Incentivizing Exploration with Heterogeneous Value of Money

Recently, Frazier et al. proposed a natural model for crowdsourced exploration of different a priori unknown options: a principal is interested in the long-term welfare of a population of agents who arrive one by one in a multi-armed bandit setting. However, each agent is myopic, so in order to incentivize him to explore options with better long-term prospects, the principal must offer the agent money. Frazier et al. showed that a simple class of policies called time-expanded are optimal in the worst case, and characterized their budget-reward tradeoff. The previous work assumed that all agents are equally and uniformly susceptible to financial incentives. In reality, agents may have different utility for money. We therefore extend the model of Frazier et al. to allow agents that have heterogeneous and non-linear utilities for money. The principal is informed of the agent's tradeoff via a signal that could be more or less informative. Our main result is to show that a convex program can be used to derive a signal-dependent time-expanded policy which achieves the best possible Lagrangian reward in the worst case. The worst-case guarantee is matched by so-called "Diamonds in the Rough" instances; the proof that the guarantees match is based on showing that two different convex programs have the same optimal solution for these specific instances. These results also extend to the budgeted case as in Frazier et al. We also show that the optimal policy is monotone with respect to information, i.e., the approximation ratio of the optimal policy improves as the signals become more informative.Comment: WINE 201

Agouti protein, mahogunin, and attractin in pheomelanogenesis and melanoblast-like alteration of melanocytes: a cAMP-independent pathway

Melanocortin-1 receptor (MC1R) and its ligands, a-melanocyte stimulating hormone (aMSH) and agouti signaling protein (ASIP), regulate switching between eumelanin and pheomelanin synthesis in melanocytes. Here we investigated biological effects and signaling pathways of ASIP. Melan-a non agouti (a ⁄ a) mouse melanocytes produce mainly eumelanin, but ASIP combined with phenylthiourea and extra cysteine could induce over 200-fold increases in the pheomelanin to eumelanin ratio, and a tan-yellow color in pelletted cells.Moreover, ASIP-treated cells showed reduced proliferation and a melanoblast-like appearance, seen also in melanocyte lines from yellow (Ay ⁄ a and Mc1re ⁄ Mc1re) mice. However ASIP-YY, a C-terminal fragment of ASIP, induced neither biological nor pigmentary changes. As, like ASIP, ASIP-YY inhibited the cAMP rise induced by aMSH analog NDP-MSH, and reduced cAMP level without added MSH, the morphological changes and depigmentation seemed independent of cAMP signaling. Melanocytes genetically null for ASIP mediators attractin or mahogunin (Atrnmg-3J ⁄ mg-3J or Mgrn1md-nc ⁄ md-nc) also responded to both ASIP and ASIP-YY in cAMP level, while only ASIP altered their proliferation and (in part) shape. Thus, ASIP–MC1R signaling includes a cAMP-independent pathway through attractin and mahogunin, while the known cAMP-dependent component requires neither attractin nor mahogunin.Parts of the research were supported by Wellcome Trust program grants 064583 and 078327 to D.C.B. and E.V.S.; the Japan Society for the Promotion of Science KAKENHI (grants 20790808 to T.H. and 18591262 and 20591357 to K.W. and S.I.); a Grant-in-Aid from the Japanese Ministry of Health, Labour and Welfare (K.J.), the Spanish Ministry of Education and Science BFU2006-12185 (L.M.), the South West Academic Network (A.J.D. and E.V.S.), and NIH grant DK064265 (B.Y. and G.L.M.).Peer reviewe

Yield conditions for deformation of amorphous polymer glasses

Shear yielding of glassy polymers is usually described in terms of the pressure-dependent Tresca or von Mises yield criteria. We test these criteria against molecular dynamics simulations of deformation in amorphous polymer glasses under triaxial loading conditions that are difficult to realize in experiments. Difficulties and ambiguities in extending several standard definitions of the yield point to triaxial loads are described. Two definitions, the maximum and offset octahedral stresses, are then used to evaluate the yield stress for a wide range of model parameters. In all cases, the onset of shear is consistent with the pressure-modified von Mises criterion, and the pressure coefficient is nearly independent of many parameters. Under triaxial tensile loading, the mode of failure changes to cavitation.Comment: 9 pages, 8 figures, revte

