21 research outputs found
Brexpiprazole II: Antipsychotic-Like and Procognitive Effects of a Novel Serotonin-Dopamine Activity Modulator
ABSTRACT Brexpiprazole piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel serotonin-dopamine activity modulator with partial agonist activity at serotonin 1A (5-HT 1A ) and D 2/3 receptors, combined with potent antagonist effects on 5-HT 2A , a 1B -, and a 2C -adrenergic receptors. Brexpiprazole inhibited conditioned avoidance response (ED 50 = 6.0 mg/kg), apomorphine-or D-amphetamine-induced hyperactivity (ED 50 = 2.3 and 0.90, respectively), and apomorphine-induced stereotypy (ED 50 = 2.9) in rats at clinically relevant D 2 receptor occupancies. Brexpiprazole also potently inhibited apomorphine-induced eye blinking in monkeys. The results suggest that brexpiprazole has antipsychotic potential. Brexpiprazole induced catalepsy (ED 50 = 20) well above clinically relevant D 2 receptor occupancies, suggesting a low risk for extrapyramidal side effects. Subchronic treatment with phencyclidine (PCP) induced cognitive impairment in both novel object recognition (NOR) and attentional set-shifting (ID-ED) tests in rats. Brexpiprazole reversed the PCP-induced cognitive impairment in the NOR test at 1.0 and 3.0 mg/kg, and in the ID-ED test at 1.0 mg/kg. However, aripiprazole (10 mg/kg) was ineffective in both tests, despite achieving relevant D 2 occupancies. In the NOR test
International Journal on Artificial Intelligence Tools ❢c World Scientific Publishing Company EXPERIMENTS WITH LEARNING OPENING STRATEGY IN THE GAME OF GO
We present an experimental methodology and results for a machine learning approach to learning opening strategy in the game of Go, a game for which the best computer programs play only at the level of an advanced beginning human player. While the evaluation function in most computer Go programs consists of a carefully crafted combination of pattern matchers, expert rules, and selective search, we employ a neural network trained by self-play using temporal difference learning. Our focus is on the sequence of moves made at the beginning of the game. Experimental results indicate that our approach is effective for learning opening strategy, that including higher-level features of the game can improve the quality of the learned evaluation function, and that different input representations of higher-level information can substantially affect performance. Keywords: Temporal difference learning, neural networks, strategy games, game of Go. 1
Learning Opening Strategy in the Game of Go
In this paper, we present an experimental methodology and results for a machine learning approach to learning opening strategy in the game of Go, a game for which the best computer programs play only at the level of an advanced beginning human player. While the evaluation function in most computer Go programs consists of a carefully crafted combination of pattern matchers, expert rules, and selective search, we employ a neural network trained by self-play using temporal difference learning. Our focus is on the sequence of moves made at the beginning of the game. Experimental results indicate that our approach is effective for learning opening strategy, and they also identify higherlevel features of the game that improve the quality of the learned evaluation function
Integrative oncology consultations at a comprehensive cancer center: Analysis of patient reported outcomes.
An Engineered Synthetic Biologic Protects Against Clostridium difficile Infection
Morbidity and mortality attributed to Clostridium difficile infection (CDI) have increased over the past 20 years. Currently, antibiotics are the only US FDA-approved treatment for primary C. difficile infection, and these are, ironically, associated with disease relapse and the threat of burgeoning drug resistance. We previously showed that non-toxin virulence factors play key roles in CDI, and that colonization factors are critical for disease. Specifically, a C. difficile adhesin, Surface Layer Protein A (SlpA) is a major contributor to host cell attachment. In this work, we engineered Syn-LAB 2.0 and Syn-LAB 2.1, two synthetic biologic agents derived from lactic acid bacteria, to stably and constitutively express a host-cell binding fragment of the C. difficile adhesin SlpA on their cell-surface. Both agents harbor conditional suicide plasmids expressing a codonoptimized chimera of the lactic acid bacterium's cell-wall anchoring surface-protein domain, fused to the conserved, highly adherent, host-cell-binding domain of C. difficile SlpA. Both agents also incorporate engineered biocontrol, obviating the need for any antibiotic selection. Syn-LAB 2.0 and Syn-LAB 2.1 possess positive biophysical and in vivo properties compared with their parental antecedents in that they robustly and constitutively display the SlpA chimera on their cell surface, potentiate human intestinal epithelial barrier function in vitro, are safe, tolerable and palatable to Golden Syrian hamsters and neonatal piglets at high daily doses, and are detectable in animal feces within 24 h of dosing, confirming robust colonization. In combination, the engineered strains also delay (in fixed doses) or prevent (when continuously administered) death of infected hamsters upon challenge with high doses of virulent C. difficile. Finally, fixeddose Syn-LAB ameliorates diarrhea in a non-lethal model of neonatal piglet enteritis. Taken together, our findings suggest that the two synthetic biologics may be effectively employed as non-antibiotic interventions for CDI.National Institutes of Health [AI121590]; US Department of Veterans Affairs [1I01BX001183-01]; USDA CSREES Hatch Program [ARZT-570410-A-02-139]; Asset Development Award from Tech Launch ArizonaOpen access journal.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
Brexpiprazole I: In Vitro and in Vivo Characterization of a Novel Serotonin-Dopamine Activity Modulator
Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl) piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (K i \u3c 1 nM) to human serotonin 1A (h5-HT 1A )-, h5-HT 2A -, long form of human D 2 (hD 2L )-, hα 1B -, and hα 2C -adrenergic receptors. It displayed partial agonism at h5-HT 1A and hD 2 receptors in cloned receptor systems and potent antagonism of h5-HT 2A receptors and hα 1B/2C -adrenoceptors. Brexpiprazole also had affinity (K i \u3c 5 nM) for hD 3- , h5-HT 2B -, h5-HT 7 -, hα 1A -, and hα 1D -adrenergic receptors, moderate affinity for hH 1 (K i = 19 nM), and low affinity for hM 1 receptors (K i \u3e 1000 nM). Brexpiprazole potently bound to rat 5-HT 2A and D 2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT 1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT 2A antagonism. Furthermore, in vivo D 2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D 2 partial agonist activity. In particular, based on a lower intrinsic activity at D 2 receptors and higher binding affinities for 5-HT 1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D 2 receptor agonist-and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders