Searching for the Role of Mergers in Fast and Early SMBH Growth: Morphological Decomposition of Quasars and Their Hosts at z∼4.8z \sim 4.8

We present rest-frame ultraviolet (UV) images of six luminous quasars at $z \sim 4.8$ obtained with the Hubble Space Telescope (HST). These quasars exhibit a wide range of star formation rates (SFRs) and lie in a wide range of environments. We carefully model and subtract the point-like quasar emission and investigate the morphology of the underlying host galaxies at kpc scales. The residual images allowed identification of potential companion sources, which enabled us to explore the role of galaxy merger scenarios in the co-evolution of the quasars and their hosts. We also search for the mechanism driving extreme SFRs in three of the quasars. We find that the rate of detection of potential companions to the host galaxies does not follow trends between high- and low-SFR sources; i.e., the HST imaging suggests that both high- and low-SFR sources are found in both dense and sparse galactic environments. The suggested role of major mergers driving extreme SFRs cannot be supported by the multiwavelength data in hand. Three of four companion sources, previously revealed by sub-millimeter observations, are not detected in the HST images of three of our quasars. An adapted high-resolution imaging strategy focused on high-SFR sources and extended to a larger quasar sample is required to determine the role of mergers in the processes of star formation and supermassive black hole growth at high redshift.Comment: 22 pages, 10 figures; accepted for publication in Ap

CD45 regulates retention, motility, and numbers of hematopoietic progenitors, and affects osteoclast remodeling of metaphyseal trabecules

The CD45 phosphatase is uniquely expressed by all leukocytes, but its role in regulating hematopoietic progenitors is poorly understood. We show that enhanced CD45 expression on bone marrow (BM) leukocytes correlates with increased cell motility in response to stress signals. Moreover, immature CD45 knockout (KO) cells showed defective motility, including reduced homing (both steady state and in response to stromal-derived factor 1) and reduced granulocyte colony-stimulating factor mobilization. These defects were associated with increased cell adhesion mediated by reduced matrix metalloproteinase 9 secretion and imbalanced Src kinase activity. Poor mobilization of CD45KO progenitors by the receptor activator of nuclear factor κB ligand, and impaired modulation of the endosteal components osteopontin and stem cell factor, suggested defective osteoclast function. Indeed, CD45KO osteoclasts exhibited impaired bone remodeling and abnormal morphology, which we attributed to defective cell fusion and Src function. This led to irregular distribution of metaphyseal bone trabecules, a region enriched with stem cell niches. Consequently, CD45KO mice had less primitive cells in the BM and increased numbers of these cells in the spleen, yet with reduced homing and repopulation potential. Uncoupling environmental and intrinsic defects in chimeric mice, we demonstrated that CD45 regulates progenitor movement and retention by influencing both the hematopoietic and nonhematopoietic compartments

Searching for the Role of Mergers in Fast and Early SMBH Growth : Morphological Decomposition of Quasars and Their Hosts at z ∼ 4.8

We present rest-frame ultraviolet images of six luminous quasars at z ∼ 4.8 obtained with the Hubble Space Telescope (HST). These quasars exhibit a wide range of star formation rates (SFRs) and lie in a wide range of environments. We carefully model and subtract the point-like quasar emission and investigate the morphology of the underlying host galaxies at kpc scales. The residual images allowed identification of potential companion sources, which enabled us to explore the role of galaxy merger scenarios in the coevolution of the quasars and their hosts. We also search for the mechanism driving extreme SFRs in three of the six quasars. We find that the rate of detection of potential companions to the host galaxies does not follow trends between high- and low-SFR sources; i.e., the HST imaging suggests that both high- and low-SFR sources are found in both dense and sparse galactic environments. The suggested role of major mergers driving extreme SFRs cannot be supported by the multiwavelength data in hand. Three of four companion sources, previously revealed by submillimeter observations, are not detected in the HST images of three of our quasars. An adapted high-resolution imaging strategy focused on high-SFR sources and extended to a larger quasar sample is required in order to determine the role of mergers in the processes of star formation and supermassive black hole growth at high redshift

AMD3100 Signals Via the Nervous System, Inducing Release to the Circulation of Bone Marrow SDF-1, Which Is Crucial for Progenitor Cell Mobilization.