Simulations of the Static Friction Due to Adsorbed Molecules

The static friction between crystalline surfaces separated by a molecularly thin layer of adsorbed molecules is calculated using molecular dynamics simulations. These molecules naturally lead to a finite static friction that is consistent with macroscopic friction laws. Crystalline alignment, sliding direction, and the number of adsorbed molecules are not controlled in most experiments and are shown to have little effect on the friction. Temperature, molecular geometry and interaction potentials can have larger effects on friction. The observed trends in friction can be understood in terms of a simple hard sphere model.Comment: 13 pages, 13 figure

Functional divergence in the role of N-linked glycosylation in smoothened signaling

The G protein-coupled receptor (GPCR) Smoothened (Smo) is the requisite signal transducer of the evolutionarily conserved Hedgehog (Hh) pathway. Although aspects of Smo signaling are conserved from Drosophila to vertebrates, significant differences have evolved. These include changes in its active sub-cellular localization, and the ability of vertebrate Smo to induce distinct G protein-dependent and independent signals in response to ligand. Whereas the canonical Smo signal to Gli transcriptional effectors occurs in a G protein-independent manner, its non-canonical signal employs Gαi. Whether vertebrate Smo can selectively bias its signal between these routes is not yet known. N-linked glycosylation is a post-translational modification that can influence GPCR trafficking, ligand responsiveness and signal output. Smo proteins in Drosophila and vertebrate systems harbor N-linked glycans, but their role in Smo signaling has not been established. Herein, we present a comprehensive analysis of Drosophila and murine Smo glycosylation that supports a functional divergence in the contribution of N-linked glycans to signaling. Of the seven predicted glycan acceptor sites in Drosophila Smo, one is essential. Loss of N-glycosylation at this site disrupted Smo trafficking and attenuated its signaling capability. In stark contrast, we found that all four predicted N-glycosylation sites on murine Smo were dispensable for proper trafficking, agonist binding and canonical signal induction. However, the under-glycosylated protein was compromised in its ability to induce a non-canonical signal through Gαi, providing for the first time evidence that Smo can bias its signal and that a post-translational modification can impact this process. As such, we postulate a profound shift in N-glycan function from affecting Smo ER exit in flies to influencing its signal output in mice

Carrots and sticks fail to change behavior in cocaine addiction.

Cocaine addiction is a major public health problem that is particularly difficult to treat. Without medically proven pharmacological treatments, interventions to change the maladaptive behavior of addicted individuals mainly rely on psychosocial approaches. Here we report on impairments in cocaine-addicted patients to act purposefully toward a given goal and on the influence of extended training on their behavior. When patients were rewarded for their behavior, prolonged training improved their response rate toward the goal but simultaneously rendered them insensitive to the consequences of their actions. By contrast, overtraining of avoidance behavior had no effect on patient performance. Our findings illustrate the ineffectiveness of punitive approaches and highlight the potential for interventions that focus on improving goal-directed behavior and implementing more desirable habits to replace habitual drug-taking.Sir Henry Wellcome Postdoctoral Fellowship (Grant ID: 101521/Z/12/Z)This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aaf370

Scaling properties of driven interfaces in disordered media

We perform a systematic study of several models that have been proposed for the purpose of understanding the motion of driven interfaces in disordered media. We identify two distinct universality classes: (i) One of these, referred to as directed percolation depinning (DPD), can be described by a Langevin equation similar to the Kardar-Parisi-Zhang equation, but with quenched disorder. (ii) The other, referred to as quenched Edwards-Wilkinson (QEW), can be described by a Langevin equation similar to the Edwards-Wilkinson equation but with quenched disorder. We find that for the DPD universality class the coefficient $\lambda$ of the nonlinear term diverges at the depinning transition, while for the QEW universality class either $\lambda = 0$ or $\lambda \to 0$ as the depinning transition is approached. The identification of the two universality classes allows us to better understand many of the results previously obtained experimentally and numerically. However, we find that some results cannot be understood in terms of the exponents obtained for the two universality classes {\it at\/} the depinning transition. In order to understand these remaining disagreements, we investigate the scaling properties of models in each of the two universality classes {\it above\/} the depinning transition. For the DPD universality class, we find for the roughness exponent $\alpha_P = 0.63 \pm 0.03$ for the pinned phase, and $\alpha_M = 0.75 \pm 0.05$ for the moving phase. For the growth exponent, we find $\beta_P = 0.67 \pm 0.05$ for the pinned phase, and $\beta_M = 0.74 \pm 0.06$ for the moving phase. Furthermore, we find an anomalous scaling of the prefactor of the width on the driving force. A new exponent $\varphi_M = -0.12 \pm 0.06$, characterizing the scaling of this prefactor, is shown to relate the values of the roughnessComment: Latex manuscript, Revtex 3.0, 15 pages, and 15 figures also available via anonymous ftp from ftp://jhilad.bu.edu/pub/abms/ (128.197.42.52

