C/EBPβ-induced lymphoid-to-myeloid transdifferentiation emulates granulocyte-monocyte progenitor biology

CCAAT/enhancer-binding protein beta (C/EBPβ) induces primary v-Abl immortalized mouse B cells to transdifferentiate (BT) into granulocyte-macrophage progenitor-like cells (GMPBT). GMPBT maintain cytokine-independent self-renewal, lineage choice, and multilineage differentiation. Single-cell transcriptomics demonstrated that GMPBT comprise a continuum of myelomonopoietic differentiation states that seamlessly fit into state-to-fate maps of normal GMP. Inactivating v-Abl kinase revealed the dependence on activated CSF2-JAK2-STAT5 signaling. Deleting IRF8 diminished monopoiesis and enhanced granulopoiesis while removing C/EBPβ abrogated self-renewal and granulopoiesis yet permitted macrophage differentiation. The GMPBT culture system is easily scalable to explore the basics of GMP biology and lineage commitment and largely reduces ethically and legislatively debatable, labor-intensive, and costly animal experiments

Myeloid transformation by MLL-ENL depends strictly on C/EBP

Chromosomal rearrangements of the mixed-lineage leukemia gene MLL1 are the hallmark of infant acute leukemia. The granulocyte-macrophage progenitor state forms the epigenetic basis for myelomonocytic leukemia stemness and transformation by MLL-type oncoproteins. Previously, it was shown that the establishment of murine myelomonocytic MLL-ENL transformation, but not its maintenance, depends on the transcription factor C/EBPα, suggesting an epigenetic hit-and-run mechanism of MLL-driven oncogenesis. Here, we demonstrate that compound deletion of Cebpa/Cebpb almost entirely abrogated the growth and survival of MLL-ENL–transformed cells. Rare, slow-growing, and apoptosis-prone MLL-ENL–transformed escapees were recovered from compound Cebpa/Cebpb deletions. The escapees were uniformly characterized by high expression of the resident Cebpe gene, suggesting inferior functional compensation of C/EBPα/C/EBPβ deficiency by C/EBPε. Complementation was augmented by ectopic C/EBPβ expression and downstream activation of IGF1 that enhanced growth. Cebpe gene inactivation was accomplished only in the presence of complementing C/EBPβ, but not in its absence, confirming the Cebpe dependency of the Cebpa/Cebpb double knockouts. Our data show that MLL-transformed myeloid cells are dependent on C/EBPs during the initiation and maintenance of transformation

Nuclear Clusters as a Probe for Expansion Flow in Heavy Ion Reactions at 10-15AGeV

A phase space coalescence description based on the Wigner-function method for cluster formation in relativistic nucleus-nucleus collisions is presented. The momentum distributions of nuclear clusters d,t and He are predicted for central Au(11.6AGeV)Au and Si(14.6AGeV)Si reactions in the framework of the RQMD transport approach. Transverse expansion leads to a strong shoulder-arm shape and different inverse slope parameters in the transverse spectra of nuclear clusters deviating markedly from thermal distributions. A clear ``bounce-off'' event shape is seen: the averaged transverse flow velocities in the reaction plane are for clusters larger than for protons. The cluster yields --particularly at low $p_t$ at midrapidities-- and the in-plane (anti)flow of clusters and pions change if suitably strong baryon potential interactions are included. This allows to study the transient pressure at high density via the event shape analysis of nucleons, nucleon clusters and other hadrons.Comment: 38 pages, 9 figures, LaTeX type, eps used, subm. to Phys. Rev.

Attitudes toward westbound refugees in the East German press

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67107/2/10.1177_002200277001400303.pd

Pharmacokinetic Profile Of Two Different Pharmaceutical Forms Of Theophylline (a Slow Release Tablet And A Syrup) After Multiple Dose Administration To Healthy Human Volunteers.

Due to the narrow therapeutic range of theophylline, plasma concentrations of this drug are monitored in patients undergoing chronic therapy. Slow-release preparations avoid the fluctuations in plasma levels and improve patient compliance. In this study, we have compared the pharmacokinetic profiles of a theophylline slow-release tablet and a syrup form, when administered in multiple doses to healthy adult volunteers. The classification based upon releasing patterns is confirmed.88155-