Abstract AMD3100, a bicyclam antagonist of the chemokine receptor CXCR4 in vitro, has been shown to induce rapid mobilization of human and murine maturing leukocytes and immature hematopoietic stem and progenitor cells in vivo. In addition, AMD3100 combined with G-CSF, synergistically augments mobilization of human progenitor cells (Broxmeyer &amp; Srour et al, JEM, 2005). However, the mechanism of AMD3100-induced mobilization is currently poorly understood. We report that AMD3100-induced mobilization in mice was accompanied with rapid increase in functional SDF-1 concentrations in the circulation and their parallel decrease in the bone marrow within 1 hour. Biotinylated SDF-1 (bSDF-1) directly injected into the femur was detected in the peripheral blood, adjacent bones and spleen as early as 10 minutes post administration. Interestingly, AMD3100 induced significant elevations in bone marrow-derived bSDF-1 concentrations in the peripheral blood. Similarly, G-CSF induced mobilization was initiated (24 hours post a single injection of G-CSF), by SDF-1 release to the circulation. Administration of neutralizing antibodies against CXCR4 to either untreated or AMD3100 treated mice markedly reduced SDF-1 levels in the peripheral blood, coinciding with increased retention levels of this ligand in the bone marrow. In vitro, AMD3100 directly induced SDF-1 release from the human osteoblast cell line MG-63 in a bell shaped dose response. Inhibition of CXCR4-dependent release of SDF-1 during homeostasis or upon treatment with AMD3100, correlated with selective reduction in recruitment of hematopoietic progenitor cells but not mature leukocytes to the circulation. Importantly, injection of neutralizing antibodies against SDF-1 (but not matched control antibodies) resulted in decreased steady state egress and AMD3100-induced mobilization of hematopoietic progenitor cells. Rapid recruitment (within 1 hour) of hematopoietic progenitor cells and maturing leukocytes out of the bone marrow as well as SDF-1 release were dependent on signals from the nervous system. Administration of the b2 adrenergic agonist (clenbuterol) inhibited endogenous SDF-1 and exogenous bSDF-1 release to the circulation and reduced progenitor cell egress, both during steady state and AMD3100-induced mobilization, while administration of the b2 adrenergic antagonist (propranolol) resulted in opposite effects. Based on our results we propose a model in which egress and mobilization of immature progenitor cells differs from that of maturing leukocytes and is more dependent on SDF-1/CXCR4 interactions. In addition to hematopoietic progenitor cells, also bone marrow stromal cells induce homeostatic secretion of SDF-1, which is increased during mobilization and stress induced recruitment. Secretion of this ligand is also CXCR4-dependent, revealing orchestrated mutual and reciprocal SDF1/CXCR4 interactions and a cross-talk with the nervous system, which regulates progenitor cell egress and recruitment.</jats:p

Functional CXCR4 Expressing Microparticles and SDF-1 Correlate with Circulating AML Cell Counts.

Abstract Stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptor CXCR4 are implicated in the pathogenesis and prognosis of AML. Cellular microparticles (MPs), the submicron vesicles shed from the plasma membrane of various circulating cells, are associated with numerous human disorders. In the present study, we studied the putative relationships between CXCR4/SDF-1 axis and MPs in AML. We detected CXCR4 expressing MPs (CXCR4+MPs) in the peripheral blood and bone marrow plasma samples of normal donors (n=24) and newly diagnosed adult AML patients (n=26). The majority of CXCR4+MPs in AML patients were CD45+ whereas in normal individuals they were mostly CD41+. In samples from AML patients, the levels of CXCR4+MPs and total SDF-1 were significantly elevated as compared to normal individuals. Importantly, we found a strong correlation between the levels of CXCR4+MP and white blood cell (WBC) counts in the peripheral blood and bone marrow plasma obtained from the AML patients. Of interest, functional, non-cleaved SDF-1 levels were reduced in these patients compared to normal individuals, and also strongly correlated with the WBC counts. Furthermore, our data indicate N-terminal truncation of the CXCR4 molecule in the MPs of AML patients. This was found also in MPs obtained from the conditioned media of normal human CD34+ progenitors lentiviarlly transduced with CXCR4 vector in vitro. Appearance of MPs possessing N-terminally truncated CXCR4 in AML patients is likely to be dependent on proteolytic enzymes, such as elastase, which was elevated. However, MPs isolated from AML patients were capable of transferring functional CXCR4 molecule to the AML-derived HL-60 cells, enhancing their migration to SDF-1 in vitro and increasing their homing to the bone marrow of irradiated NOD/SCID mice. The CXCR4 antagonist AMD3100 reduced the increased migration and homing of MP treated HL-60 cells. Taken together, these findings suggest that functional CXCR4+MPs and SDF-1 are involved in the progression of AML. We propose that their levels are potentially valuable as an additional diagnostic AML parameter. Moreover, our findings suggest also the need for CXCR4- and SDF-1-target therapeutic approaches, clinically relevant in AML in the near future.</jats:p

Carotenoid Biosynthesis and Regulation in Plants

Carotenoids are important in photosynthesis, photo protection, and the production of a range of hormones and signaling molecules. This chapter focuses on regulatory aspects of carotenogenesis relating to: cross-talk between and within the carotenoid and MEP pathways, environmental and developmental control, epigenetic and posttranscriptional regulatory mechanisms, plastid differentiation and communication, enzyme localization and metabolon compartmentalization, and carotenoid degradation and apocarotenoid signaling metabolites. Non-enzymatic photooxidation and enzymatic cleavage of carotenoids are two well-studied processes that can degrade carotenoids to apocarotenoid signaling molecules. Carotenoid biosynthetic pathway in plants is complex and tightly regulated. The carotenoid biosynthetic pathway bifurcates after lycopene to produce lutein or ß-carotenes, and their derivatives. By enhancing our knowledge of the regulation of biosynthetic processes and flux through the pathway, undoubtedly new possibilities will emerge to enhance plant biofortification as a convenient resource to produce valuable micronutrient compounds