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 cancer’s glycolytic phenotype, catalysing the regeneration of nicotinamide adenine dinucleotide (NAD þ ) 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,weuncoveredanovelroleforp53intheregulationofcancercellNADþ 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:NADþ.Thiseffectwasspecificforp53þ/þ cancercellsandcorrelatedwith(i)reducedactivityofNADþ-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 þ / þ cancer cells, attributable to increased activity of NAD(P)H-dependent oxidoreductase NQO1 (NAD(P)H quinone oxidoreductase 1). Suppressing LDH-A increased EO9-inducedDNAdamageinp53þ/þ cancercells,butimportantlyhadnoadditiveeffectinnon-cancercells.Ourresultsidentifya unique strategy by which the NADH/NADþ 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

Black Hole Entropy is Noether Charge

We consider a general, classical theory of gravity in $n$ dimensions, arising from a diffeomorphism invariant Lagrangian. In any such theory, to each vector field, $\xi^a$, on spacetime one can associate a local symmetry and, hence, a Noether current $(n-1)$-form, ${\bf j}$, and (for solutions to the field equations) a Noether charge $(n-2)$-form, ${\bf Q}$. Assuming only that the theory admits stationary black hole solutions with a bifurcate Killing horizon, and that the canonical mass and angular momentum of solutions are well defined at infinity, we show that the first law of black hole mechanics always holds for perturbations to nearby stationary black hole solutions. The quantity playing the role of black hole entropy in this formula is simply $2 \pi$ times the integral over $\Sigma$ of the Noether charge $(n-2)$-form associated with the horizon Killing field, normalized so as to have unit surface gravity. Furthermore, we show that this black hole entropy always is given by a local geometrical expression on the horizon of the black hole. We thereby obtain a natural candidate for the entropy of a dynamical black hole in a general theory of gravity. Our results show that the validity of the ``second law" of black hole mechanics in dynamical evolution from an initially stationary black hole to a final stationary state is equivalent to the positivity of a total Noether flux, and thus may be intimately related to the positive energy properties of the theory. The relationship between the derivation of our formula for black hole entropy and the derivation via ``Euclidean methods" also is explained.Comment: 16 pages, EFI 93-4

Quantum speedup for graph sparsification, cut approximation and Laplacian solving

Graph sparsification underlies a large number of algorithms, ranging from approximation algorithms for cut problems to solvers for linear systems in the graph Laplacian. In its strongest form, "spectral sparsification" reduces the number of edges to near-linear in the number of nodes, while approximately preserving the cut and spectral structure of the graph. The breakthrough work by Benczúr and Karger (STOC'96) and Spielman and Teng (STOC'04) showed that sparsification can be done optimally in time near-linear in the number of edges of the original graph. In this work we show that quantum algorithms allow to speed up spectral sparsification, and thereby many of the derived algorithms. Given adjacency-list access to a weighted graph with

Quantum speedup for graph sparsification, cut approximation, and Laplacian solving

Graph sparsification underlies a large number of algorithms, ranging from approximation algorithms for cut problems to solvers for linear systems in the graph Laplacian. In its strongest form, “spectral sparsification” reduces the number of edges to near-linear in the number of nodes, while approximately preserving the cut and spectral structure of the graph. In this work we demonstrate a polynomial quantum speedup for spectral sparsification and many of its applications. In particular, we give a quantum algorithm that, given a weighted graph with n nodes and m edges, outputs a classical description of an ϵ -spectral sparsifier in sublinear time O˜(mn−−−√/ϵ) . This contrasts with the optimal classical complexity O˜(m) . We also prove that our quantum algorithm is optimal up to polylog-factors. The algorithm builds on a string of existing results on sparsification, graph spanners, quantum algorithms for shortest paths, and efficient constructions for k -wise independent random strings. Our algorithm implies a quantum speedup for solving Laplacian systems and for approximating a range of cut problems such as min cut and sparsest cut

Charged black holes in quadratic gravity

Iterative solutions to fourth-order gravity describing static and electrically charged black holes are constructed. Obtained solutions are parametrized by two integration constants which are related to the electric charge and the exact location of the event horizon. Special emphasis is put on the extremal black holes. It is explicitly demonstrated that in the extremal limit, the exact location of the (degenerate) event horizon is given by \rp = |e|. Similarly to the classical Reissner-Nordstr\"om solution, the near-horizon geometry of the charged black holes in quadratic gravity, when expanded into the whole manifold, is simply that of Bertotti and Robinson. Similar considerations have been carried out for the boundary conditions of second type which employ the electric charge and the mass of the system as seen by a distant observer. The relations between results obtained within the framework of each method are briefly discussed

Facilitating the analysis of a UK national blood service supply chain using distributed simulation

In an attempt to investigate blood unit ordering policies, researchers have created a discrete-event model of the UK National Blood Service (NBS) supply chain in the Southampton area of the UK. The model has been created using Simul8, a commercial-off-the-shelf discrete-event simulation package (CSP). However, as more hospitals were added to the model, it was discovered that the length of time needed to perform a single simulation severely increased. It has been claimed that distributed simulation, a technique that uses the resources of many computers to execute a simulation model, can reduce simulation runtime. Further, an emerging standardized approach exists that supports distributed simulation with CSPs. These CSP Interoperability (CSPI) standards are compatible with the IEEE 1516 standard The High Level Architecture, the defacto interoperability standard for distributed simulation. To investigate if distributed simulation can reduce the execution time of NBS supply chain simulation, this paper presents experiences of creating a distributed version of the CSP Simul8 according to the CSPI/HLA standards. It shows that the distributed version of the simulation does indeed run faster when the model reaches a certain size. Further, we argue that understanding the relationship of model features is key to performance. This is illustrated by experimentation with two different protocols implementations (using Time Advance Request (TAR) and Next Event Request (NER)). Our contribution is therefore the demonstration that distributed simulation is a useful technique in the timely execution of supply chains of this type and that careful analysis of model features can further increase performance

Replication, Pathogenesis and Transmission of Pandemic (H1N1) 2009 Virus in Non-Immune Pigs

The declaration of the human influenza A pandemic (H1N1) 2009 (H1N1/09) raised important questions, including origin and host range [1,2]. Two of the three pandemics in the last century resulted in the spread of virus to pigs (H1N1, 1918; H3N2, 1968) with subsequent independent establishment and evolution within swine worldwide [3]. A key public and veterinary health consideration in the context of the evolving pandemic is whether the H1N1/09 virus could become established in pig populations [4]. We performed an infection and transmission study in pigs with A/California/07/09. In combination, clinical, pathological, modified influenza A matrix gene real time RT-PCR and viral genomic analyses have shown that infection results in the induction of clinical signs, viral pathogenesis restricted to the respiratory tract, infection dynamics consistent with endemic strains of influenza A in pigs, virus transmissibility between pigs and virus-host adaptation events. Our results demonstrate that extant H1N1/09 is fully capable of becoming established in global pig populations. We also show the roles of viral receptor specificity in both transmission and tissue tropism. Remarkably, following direct inoculation of pigs with virus quasispecies differing by amino acid substitutions in the haemagglutinin receptor-binding site, only virus with aspartic acid at position 225 (225D) was detected in nasal secretions of contact infected pigs. In contrast, in lower respiratory tract samples from directly inoculated pigs, with clearly demonstrable pulmonary pathology, there was apparent selection of a virus variant with glycine (225G). These findings provide potential clues to the existence and biological significance of viral receptor-binding variants with 225D and 225G during the 1918 pandemic [5]

Discovery and Observations of ASASSN-13db, an EX Lupi-Type Accretion Event on a Low-Mass T Tauri Star

