1,509 research outputs found
Identification of LDH-A as a therapeutic target for cancer cell killing via (i) p53/NAD(H)-dependent and (ii) p53 independent pathways
Most cancer cells use aerobic glycolysis to fuel their growth. The enzyme lactate dehydrogenase-A (LDH-A) is key to cancerâs glycolytic phenotype, catalysing the regeneration of nicotinamide adenine dinucleotide (NAD ĂŸ ) from reduced nicotinamide adenine dinucleotide (NADH) necessary to sustain glycolysis. As such, LDH-A is a promising target for anticancer therapy. Here we ask if the tumour suppressor p53, a major regulator of cellular metabolism, influences the response of cancer cells to LDH-A suppression. LDH-A knockdown by RNA interference (RNAi) induced cancer cell death in p53 wild-type, mutant and p53-null human cancer cell lines, indicating that endogenous LDH-A promotes cancer cell survival irrespective of cancer cell p53 status. Unexpectedly,however,weuncoveredanovelroleforp53intheregulationofcancercellNADĂŸ anditsreducedformNADH.Thus, LDH-A silencing by RNAi, or its inhibition using a small-molecule inhibitor, resulted in a p53-dependent increase in the cancer cell ratioofNADH:NADĂŸ.Thiseffectwasspecificforp53ĂŸ/ĂŸ cancercellsandcorrelatedwith(i)reducedactivityofNADĂŸ-dependent deacetylase sirtuin 1 (SIRT1) and (ii) an increase in acetylated p53, a known target of SIRT1 deacetylation activity. In addition, activation of the redox-sensitive anticancer drug EO9 was enhanced selectively in p53 ĂŸ / ĂŸ cancer cells, attributable to increased activity of NAD(P)H-dependent oxidoreductase NQO1 (NAD(P)H quinone oxidoreductase 1). Suppressing LDH-A increased EO9-inducedDNAdamageinp53ĂŸ/ĂŸ cancercells,butimportantlyhadnoadditiveeffectinnon-cancercells.Ourresultsidentifya unique strategy by which the NADH/NADĂŸ cellular redox status can be modulated in a cancer-specific, p53-dependent manner and we show that this can impact upon the activity of important NAD(H)-dependent enzymes. To summarise, this work indicates two distinct mechanisms by which suppressing LDH-A could potentially be used to kill cancer cells selectively, (i) through induction of apoptosis, irrespective of cancer cell p53 status and (ii) as a part of a combinatorial approach with redox-sensitive anticancer drugs via a novel p53/NAD(H)-dependent mechanism
Changes in the carbon balance of tropical forest: evidence from long-term plots
The role of the worldâs forests as a âsinkâ for atmospheric carbon dioxide is the subject of active debate. Long-term monitoring of plots in mature humid tropical forests concentrated in South America revealed that biomass gain by tree growth exceeded losses from tree death in 38 out of 50 neotropical sites. These forest plots have accumulated 0.71 + 0.34 tons of carbon per hectare per year in recent decades. The data suggest that neotropical forests may be a significant carbon sink, reducing the rate of increase in atmospheric CO2
Lattice-Boltzmann Method for Geophysical Plastic Flows
We explore possible applications of the Lattice-Boltzmann Method for the
simulation of geophysical flows. This fluid solver, while successful in other
fields, is still rarely used for geotechnical applications. We show how the
standard method can be modified to represent free-surface realization of
mudflows, debris flows, and in general any plastic flow, through the
implementation of a Bingham constitutive model. The chapter is completed by an
example of a full-scale simulation of a plastic fluid flowing down an inclined
channel and depositing on a flat surface. An application is given, where the
fluid interacts with a vertical obstacle in the channel.Comment: in W. Wu, R.I. Borja (Edts.) Recent advances in modelling landslides
and debris flow, Springer Series in Geomechanics and Geoengineering (2014),
ISBN 978-3-319-11052-3, pp. 131-14
Neutral and cationic half-sandwich arene ruthenium, Cp*Rh and Cp*Ir oximato and oxime complexes: Synthesis, structural, DFT and biological studies
The reaction of [(p-cymene)RuCl2]2 and [Cp*MCl2]2 (M = Rh/Ir) with chelating ligand 2-pyridylcyanoxime {pyC(CN)NOH} leads to the formation of neutral oximato complexes having the general formula [(arene)M{pyC(CN)NO}Cl] {arene = p-cymene, M = Ru, (1); Cp*, M = Rh (2);Cp*, M = Ir (3)}. Whereas the reaction of 2-pyridyl phenyloxime {pyC(Ph)NOH} and 2-thiazolyl methyloxime {tzC(Me)NOH} with precursor compounds afforded the cationic oxide complexes bearing formula [(arene)M{pyC(ph)NOH}Cl]+ and [(arene)M{tzC(Me)NOH}Cl]+{arene = p-cymene M = Ru, (4), (7); Cp*, M = Rh (5), (8); Cp*, M = Ir (6), (9)}. The cationic complexes were isolated as their hexafluorophosphate salts. All these complexes were fully characterized by analytical, spectroscopic and X-ray diffraction studies. The molecular structures of the complexes revealed typical piano stool geometry around the metal center within which the ligand acts as a NNÊč donor chelating ligand. The Chemo-sensitivity activities of the complexes evaluated against HT-29 (human colorectal cancer), and MIAPaCa-2 (human pancreatic cancer) cell line showed that the iridium-based complexes are much more potent than the ruthenium and rhodium analogues. Theoretical studies were carried out to have a deeper understanding about the charge distribution pattern and the various electronic transitions occurring in the complexes
Low-Loss All-Optical Zeno Switch in a Microdisk Cavity Using EIT
We present theoretical results of a low-loss all-optical switch based on
electromagnetically induced transparency and the classical Zeno effect in a
microdisk resonator. We show that a control beam can modify the atomic
absorption of the evanescent field which suppresses the cavity field buildup
and alters the path of a weak signal beam. We predict more than 35 dB of
switching contrast with less than 0.1 dB loss using just 2 micro-Watts of
control-beam power for signal beams with less than single photon intensities
inside the cavity.Comment: Updated with new references, corrected Eq 2a, and added introductory
text. 7 pages, 5 figures, 3 table
Signature of small rings in the Raman spectra of normal and compressed amorphous silica: A combined classical and ab initio study
We calculate the parallel (VV) and perpendicular (VH) polarized Raman spectra
of amorphous silica. Model SiO2 glasses, uncompressed and compressed, were
generated by a combination of classical and ab initio molecular-dynamics
simulations and their dynamical matrices were computed within the framework of
the density functional theory. The Raman scattering intensities were determined
using the bond-polarizability model and a good agreement with experimental
spectra was found. We confirm that the modes associated to the fourfold and
threefold rings produce most of the Raman intensity of the D1 and D2 peaks,
respectively, in the VV Raman spectra. Modifications of the Raman spectra upon
compression are found to be in agreement with experimental data. We show that
the modes associated to the fourfold rings still exist upon compression but do
not produce a strong Raman intensity, whereas the ones associated to the
threefold rings do. This result strongly suggests that the area under the D1
and D2 peaks is not directly proportional to the concentration of small rings
in amorphous SiO2.Comment: 21 pages, 8 figures. Phys. Rev. B, in pres
Mathematical and computational models of drug transport in tumours
The ability to predict how far a drug will penetrate into the tumour microenvironment within its pharmacokinetic (PK) lifespan would provide valuable information about therapeutic response. As the PK profile is directly related to the route and schedule of drug administration, an in silico tool that can predict the drug administration schedule that results in optimal drug delivery to tumours would streamline clinical trial design. This paper investigates the application of mathematical and computational modelling techniques to help improve our understanding of the fundamental mechanisms underlying drug delivery, and compares the performance of a simple model with more complex approaches. Three models of drug transport are developed, all based on the same drug binding model and parametrized by bespoke in vitro experiments. Their predictions, compared for a âtumour cordâ geometry, are qualitatively and quantitatively similar. We assess the effect of varying the PK profile of the supplied drug, and the binding affinity of the drug to tumour cells, on the concentration of drug reaching cells and the accumulated exposure of cells to drug at arbitrary distances from a supplying blood vessel. This is a contribution towards developing a useful drug transport modelling tool for informing strategies for the treatment of tumour cells which are âpharmacokinetically resistantâ to chemotherapeutic strategies
