Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) Inhibitors

Many inflammatory diseases may be linked to pathologically elevated signaling via the receptor for lipopolysaccharide (LPS), toll-like receptor 4 (TLR4). There has thus been great interest in the discovery of TLR4 inhibitors as potential anti-inflammatory agents. Recently, the structure of TLR4 bound to the inhibitor E5564 was solved, raising the possibility that novel TLR4 inhibitors that target the E5564-binding domain could be designed. We utilized a similarity search algorithm in conjunction with a limited screening approach of small molecule libraries to identify compounds that bind to the E5564 site and inhibit TLR4. Our lead compound, C34, is a 2-acetamidopyranoside (MW 389) with the formula C17H27NO9, which inhibited TLR4 in enterocytes and macrophages in vitro, and reduced systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. Molecular docking of C34 to the hydrophobic internal pocket of the TLR4 co-receptor MD-2 demonstrated a tight fit, embedding the pyran ring deep inside the pocket. Strikingly, C34 inhibited LPS signaling ex-vivo in human ileum that was resected from infants with necrotizing enterocolitis. These findings identify C34 and the β-anomeric cyclohexyl analog C35 as novel leads for small molecule TLR4 inhibitors that have potential therapeutic benefit for TLR4-mediated inflammatory diseases. © 2013 Neal et al

D-brane Charges in Gravitational Duals of 2+1 Dimensional Gauge Theories and Duality Cascades

We perform a systematic analysis of the D-brane charges associated with string theory realizations of d=3 gauge theories, focusing on the examples of the N=4 supersymmetric U(N)xU(N+M) Yang-Mills theory and the N=3 supersymmetric U(N)xU(N+M) Yang-Mills-Chern-Simons theory. We use both the brane construction of these theories and their dual string theory backgrounds in the supergravity approximation. In the N=4 case we generalize the previously known gravitational duals to arbitrary values of the gauge couplings, and present a precise mapping between the gravity and field theory parameters. In the N=3 case, which (for some values of N and M) flows to an N=6 supersymmetric Chern-Simons-matter theory in the IR, we argue that the careful analysis of the charges leads to a shift in the value of the B-field in the IR solution by 1/2, in units where its periodicity is one, compared to previous claims. We also suggest that the N=3 theories may exhibit, for some values of N and M, duality cascades similar to those of the Klebanov-Strassler theory.Comment: 47 pages, 9 figures; minor changes, references adde

Multicore and FPGA implementations of emotional-based agent architectures

The final publication is available at Springer via http://dx.doi.org/10.1007/s11227-014-1307-6.Control architectures based on Emotions are becoming promising solutions for the implementation of future robotic agents. The basic controllers of the architecture are the emotional processes that decide which behaviors of the robot must activate to fulfill the objectives. The number of emotional processes increases (hundreds of millions/s) with the complexity level of the application, reducing the processing capacity of the main processor to solve complex problems (millions of decisions in a given instant). However, the potential parallelism of the emotional processes permits their execution in parallel on FPGAs or Multicores, thus enabling slack computing in the main processor to tackle more complex dynamic problems. In this paper, an emotional architecture for mobile robotic agents is presented. The workload of the emotional processes is evaluated. Then, the main processor is extended with FPGA co-processors through Ethernet link. The FPGAs will be in charge of the execution of the emotional processes in parallel. Different Stratix FPGAs are compared to analyze their suitability to cope with the proposed mobile robotic agent applications. The applications are set up taking into account different environmental conditions, robot dynamics and emotional states. Moreover, the applications are run also on Multicore processors to compare their performance in relation to the FPGAs. Experimental results show that Stratix IV FPGA increases the performance in about one order of magnitude over the main processor and solves all the considered problems. Quad-Core increases the performance in 3.64 times, allowing to tackle about 89 % of the considered problems. Quad-Core has a lower cost than a Stratix IV, so more adequate solution but not for the most complex application. Stratix III could be applied to solve problems with around the double of the requirements that the main processor could support. Finally, a Dual-Core provides slightly better performance than stratix III and it is relatively cheaper.This work was supported in part under Spanish Grant PAID/2012/325 of "Programa de Apoyo a la Investigacion y Desarrollo. Proyectos multidisciplinares", Universitat Politecnica de Valencia, Spain.Domínguez Montagud, CP.; Hassan Mohamed, H.; Crespo, A.; Albaladejo Meroño, J. (2015). Multicore and FPGA implementations of emotional-based agent architectures. Journal of Supercomputing. 71(2):479-507. https://doi.org/10.1007/s11227-014-1307-6S479507712Malfaz M, Salichs MA (2010) Using MUDs as an experimental platform for testing a decision making system for self-motivated autonomous agents. Artif Intell Simul Behav J 2(1):21–44Damiano L, Cañamero L (2010) Constructing emotions. Epistemological groundings and applications in robotics for a synthetic approach to emotions. In: Proceedings of international symposium on aI-inspired biology, The Society for the Study of Artificial Intelligence, pp 20–28Hawes N, Wyatt J, Sloman A (2009) Exploring design space for an integrated intelligent system. Knowl Based Syst 22(7):509–515Sloman A (2009) Some requirements for human-like robots: why the recent over-emphasis on embodiment has held up progress. Creat Brain Like Intell 2009:248–277Arkin RC, Ulam P, Wagner AR (2012) Moral decision-making in autonomous systems: enforcement, moral emotions, dignity, trust and deception. In: Proceedings of the IEEE, Mar 2012, vol 100, no 3, pp 571–589iRobot industrial robots website. http://www.irobot.com/gi/ground/ . Accessed 22 Sept 2014Moravec H (2009) Rise of the robots: the future of artificial intelligence. Scientific American, March 2009. http://www.scientificamerican.com/article/rise-of-the-robots/ . Accessed 14 Oct 2014.Thu Bui L, Abbass HA, Barlow M, Bender A (2012) Robustness against the decision-maker’s attitude to risk in problems with conflicting objectives. IEEE Trans Evolut Comput 16(1):1–19Pedrycz W, Song M (2011) Analytic hierarchy process (AHP) in group decision making and its optimization with an allocation of information granularity. IEEE Trans Fuzzy Syst 19(3):527–539Lee-Johnson CP, Carnegie DA (2010) Mobile robot navigation modulated by artificial emotions. IEEE Trans Syst Man Cybern Part B 40(2):469–480Daglarli E, Temeltas H, Yesiloglu M (2009) Behavioral task processing for cognitive robots using artificial emotions. Neurocomputing 72(13):2835–2844Ventura R, Pinto-Ferreira C (2009) Responding efficiently to relevant stimuli using an emotion-based agent architecture. Neurocomputing 72(13):2923–2930Arkin RC, Ulam P, Wagner AR (2012) Moral decision-making in autonomous systems: enforcement, moral emotions, dignity, trust and deception. Proc IEEE 100(3):571–589Salichs MA, Malfaz M (2012) A new approach to modeling emotions and their use on a decision-making system for artificial agents. Affect Comput IEEE Trans 3(1):56–68Altera Corporation (2011) Stratix III device handbook, vol 1–2, version 2.2. http://www.altera.com/literature/lit-stx3.jsp . Accessed 14 Oct 2014.Altera Corporation (2014) Stratix IV device handbook, vol 1–4, version 5.9. http://www.altera.com/literature/lit-stratix-iv.jsp . Accessed 14 Oct 2014.Naouar MW, Monmasson E, Naassani AA, Slama-Belkhodja I, Patin N (2007) FPGA-based current controllers for AC machine drives: a review. IEEE Trans Ind Electr 54(4):1907–1925Intel Corporation (2014) Desktop 4th generation Intel Core Processor Family, Desktop Intel Pentium Processor Family, and Desktop Intel Celeron Processor Family, Datasheet, vol 1, 2March JL, Sahuquillo J, Hassan H, Petit S, Duato J (2011) A new energy-aware dynamic task set partitioning algorithm for soft and hard embedded real-time systems. Comput J 54(8):1282–1294Del Campo I, Basterretxea K, Echanobe J, Bosque G, Doctor F (2012) A system-on-chip development of a neuro-fuzzy embedded agent for ambient-intelligence environments. IEEE Trans Syst Man Cybern Part B 42(2):501–512Pedraza C, Castillo J, Martínez JI, Huerta P, Bosque JL, Cano J (2011) Genetic algorithm for Boolean minimization in an FPGA cluster. J Supercomput 58(2):244–252Orlowska-Kowalska T, Kaminski M (2011) FPGA implementation of the multilayer neural network for the speed estimation of the two-mass drive system. IEEE Trans Ind Inf 7(3):436–445Cassidy AS, Merolla P, Arthur JV, Esser SK, Jackson B, Alvarez-icaza R, Datta P, Sawada J, Wong TM, Feldman V, Amir A, Ben-dayan D, Mcquinn E, Risk WP, Modha DS (2013) Cognitive computing building block: a versatile and efficient digital neuron model for neurosynaptic cores. In: Proceedings of international joint conference on neural networks, IEEE (IJCNN’2013)IBM Cognitive Computing and Neurosynaptic chips website. http://www.research.ibm.com/cognitive-computing/neurosynaptic-chips.shtml . Accessed 22 Sept 2014Seo E, Jeong J, Park S, Lee J (2008) Energy efficient scheduling of real-time tasks on multicore processors. IEEE Trans Parallel Distrib Syst 19(11):1540–1552Lehoczky J, Sha L, Ding Y (1989) The rate monotonic scheduling algorithm: exact characterization and average case behavior. In: Proceedings of real time systems symposium, IEEE 1989, pp 166–171Ng-Thow-Hing V, Lim J, Wormer J, Sarvadevabhatla RK, Rocha C, Fujimura K, Sakagami Y (2008) The memory game: creating a human-robot interactive scenario for ASIMO. In: Proceedings of intelligent robots and systems, 2008, IROS 2008, IEEE/RSJ international conference, pp 779–78

