Automatic discovery of ranking formulas for playing with multi-armed bandits

We propose an approach for discovering in an automatic way formulas for ranking arms while playing with multi-armed bandits. The approach works by de ning a grammar made of basic elements such as for example addition, subtraction, the max operator, the average values of rewards collected by an arm, their standard deviation etc., and by exploiting this grammar to generate and test a large number of formulas. The systematic search for good candidate formulas is carried out by a built-on-purpose optimization algorithm used to navigate inside this large set of candidate formulas towards those that give high performances when using them on some multi-armed bandit problems. We have applied this approach on a set of bandit problems made of Bernoulli, Gaussian and truncated Gaussian distributions and have identi ed a few simple ranking formulas that provide interesting results on every problem of this set. In particular, they clearly outperform several reference policies previously introduced in the literature. We argue that these newly found formulas as well as the procedure for generating them may suggest new directions for studying bandit problems.Peer reviewe

Role of tumor necrosis factor-α and its receptors in diesel exhaust particle-induced pulmonary inflammation

Inhalation of diesel exhaust particles (DEP) induces an inflammatory reaction in the lung. However, the underlying mechanisms remain to be elucidated. Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that operates by binding to tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2). The role of TNF-alpha signaling and the importance of either TNFR1 or TNFR2 in the DEP-induced inflammatory response has not yet been elucidated. TNF-alpha knockout (KO), TNFR1 KO, TNFR2 KO, TNFR1/TNFR2 double KO (TNFR-DKO) and wild type (WT) mice were intratracheally exposed to saline or DEP. Pro-inflammatory cells and cytokines were assessed in the bronchoalveolar lavage fluid (BALF). Exposure to DEP induced a dose-dependent inflammation in the BALF in WT mice. In addition, levels of TNF-alpha and its soluble receptors were increased upon exposure to DEP. The DEP-induced inflammation in the BALF was decreased in TNF-alpha KO, TNFR-DKO and TNFR2 KO mice. In contrast, the inflammatory response in the BALF of DEP-exposed TNFR1 KO mice was largely comparable with WT controls. In conclusion, these data provide evidence for a regulatory role of TNF-alpha in DEP-induced pulmonary inflammation and identify TNFR2 as the most important receptor in mediating these inflammatory effects

Optimized look-ahead tree policies

peer reviewedWe consider in this paper look-ahead tree techniques for the discrete-time control of a deterministic dynamical system so as to maximize a sum of discounted rewards over an in finite time horizon. Given the current system state xt at time t, these techniques explore the look-ahead tree representing possible evolutions of the system states and rewards conditioned on subsequent actions ut, ut+1, ... . When the computing budget is exhausted, they output the action ut that led to the best found sequence of discounted rewards. In this context, we are interested in computing good strategies for exploring the look-ahead tree. We propose a generic approach that looks for such strategies by solving an optimization problem whose objective is to compute a (budget compliant) tree-exploration strategy yielding a control policy maximizing the average return over a postulated set of initial states. This generic approach is fully speci ed to the case where the space of candidate tree-exploration strategies are "best-first" strategies parameterized by a linear combination of look-ahead path features - some of them having been advocated in the literature before - and where the optimization problem is solved by using an EDA-algorithm based on Gaussian distributions. Numerical experiments carried out on a model of the treatment of the HIV infection show that the optimized tree-exploration strategy is orders of magnitudes better than the previously advocated ones

Linking In Vitro and In Vivo Survival of Clinical Leishmania donovani Strains

BACKGROUND: Leishmania donovani is an intracellular protozoan parasite that causes a lethal systemic disease, visceral leishmaniasis (VL), and is transmitted between mammalian hosts by phlebotomine sandflies. Leishmania expertly survives in these 'hostile' environments with a unique redox system protecting against oxidative damage, and host manipulation skills suppressing oxidative outbursts of the mammalian host. Treating patients imposes an additional stress on the parasite and sodium stibogluconate (SSG) was used for over 70 years in the Indian subcontinent. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated whether the survival capacity of clinical L. donovani isolates varies significantly at different stages of their life cycle by comparing proliferation, oxidative stress tolerance and infection capacity of 3 Nepalese L. donovani strains in several in vitro and in vivo models. In general, the two strains that were resistant to SSG, a stress encountered in patients, attained stationary phase at a higher parasite density, contained a higher amount of metacyclic parasites and had a greater capacity to cause in vivo infection in mice compared to the SSG-sensitive strain. CONCLUSIONS/SIGNIFICANCE: The 2 SSG-resistant strains had superior survival skills as promastigotes and as amastigotes compared to the SSG-sensitive strain. These results could indicate that Leishmania parasites adapting successfully to antimonial drug pressure acquire an overall increased fitness, which stands in contrast to what is found for other organisms, where drug resistance is usually linked to a fitness cost. Further validation experiments are under way to verify this hypothesi

3-nitroimidazo[1,2-b]pyridazine as a novel scaffold for antiparasitics with sub-nanomolar anti-Giardia lamblia activity.

As there is a continuous need for novel anti-infectives, the present study aimed to fuse two modes of action into a novel 3-nitroimidazo[1,2-b]pyridazine scaffold to improve antiparasitic efficacy. For this purpose, we combined known structural elements of phosphodiesterase inhibitors, a target recently proposed for Trypanosoma brucei and Giardia lamblia, with a nitroimidazole scaffold to generate nitrosative stress. The compounds were evaluated in vitro against a panel of protozoal parasites, namely Giardia lamblia, Trypanosoma brucei, T. cruzi, Leishmania infantum and Plasmodium falciparum and for cytotoxicity on MRC-5 cells. Interestingly, selective sub-nanomolar activity was obtained against G. lamblia, and by testing several analogues with and without the nitro group, it was shown that the presence of a nitro group, but not PDE inhibition, is responsible for the low IC50 values of these novel compounds. Adding the favourable drug-like properties (low molecular weight, cLogP (1.2-4.1) and low polar surface area), the key compounds from the 3-nitroimidazo[1,2-b]pyridazine series can be considered as valuable hits for further anti-giardiasis drug exploration and development

Revisiting tubercidin against kinetoplastid parasites: Aromatic substitutions at position 7 improve activity and reduce toxicity

The nucleoside antibiotic tubercidin displays strong activity against different target organisms, but it is notoriously toxic to mammalian cells. The effects of tubercidin against T. brucei parasites inspired us to synthesize several C7 substituted analogs for in vitro evaluation in order to find suitable hit compounds. C7 Deazaadenosines substituted with electron-poor phenyl groups were found to have micromolar activity against T. brucei in vitro. Replacement of the phenyl for a pyridine ring gave compound 13, with submicromolar potency and much-attenuated cytotoxicity compared to tubercidin. The veterinary pathogen T. congolense was equally affected by 13 in vitro. Transporter studies in T. b. brucei indicated that 13 is taken up efficiently by both the P1 and P2 adenosine transporters, making the occurrence of transporter-related resistance and cross-resistance with diamidine drugs such as diminazene aceturate and pentamidine as well as with melaminophenyl arsenicals unlikely. Evaluation of the in vitro metabolic stability of analog 13 indicated that this analog was significantly metabolized in mouse microsomal fractions, precluding further in vivo evaluation in mouse models of HAT

6-O-alkylated 7-deazainosine nucleoside analogues : discovery of potent and selective anti-sleeping sickness agents

African trypanosomiasis, a deadly infectious disease caused by the protozoan Trypanosoma brucei spp., is spread to new hosts by bites of infected tsetse flies. Currently approved therapies all have their specific drawbacks, prompting a search for novel therapeutic agents. T. brucei lacks the enzymes necessary to forge the purine ring from amino acid precursors, rendering them dependent on the uptake and interconversion of host purines. This dependency renders analogues of purines and corresponding nucleosides an interesting source of potential anti-T. brucei agents. In this study, we synthesized and evaluated a series of 7-substituted 7-deazainosine derivatives and found that 6-O-alkylated analogues in particular showed highly promising in vitro activity with EC50 values in the mid-nanomolar range. SAR investigation of the O-alkyl chain showed that antitrypanosomal activity increased, and also cytotoxicity, with alkyl chain length, at least in the linear alkyl chain series. However, this could be attenuated by introducing a terminal branch point, resulting in the highly potent and selective analogues, 36, 37 and 38. No resistance related to transporter-mediated uptake could be identified, earmarking several of these analogues for further in vivo follow-up studies

Different mutations in a P-type ATPase transporter in Leishmania parasites are associated with cross-resistance to two leading drugs by distinct mechanisms

Work in TKS’s lab is supported by the Wellcome Trust grant 093228 and European Community’s Seventh Framework Programme under grant agreement No. 602773 (Project KINDRED).Leishmania infantum is an etiological agent of the life-threatening visceral form of leishmaniasis. Liposomal amphotericin B (AmB) followed by a short administration of miltefosine (MF) is a drug combination effective for treating visceral leishmaniasis in endemic regions of India. Resistance to MF can be due to point mutations in the miltefosine transporter (MT). Here we show that mutations in MT are also observed in Leishmania AmB-resistant mutants. The MF-induced MT mutations, but not the AmB induced mutations in MT, alter the translocation/uptake of MF. Moreover, mutations in the MT selected by AmB or MF have a major impact on lipid species that is linked to cross-resistance between both drugs. These alterations include changes of specific phospholipids, some of which are enriched with cyclopropanated fatty acids, as well as an increase in inositolphosphoceramide species. Collectively these results provide evidence of the risk of cross-resistance emergence derived from current AmB-MF sequential or co-treatments for visceral leishmaniasis.Publisher PDFPeer reviewe

4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma brucei

Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets. The activity of known nucleoside analogues such as tubercidin and cordycepin led to the development of a series of C7-substituted nucleoside analogues. Here, we use RNA interference (RNAi) libraries to gain insight into the mode-of-action of these novel nucleoside analogues. Whole-genome RNAi screening revealed the involvement of adenosine kinase and 4E interacting protein into the mode-of-action of certain antitrypanosomal nucleoside analogues. Using RNAi lines and gene-deficient parasites, 4E interacting protein was found to be essential for parasite growth and infectivity in the vertebrate host. The essential nature of this gene product and involvement in the activity of certain nucleoside analogues indicates that it represents a potential novel drug target.</jats:p