167 research outputs found
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
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
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
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
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