Doxorubicin sensitizes human tumor cells to NK and T cell-mediated killing by augmented TRAIL-receptor signaling

Doxorubicin (DOX) is an anthracycline antibiotic that is widely used to treat different types of malignancy. In this study, it was studied whether DOX could be used to render tumor cells susceptible to apoptosis by NK and T cells. Pretreatment with subapoptotic doses of DOX sensitized tumor cell lines of various histotypes to both NK and T cells resulting in a 3.7 to 32.7% increase in lysis (2.5 mean fold increase, p < 0.0001) and a 2.9 to 14.2% increase in lysis (3.0 mean-fold increase, p < 0.05), respectively. The sensitizing effect of the drug was primarily dependent on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL-receptor signaling, but not on Fas-ligand, perforin, NKG2D or DNAM-1. The central role of the TRAIL signaling pathway was further supported by an increased expression of TRAIL-R2 on DOX-treated tumor cells and by downregulation of cellular FLICE inhibitory protein, the inhibitors of death receptor-mediated apoptosis. Compared to untreated cells, pretreatment of tumor cells with DOX showed increased processing and activation of caspase-8 on coculture with NK or T cells. The significance of this treatment strategy was confirmed using a xenogeneic tumor-bearing mouse model. Tumor progression was delayed in mice that received either NK cells (p < 0.05) or T cells (p < 0.0001) following DOX treatment compared to mice receiving either cell type alone. Moreover, combined infusion of both NK and T cells following DOX treatment not only delayed tumor progression but also significantly improved the long-term survival (p < 0.01). Based on these findings, it was proposed that DOX can be used to improve the efficacy of adoptive cell therapy in patients with cancer.Swedish Research CouncilEuropean Research CouncilManuscrip

Anisotropic Scaling in Threshold Critical Dynamics of Driven Directed Lines

The dynamical critical behavior of a single directed line driven in a random medium near the depinning threshold is studied both analytically (by renormalization group) and numerically, in the context of a Flux Line in a Type-II superconductor with a bulk current $\vec J$. In the absence of transverse fluctuations, the system reduces to recently studied models of interface depinning. In most cases, the presence of transverse fluctuations are found not to influence the critical exponents that describe longitudinal correlations. For a manifold with $d=4-\epsilon$ internal dimensions, longitudinal fluctuations in an isotropic medium are described by a roughness exponent $\zeta_\parallel=\epsilon/3$ to all orders in $\epsilon$, and a dynamical exponent $z_\parallel=2-2\epsilon/9+O(\epsilon^2)$. Transverse fluctuations have a distinct and smaller roughness exponent $\zeta_\perp=\zeta_\parallel-d/2$ for an isotropic medium. Furthermore, their relaxation is much slower, characterized by a dynamical exponent $z_\perp=z_\parallel+1/\nu$, where $\nu=1/(2-\zeta_\parallel)$ is the correlation length exponent. The predicted exponents agree well with numerical results for a flux line in three dimensions. As in the case of interface depinning models, anisotropy leads to additional universality classes. A nonzero Hall angle, which has no analogue in the interface models, also affects the critical behavior.Comment: 26 pages, 8 Postscript figures packed together with RevTeX 3.0 manuscript using uufiles, uses multicol.sty and epsf.sty, e-mail [email protected] in case of problem