Behavioral Mechanisms of Pramipexole-Induced Impulsivity: Discrimination Processes Underlying Decision-Making

Faced with an intertemporal choice, an organism that chooses a “smaller-sooner” reinforcer over a “larger-later” reinforcer is said to behave impulsively. Individual differences in intertemporal choice are effectively modeled by generalized matching law and delay discounting equations that incorporate parameters corresponding to behavioral processes such as sensitivity to reinforcer amount or delay. By simulating changes in these processes and identifying conditions under which impulsive choice is likely to result, researchers are in a position to anticipate and examine potential behavioral mechanisms underlying clinical instances of impulsivity. Pramipexole, a dopamine agonist medication, is associated with reports of impulsive behavior in populations prescribed the drug, as well as in experimental subjects administered the compound prior to intertemporal choice sessions, although the latter findings are mixed. The present set of experiments was designed (a) to systematically replicate conditions under which pramipexole increased impulsive choice, but also nonspecifically disrupted behavior, and (b) to elucidate behavioral mechanisms of pramipexole-induced impulsivity in rats. In Chapter 2, a behavioral task used previously by researchers reporting a nonspecific effect of pramipexole was modified to include procedural controls common in the intertemporal choice literature (centering response, no-delay sessions). In accord with previous findings, acute pramipexole nonspecifically disrupted choice behavior, while chronic pramipexole partially remediated elements of the disruption (i.e., decrease in initial-block choice). In Chapter 3, three experiments targeted behavioral processes critical for intertemporal choice. Experiment 1 evaluated the acute and chronic effects of pramipexole on rats’ sensitivity to relative reinforcer delays in a concurrent-chains procedure. Contrary to the predicted effect, the drug decreased this measure, indicating the possibility of impaired stimulus control. Experiments 2 and 3 assessed the drug effect on discrimination of response-reinforcer contingencies and of reinforcer amounts, respectively, and revealed deficits in accuracy of similar magnitude across both preparations. Collectively, the results of these experiments suggest that previous findings of pramipexole-induced impulsivity and nonspecific disruption of behavior can be explained as impairments in discrimination processes required for intertemporal choice. Although the generality of the present findings may be limited to experimental settings with nonhumans, they demonstrate the utility of quantitatively modeling impulsivity

Biochemical Properties of a Decoy Oligodeoxynucleotide Inhibitor of STAT3 Transcription Factor.

Cyclic STAT3 decoy (CS3D) is a second-generation, double-stranded oligodeoxynucleotide (ODN) that mimics a genomic response element for signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. CS3D competitively inhibits STAT3 binding to target gene promoters, resulting in decreased expression of proteins that promote cellular proliferation and survival. Previous studies have demonstrated antitumor activity of CS3D in preclinical models of solid tumors. However, prior to entering human clinical trials, the efficiency of generating the CS3D molecule and its stability in biological fluids should be determined. CS3D is synthesized as a single-stranded ODN and must have its free ends ligated to generate the final cyclic form. In this study, we report a ligation efficiency of nearly 95 percent. The ligated CS3D demonstrated a half-life of 7.9 h in human serum, indicating adequate stability for intravenous delivery. These results provide requisite biochemical characterization of CS3D that will inform upcoming clinical trials

A Delay-Discounting Primer

Given the importance of research findings and the potential of further research to aid in the prediction and control of impulsivity, the primary focus of this chapter (and this book) is on choice and the failure of future events to affect current decisions. In this primer chapter, we consider two types of impulsive choice: (a) preferring a smaller-sooner reward while forgoing a larger-later one and (b) preferring a larger-later aversive outcome over a smaller-sooner one. The first of these is exemplified by the toy-pilfering child with whom we opened this chapter. Taking the toy is immediately rewarded, but it is a short-lived reward because the caretaker soon returns the toy to the victimized peer. Undoubtedly, the child would prefer to play with the toy for a longer period of time, but waiting until the toy is dropped by the peer seems a weak reinforcer when compared with brief access now. To put an economic term on this phenomenon, the child appears to have discounted the value of the delayed but otherwise preferred reward. Delay discounting describes the process of devaluing behavioral outcomes, be they rewarding or aversive events, that happen in the future (and perhaps the past; see chap. 7, this volume). This chapter provides a primer in delay discounting; it is intended for readers who have only a limited background in the procedures, measures, and outcomes of studies examining this form of impulsive choice. Following an overview of the delay-discounting process, its quantification, and its implications for the human condition, emphasis is placed on procedures (and critiques of these procedures). The remainder of the book is concerned with experimental findings, and for the most part, we do not review these here

