Metabolic sensitivity of pancreatic tumour cell apoptosis to glycogen phosphorylase inhibitor treatment

Inhibitors of glycogen breakdown regulate glucose homeostasis by limiting glucose production in diabetes. Here we demonstrate that restrained glycogen breakdown also inhibits cancer cell proliferation and induces apoptosis through limiting glucose oxidation, as well as nucleic acid and de novo fatty acid synthesis. Increasing doses (50-100 microM) of the glycogen phosphorylase inhibitor CP-320626 inhibited [1,2-(13)C(2)]glucose stable isotope substrate re-distribution among glycolysis, pentose and de novo fatty acid synthesis in MIA pancreatic adenocarcinoma cells. Limited oxidative pentose-phosphate synthesis, glucose contribution to acetyl CoA and de novo fatty acid synthesis closely correlated with decreased cell proliferation. The stable isotope-based dynamic metabolic profile of MIA cells indicated a significant dose-dependent decrease in macromolecule synthesis, which was detected at lower drug doses and before the appearance of apoptosis markers. Normal fibroblasts (CRL-1501) did not show morphological or metabolic signs of apoptosis likely due to their slow rate of growth and metabolic activity. This indicates that limiting carbon re-cycling and rapid substrate mobilisation from glycogen may be an effective and selective target site for new drug development in rapidly dividing cancer cells. In conclusion, pancreatic cancer cell growth arrest and death are closely associated with a characteristic decrease in glycogen breakdown and glucose carbon re-distribution towards RNA/DNA and fatty acids during CP-320626 treatment

Climate change adaptation in European river basins

This paper contains an assessment and standardized comparative analysis of the current water management regimes in four case-studies in three European river basins: the Hungarian part of the Upper Tisza, the Ukrainian part of the Upper Tisza (also called Zacarpathian Tisza), Alentejo Region (including the Alqueva Reservoir) in the Lower Guadiana in Portugal, and Rivierenland in the Netherlands. The analysis comprises several regime elements considered to be important in adaptive and integrated water management: agency, awareness raising and education, type of governance and cooperation structures, information management and—exchange, policy development and—implementation, risk management, and finances and cost recovery. This comparative analysis has an explorative character intended to identify general patterns in adaptive and integrated water management and to determine its role in coping with the impacts of climate change on floods and droughts. The results show that there is a strong interdependence of the elements within a water management regime, and as such this interdependence is a stabilizing factor in current management regimes. For example, this research provides evidence that a lack of joint/participative knowledge is an important obstacle for cooperation, or vice versa. We argue that there is a two-way relationship between information management and collaboration. Moreover, this research suggests that bottom-up governance is not a straightforward solution to water management problems in large-scale, complex, multiple-use systems, such as river basins. Instead, all the regimes being analyzed are in a process of finding a balance between bottom-up and top–down governance. Finally, this research shows that in a basin where one type of extreme is dominant—like droughts in the Alentejo (Portugal) and floods in Rivierenland (Netherlands)—the potential impacts of other extremes are somehow ignored or not perceived with the urgency they might deserv

Standardizing Visual Control Devices for Tsetse Flies: West African Species Glossina tachinoides, G. palpalis gambiensis and G. morsitans submorsitans

Here we describe field trials designed to standardize tools for the control of Glossina tachinoides, G. palpalis gambiensis and G.morsitans submorsitans in West Africa based on existing trap/target/bait technology. Blue and black biconical and monoconical traps and 1 m2 targets were made in either phthalogen blue cotton, phthalogen blue cotton/polyester or turquoise blue polyester/viscose (all with a peak reflectance between 450–480 nm) and a black polyester. Because targets were covered in adhesive film, they proved to be significantly better trapping devices than either of the two trap types for all three species (up to 14 times more for G. tachinoides, 10 times more for G. palpalis gambiensis, and 6.5 times for G. morsitans submorsitans). The relative performance of the devices in the three blue cloths tested was the same when unbaited or baited with a mixture of phenols, 1-octen-3-ol and acetone. Since insecticide-impregnated devices act via contact with flies, we enumerated which device (traps or targets) served as the best object for flies to land on by also covering the cloth parts of traps with adhesive film. Despite the fact that the biconical trap proved to be the best landing device for the three species, the difference over the target (20–30%) was not significant. This experiment also allowed an estimation of trap efficiency, i.e. the proportion of flies landing on a trap that are caught in its cage. A low overall efficiency of the biconical or monoconical traps of between 11–24% was recorded for all three species. These results show that targets can be used as practical devices for population suppression of the three species studied. Biconical traps can be used for population monitoring, but a correction factor of 5–10 fold needs to be applied to captures to compensate for the poor trapping efficiency of this device for the three species

