (IMS) are reported. The High Energy Range Spectrometer (HERS) of the IMS obtained measurements of protons and alpha particles from the far upstream region to the near ionopause region and of ions from mass 12 to 32 at distances of about 250,000 to 40,000 km from the nucleus. Plasma parameters from the High Intensity Spectrometer (HIS) of the IMS obtained between 150,000 to 5000 km from the nucleus are also discussed. The distribution functions of water group ions (water group will be used to refer to ions of 16 to 18 m/q, where m is in AMU and q is in unit charges) are observed to be spherically symmetric in velocity space, indicating strong pitch angle scattering. The discontinuity known as the magnetic pile-up boundary (MPB) is apparent only in proton, alpha, and magnetometer data, indicating that it is a tangential discontinuity of solar wind origin. HERS observations show no significant change in the properties of the heavy ions across the MPB. A comparison of the observations to an MHD model is made. The plasma flow directions at all distances greater than 30,000 km from the nucleus are in agreement with MHD calculations. However, despite the agreement in flow direction, within 200,000 km of the nucleus the magnitude of the velocity is lower than predicted by the MHD model and the density is much larger (a factor of 4). Within 30,000 km of the nucleus there are large theoretical differences between the MHD model flow calculations for the plane containing the magnetic field and for the plane perpendicular to the magnetic field. The observations agreed much better with the pattern calculated for the plane perpendicular to the magnetic field. The data obtained by the High Energy Range Spectrometer (HERS) of the IMS that are published herein were provided to the International Halley Watch archive

Assembly of Multi‐Spheroid Cellular Architectures by Programmable Droplet Merging

Artificial multicellular systems are gaining importance in the field of tissue engineering and regenerative medicine. Reconstruction of complex tissue architectures in vitro is nevertheless challenging, and methods permitting controllable and high‐throughput fabrication of complex multicellular architectures are needed. Here, a facile and high‐throughput method is developed based on a tunable droplet‐fusion technique, allowing programmed assembly of multiple cell spheroids into complex multicellular architectures. The droplet‐fusion technique allows for construction of various multicellular architectures (double‐spheroids, multi‐spheroids, hetero‐spheroids) in a miniaturized high‐density array format. As an example of application, the propagation of Wnt signaling is investigated within hetero‐spheroids formed from two fused Wnt‐releasing and Wnt‐reporter cell spheroids. The developed method provides an approach for miniaturized, high‐throughput construction of complex 3D multicellular architectures and can be applied for studying various biological processes including cell signaling, cancer invasion, embryogenesis, and neural development

Beagle 2: Mission to Mars — current status

Beagle 2, developed in the UK, was launched on June 2, 2003. It landed on Mars on December 25th, 2003 in Isidis Planitia, a large sedimentary basin. To date, the team is awaiting signals from the Beagle 2 lander. Current status of the mission will be reported

Molecular Genetics of T Cell Development

T cell development is guided by a complex set of transcription factors that act recursively, in different combinations, at each of the developmental choice points from T-lineage specification to peripheral T cell specialization. This review describes the modes of action of the major T-lineage-defining transcription factors and the signal pathways that activate them during intrathymic differentiation from pluripotent precursors. Roles of Notch and its effector RBPSuh (CSL), GATA-3, E2A/HEB and Id proteins, c-Myb, TCF-1, and members of the Runx, Ets, and Ikaros families are critical. Less known transcription factors that are newly recognized as being required for T cell development at particular checkpoints are also described. The transcriptional regulation of T cell development is contrasted with that of B cell development, in terms of their different degrees of overlap with the stem-cell program and the different roles of key transcription factors in gene regulatory networks leading to lineage commitment