Oil-Isolated Hydrogel Microstructures for Sensitive Bioassays On-Chip

Multiplexed, sensitive, and on-chip molecular diagnostic assays are essential in both clinical and research settings. In past work, running reactions in nanoliter- to femtoliter-sized volumes such as microwells or droplets has led to significant increases in detection sensitivities. At the same time, hydrogels have emerged as attractive scaffolds for bioassays due to their nonfouling, flexible, and aqueous properties. In this paper, we combine these concepts and develop a novel platform in which hydrogel compartments are used as individually confined reaction volumes within a fluorinated oil phase. We fabricate functional and versatile hydrogel microstructures in microfluidic channels that are physically isolated from each other using a surfactant-free fluorinated oil phase, generating picoliter- to nanoliter-sized immobilized aqueous reaction compartments that are readily functionalized with biomolecules. In doing so, we achieve monodisperse reaction volumes with an aqueous interior while exploiting the unique chemistry of a hydrogel, which provides a solid and porous binding scaffold for biomolecules and is impenetrable to oil. Furthermore, our lithographically defined reaction volumes are readily customized with respect to geometry and chemistry within the same channel, allowing rational tuning of the confined reaction volume on a post-to-post basis without needing to use surfactants to maintain stability. We design and implement a multiplexed signal amplification assay in which gel-bound enzymes turn over small molecule substrate into fluorescent product in the oil-confined gel compartment, providing significant signal enhancement. Using short (20 min) amplification times, the encapsulation scheme provides up to 2 orders of magnitude boost of signal in nucleic acid detection assays relative to direct labeling and does not suffer from any cross-talk between the posts. We ultimately demonstrate up to 57-fold increase in nucleic acid detection sensitivity compared to a direct labeling scheme.National Institutes of Health (U.S.). Center for Future Technologies in Cancer Care (U54-EB-015403-01)National Institutes of Health (U.S.) (Interdepartmental Biotechnology Training Grant T32 GM08334)National Science Foundation (U.S.) (Grant CMMI-1120724

A Framework for Bioacoustic Vocalization Analysis Using Hidden Markov Models

Using Hidden Markov Models (HMMs) as a recognition framework for automatic classification of animal vocalizations has a number of benefits, including the ability to handle duration variability through nonlinear time alignment, the ability to incorporate complex language or recognition constraints, and easy extendibility to continuous recognition and detection domains. In this work, we apply HMMs to several different species and bioacoustic tasks using generalized spectral features that can be easily adjusted across species and HMM network topologies suited to each task. This experimental work includes a simple call type classification task using one HMM per vocalization for repertoire analysis of Asian elephants, a language-constrained song recognition task using syllable models as base units for ortolan bunting vocalizations, and a stress stimulus differentiation task in poultry vocalizations using a non-sequential model via a one-state HMM with Gaussian mixtures. Results show strong performance across all tasks and illustrate the flexibility of the HMM framework for a variety of species, vocalization types, and analysis tasks

A Framework for Bioacoustic Vocalization Analysis Using Hidden Markov Models

Using Hidden Markov Models (HMMs) as a recognition framework for automatic classification of animal vocalizations has a number of benefits, including the ability to handle duration variability through nonlinear time alignment, the ability to incorporate complex language or recognition constraints, and easy extendibility to continuous recognition and detection domains. In this work, we apply HMMs to several different species and bioacoustic tasks using generalized spectral features that can be easily adjusted across species and HMM network topologies suited to each task. This experimental work includes a simple call type classification task using one HMM per vocalization for repertoire analysis of Asian elephants, a language-constrained song recognition task using syllable models as base units for ortolan bunting vocalizations, and a stress stimulus differentiation task in poultry vocalizations using a non-sequential model via a one-state HMM with Gaussian mixtures. Results show strong performance across all tasks and illustrate the flexibility of the HMM framework for a variety of species, vocalization types, and analysis tasks

Fracture resistance of zirconia-composite veneered crowns in comparison with zirconia-porcelain crowns.

The objectives were to evaluate the fracture resistance and stress concentration in zirconia/composite veneered crowns in comparison to zirconia/porcelain crowns using occlusal fracture resistance and by stress analysis using finite element analysis method. Zirconia substructures were divided into two groups based on the veneering material. A static load was applied occlusally using a ball indenter and the load to fracture was recorded in Newtons (N). The same crown design was used to create 3D crown models and evaluated using FEA. The zirconia/composite crowns subjected to static occlusal load showed comparable results to the zirconia/porcelain crowns. Zirconia/composite crowns showed higher stress on the zirconia substructure at 63.6 and 50.9 MPa on the zirconia substructure veneered with porcelain. In conclusion, zirconia/composite crowns withstood high occlusal loads similar to zirconia/porcelain crowns with no significant difference. However, the zirconia/composite crowns showed higher stress values than the zirconia/porcelain crowns at the zirconia substructure

Fossilized skin reveals coevolution with feathers and metabolism in feathered dinosaurs and early birds

Feathers are remarkable evolutionary innovations that are associated with complex adaptations of the skin in modern birds. Fossilised feathers in non-avian dinosaurs and basal birds provide insights into feather evolution, but how associated integumentary adaptations evolved is unclear. Here we report the discovery of fossil skin, preserved with remarkable nanoscale fidelity, in three non-avian maniraptoran dinosaurs and a basal bird from the Cretaceous Jehol biota (China). The skin comprises patches of desquamating epidermal corneocytes that preserve a cytoskeletal array of helically coiled α-keratin tonofibrils. This structure confirms that basal birds and non-avian dinosaurs shed small epidermal flakes as in modern mammals and birds, but structural differences imply that these Cretaceous taxa had lower body heat production than modern birds. Feathered epidermis acquired many, but not all, anatomically modern attributes close to the base of the Maniraptora by the Middle Jurassic

A Review of NASA's Radiation-Hardened Electronics for Space Environments Project

NASA's Radiation Hardened Electronics for Space Exploration (RHESE) project develops the advanced technologies required to produce radiation hardened electronics, processors, and devices in support of the requirements of NASA's Constellation program. Over the past year, multiple advancements have been made within each of the RHESE technology development tasks that will facilitate the success of the Constellation program elements. This paper provides a brief review of these advancements, discusses their application to Constellation projects, and addresses the plans for the coming year