A criterion for separating process calculi
We introduce a new criterion, replacement freeness, to discern the relative
expressiveness of process calculi. Intuitively, a calculus is strongly
replacement free if replacing, within an enclosing context, a process that
cannot perform any visible action by an arbitrary process never inhibits the
capability of the resulting process to perform a visible action. We prove that
there exists no compositional and interaction sensitive encoding of a not
strongly replacement free calculus into any strongly replacement free one. We
then define a weaker version of replacement freeness, by only considering
replacement of closed processes, and prove that, if we additionally require the
encoding to preserve name independence, it is not even possible to encode a non
replacement free calculus into a weakly replacement free one. As a consequence
of our encodability results, we get that many calculi equipped with priority
are not replacement free and hence are not encodable into mainstream calculi
like CCS and pi-calculus, that instead are strongly replacement free. We also
prove that variants of pi-calculus with match among names, pattern matching or
polyadic synchronization are only weakly replacement free, hence they are
separated both from process calculi with priority and from mainstream calculi.Comment: In Proceedings EXPRESS'10, arXiv:1011.601
Fluctuations of an evaporating black hole from back reaction of its Hawking radiation: Questioning a premise in earlier work
This paper delineates the first steps in a systematic quantitative study of
the spacetime fluctuations induced by quantum fields in an evaporating black
hole. We explain how the stochastic gravity formalism can be a useful tool for
that purpose within a low-energy effective field theory approach to quantum
gravity. As an explicit example we apply it to the study of the
spherically-symmetric sector of metric perturbations around an evaporating
black hole background geometry. For macroscopic black holes we find that those
fluctuations grow and eventually become important when considering sufficiently
long periods of time (of the order of the evaporation time), but well before
the Planckian regime is reached. In addition, the assumption of a simple
correlation between the fluctuations of the energy flux crossing the horizon
and far from it, which was made in earlier work on spherically-symmetric
induced fluctuations, is carefully analyzed and found to be invalid. Our
analysis suggests the existence of an infinite amplitude for the fluctuations
of the horizon as a three-dimensional hypersurface. We emphasize the need for
understanding and designing operational ways of probing quantum metric
fluctuations near the horizon and extracting physically meaningful information.Comment: 10 pages, REVTeX; minor changes, a few references added and a brief
discussion of their relevance included. To appear in the proceedings of the
10th Peyresq meeting. Dedicated to Rafael Sorkin on the occasion of his 60th
birthda
Relativistic effects and quasipotential equations
We compare the scattering amplitude resulting from the several quasipotential
equations for scalar particles. We consider the Blankenbecler-Sugar, Spectator,
Thompson, Erkelenz-Holinde and Equal-Time equations, which were solved
numerically without decomposition into partial waves. We analyze both
negative-energy state components of the propagators and retardation effects. We
found that the scattering solutions of the Spectator and the Equal-Time
equations are very close to the nonrelativistic solution even at high energies.
The overall relativistic effect increases with the energy. The width of the
band for the relative uncertainty in the real part of the scattering
matrix, due to different dynamical equations, is largest for
backward-scattering angles where it can be as large as 40%.Comment: Accepted for publication in Phys. Rev.
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