Megakaryocytes promote murine osteoblastic HSC niche expansion and stem cell engraftment after radioablative conditioning

Successful hematopoietic stem cell (HSC) transplantation requires donor HSC engraftment within specialized bone marrow microenvironments known as HSC niches. We have previously reported a profound remodeling of the endosteal osteoblastic HSC niche after total body irradiation (TBI), defined as relocalization of surviving megakaryocytes to the niche site and marked expansion of endosteal osteoblasts. We now demonstrate that host megakaryocytes function critically in expansion of the endosteal niche after preparative radioablation and in the engraftment of donor HSC. We show that TBI-induced migration of megakaryocytes to the endosteal niche depends on thrombopoietin signaling through the c-MPL receptor on megakaryocytes, as well as CD41 integrin-mediated adhesion. Moreover, niche osteoblast proliferation post-TBI required megakaryocyte-secreted platelet-derived growth factor-BB. Furthermore, blockade of c-MPL-dependent megakaryocyte migration and function after TBI resulted in a significant decrease in donor HSC engraftment in primary and competitive secondary transplantation assays. Finally, we administered thrombopoietin to mice beginning 5 days before marrow radioablation and ending 24 hours before transplant to enhance megakaryocyte function post-TBI, and found that this strategy significantly enhanced donor HSC engraftment, providing a rationale for improving hematopoietic recovery and perhaps overall outcome after clinical HSC transplantation.Successful hematopoietic stem cell (HSC) transplantation requires donor HSC engraftment within specialized bone marrow microenvironments known as HSC niches. We have previously reported a profound remodeling of the endosteal osteoblastic HSC niche after total body irradiation (TBI), defined as relocalization of surviving megakaryocytes to the niche site and marked expansion of endosteal osteoblasts. We now demonstrate that host megakaryocytes function critically in expansion of the endosteal niche after preparative radioablation and in the engraftment of donor HSC. We show that TBI-induced migration of megakaryocytes to the endosteal niche depends on thrombopoietin signaling through the c-MPL receptor on megakaryocytes, as well as CD41 integrin-mediated adhesion. Moreover, niche osteoblast proliferation post-TBI required megakaryocyte-secreted platelet-derived growth factor-BB. Furthermore, blockade of c-MPL-dependent megakaryocyte migration and function after TBI resulted in a significant decrease in donor HSC engraftment in primary and competitive secondary transplantation assays. Finally, we administered thrombopoietin to mice beginning 5 days before marrow radioablation and ending 24 hours before transplant to enhance megakaryocyte function post-TBI, and found that this strategy significantly enhanced donor HSC engraftment, providing a rationale for improving hematopoietic recovery and perhaps overall outcome after clinical HSC transplantation

IGF-1-mediated osteoblastic niche expansion enhances long-term hematopoietic stem cell engraftment after murine bone marrow transplantation

The efficiency of hematopoietic stem cell (HSC) engraftment after bone marrow (BM) transplantation depends largely on the capacity of the marrow microenvironment to accept the transplanted cells. While radioablation of BM damages osteoblastic stem cell niches, little is known about their restoration and mechanisms governing their receptivity to engraft transplanted HSCs. We previously reported rapid restoration and profound expansion of the marrow endosteal microenvironment in response to marrow radioablation. Here, we show that this reorganization represents proliferation of mature endosteal osteoblasts which seem to arise from a small subset of high-proliferative, relatively radio-resistant endosteal cells. Multiple layers of osteoblasts form along the endosteal surface within 48 hours after total-body irradiation, concomitant with a peak in marrow cytokine expression. This niche reorganization fosters homing of the transplanted hematopoietic cells to the host marrow space and engraftment of long-term (LT)-HSC. Inhibition of insulin-like growth factor (IGF)-1-receptor tyrosine kinase signaling abrogates endosteal osteoblast proliferation and donor HSC engraftment, suggesting that the cytokine IGF-1 is a crucial mediator of endosteal niche reorganization and consequently donor HSC engraftment. Further understanding of this novel mechanism of IGF-1-dependent osteoblastic niche expansion and HSC engraftment may yield clinical applications for improving engraftment efficiency after clinical HSC transplantation.The efficiency of hematopoietic stem cell (HSC) engraft-ment after bone marrow (BM) transplantation depends largely on the capacity of the marrow microenvironment to accept the transplanted cells. While radioablation of BM damages osteoblastic stem cell niches, little is known about their restoration and mechanisms governing their receptivity to engraft transplanted HSCs. We previously reported rapid restoration and profound expansion of the marrow endosteal microenvironment in response to marrow radioablation. Here, we show that this reorganization represents proliferation of mature endosteal osteoblasts which seem to arise from a small subset of high-proliferative, relatively radio-resistant endosteal cells. Multiple layers of osteoblasts form along the endosteal surface within 48 hours after total body irradiation, concomitant with a peak in marrow cytokine expression. This niche reorganization fosters homing of the transplanted hematopoietic cells to the host marrow space and engraft-ment of long-term-HSC. Inhibition of insulin-like growth factor (IGF)-1-receptor tyrosine kinase signaling abrogates endosteal osteoblast proliferation and donor HSC engraft-ment, suggesting that the cytokine IGF-1 is a crucial mediator of endosteal niche reorganization and consequently donor HSC engraftment. Further understanding of this novel mechanism of IGF-1-dependent osteoblastic niche expansion and HSC engraftment may yield clinical applications for improving engraftment efficiency after clinical HSC transplantation. © AlphaMed Press

Finding Correlations of the Oxygen Reduction Reaction Activity of Transition Metal Catalysts with Parameters Obtained from Quantum Mechanics

To facilitate a less empirical approach to developing improved catalysts, it is important to correlate catalytic performance to surrogate properties that can be measured or predicted accurately and quickly, allowing experimental synthesis and testing of catalysts to focus on the most promising cases. Particularly hopeful is correlating catalysis performance to the electronic density of states (DOS). Indeed, there has been success in using just the center of the d-electron density, which in some cases correlates linearly with oxygen atom chemisorption energy, leading to a volcano plot for catalytic performance versus “d-band center”. To test such concepts we calculated the barriers and binding energies for the various reactions and intermediates involved in the oxygen reduction reaction (ORR) for all 12 transition metals in groups 8–11 (Fe–Cu columns). Our results show that the oxygen binding energy can serve as a useful parameter in describing the catalytic activity for pure metals, but it does not necessarily correlate with the d-band center. In addition, we find that the d-band center depends substantially on the calculation method or the experimental setup, making it a much less reliable indicator for ORR activity than the oxygen binding energy. We further examine several surfaces of the same pure metals to evaluate how the d-band center and oxygen binding energy depend on the surface

Delayed marrow infusion in mice enhances hematopoietic and osteopoietic engraftment by facilitating transient expansion of the osteoblastic niche

