A Scalable System for Production of Functional Pancreatic Progenitors from Human Embryonic Stem Cells

Development of a human embryonic stem cell (hESC)-based therapy for type 1 diabetes will require the translation of proof-of-principle concepts into a scalable, controlled, and regulated cell manufacturing process. We have previously demonstrated that hESC can be directed to differentiate into pancreatic progenitors that mature into functional glucose-responsive, insulin-secreting cells in vivo. In this study we describe hESC expansion and banking methods and a suspension-based differentiation system, which together underpin an integrated scalable manufacturing process for producing pancreatic progenitors. This system has been optimized for the CyT49 cell line. Accordingly, qualified large-scale single-cell master and working cGMP cell banks of CyT49 have been generated to provide a virtually unlimited starting resource for manufacturing. Upon thaw from these banks, we expanded CyT49 for two weeks in an adherent culture format that achieves 50–100 fold expansion per week. Undifferentiated CyT49 were then aggregated into clusters in dynamic rotational suspension culture, followed by differentiation en masse for two weeks with a four-stage protocol. Numerous scaled differentiation runs generated reproducible and defined population compositions highly enriched for pancreatic cell lineages, as shown by examining mRNA expression at each stage of differentiation and flow cytometry of the final population. Islet-like tissue containing glucose-responsive, insulin-secreting cells was generated upon implantation into mice. By four- to five-months post-engraftment, mature neo-pancreatic tissue was sufficient to protect against streptozotocin (STZ)-induced hyperglycemia. In summary, we have developed a tractable manufacturing process for the generation of functional pancreatic progenitors from hESC on a scale amenable to clinical entry

J/psi production from proton-proton collisions at sqrt(s) = 200 GeV

J/psi production has been measured in proton-proton collisions at sqrt(s)= 200 GeV over a wide rapidity and transverse momentum range by the PHENIX experiment at RHIC. Distributions of the rapidity and transverse momentum, along with measurements of the mean transverse momentum and total production cross section are presented and compared to available theoretical calculations. The total J/psi cross section is 3.99 +/- 0.61(stat) +/- 0.58(sys) +/- 0.40(abs) micro barns. The mean transverse momentum is 1.80 +/- 0.23(stat) +/- 0.16(sys) GeV/c.Comment: 326 authors, 6 pages text, 4 figures, 1 table, RevTeX 4. To be submitted to PRL. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Centrality Dependence of Charm Production from Single Electrons in Au+Au Collisions at sqrt(s_NN) = 200 GeV

The PHENIX experiment has measured mid-rapidity transverse momentum spectra (0.4 < p_T < 4.0 GeV/c) of single electrons as a function of centrality in Au+Au collisions at sqrt(s_NN) = 200 GeV. Contributions to the raw spectra from photon conversions and Dalitz decays of light neutral mesons are measured by introducing a thin (1.7% X_0) converter into the PHENIX acceptance and are statistically removed. The subtracted ``non-photonic'' electron spectra are primarily due to the semi-leptonic decays of hadrons containing heavy quarks (charm and bottom). For all centralities, charm production is found to scale with the nuclear overlap function, T_AA. For minimum-bias collisions the charm cross section per binary collision is N_cc^bar/T_AA = 622 +/- 57 (stat.) +/- 160 (sys.) microbarns.Comment: 326 authors, 4 pages text, 3 figures, 1 table, RevTeX 4. To be submitted to Physical Review Letters. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Measurement of direct photon production in p + p collisions at sqrt(s) = 200 GeV

Cross sections for mid-rapidity production of direct photons in p+p collisions at the Relativistic Heavy Ion Collider (RHIC) are reported for 3 < p_T < 16 GeV/c. Next-to-leading order (NLO) perturbative QCD (pQCD) describes the data well for p_T > 5 GeV/c, where the uncertainties of the measurement and theory are comparable. We also report on the effect of requiring the photons to be isolated from parton jet energy. The observed fraction of isolated photons is well described by pQCD for p_T > 7 GeV/c.Comment: 330 authors, 6 pages text, 3 figures, one table. Submitted to Phys. Rev. Lett. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Elliptic flow for phi mesons and (anti)deuterons in Au+Au collisions at sqrt(s_NN) = 200 GeV

Differential elliptic flow (v_2) for phi mesons and (anti)deuterons (d^bar)d is measured for Au+Au collisions at sqrt(s_NN) = 200 GeV. The v_2 for phi mesons follows the trend of lighter pi^+/- and K^+/- mesons, suggesting that ordinary hadrons interacting with standard hadronic cross sections are not the primary driver for elliptic flow development. The v_2 values for (d^bar)d suggest that elliptic flow is additive for composite particles. This further validation of the universal scaling of v_2 per constituent quark for baryons and mesons suggests that partonic collectivity dominates the transverse expansion dynamics.Comment: 343 authors, 6 pages text, 3 figures, REVTeX4. To be submitted to Physical Review Letters. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

NUP98–HOXA9 expression in hemopoietic stem cells induces chronic and acute myeloid leukemias in mice

Here we describe hemopoietic chimeras serving as a mouse model for NUP98–HOXA9-induced leukemia, which reproduced several of the phenotypes observed in human disease. Mice transplanted with bone marrow cells expressing NUP98–HOXA9 through retroviral transduction acquire a myeloproliferative disease (MPD) and eventually succumb to acute myeloid leukemia (AML). The NUP98 portion of the fusion protein was shown to be responsible for transforming a clinically silent pre-leukemic phase observed for Hoxa9 into a chronic, stem cell-derived MPD. The co-expression of NUP98–HOXA9 and Meis1 accelerated the transformation of MPD to AML, identifying a genetic interaction previously observed for Hoxa9 and Meis1. Our findings demonstrate the presence of overlapping yet distinct molecular mechanisms for MPD versus AML, illustrating the complexity of leukemic transformation

Beïnvloeden van landgebonden broeikasgasemissies : Naar een klimaatneutrale(re) inrichting van het landelijke gebied

Onderzocht is of mitigatie mogelijk terug te dringen is in de veenweidegebieden en of het door de vastlegging van koolstof in bossen te verhogen is. Daarnaast is bepaald wat de effecten zijn van het Nederlandse landgebruik in de toekomst (scenario's) op de broeikasemissie