Managing Incidental Genomic Findings in Clinical Trials: Fulfillment of the Principle of Justice

<p>Managing Incidental Genomic Findings in Clinical Trials: Fulfillment of the Principle of Justice</p

Pseudomonas aeruginosa 4-Amino-4-Deoxychorismate Lyase: Spatial Conservation of an Active Site Tyrosine and Classification of Two Types of Enzyme

4-Amino-4-deoxychorismate lyase (PabC) catalyzes the formation of 4-aminobenzoate, and release of pyruvate, during folate biosynthesis. This is an essential activity for the growth of Gram-negative bacteria, including important pathogens such as Pseudomonas aeruginosa. A high-resolution (1.75 Å) crystal structure of PabC from P. aeruginosa has been determined, and sequence-structure comparisons with orthologous structures are reported. Residues around the pyridoxal 5′-phosphate cofactor are highly conserved adding support to aspects of a mechanism generic for enzymes carrying that cofactor. However, we suggest that PabC can be classified into two groups depending upon whether an active site and structurally conserved tyrosine is provided from the polypeptide that mainly forms an active site or from the partner subunit in the dimeric assembly. We considered that the conserved tyrosine might indicate a direct role in catalysis: that of providing a proton to reduce the olefin moiety of substrate as pyruvate is released. A threonine had previously been suggested to fulfill such a role prior to our observation of the structurally conserved tyrosine. We have been unable to elucidate an experimentally determined structure of PabC in complex with ligands to inform on mechanism and substrate specificity. Therefore we constructed a computational model of the catalytic intermediate docked into the enzyme active site. The model suggests that the conserved tyrosine helps to create a hydrophobic wall on one side of the active site that provides important interactions to bind the catalytic intermediate. However, this residue does not appear to participate in interactions with the C atom that undergoes an sp2 to sp3 conversion as pyruvate is produced. The model and our comparisons rather support the hypothesis that an active site threonine hydroxyl contributes a proton used in the reduction of the substrate methylene to pyruvate methyl in the final stage of the mechanism

Role of the monocarboxylate transporter MCT1 in the uptake of lactate during active recovery

Purpose We assessed the role of monocarboxylate transporter 1 (MCT1) on lactate clearance during an active recovery after high-intensity exercise, by comparing genetic groups based on the T1470A (rs1049434) MCT1 polymorphism, whose influence on lactate transport has been proven. Methods Sixteen young male elite field hockey players participated in this study. All of them completed two 400 m maximal run tests performed on different days, followed by 40 min of active or passive recovery. Lactate samples were measured immediately after the tests, and at min 10, 20, 30 and 40 of the recoveries. Blood lactate decreases were calculated for each 10-min period. Participants were distributed into three groups according to the T1470A polymorphism (TT, TA and AA). Results TT group had a lower blood lactate decrease than AA group during the 10?20 min period of the active recovery (p = 0.018). This period had the highest blood lactate for the whole sample, significantly differing from the other periods (p ? 0.003). During the passive recovery, lactate declines were constant except for the 0?10-min period (p ? 0.003), suggesting that liver uptake is similar in all the genetic groups, and that the difference seen during the active recovery is mainly due to muscle lactate uptake. Conclusions These differences according to the polymorphic variant T1470A suggest that MCT1 affects the plasma lactate decrease during a crucial period of active recovery, where the maximal lactate amount is cleared (i.e. 10?20 min period)

X-ray Absorption and Reflection in Active Galactic Nuclei

X-ray spectroscopy offers an opportunity to study the complex mixture of emitting and absorbing components in the circumnuclear regions of active galactic nuclei, and to learn about the accretion process that fuels AGN and the feedback of material to their host galaxies. We describe the spectral signatures that may be studied and review the X-ray spectra and spectral variability of active galaxies, concentrating on progress from recent Chandra, XMM-Newton and Suzaku data for local type 1 AGN. We describe the evidence for absorption covering a wide range of column densities, ionization and dynamics, and discuss the growing evidence for partial-covering absorption from data at energies > 10 keV. Such absorption can also explain the observed X-ray spectral curvature and variability in AGN at lower energies and is likely an important factor in shaping the observed properties of this class of source. Consideration of self-consistent models for local AGN indicates that X-ray spectra likely comprise a combination of absorption and reflection effects from material originating within a few light days of the black hole as well as on larger scales. It is likely that AGN X-ray spectra may be strongly affected by the presence of disk-wind outflows that are expected in systems with high accretion rates, and we describe models that attempt to predict the effects of radiative transfer through such winds, and discuss the prospects for new data to test and address these ideas.Comment: Accepted for publication in the Astronomy and Astrophysics Review. 58 pages, 9 figures. V2 has fixed an error in footnote

Measurement of the branching fraction and CP content for the decay B(0) -> D(*+)D(*-)

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APS.We report a measurement of the branching fraction of the decay B0→D*+D*- and of the CP-odd component of its final state using the BABAR detector. With data corresponding to an integrated luminosity of 20.4  fb-1 collected at the Υ(4S) resonance during 1999–2000, we have reconstructed 38 candidate signal events in the mode B0→D*+D*- with an estimated background of 6.2±0.5 events. From these events, we determine the branching fraction to be B(B0→D*+D*-)=[8.3±1.6(stat)±1.2(syst)]×10-4. The measured CP-odd fraction of the final state is 0.22±0.18(stat)±0.03(syst).This work is supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the A.P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation

Measurement of D-s(+) and D-s(*+) production in B meson decays and from continuum e(+)e(-) annihilation at √s=10.6 GeV

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APSNew measurements of Ds+ and Ds*+ meson production rates from B decays and from qq̅ continuum events near the Υ(4S) resonance are presented. Using 20.8 fb-1 of data on the Υ(4S) resonance and 2.6 fb-1 off-resonance, we find the inclusive branching fractions B(B⃗Ds+X)=(10.93±0.19±0.58±2.73)% and B(B⃗Ds*+X)=(7.9±0.8±0.7±2.0)%, where the first error is statistical, the second is systematic, and the third is due to the Ds+→φπ+ branching fraction uncertainty. The production cross sections σ(e+e-→Ds+X)×B(Ds+→φπ+)=7.55±0.20±0.34pb and σ(e+e-→Ds*±X)×B(Ds+→φπ+)=5.8±0.7±0.5pb are measured at center-of-mass energies about 40 MeV below the Υ(4S) mass. The branching fractions ΣB(B⃗Ds(*)+D(*))=(5.07±0.14±0.30±1.27)% and ΣB(B⃗Ds*+D(*))=(4.1±0.2±0.4±1.0)% are determined from the Ds(*)+ momentum spectra. The mass difference m(Ds+)-m(D+)=98.4±0.1±0.3MeV/c2 is also measured.This work was supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the Swiss NSF, A. P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation

Search for rare quark-annihilation decays, B --> Ds(*) Phi

We report on searches for B- --> Ds- Phi and B- --> Ds*- Phi. In the context of the Standard Model, these decays are expected to be highly suppressed since they proceed through annihilation of the b and u-bar quarks in the B- meson. Our results are based on 234 million Upsilon(4S) --> B Bbar decays collected with the BABAR detector at SLAC. We find no evidence for these decays, and we set Bayesian 90% confidence level upper limits on the branching fractions BF(B- --> Ds- Phi) Ds*- Phi)<1.2x10^(-5). These results are consistent with Standard Model expectations.Comment: 8 pages, 3 postscript figues, submitted to Phys. Rev. D (Rapid Communications