We discuss ASASSN-13db, an EX Lupi-type ("EXor") accretion event on the young stellar object (YSO) SDSS J051011.01$-$032826.2 (hereafter SDSSJ0510) discovered by the All-Sky Automated Survey for SuperNovae (ASAS-SN). Using archival photometric data of SDSSJ0510 we construct a pre-outburst spectral energy distribution (SED) and find that it is consistent with a low-mass class II YSO near the Orion star forming region ($d \sim 420$ pc). We present follow-up photometric and spectroscopic observations of the source after the $\Delta V \sim-$5.4 magnitude outburst that began in September 2013 and ended in early 2014. These data indicate an increase in temperature and luminosity consistent with an accretion rate of $\sim10^{-7}$ $\rm{M}_\odot$ yr$^{-1}$, three or more orders of magnitude greater than in quiescence. Spectroscopic observations show a forest of narrow emission lines dominated by neutral metallic lines from Fe I and some low-ionization lines. The properties of ASASSN-13db are similar to those of the EXor prototype EX Lupi during its strongest observed outburst in late 2008.Comment: 14 pages, 4 figures, 1 table. Updated May 2014 to reflect changes in the final version published in ApJL. Photometric data presented in this submission are included as ancillary files. For a brief video explaining this paper, see http://youtu.be/yRCCrNJnvt

Radioactive waste microbiology: predicting microbial survival and activity in changing extreme environments

The potential for microbial activity to occur within the engineered barrier system (EBS) of a geological disposal facility (GDF) for radioactive waste is acknowledged by waste management organizations as it could affect many aspects of the safety functions of a GDF. Microorganisms within an EBS will be exposed to changing temperature, pH, radiation, salinity, saturation, and availability of nutrient and energy sources, which can limit microbial survival and activity. Some of the limiting conditions are incorporated into GDF designs for safety reasons, including the high pH of cementitious repositories, the limited pore space of bentonite-based repositories, or the high salinity of GDFs in evaporitic geologies. Other environmental conditions such as elevated radiation, temperature, and desiccation, arise as a result of the presence of high heat generating waste (HHGW). Here, we present a comprehensive review of how environmental conditions in the EBS may limit microbial activity, covering HHGW and lower heat generating waste (LHGW) in a range of geological environments. We present data from the literature on the currently recognized limits to life for each of the environmental conditions described above, and nutrient availability to establish the potential for life in these environments. Using examples where each variable has been modelled for a particular GDF, we outline the times and locations when that variable can be expected to limit microbial activity. Finally, we show how this information for multiple variables can be used to improve our understanding of the potential for microbial activity to occur within the EBS of a GDF and, more broadly, to understand microbial life in changing environments exposed to multiple extreme conditions

Arnowitt-Deser-Misner representation and Hamiltonian analysis of covariant renormalizable gravity

We study the recently proposed Covariant Renormalizable Gravity (CRG), which aims to provide a generally covariant ultraviolet completion of general relativity. We obtain a space-time decomposed form --- an Arnowitt-Deser-Misner (ADM) representation --- of the CRG action. The action is found to contain time derivatives of the gravitational fields up to fourth order. Some ways to reduce the order of these time derivatives are considered. The resulting action is analyzed using the Hamiltonian formalism, which was originally adapted for constrained theories by Dirac. It is shown that the theory has a consistent set of constraints. It is, however, found that the theory exhibits four propagating physical degrees of freedom. This is one degree of freedom more than in Ho\v{r}ava-Lifshitz (HL) gravity and two more propagating modes than in general relativity. One extra physical degree of freedom has its origin in the higher order nature of the CRG action. The other extra propagating mode is a consequence of a projectability condition similarly as in HL gravity. Some additional gauge symmetry may need to be introduced in order to get rid of the extra gravitational degrees of freedom.Comment: 21 pages, LaTeX. A correction inserted to Hamiltonian formalism in Sec.