Transplantation of bone marrow cells leads to engraftment of osteopoietic and hematopoietic progenitors. We sought to determine whether the recently described transient expansion of the host osteoblastic niche after marrow radioablation promotes engraftment of both osteopoietic and hematopoietic progenitor cells. Mice infused with marrow cells 24 hours after total body irradiation (TBI) demonstrated significantly greater osteopoietic and hematopoietic progenitor chimerism than did mice infused at 30 minutes or 6 hours. Irradiated mice with a lead shield over 1 hind limb showed greater hematopoietic chimerism in the irradiated limb than in the shielded limb at both the 6- and 24-hour intervals. By contrast, the osteopoietic chimerism was essentially equal in the 2 limbs at each of these intervals, although it significantly increased when cells were infused 24 hours compared with 6 hours after TBI. Similarly, the number of donor phenotypic long-term hematopoietic stem cells was equivalent in the irradiated and shielded limbs after each irradiation-to-infusion interval but was significantly increased at the 24-hour interval. Our findings indicate that a 24-hour delay in marrow cell infusion after TBI facilitates expansion of the endosteal osteoblastic niche, leading to enhanced osteopoietic and hematopoietic engraftment.Transplantation of bone marrow cells leads to engraftment of osteopoietic and hematopoietic progenitors. We sought to determine whether the recently described transient expansion of the host osteoblastic niche after marrow radioablation promotes engraftment of both osteopoietic and hematopoietic progenitor cells. Mice infused with marrow cells 24hours after total body irradiation (TBI) demonstrated significantly greater osteopoietic and hematopoietic progenitor chimerism than did mice infused at 30minutes or 6hours. Irradiated mice with a lead shield over 1 hind limb showed greater hematopoietic chimerism in the irradiated limb than in the shielded limb at both the 6- and 24-hour intervals. By contrast, the osteopoietic chimerism was essentially equal in the 2 limbs at each of these intervals, although it significantly increased when cells were infused 24hours compared with 6hours after TBI. Similarly, the number of donor phenotypic long-term hematopoietic stem cells was equivalent in the irradiated and shielded limbs after each irradiation-to-infusion interval but was significantly increased at the 24-hour interval. Our findings indicate that a 24-hour delay in marrow cell infusion after TBI facilitates expansion of the endosteal osteoblastic niche, leading to enhanced osteopoietic and hematopoietic engraftment. © 2013

Using Photoelectron Spectroscopy and Quantum Mechanics to Determine d-Band Energies of Metals for Catalytic Applications

The valence band structures (VBS) of eight transition metals (Fe, Co, Ni, Cu, Pd, Ag, Pt, Au) were investigated by photoelectron spectroscopy (PES) using He I, He II, and monochromatized Al Kα excitation. The influence of final states, photoionization cross-section, and adsorption of residual gas molecules in an ultrahigh vacuum environment are discussed in terms of their impact on the VBS. We find that VBSs recorded with monochromatized Al Kα radiation are most closely comparable to the ground state density of states (DOS) derived from quantum mechanics calculations. We use the Al Kα-excited PES measurements to correct the energy scale of the calculated ground-state DOS to approximate the “true” ground-state d-band structure. Finally, we use this data to test the d-band center model commonly used to predict the electronic-property/catalytic-activity relationship of metals. We find that a simple continuous dependence of activity on d-band center position is not supported by our results (both experimentally and computationally)

Delivering sustained, coordinated and integrated observations of the Southern Ocean for global impact

The Southern Ocean is disproportionately important in its effect on the Earth system, impacting climatic, biogeochemical, and ecological systems, which makes recent observed changes to this system cause for global concern. The enhanced understanding and improvements in predictive skill needed for understanding and projecting future states of the Southern Ocean require sustained observations. Over the last decade, the Southern Ocean Observing System (SOOS) has established networks for enhancing regional coordination and research community groups to advance development of observing system capabilities. These networks support delivery of the SOOS 20-year vision, which is to develop a circumpolar system that ensures time series of key variables, and delivers the greatest impact from data to all key end-users. Although the Southern Ocean remains one of the least-observed ocean regions, enhanced international coordination and advances in autonomous platforms have resulted in progress toward sustained observations of this region. Since 2009, the Southern Ocean community has deployed over 5700 observational platforms south of 40°S. Large-scale, multi-year or sustained, multidisciplinary efforts have been supported and are now delivering observations of essential variables at space and time scales that enable assessment of changes being observed in Southern Ocean systems. The improved observational coverage, however, is predominantly for the open ocean, encompasses the summer, consists of primarily physical oceanographic variables, and covers surface to 2000 m. Significant gaps remain in observations of the ice-impacted ocean, the sea ice, depths >2000 m, the air-ocean-ice interface, biogeochemical and biological variables, and for seasons other than summer. Addressing these data gaps in a sustained way requires parallel advances in coordination networks, cyberinfrastructure and data management tools, observational platform and sensor technology, two-way platform interrogation and data-transmission technologies, modeling frameworks, intercalibration experiments, and development of internationally agreed sampling standards and requirements of key variables. This paper presents a community statement on the major scientific and observational progress of the last decade, and importantly, an assessment of key priorities for the coming decade, toward achieving the SOOS vision and delivering essential data to all end-users.Fil: Newman, Louise. University of Tasmania; AustraliaFil: Heil, Petra. Australian Antarctic Division; Australia. Antarctic Climate And Ecosystems Cooperative Research Centre; AustraliaFil: Trebilco, Rowan. Australian Antarctic Division; Australia. Antarctic Climate And Ecosystems Cooperative Research Centre; AustraliaFil: Katsumata, Katsuro. Japan Agency For Marine earth Science And Technology; JapónFil: Constable, Andrew J.. Antarctic Climate And Ecosystems Cooperative Research Centre; Australia. Australian Antarctic Division; AustraliaFil: Wijk, Esmee van. Commonwealth Scientific And Industrial Research Organization; Australia. Antarctic Climate And Ecosystems Cooperative Research Centre; AustraliaFil: Assmann, Karen. University Goteborg; SueciaFil: Beja, Joana. British Oceanographic Data Centre; AustraliaFil: Bricher, Phillippa. University of Tasmania; AustraliaFil: Coleman, Richard. University of Tasmania; AustraliaFil: Costa, Daniel. University of California; Estados UnidosFil: Diggs, Steve. University of California; Estados UnidosFil: Farneti, Riccardo. The Abdus Salam; Italia. The Abdus Salam. International Centre for Theoretical Physics; ItaliaFil: Fawcett, Sarah. University of Cape Town; SudáfricaFil: Gille, Sarah. University of California; Estados UnidosFil: Hendry, Katharine R.. University of Bristol; Reino UnidoFil: Henley, Sian F.. University of Edinburgh; Reino UnidoFil: Hofmann, Eileen. Old Dominion University; Estados UnidosFil: Maksym, Ted. University of California; Estados UnidosFil: Mazloff, Matthew. University of California; Estados UnidosFil: Meijers, Andrew J.. British Antartic Survey; Reino UnidoFil: Meredith, Michael. British Antartic Survey; Reino UnidoFil: Moreau, Sebastien. Norwegian Polar Institute; NoruegaFil: Ozsoy, Burcu. Istanbul Teknik Üniversitesi; TurquíaFil: Robertson, Robin. Xiamen University; ChinaFil: Schloss, Irene Ruth. Universidad Nacional de Tierra del Fuego; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Schofield, Oscar. State University of New Jersey; Estados UnidosFil: Shi, Jiuxin. Ocean University Of China; ChinaFil: Sikes, Elisabeth L.. State University of New Jersey; Estados UnidosFil: Smith, Inga J.. University of Otago; Nueva Zeland

The genomic substrate for adaptive radiation in African cichlid fish

Cichlid fishes are famous for large, diverse and replicated adaptive radiations in the Great Lakes of East Africa. To understand the molecular mechanisms underlying cichlid phenotypic diversity, we sequenced the genomes and transcriptomes of five lineages of African cichlids: the Nile tilapia (Oreochromis niloticus), an ancestral lineage with low diversity; and four members of the East African lineage: Neolamprologus brichardi/pulcher (older radiation, Lake Tanganyika), Metriaclima zebra (recent radiation, Lake Malawi), Pundamilia nyererei (very recent radiation, Lake Victoria), and Astatotilapia burtoni (riverine species around Lake Tanganyika). We found an excess of gene duplications in the East African lineage compared to tilapia and other teleosts, an abundance of non-coding element divergence, accelerated coding sequence evolution, expression divergence associated with transposable element insertions, and regulation by novel microRNAs. In addition, we analysed sequence data from sixty individuals representing six closely related species from Lake Victoria, and show genome-wide diversifying selection on coding and regulatory variants, some of which were recruited from ancient polymorphisms. We conclude that a number of molecular mechanisms shaped East African cichlid genomes, and that amassing of standing variation during periods of relaxed purifying selection may have been important in facilitating subsequent evolutionary diversification