Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.National Institutes of Health (U.S.) (NIH grant R01 GM56203)National Institutes of Health (U.S.) (grant NIH 5P01CA120964)Dana-Farber/Harvard Cancer Center (NIH 5P30CA006516)National Institutes of Health (U.S.) (NIH grant R03MH085679)National Human Genome Research Institute (U.S.) (Intramural Research Program)National Institutes of Health (U.S.) (Molecular Libraries Initiative of the NIH Roadmap for Medical Research

Discovery of extreme particle acceleration in the microquasar Cygnus X-3

The study of relativistic particle acceleration is a major topic of high-energy astrophysics. It is well known that massive black holes in active galaxies can release a substantial fraction of their accretion power into energetic particles, producing gamma-rays and relativistic jets. Galactic microquasars (hosting a compact star of 1-10 solar masses which accretes matter from a binary companion) also produce relativistic jets. However, no direct evidence of particle acceleration above GeV energies has ever been obtained in microquasar ejections, leaving open the issue of the occurrence and timing of extreme matter energization during jet formation. Here we report the detection of transient gamma-ray emission above 100 MeV from the microquasar Cygnus X-3, an exceptional X-ray binary which sporadically produces powerful radio jets. Four gamma-ray flares (each lasting 1-2 days) were detected by the AGILE satellite simultaneously with special spectral states of Cygnus X-3 during the period mid-2007/mid-2009. Our observations show that very efficient particle acceleration and gamma-ray propagation out of the inner disk of a microquasar usually occur a few days before major relativistic jet ejections. Flaring particle energies can be thousands of times larger than previously detected maximum values (with Lorentz factors of 105 and 102 for electrons and protons, respectively). We show that the transitional nature of gamma-ray flares and particle acceleration above GeV energies in Cygnus X-3 is clearly linked to special radio/X-ray states preceding strong radio flares. Thus gamma-rays provide unique insight into the nature of physical processes in microquasars.Comment: 29 pages (including Supplementary Information), 8 figures, 2 tables version submitted to Nature on August 7, 2009 (accepted version available at http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature08578.pdf

The VLT-VIRMOS Mask Manufacturing Unit

The VIRMOS Consortium has the task to design and manufacture two spectrographs for ESO VLT, VIMOS (Visible Multi-Object Spectrograph) and NIRMOS (Near Infrared Multi-Object Spectrograph). This paper describes how the Mask Manufacturing Unit (MMU), which cuts the slit masks to be used with both instruments, meets the scientific requirements and manages the storage and the insertion of the masks into the instrument. The components and the software of the two main parts of the MMU, the Mask Manufacturing Machine and the Mask Handling System, are illustrated together with the mask material and with the slit properties. Slit positioning is accurate within 15 micron, equivalent to 0.03 arcsec on the sky, while the slit edge roughness has an rms on the order of 0.03 pixels on scales of a slit 5 arcsec long and of 0.01 pixels on the pixel scale (0.205 arcsec). The MMU has been successfully installed during July/August 2000 at the Paranal Observatory and is now operational for spectroscopic mask cutting, compliant with the requested specifications.Comment: Accepted for publication in PASP April 2001 PASP Latex preprint style, 31 pages including 9 figures (5 jpg2eps compressed

One-carbon metabolism in cancer

Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism

First AGILE Catalog of High Confidence Gamma-Ray Sources

We present the first catalog of high-confidence gamma-ray sources detected by the AGILE satellite during observations performed from July 9, 2007 to June 30, 2008. Catalogued sources are detected by merging all the available data over the entire time period. AGILE, launched in April 2007, is an ASI mission devoted to gamma-ray observations in the 30 MeV - 50 GeV energy range, with simultaneous X-ray imaging capability in the 18-60 keV band. This catalog is based on Gamma-Ray Imaging Detector (GRID) data for energies greater than 100 MeV. For the first AGILE catalog we adopted a conservative analysis, with a high-quality event filter optimized to select gamma-ray events within the central zone of the instrument Field of View (radius of 40 degrees). This is a significance-limited (4 sigma) catalog, and it is not a complete flux-limited sample due to the non-uniform first year AGILE sky coverage. The catalog includes 47 sources, 21 of which are associated with confirmed or candidate pulsars, 13 with Blazars (7 FSRQ, 4 BL Lacs, 2 unknown type), 2 with HMXRBs, 2 with SNRs, 1 with a colliding-wind binary system, 8 with unidentified sources.Comment: Revised version, 15 pages, 3 figures, 3 tables. To be published in Astronomy and Astrophysics. Text improved and clarified. Refined analysis of complex regions of the Galactic plane yields a new list of high-confidence sources including 47 sources (compared with the 40 sources appearing in the first version

Gamma-ray burst detection with the AGILE mini-calorimeter

The mini-calorimeter (MCAL) instrument on-board the AGILE satellite is a non-imaging gamma-ray scintillation detector sensitive in the 300 keV-100 MeV energy range with a total on-axis geometrical area of 1400 cm(2). Gamma-ray bursts (GRBs) are one of the main scientific targets of the AGILE mission and the MCAL design as an independent self-triggering detector makes it a valuable all-sky monitor for GRBs. Furthermore MCAL is one of the very few operative instruments with microsecond timing capabilities in the MeV range