Branes and fluxes in special holonomy manifolds and cascading field theories

We conduct a study of holographic RG flows whose UV is a theory in 2+1 dimensions decoupled from gravity, and the IR is the N=6,8 superconformal fixed point of ABJM. The solutions we consider are constructed by warping the M-theory background whose eight spatial dimensions are manifolds of special holonomies sp(1) times sp(1) and spin(7). Our main example for the spin(7) holonomy manifold is the A8 geometry originally constructed by Cvetic, Gibbons, Lu, and Pope. On the gravity side, our constructions generalize the earlier construction of RG flow where the UV was N=3 Yang-Mills-Chern-Simons matter system and are simpler in a number of ways. Through careful consideration of Page, Maxwell, and brane charges, we identify the discrete and continuous parameters characterizing each system. We then determine the range of the discrete data, corresponding to the flux/rank for which the supersymmetry is unbroken, and estimate the dynamical supersymmetry breaking scale as a function of these data. We then point out the similarity between the physics of supersymmetry breaking between our system and the system considered by Maldacena and Nastase. We also describe the condition for unbroken supersymmetry on class of construction based on a different class of spin(7) manifolds known as B8 spaces whose IR is different from that of ABJM and exhibit some interesting features.Comment: 51 pages, 12 figures. Update in quantization of G4 on B8 in equations (5.12) and (5.13

Effectiveness of Carboplatin and Paclitaxel as First- and Second-Line Treatment in 61 Patients with Metastatic Melanoma

BACKGROUND: Patients with metastatic melanoma have a very unfavorable prognosis with few therapeutic options. Based on previous promising experiences within a clinical trial involving carboplatin and paclitaxel a series of advanced metastatic melanoma patients were treated with this combination. METHODS: Data of all patients with cutaneous metastatic melanoma treated with carboplatin and paclitaxel (CP) at our institution between October 2005 and December 2007 were retrospectively evaluated. For all patients a once-every-3-weeks dose-intensified regimen was used. Overall and progression free survival were calculated using the method of Kaplan and Meier. Tumour response was evaluated according to RECIST criteria. RESULTS: 61 patients with cutaneous metastatic melanoma were treated with CP. 20 patients (85% M1c) received CP as first-line treatment, 41 patients (90.2% M1c) had received at least one prior systemic therapy for metastatic disease. Main toxicities were myelosuppression, fatigue and peripheral neuropathy. Partial responses were noted in 4.9% of patients, stable disease in 23% of patients. No complete response was observed. Median progression free survival was 10 weeks. Median overall survival was 31 weeks. Response, progression-free and overall survival were equivalent in first- and second-line patients. 60 patients of 61 died after a median follow up of 7 months. Median overall survival differed for patients with controlled disease (PR+SD) (49 weeks) compared to patients with progressive disease (18 weeks). CONCLUSIONS: Among patients with metastatic melanoma a subgroup achieved disease control under CP therapy which may be associated with a survival benefit. This potential advantage has to be weighed against considerable toxicity. Since response rates and survival were not improved in previously untreated patients compared to pretreated patients, CP should thus not be applied as first-line treatment

Association between footwear use and neglected tropical diseases: a systematic review and meta-analysis

