Synergistic action of dual IGF1/R and MEK inhibition sensitizes childhood acute lymphoblastic leukemia (ALL) cells to cytotoxic agents and involves downregulation of STAT6 and PDAP1.

Heterogeneous upregulation of multiple prosurvival pathways underlies resistance to damage-induced apoptosis in acute lymphoblastic leukemia (ALL) cells despite normal p53 responses. Here, we show that the dual combination of insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1/R) and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition using AG1024 + U0126 can sensitize apoptosis-resistant ALL cells to ionizing radiation-induced DNA damage irrespective of effect of single pathway inhibition in vitro. This AG1024 + U0126 combination also significantly potentiates the ability of the core chemotherapy compounds vincristine, dexamethasone, and daunorubicin to kill ALL cells in vitro. Evidence of the synergistic action of AG1024 + U0126 in samples with variable basal levels of phosphorylated IGF1/Rβ and ERK1/2 suggested additional targets of this drug combination. Consistent with this, gene expression profiling identified 32 "synergy genes" differentially targeted by IGF1/R + MEK inhibition and, among these, Signal transducer and activator of transcription 6 (STAT6) and platelet-derived growth factor-associated protein 1 (PDAP1) were the most differentially downregulated cluster. Pearson correlation analyses revealed that STAT6 and PDAP1 display significant expression codependency and a common expression pattern linked with other key "synergy" genes, supporting their predicted role in an STAT6-ERK-nuclear factor kappa beta (NF-κB) network. Knockdown studies revealed that loss of STAT6, but not PDAP1, impinges on the cell cycle, causing reduced numbers of viable cells. In combination with daunorubicin, STAT6 loss has an additive effect on cell killing, whereas PDAP1 loss is synergistic, indicating an important role of PDAP1 in the cellular response to this anthracycline. Inhibition of STAT6 or PDAP1 may therefore represent a potential novel therapeutic strategy for resistant ALL by enhancing sensitivity to chemotherapy

Fragile three-dimensionality in the quasi-one-dimensional cuprate PrBa_2Cu_4O_8

In this article we report on the experimental realization of dimensional crossover phenomena in the chain compound PrBa$_2$Cu$_4$O$_8$ using temperature, high magnetic fields and disorder as independent tuning parameters. In purer crystals of PrBa$_2$Cu$_4$O$_8$, a highly anisotropic three-dimensional Fermi-liquid state develops at low temperatures. This metallic state is extremely susceptible to disorder however and localization rapidly sets in. We show, through quantitative comparison of the relevant energy scales, that this metal/insulator crossover occurs precisely when the scattering rate within the chain exceeds the interchain hopping rate(s), i.e. once carriers become confined to a single conducting element.Comment: 12 pages, 5 figures, published at http://www.iop.org/EJ/article/1367-2630/8/9/172/njp6_9_172.htm

Untangling CP Violation and the Mass Hierarchy in Long Baseline Experiments

In the overlap region, for the normal and inverted hierarchies, of the neutrino-antineutrino bi-probability space for $\nu_\mu \to \nu_e$ appearance, we derive a simple identity between the solutions in the ($\sin^2 2\theta_{13}$, $\sin \delta$) plane for the different hierarchies. The parameter $\sin^2 2\theta_{13}$ sets the scale of the $\nu_\mu \to \nu_e$ appearance probabilities at the atmospheric $\delta m^2_{atm} \approx 2.4 \times 10^{-3}$ eV$^2$ whereas $\sin \delta$ controls the amount of CP violation in the lepton sector. The identity between the solutions is that the difference in the values of $\sin \delta$ for the two hierarchies equals twice the value of $\sqrt{\sin^2 2\theta_{13}}$ divided by the {\it critical} value of $\sqrt{\sin^2 2\theta_{13}}$. We apply this identity to the two proposed long baseline experiments, T2K and NO$\nu$A, and we show how it can be used to provide a simple understanding of when and why fake solutions are excluded when two or more experiments are combined. The identity demonstrates the true complimentarity of T2K and NO$\nu$A.Comment: 15 pages, Latex, 4 postscript figures. Submitted to New Journal of Physics, ``Focus on Neutrino Physics'' issu

Measuring the Small-Scale Power Spectrum of Cosmic Density Fluctuations Through 21 cm Tomography Prior to the Epoch of Structure Formation

The thermal evolution of the cosmic gas decoupled from that of the cosmic microwave background (CMB) at a redshift z~200. Afterwards and before the first stars had formed, the cosmic neutral hydrogen absorbed the CMB flux at its resonant 21cm spin-flip transition. We calculate the evolution of the spin temperature for this transition and the resulting anisotropies that are imprinted on the CMB sky due to linear density fluctuations during this epoch. These anisotropies at an observed wavelength of 10.56[(1+z)/50] meters, contain an amount of information that is orders of magnitude larger than any other cosmological probe. Their detection, although challenging, could tightly constrain any possible running of the spectral index from inflation (as suggested by WMAP), small deviations from Gaussianity, or any significant contribution from neutrinos or warm dark matter to the cosmic mass budget.Comment: 4 pages, 3 figures, accepted for publication in Physical Review Letter

Living IoT: A Flying Wireless Platform on Live Insects

Sensor networks with devices capable of moving could enable applications ranging from precision irrigation to environmental sensing. Using mechanical drones to move sensors, however, severely limits operation time since flight time is limited by the energy density of current battery technology. We explore an alternative, biology-based solution: integrate sensing, computing and communication functionalities onto live flying insects to create a mobile IoT platform. Such an approach takes advantage of these tiny, highly efficient biological insects which are ubiquitous in many outdoor ecosystems, to essentially provide mobility for free. Doing so however requires addressing key technical challenges of power, size, weight and self-localization in order for the insects to perform location-dependent sensing operations as they carry our IoT payload through the environment. We develop and deploy our platform on bumblebees which includes backscatter communication, low-power self-localization hardware, sensors, and a power source. We show that our platform is capable of sensing, backscattering data at 1 kbps when the insects are back at the hive, and localizing itself up to distances of 80 m from the access points, all within a total weight budget of 102 mg.Comment: Co-primary authors: Vikram Iyer, Rajalakshmi Nandakumar, Anran Wang, In Proceedings of Mobicom. ACM, New York, NY, USA, 15 pages, 201

Rational bidding using reinforcement learning: an application in automated resource allocation

The application of autonomous agents by the provisioning and usage of computational resources is an attractive research field. Various methods and technologies in the area of artificial intelligence, statistics and economics are playing together to achieve i) autonomic resource provisioning and usage of computational resources, to invent ii) competitive bidding strategies for widely used market mechanisms and to iii) incentivize consumers and providers to use such market-based systems. The contributions of the paper are threefold. First, we present a framework for supporting consumers and providers in technical and economic preference elicitation and the generation of bids. Secondly, we introduce a consumer-side reinforcement learning bidding strategy which enables rational behavior by the generation and selection of bids. Thirdly, we evaluate and compare this bidding strategy against a truth-telling bidding strategy for two kinds of market mechanisms – one centralized and one decentralized

The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53

YesTopoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response (DDR) genes, such as ATM and TP53. Here, we characterise the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DDR at nano-molar concentrations and this is mediated primarily through ATR- and DNA-PK- but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest, was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model. Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DDR genes

Bayesian reinforcement learning with exploration

We consider a general reinforcement learning problem and show that carefully combining the Bayesian optimal policy and an exploring policy leads to minimax sample-complexity bounds in a very general class of (history-based) environments. We also prove lower bounds and show that the new algorithm displays adaptive behaviour when the environment is easier than worst-case

PYTHIA hadronization process tuning in the GENIE neutrino interaction generator

9 pages, 7 figures, proceedings of the CETUP*-Workshop on Neutrino Interactions, July 22-31, 2014 at Lead/Dead Wood, South Dakota, USA9 pages, 7 figures, proceedings of the CETUP*-Workshop on Neutrino Interactions, July 22-31, 2014 at Lead/Dead Wood, South Dakota, USAv1: 9 pages, 7 figures, proceedings of the CETUP*-Workshop on Neutrino Interactions, July 22-31, 2014 at Lead/Dead Wood, South Dakota, USA. v2: 15 pages, 8 figures, 1 table, will be published by Journal of Physics G: Nuclear and Particle Physics (IoP

Next nearest neighbour Ising models on random graphs

This paper develops results for the next nearest neighbour Ising model on random graphs. Besides being an essential ingredient in classic models for frustrated systems, second neighbour interactions interactions arise naturally in several applications such as the colour diversity problem and graphical games. We demonstrate ensembles of random graphs, including regular connectivity graphs, that have a periodic variation of free energy, with either the ratio of nearest to next nearest couplings, or the mean number of nearest neighbours. When the coupling ratio is integer paramagnetic phases can be found at zero temperature. This is shown to be related to the locked or unlocked nature of the interactions. For anti-ferromagnetic couplings, spin glass phases are demonstrated at low temperature. The interaction structure is formulated as a factor graph, the solution on a tree is developed. The replica symmetric and energetic one-step replica symmetry breaking solution is developed using the cavity method. We calculate within these frameworks the phase diagram and demonstrate the existence of dynamical transitions at zero temperature for cases of anti-ferromagnetic coupling on regular and inhomogeneous random graphs.Comment: 55 pages, 15 figures, version 2 with minor revisions, to be published J. Stat. Mec