A Theory of Cheap Control in Embodied Systems

We present a framework for designing cheap control architectures for embodied agents. Our derivation is guided by the classical problem of universal approximation, whereby we explore the possibility of exploiting the agent's embodiment for a new and more efficient universal approximation of behaviors generated by sensorimotor control. This embodied universal approximation is compared with the classical non-embodied universal approximation. To exemplify our approach, we present a detailed quantitative case study for policy models defined in terms of conditional restricted Boltzmann machines. In contrast to non-embodied universal approximation, which requires an exponential number of parameters, in the embodied setting we are able to generate all possible behaviors with a drastically smaller model, thus obtaining cheap universal approximation. We test and corroborate the theory experimentally with a six-legged walking machine. The experiments show that the sufficient controller complexity predicted by our theory is tight, which means that the theory has direct practical implications. Keywords: cheap design, embodiment, sensorimotor loop, universal approximation, conditional restricted Boltzmann machineComment: 27 pages, 10 figure

Preclinical Pharmacokinetic Evaluation to Facilitate Repurposing of Tyrosine Kinase Inhibitors Nilotinib and Imatinib as Antiviral Agents

Background Several tyrosine kinase inhibitors (TKIs) developed as anti-cancer drugs, also have anti-viral activity due to their ability to disrupt productive replication and dissemination in infected cells. Consequently, such drugs are attractive candidates for “repurposing” as anti-viral agents. However, clinical evaluation of therapeutics against infectious agents associated with high mortality, but low or infrequent incidence, is often unfeasible. The United States Food and Drug Administration formulated the “Animal Rule” to facilitate use of validated animal models for conducting anti-viral efficacy studies. Methods To enable such efficacy studies of two clinically approved TKIs, nilotinib, and imatinib, we first conducted comprehensive pharmacokinetic (PK) studies in relevant rodent and non-rodent animal models. PK of these agents following intravenous and oral dosing were evaluated in C57BL/6 mice, prairie dogs, guinea pigs and Cynomolgus monkeys. Plasma samples were analyzed using an LC-MS/MS method. Secondarily, we evaluated the utility of allometry-based inter-species scaling derived from previously published data to predict the PK parameters, systemic clearance (CL) and the steady state volume of distribution (Vss) of these two drugs in prairie dogs, an animal model not tested thus far. Results Marked inter-species variability in PK parameters and resulting oral bioavailability was observed. In general, elimination half-lives of these agents in mice and guinea pigs were much shorter (1–3 h) relative to those in larger species such as prairie dogs and monkeys. The longer nilotinib elimination half-life in prairie dogs (i.v., 6.5 h and oral, 7.5 h), facilitated multiple dosing PK and safety assessment. The allometry-based predicted values of the Vss and CL were within 2.0 and 2.5-fold, respectively, of the observed values. Conclusions Our results suggest that prairie dogs and monkeys may be suitable rodent and non-rodent species to perform further efficacy testing of these TKIs against orthopoxvirus infections. The use of rodent models such as C57BL/6 mice and guinea pigs for assessing pre-clinical anti-viral efficacy of these two TKIs may be limited due to short elimination and/or low oral bioavailability. Allometry-based correlations, derived from existing literature data, may provide initial estimates, which may serve as a useful guide for pre-clinical PK studies in untested animal models

Dark Control: The Default Mode Network as a Reinforcement Learning Agent

International audienceThe default mode network (DMN) is believed to subserve the baseline mental activity in humans. Its higher energy consumption compared to other brain networks and its intimate coupling with conscious awareness are both pointing to an unknown overarching function. Many research streams speak in favor of an evolutionarily adaptive role in envisioning experience to anticipate the future. In the present work, we propose a process model that tries to explain how the DMN may implement continuous evaluation and prediction of the environment to guide behavior. The main purpose of DMN activity, we argue, may be described by Markov Decision Processes that optimize action policies via value estimates based through vicarious trial and error. Our formal perspective on DMN function naturally accommodates as special cases previous interpretations based on (1) predictive coding, (2) semantic associations, and (3) a sentinel role. Moreover, this process model for the neural optimization of complex behavior in the DMN offers parsimonious explanations for recent experimental findings in animals and humans

Puccinia dayi

Fung

Nyssopsora clavellosa

Fung

Biologically Relevant Oxidants Cause Bound Proteins To Readily Oxidatively Cross-Link at Guanine

Oxidative DNA–protein cross-links have received less attention than other types of DNA damage and remain as one of the least understood types of oxidative lesion. A model system using ribonuclease A and a 27-nucleotide DNA was used to determine the propensity of oxidative cross-linking to occur in the presence of oxidants. Cross-link formation was examined using four different oxidation systems that generate singlet oxygen, superoxide, and metal-based Fenton reactions. It is shown that oxidative cross-linking occurs in yields ranging from 14% to a maximal yield of 61% in all oxidative systems when equivalent concentrations of DNA and protein are present. Because singlet oxygen is the most efficient oxidation system in generating DNA–protein cross-links, it was chosen for further analyses. Cross-linking occurred with single-stranded DNA binding protein and not with bovine serum albumin. Addition of salt lowered nonspecific binding affinity and lowered cross-link yield by up to 59%. The yield of cross-linking increased with increased ratios of protein compared with DNA. Cross-linking was highly dependent on the number of guanines in a DNA sequence. Loss of guanine content on the 27-nucleotide DNA led to nearly complete loss in cross-linking, while primer extension studies showed cross-links to predominantly occur at guanine base on a 100-nucleotide DNA. The chemical species generated were examined using two peptides derived from the ribonuclease A sequence, <i>N</i>-acetyl-AAAKF and <i>N</i>-acetyl-AYKTT, which were cross-linked to 2′-deoxyguanosine. The cross-link products were spiroiminodihydantoin, guanidinohydantoin, and tyrosyl-based adducts. Formation of tyrosine-based adducts may be competitive with the more well-studied lysine-based cross-links. We conclude that oxidative cross-links may be present at high levels in cells since the propensity to oxidatively cross-link is high and so much of the genomic DNA is coated with protein