BACKGROUND The control of neglected tropical diseases (NTDs) has primarily focused on preventive chemotherapy and case management. Less attention has been placed on the role of ensuring access to adequate water, sanitation, and hygiene and personal preventive measures in reducing exposure to infection. Our aim was to assess whether footwear use was associated with a lower risk of selected NTDs. METHODOLOGY We conducted a systematic review and meta-analysis to assess the association between footwear use and infection or disease for those NTDs for which the route of transmission or occurrence may be through the feet. We included Buruli ulcer, cutaneous larva migrans (CLM), leptospirosis, mycetoma, myiasis, podoconiosis, snakebite, tungiasis, and soil-transmitted helminth (STH) infections, particularly hookworm infection and strongyloidiasis. We searched Medline, Embase, Cochrane, Web of Science, CINAHL Plus, and Popline databases, contacted experts, and hand-searched reference lists for eligible studies. The search was conducted in English without language, publication status, or date restrictions up to January 2014. Studies were eligible for inclusion if they reported a measure of the association between footwear use and the risk of each NTD. Publication bias was assessed using funnel plots. Descriptive study characteristics and methodological quality of the included studies were summarized. For each study outcome, both outcome and exposure data were abstracted and crude and adjusted effect estimates presented. Individual and summary odds ratio (OR) estimates and corresponding 95% confidence intervals (CIs) were calculated as a measure of intervention effect, using random effects meta-analyses. PRINCIPAL FINDINGS Among the 427 studies screened, 53 met our inclusion criteria. Footwear use was significantly associated with a lower odds of infection of Buruli ulcer (OR=0.15; 95% CI: 0.08-0.29), CLM (OR=0.24; 95% CI: 0.06-0.96), tungiasis (OR=0.42; 95% CI: 0.26-0.70), hookworm infection (OR=0.48; 95% CI: 0.37-0.61), any STH infection (OR=0.57; 95% CI: 0.39-0.84), strongyloidiasis (OR=0.56; 95% CI: 0.38-0.83), and leptospirosis (OR=0.59; 95% CI: 0.37-0.94). No significant association between footwear use and podoconiosis (OR=0.63; 95% CI: 0.38-1.05) was found and no data were available for mycetoma, myiasis, and snakebite. The main limitations were evidence of heterogeneity and poor study quality inherent to the observational studies included. CONCLUSIONS/SIGNIFICANCE Our results show that footwear use was associated with a lower odds of several different NTDs. Access to footwear should be prioritized alongside existing NTD interventions to ensure a lasting reduction of multiple NTDs and to accelerate their control and elimination. PROTOCOL REGISTRATION PROSPERO International prospective register of systematic reviews CRD42012003338

Improved Measurement of the Pseudoscalar Decay Constant fDsf_{D_{s}}

We present a new determination of the Ds decay constant, f_{Ds} using 5 million continuum charm events obtained with the CLEO II detector. Our value is derived from our new measured ratio of widths for Ds -> mu nu/Ds -> phi pi of 0.173+/- 0.021 +/- 0.031. Taking the branching ratio for Ds -> phi pi as (3.6 +/- 0.9)% from the PDG, we extract f_{Ds} = (280 +/- 17 +/- 25 +/- 34){MeV}. We compare this result with various model calculations.Comment: 23 page postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN

First Observation of τ→3πηντ\tau\to 3\pi\eta\nu_{\tau} and τ→f1πντ\tau\to f_{1}\pi\nu_{\tau} Decays

We have observed new channels for $\tau$ decays with an $\eta$ in the final state. We study 3-prong tau decays, using the $\eta\to\gamma\gamma$ and \eta\to 3\piz decay modes and 1-prong decays with two \piz's using the $\eta\to\gamma\gamma$ channel. The measured branching fractions are \B(\tau^{-}\to \pi^{-}\pi^{-}\pi^{+}\eta\nu_{\tau}) =(3.4^{+0.6}_{-0.5}\pm0.6)\times10^{-4} and \B(\tau^{-}\to \pi^{-}2\piz\eta\nu_{\tau} =(1.4\pm0.6\pm0.3)\times10^{-4}. We observe clear evidence for $f_1\to\eta\pi\pi$ substructure and measure \B(\tau^{-}\to f_1\pi^{-}\nu_{\tau})=(5.8^{+1.4}_{-1.3}\pm1.8)\times10^{-4}. We have also searched for $\eta'(958)$ production and obtain 90% CL upper limits \B(\tau^{-}\to \pi^{-}\eta'\nu_\tau)<7.4\times10^{-5} and \B(\tau^{-}\to \pi^{-}\piz\eta'\nu_\tau)<8.0\times10^{-5}.Comment: 11 page postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN