Some implications of the technology assessment function for the effective public decision-making process

NASA Technical Reports Server (NTRS)

Mayo, L. H.

1971-01-01

A preliminary provisional assessment of the prospects for the establishment of an adequate technology assessment function and the implications of the assessment function for the public decision process are presented. Effects of the technology assessment function on each phase of the public decision process and briefly explored. Significant implications during the next decade are projected with respect to the following phases: invention and development of alternative means (technological configurations); evaluation, selection and promotion of preferred courses of action; and modification of statutory scheme or social action program as an outcome of continuing monitoring and appraisal.

A Biologically Inspired Computational Model of Basal Ganglia in Action Selection.

PubMed

Baston, Chiara; Ursino, Mauro

2015-01-01

The basal ganglia (BG) are a subcortical structure implicated in action selection. The aim of this work is to present a new cognitive neuroscience model of the BG, which aspires to represent a parsimonious balance between simplicity and completeness. The model includes the 3 main pathways operating in the BG circuitry, that is, the direct (Go), indirect (NoGo), and hyperdirect pathways. The main original aspects, compared with previous models, are the use of a two-term Hebb rule to train synapses in the striatum, based exclusively on neuronal activity changes caused by dopamine peaks or dips, and the role of the cholinergic interneurons (affected by dopamine themselves) during learning. Some examples are displayed, concerning a few paradigmatic cases: action selection in basal conditions, action selection in the presence of a strong conflict (where the role of the hyperdirect pathway emerges), synapse changes induced by phasic dopamine, and learning new actions based on a previous history of rewards and punishments. Finally, some simulations show model working in conditions of altered dopamine levels, to illustrate pathological cases (dopamine depletion in parkinsonian subjects or dopamine hypermedication). Due to its parsimonious approach, the model may represent a straightforward tool to analyze BG functionality in behavioral experiments.

Incidental and context-responsive activation of structure- and function-based action features during object identification

PubMed Central

Lee, Chia-lin; Middleton, Erica; Mirman, Daniel; Kalénine, Solène; Buxbaum, Laurel J.

2012-01-01

Previous studies suggest that action representations are activated during object processing, even when task-irrelevant. In addition, there is evidence that lexical-semantic context may affect such activation during object processing. Finally, prior work from our laboratory and others indicates that function-based (“use”) and structure-based (“move”) action subtypes may differ in their activation characteristics. Most studies assessing such effects, however, have required manual object-relevant motor responses, thereby plausibly influencing the activation of action representations. The present work utilizes eyetracking and a Visual World Paradigm task without object-relevant actions to assess the time course of activation of action representations, as well as their responsiveness to lexical-semantic context. In two experiments, participants heard a target word and selected its referent from an array of four objects. Gaze fixations on non-target objects signal activation of features shared between targets and non-targets. The experiments assessed activation of structure-based (Experiment 1) or function-based (Experiment 2) distractors, using neutral sentences (“S/he saw the …”) or sentences with a relevant action verb (Experiment 1: “S/he picked up the……”; Experiment 2: “S/he used the….”). We observed task-irrelevant activations of action information in both experiments. In neutral contexts, structure-based activation was relatively faster-rising but more transient than function-based activation. Additionally, action verb contexts reliably modified patterns of activation in both Experiments. These data provide fine-grained information about the dynamics of activation of function-based and structure-based actions in neutral and action-relevant contexts, in support of the “Two Action System” model of object and action processing (e.g., Buxbaum & Kalénine, 2010). PMID:22390294

Adaptive Skeletal Muscle Action Requires Anticipation and “Conscious Broadcasting”

PubMed Central

Poehlman, T. Andrew; Jantz, Tiffany K.; Morsella, Ezequiel

2012-01-01

Historically, the conscious and anticipatory processes involved in voluntary action have been associated with the loftiest heights of nervous function. Concepts like mental time travel, “theory of mind,” and the formation of “the self” have been at the center of many attempts to determine the purpose of consciousness. Eventually, more reductionistic accounts of consciousness emerged, proposing rather that conscious states play a much more basic role in nervous function. Though the widely held integration consensus proposes that conscious states integrate information-processing structures and events that would otherwise be independent, Supramodular Interaction Theory (SIT) argues that conscious states are necessary for the integration of only certain kinds of information. As revealed in this selective review, this integration is related to what is casually referred to as “voluntary” action, which is intimately related to the skeletal muscle output system. Through a peculiar form of broadcasting, conscious integration often controls and guides action via “ideomotor” mechanisms, where anticipatory processes play a central role. Our selective review covers evidence (including findings from anesthesia research) for the integration consensus, SIT, and ideomotor theory. PMID:23264766

Optimal timing in biological processes

USGS Publications Warehouse

Williams, B.K.; Nichols, J.D.

1984-01-01

A general approach for obtaining solutions to a class of biological optimization problems is provided. The general problem is one of determining the appropriate time to take some action, when the action can be taken only once during some finite time frame. The approach can also be extended to cover a number of other problems involving animal choice (e.g., mate selection, habitat selection). Returns (assumed to index fitness) are treated as random variables with time-specific distributions, and can be either observable or unobservable at the time action is taken. In the case of unobservable returns, the organism is assumed to base decisions on some ancillary variable that is associated with returns. Optimal policies are derived for both situations and their properties are discussed. Various extensions are also considered, including objective functions based on functions of returns other than the mean, nonmonotonic relationships between the observable variable and returns; possible death of the organism before action is taken; and discounting of future returns. A general feature of the optimal solutions for many of these problems is that an organism should be very selective (i.e., should act only when returns or expected returns are relatively high) at the beginning of the time frame and should become less and less selective as time progresses. An example of the application of optimal timing to a problem involving the timing of bird migration is discussed, and a number of other examples for which the approach is applicable are described.

Dissociable intrinsic functional networks support noun-object and verb-action processing.

PubMed

Yang, Huichao; Lin, Qixiang; Han, Zaizhu; Li, Hongyu; Song, Luping; Chen, Lingjuan; He, Yong; Bi, Yanchao

2017-12-01

The processing mechanism of verbs-actions and nouns-objects is a central topic of language research, with robust evidence for behavioral dissociation. The neural basis for these two major word and/or conceptual classes, however, remains controversial. Two experiments were conducted to study this question from the network perspective. Experiment 1 found that nodes of the same class, obtained through task-evoked brain imaging meta-analyses, were more strongly connected with each other than nodes of different classes during resting-state, forming segregated network modules. Experiment 2 examined the behavioral relevance of these intrinsic networks using data from 88 brain-damaged patients, finding that across patients the relative strength of functional connectivity of the two networks significantly correlated with the noun-object vs. verb-action relative behavioral performances. In summary, we found that verbs-actions and nouns-objects are supported by separable intrinsic functional networks and that the integrity of such networks accounts for the relative noun-object- and verb-action-selective deficits. Copyright © 2017 Elsevier Inc. All rights reserved.

Pedagogical Cues Encourage Toddlers' Transmission of Recently Demonstrated Functions to Unfamiliar Adults

ERIC Educational Resources Information Center

Vredenburgh, Christopher; Kushnir, Tamar; Casasola, Marianella

2015-01-01

Young children use pedagogical cues as a signal that others' actions are social or cultural conventions. Here we show that children selectively "transmit" (enact in a new social situation) causal functions demonstrated pedagogically, even when they have learned and can produce alternative functions as well. Two-year-olds saw two novel…

Functional Deficits in the Extrastriate Body Area During Observation of Sports-Related Actions in Schizophrenia

PubMed Central

Takahashi, Hidehiko; Kato, Motoichiro; Sassa, Takeshi; Shibuya, Tomohisa; Koeda, Michihiko; Yahata, Noriaki; Matsuura, Masato; Asai, Kunihiko; Suhara, Tetsuya; Okubo, Yoshiro

2010-01-01

Exercise and sports are increasingly being implemented in the management of schizophrenia. The process of action perception is as important as that of motor execution for learning and acquiring new skills. Recent studies have suggested that body-selective extrastriate body area (EBA) in the posterior temporal-occipital cortex is involved not only in static visual perception of body parts but also in the planning, imagination, and execution of actions. However, functional abnormality of the EBA in schizophrenia has yet to be investigated. Using functional magnetic resonance imaging (fMRI) with a task designed to activate the EBA by sports-related actions, we aimed to elucidate functional abnormality of the EBA during observation of sports-related actions in patients with schizophrenia. Twelve schizophrenia patients and 12 age-sex–matched control participants participated in the study. Using sports-related motions as visual stimuli, we examined brain activations during observation of context-congruent actions relative to context-incongruent actions by fMRI. Compared with controls, the patients with schizophrenia demonstrated diminished activation in the EBA during observation of sports-related context-congruent actions. Furthermore, the EBA activation in patients was negatively correlated with the severity of negative and general psychopathology symptoms measured by the Positive and Negative Syndrome Scale. Dysfunction of the EBA might reflect a difficulty in representing dynamic aspects of human actions and possibly lead to impairments of simulation, learning, and execution of actions in schizophrenia. PMID:18927345

Decoding the neural mechanisms of human tool use

PubMed Central

Gallivan, Jason P; McLean, D Adam; Valyear, Kenneth F; Culham, Jody C

2013-01-01

Sophisticated tool use is a defining characteristic of the primate species but how is it supported by the brain, particularly the human brain? Here we show, using functional MRI and pattern classification methods, that tool use is subserved by multiple distributed action-centred neural representations that are both shared with and distinct from those of the hand. In areas of frontoparietal cortex we found a common representation for planned hand- and tool-related actions. In contrast, in parietal and occipitotemporal regions implicated in hand actions and body perception we found that coding remained selectively linked to upcoming actions of the hand whereas in parietal and occipitotemporal regions implicated in tool-related processing the coding remained selectively linked to upcoming actions of the tool. The highly specialized and hierarchical nature of this coding suggests that hand- and tool-related actions are represented separately at earlier levels of sensorimotor processing before becoming integrated in frontoparietal cortex. DOI: http://dx.doi.org/10.7554/eLife.00425.001 PMID:23741616

A Biologically Inspired Computational Model of Basal Ganglia in Action Selection

PubMed Central

Baston, Chiara

2015-01-01

The basal ganglia (BG) are a subcortical structure implicated in action selection. The aim of this work is to present a new cognitive neuroscience model of the BG, which aspires to represent a parsimonious balance between simplicity and completeness. The model includes the 3 main pathways operating in the BG circuitry, that is, the direct (Go), indirect (NoGo), and hyperdirect pathways. The main original aspects, compared with previous models, are the use of a two-term Hebb rule to train synapses in the striatum, based exclusively on neuronal activity changes caused by dopamine peaks or dips, and the role of the cholinergic interneurons (affected by dopamine themselves) during learning. Some examples are displayed, concerning a few paradigmatic cases: action selection in basal conditions, action selection in the presence of a strong conflict (where the role of the hyperdirect pathway emerges), synapse changes induced by phasic dopamine, and learning new actions based on a previous history of rewards and punishments. Finally, some simulations show model working in conditions of altered dopamine levels, to illustrate pathological cases (dopamine depletion in parkinsonian subjects or dopamine hypermedication). Due to its parsimonious approach, the model may represent a straightforward tool to analyze BG functionality in behavioral experiments. PMID:26640481

Directive and incentive functions of affective action consequences: an ideomotor approach.

PubMed

Eder, Andreas B; Rothermund, Klaus; De Houwer, Jan; Hommel, Bernhard

2015-07-01

Five experiments examined whether affective consequences become associated with the responses producing them and whether anticipations of positive and negative action outcomes influence action control differently. In a learning phase, one response produced pleasant and another response unpleasant visual effects. In a subsequent test phase, the same actions were carried out in response to a neutral feature of affective stimuli. Results showed that responses were faster when the irrelevant valence of the response cue matched the valence of the response outcome, but only when the responses still produced outcomes. These results suggest that affective action consequences have a directive function in that they facilitate the selection of the associated response over other responses, even when the response outcome is unpleasant (Experiment 4A). Results of another experiment showed that affective action consequences can also have an incentive function in that responses with pleasant outcomes are generally facilitated relative to responses with unpleasant outcomes. However, this motivational effect was seen only in a free-choice test (Experiment 5). The results suggest that behavioral impulses induced by ideomotor processes are constrained by the motivational evaluation of the anticipated action outcome. A model that integrates motivational factors into ideomotor theory is presented.

Processing and Integration of Contextual Information in Monkey Ventrolateral Prefrontal Neurons during Selection and Execution of Goal-Directed Manipulative Actions.

PubMed

Bruni, Stefania; Giorgetti, Valentina; Bonini, Luca; Fogassi, Leonardo

2015-08-26

The prefrontal cortex (PFC) is deemed to underlie the complexity, flexibility, and goal-directedness of primates' behavior. Most neurophysiological studies performed so far investigated PFC functions with arm-reaching or oculomotor tasks, thus leaving unclear whether, and to which extent, PFC neurons also play a role in goal-directed manipulative actions, such as those commonly used by primates during most of their daily activities. Here we trained two macaques to perform or withhold grasp-to-eat and grasp-to-place actions, depending on the combination of two subsequently presented cues: an auditory go/no-go cue (high/low tone) and a visually presented target (food/object). By varying the order of presentation of the two cues, we could segment and independently evaluate the processing and integration of contextual information allowing the monkey to make a decision on whether or not to act, and what action to perform. We recorded 403 task-related neurons from the ventrolateral prefrontal cortex (VLPFC): unimodal sensory-driven (37%), motor-related (21%), unimodal sensory-and-motor (23%), and multisensory (19%) neurons. Target and go/no-go selectivity characterized most of the recorded neurons, particularly those endowed with motor-related discharge. Interestingly, multisensory neurons appeared to encode a behavioral decision independently from the sensory modality of the stimulus allowing the monkey to make it: some of them reflected the decision to act or refraining from acting (56%), whereas others (44%) encoded the decision to perform (or withhold) a specific action (e.g., grasp-to-eat). Our findings indicate that VLPFC neurons play a role in the processing of contextual information underlying motor decision during goal-directed manipulative actions. We demonstrated that macaque ventrolateral prefrontal cortex (VLPFC) neurons show remarkable selectivity for different aspects of the contextual information allowing the monkey to select and execute goal-directed manipulative actions. Interestingly, a set of these neurons provide multimodal representations of the intended goal of a forthcoming action, encoding a behavioral decision (e.g., grasp-to-eat) independently from the sensory information allowing the monkey to make it. Our findings expand the available knowledge on prefrontal functions by showing that VLPFC neurons play a role in the selection and execution of goal-directed manipulative actions resembling those of common primates' foraging behaviors. On these bases, we propose that VLPFC may host an abstract "vocabulary" of the intended goals pursued by primates in their natural environment. Copyright © 2015 the authors 0270-6474/15/3511877-14$15.00/0.

Action semantics: A unifying conceptual framework for the selective use of multimodal and modality-specific object knowledge

NASA Astrophysics Data System (ADS)

van Elk, Michiel; van Schie, Hein; Bekkering, Harold

2014-06-01

Our capacity to use tools and objects is often considered one of the hallmarks of the human species. Many objects greatly extend our bodily capabilities to act in the physical world, such as when using a hammer or a saw. In addition, humans have the remarkable capability to use objects in a flexible fashion and to combine multiple objects in complex actions. We prepare coffee, cook dinner and drive our car. In this review we propose that humans have developed declarative and procedural knowledge, i.e. action semantics that enables us to use objects in a meaningful way. A state-of-the-art review of research on object use is provided, involving behavioral, developmental, neuropsychological and neuroimaging studies. We show that research in each of these domains is characterized by similar discussions regarding (1) the role of object affordances, (2) the relation between goals and means in object use and (3) the functional and neural organization of action semantics. We propose a novel conceptual framework of action semantics to address these issues and to integrate the previous findings. We argue that action semantics entails both multimodal object representations and modality-specific sub-systems, involving manipulation knowledge, functional knowledge and representations of the sensory and proprioceptive consequences of object use. Furthermore, we argue that action semantics are hierarchically organized and selectively activated and used depending on the action intention of the actor and the current task context. Our framework presents an integrative account of multiple findings and perspectives on object use that may guide future studies in this interdisciplinary domain.

Semantic domain-specific functional integration for action-related vs. abstract concepts.

PubMed

Ghio, Marta; Tettamanti, Marco

2010-03-01

A central topic in cognitive neuroscience concerns the representation of concepts and the specific neural mechanisms that mediate conceptual knowledge. Recently proposed modal theories assert that concepts are grounded on the integration of multimodal, distributed representations. The aim of the present work is to complement the available neuropsychological and neuroimaging evidence suggesting partially segregated anatomo-functional correlates for concrete vs. abstract concepts, by directly testing the semantic domain-specific patterns of functional integration between language and modal semantic brain regions. We report evidence from a functional magnetic resonance imaging study, in which healthy participants listened to sentences with either an action-related (actions involving physical entities) or an abstract (no physical entities involved) content. We measured functional integration using dynamic causal modeling, and found that the left superior temporal gyrus was more strongly connected: (1) for action-related vs. abstract sentences, with the left-hemispheric action representation system, including sensorimotor areas; (2) for abstract vs. action-related sentences, with left infero-ventral frontal, temporal, and retrosplenial cingulate areas. A selective directionality effect was observed, with causal modulatory effects exerted by perisylvian language regions on peripheral modal areas, and not vice versa. The observed condition-specific modulatory effects are consistent with embodied and situated language processing theories, and indicate that linguistic areas promote a semantic content-specific reactivation of modal simulations by top-down mechanisms. Copyright 2008 Elsevier Inc. All rights reserved.

On the relationship between response selection and response inhibition: An individual differences approach.

PubMed

Bender, Angela D; Filmer, Hannah L; Garner, K G; Naughtin, Claire K; Dux, Paul E

2016-11-01

The abilities to select appropriate responses and suppress unwanted actions are key executive functions that enable flexible and goal-directed behavior. However, to date it has been unclear whether these two cognitive operations tap a common action control resource or reflect two distinct processes. In the present study, we used an individual differences approach to examine the underlying relationships across seven paradigms that varied in their response selection and response inhibition requirements: stop-signal, go-no-go, Stroop, flanker, single-response selection, psychological refractory period, and attentional blink tasks. A confirmatory factor analysis suggested that response inhibition and response selection are separable, with stop-signal and go-no-go task performance being related to response inhibition, and performance in the psychological refractory period, Stroop, single-response selection, and attentional blink tasks being related to response selection. These findings provide evidence in support of the hypothesis that response selection and response inhibition reflect two distinct cognitive operations.

Impairment of actions chains in autism and its possible role in intention understanding

PubMed Central

Cattaneo, Luigi; Fabbri-Destro, Maddalena; Boria, Sonia; Pieraccini, Cinzia; Monti, Annalisa; Cossu, Giuseppe; Rizzolatti, Giacomo

2007-01-01

Experiments in monkeys demonstrated that many parietal and premotor neurons coding a specific motor act (e.g., grasping) show a markedly different activation when this act is part of actions that have different goals (e.g., grasping for eating vs. grasping for placing). Many of these “action-constrained” neurons have mirror properties firing selectively to the observation of the initial motor act of the actions to which they belong motorically. By activating a specific action chain from its very outset, this mechanism allows the observers to have an internal copy of the whole action before its execution, thus enabling them to understand directly the agent's intention. Using electromyographic recordings, we show that a similar chained organization exists in typically developing children, whereas it is impaired in children with autism. We propose that, as a consequence of this functional impairment, high-functioning autistic children may understand the intentions of others cognitively but lack the mechanism for understanding them experientially. PMID:17965234

Impairment of actions chains in autism and its possible role in intention understanding.

PubMed

Cattaneo, Luigi; Fabbri-Destro, Maddalena; Boria, Sonia; Pieraccini, Cinzia; Monti, Annalisa; Cossu, Giuseppe; Rizzolatti, Giacomo

2007-11-06

Experiments in monkeys demonstrated that many parietal and premotor neurons coding a specific motor act (e.g., grasping) show a markedly different activation when this act is part of actions that have different goals (e.g., grasping for eating vs. grasping for placing). Many of these "action-constrained" neurons have mirror properties firing selectively to the observation of the initial motor act of the actions to which they belong motorically. By activating a specific action chain from its very outset, this mechanism allows the observers to have an internal copy of the whole action before its execution, thus enabling them to understand directly the agent's intention. Using electromyographic recordings, we show that a similar chained organization exists in typically developing children, whereas it is impaired in children with autism. We propose that, as a consequence of this functional impairment, high-functioning autistic children may understand the intentions of others cognitively but lack the mechanism for understanding them experientially.

The inferior parietal lobule: where action becomes perception.

PubMed

Rizzolatti, Giacomo; Ferrari, Pier Francesco; Rozzi, Stefano; Fogassi, Leonardo

2006-01-01

The view defended in this article is that action and perception share the same neural substrate. To substantiate this view, the anatomical and functional organization of the inferior parietal lobule (IPL) is reviewed. In particular, it will be shown that many IPL neurons discharge selectively when the monkey executes a given motor act (e.g. grasping). Most interestingly, most of them fire only if the coded motor act is followed by a subsequent specific motor act (e.g. placing). Some of these action-constrained motor neurons have mirror properties and selectively discharge during the observation of motor acts when these are embedded in a given action (e.g. grasping for eating, but not grasping for placing). Thus, the activation of these IPL neurons allows the observer not only to recognize the observed motor act, but also to predict what will be the next motor act of the action, that is to understand the intentions of the action's agent. The finding that the same neurons that are active during the execution of specific motor acts also mediate the understanding of the 'what' and the 'why' of others' actions provides strong evidence for a common neural substrate for action and perception.

Selective androgen receptor modulators as function promoting therapies.

PubMed

Bhasin, Shalender; Jasuja, Ravi

2009-05-01

The past decade has witnessed an unprecedented discovery effort to develop selective androgen receptor modulators (SARMs) that improve physical function and bone health without adversely affecting the prostate and cardiovascular outcomes. This review describes the historical evolution, the rationale for SARM development, and the mechanisms of testosterone action and SARM selectivity. Although steroidal SARMs have been around since the 1940s, a number of nonsteroidal SARMs that do not serve as substrates for CYP19 aromatase or 5alpha-reductase, act as full agonists in muscle and bone and as partial agonists in prostate are in development. The differing interactions of steroidal and nonsteroidal compounds with androgen receptor (AR) contribute to their unique pharmacologic actions. Ligand binding induces specific conformational changes in the ligand-binding domain, which could modulate surface topology and protein-protein interactions between AR and coregulators, resulting in tissue-specific gene regulation. Preclinical studies have demonstrated the ability of SARMs to increase muscle and bone mass in preclinical rodent models with varying degree of prostate sparing. Phase I trials of SARMs in humans have reported modest increments in fat-free mass. SARMs hold promise as a new class of function promoting anabolic therapies for a number of clinical indications, including functional limitations associated with aging and chronic disease, frailty, cancer cachexia, and osteoporosis.

Selective Androgen Receptor Modulators (SARMs) as Function Promoting Therapies

PubMed Central

Bhasin, Shalender; Jasuja, Ravi

2010-01-01

Purpose of review The last decade has witnessed unprecedented discovery effort to develop selective androgen receptor modulators (SARMs) that improve physical function and bone health without adversely affecting the prostate and cardiovascular outcomes. This review describes the historical evolution, the rationale for SARM development, and the mechanisms of testosterone action and SARM selectivity. Recent Findings While steroidal SARMs have been around since the 1940s, a number of nonsteroidal SARMs that do not serve as substrates for CYP19 aromatase or 5α-reductase, act as full agonists in muscle and bone and as partial agonists in prostate are in development. The differing interactions of steroidal and nonsteroidal compounds with AR contribute to their unique pharmacologic actions. Ligand binding induces specific conformational changes in the ligand binding domain, which could modulate surface topology and protein-protein interactions between AR and coregulators, resulting in tissue-specific gene regulation. Preclinical studies have demonstrated the ability of SARMs to increase muscle and bone mass in preclinical rodent models with varying degree of prostate sparing. Phase I trials of SARMs in humans have reported modest increments in fat-free mass. Summary SARMs hold promise as a new class of function promoting anabolic therapies for a number of clinical indications, including functional limitations associated with aging and chronic disease, frailty, cancer cachexia, and osteoporosis. PMID:19357508

A Flexible Approach for Assessing Functional Landscape Connectivity, with Application to Greater Sage-Grouse (Centrocercus urophasianus)

PubMed Central

Harju, Seth M.; Olson, Chad V.; Dzialak, Matthew R.; Mudd, James P.; Winstead, Jeff B.

2013-01-01

Connectivity of animal populations is an increasingly prominent concern in fragmented landscapes, yet existing methodological and conceptual approaches implicitly assume the presence of, or need for, discrete corridors. We tested this assumption by developing a flexible conceptual approach that does not assume, but allows for, the presence of discrete movement corridors. We quantified functional connectivity habitat for greater sage-grouse (Centrocercus urophasianus) across a large landscape in central western North America. We assigned sample locations to a movement state (encamped, traveling and relocating), and used Global Positioning System (GPS) location data and conditional logistic regression to estimate state-specific resource selection functions. Patterns of resource selection during different movement states reflected selection for sagebrush and general avoidance of rough topography and anthropogenic features. Distinct connectivity corridors were not common in the 5,625 km2 study area. Rather, broad areas functioned as generally high or low quality connectivity habitat. A comprehensive map predicting the quality of connectivity habitat across the study area validated well based on a set of GPS locations from independent greater sage-grouse. The functional relationship between greater sage-grouse and the landscape did not always conform to the idea of a discrete corridor. A more flexible consideration of landscape connectivity may improve the efficacy of management actions by aligning those actions with the spatial patterns by which animals interact with the landscape. PMID:24349241

A flexible approach for assessing functional landscape connectivity, with application to greater sage-grouse (Centrocercus urophasianus).

PubMed

Harju, Seth M; Olson, Chad V; Dzialak, Matthew R; Mudd, James P; Winstead, Jeff B

2013-01-01

Connectivity of animal populations is an increasingly prominent concern in fragmented landscapes, yet existing methodological and conceptual approaches implicitly assume the presence of, or need for, discrete corridors. We tested this assumption by developing a flexible conceptual approach that does not assume, but allows for, the presence of discrete movement corridors. We quantified functional connectivity habitat for greater sage-grouse (Centrocercus urophasianus) across a large landscape in central western North America. We assigned sample locations to a movement state (encamped, traveling and relocating), and used Global Positioning System (GPS) location data and conditional logistic regression to estimate state-specific resource selection functions. Patterns of resource selection during different movement states reflected selection for sagebrush and general avoidance of rough topography and anthropogenic features. Distinct connectivity corridors were not common in the 5,625 km(2) study area. Rather, broad areas functioned as generally high or low quality connectivity habitat. A comprehensive map predicting the quality of connectivity habitat across the study area validated well based on a set of GPS locations from independent greater sage-grouse. The functional relationship between greater sage-grouse and the landscape did not always conform to the idea of a discrete corridor. A more flexible consideration of landscape connectivity may improve the efficacy of management actions by aligning those actions with the spatial patterns by which animals interact with the landscape.

Action semantics: A unifying conceptual framework for the selective use of multimodal and modality-specific object knowledge.

PubMed

van Elk, Michiel; van Schie, Hein; Bekkering, Harold

2014-06-01

Our capacity to use tools and objects is often considered one of the hallmarks of the human species. Many objects greatly extend our bodily capabilities to act in the physical world, such as when using a hammer or a saw. In addition, humans have the remarkable capability to use objects in a flexible fashion and to combine multiple objects in complex actions. We prepare coffee, cook dinner and drive our car. In this review we propose that humans have developed declarative and procedural knowledge, i.e. action semantics that enables us to use objects in a meaningful way. A state-of-the-art review of research on object use is provided, involving behavioral, developmental, neuropsychological and neuroimaging studies. We show that research in each of these domains is characterized by similar discussions regarding (1) the role of object affordances, (2) the relation between goals and means in object use and (3) the functional and neural organization of action semantics. We propose a novel conceptual framework of action semantics to address these issues and to integrate the previous findings. We argue that action semantics entails both multimodal object representations and modality-specific sub-systems, involving manipulation knowledge, functional knowledge and representations of the sensory and proprioceptive consequences of object use. Furthermore, we argue that action semantics are hierarchically organized and selectively activated and used depending on the action intention of the actor and the current task context. Our framework presents an integrative account of multiple findings and perspectives on object use that may guide future studies in this interdisciplinary domain. Copyright © 2013 Elsevier B.V. All rights reserved.

28 CFR 0.45 - General functions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... industry pursuant to the Military Selective Service Act of 1967 (50 U.S.C., App. 459); reparations suits... States for penalties for violations of car service orders (49 U.S.C. 1(17a)); actions restraining...

Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology.

PubMed

Suchyna, Thomas M

2017-11-01

Discovery of Piezo channels and the reporting of their sensitivity to the inhibitor GsMTx4 were important milestones in the study of non-selective cationic mechanosensitive channels (MSCs) in normal physiology and pathogenesis. GsMTx4 had been used for years to investigate the functional role of cationic MSCs, especially in muscle tissue, but with little understanding of its target or inhibitory mechanism. The sensitivity of Piezo channels to bilayer stress and its robust mechanosensitivity when expressed in heterologous systems were keys to determining GsMTx4's mechanism of action. However, questions remain regarding Piezo's role in muscle function due to the non-selective nature of GsMTx4 inhibition toward membrane mechanoenzymes and the implication of MCS channel types by genetic knockdown. Evidence supporting Piezo like activity, at least in the developmental stages of muscle, is presented. While the MSC targets of GsMTx4 in muscle pathology are unclear, its muscle protective effects are clearly demonstrated in two recent in situ studies on normal cardiomyocytes and dystrophic skeletal muscle. The muscle protective function may be due to the combined effect of GsMTx4's inhibitory action on cationic MSCs like Piezo and TRP, and its potentiation of repolarizing K + selective MSCs like K2P and SAKCa. Paradoxically, the potent in vitro action of GsMTx4 on many physiological functions seems to conflict with its lack of in situ side-effects on normal animal physiology. Future investigations into cytoskeletal control of sarcolemma mechanics and the suspected inclusion of MSCs in membrane micro/nano sized domains with distinct mechanical properties will aide our understanding of this dichotomy. Published by Elsevier Ltd.

Possible origins of consciousness in simple control over "involuntary" neuroimmunological action.

PubMed

Clark, Kevin B

2018-05-01

The origin(s) and purpose(s) of consciousness continue to be fervently debated by neuroscientists. A recent unconventional hypothesis put forth by Morsella et al. suggests the primary function of consciousness is the integration, selection, and execution of advantageous lower-level voluntary skeletal muscle behavior on surrounding external environments. However, at main issue is whether more precise, adaptable voluntary skeletal motor action, and therefore the corresponding workings of consciousness, first emerged and evolved in animals to exert control over external environments or internal ones regulated by less flexible autonomic function. Using the example of voluntary immunomodulation, one can identify the strengths and weaknesses of either rationale. For instance, highly trained meditative techniques for immunomodulation more-or-less conform to Morsella et al.'s assumptions on higher-level indirect conscious control of autonomic function. Whereas, untrained skeletal motor resolution of infection-related approach-avoidance conflicts support conclusions contrary to those of Morsella et al. In such cases, primitive voluntary changes in host respiration rate and volume may selectively facilitate/inhibit acute autonomic psychophysiological stress responses to pathogen insult. This and other types of scenarios predictably give evolutionary and ecological rise to self-awareness of (visceral) internal states as well as to voluntary regulation of internal state action conflicts. Copyright © 2018 Elsevier Inc. All rights reserved.

Opponent and bidirectional control of movement velocity in the basal ganglia

PubMed Central

Yttri, Eric A.

2016-01-01

For goal-directed behavior it is critical that we can both select the appropriate action and learn to modify the underlying movements (e.g. the pitch of a note or velocity of a reach) to improve outcomes. The basal ganglia are a critical nexus where circuits necessary for the production of behavior, such as neocortex and thalamus, are integrated with reward signaling 1 to reinforce successful, purposive actions 2. Dorsal striatum, a major input structure of basal ganglia is composed of two opponent pathways, direct and indirect, thought to select actions that elicit positive outcomes or suppress actions that do not, respectively 3,4. Activity-dependent plasticity modulated by reward is thought to be sufficient for selecting actions in striatum 5,6. Although perturbations of basal ganglia function produce profound changes in movement 7, it remains unknown whether activity-dependent plasticity is sufficient to produce learned changes in movement kinematics, such as velocity. Here we used cell-type specific stimulation delivered in closed-loop during movement to demonstrate that activity in either the direct or indirect pathway is sufficient to produce specific and sustained increases or decreases in velocity without affecting action selection or motivation. These behavioral changes were a form of learning that accumulated over trials, persisted after the cessation of stimulation, and were abolished in the presence of dopamine antagonists. Our results reveal that the direct and indirect pathways can each bidirectionally control movement velocity, demonstrating unprecedented specificity and flexibility in the control of volition by the basal ganglia. PMID:27135927

Dynamic causal modelling of effective connectivity from fMRI: Are results reproducible and sensitive to Parkinson's disease and its treatment?

PubMed Central

Rowe, J.B.; Hughes, L.E.; Barker, R.A.; Owen, A.M.

2010-01-01

Dynamic causal modelling (DCM) of functional magnetic resonance imaging (fMRI) data offers new insights into the pathophysiology of neurological disease and mechanisms of effective therapies. Current applications can be used both to identify the most likely functional brain network underlying observed data and estimate the networks' connectivity parameters. We examined the reproducibility of DCM in healthy subjects (young 18–48 years, n = 27; old 50–80 years, n = 15) in the context of action selection. We then examined the effects of Parkinson's disease (50–78 years, Hoehn and Yahr stage 1–2.5, n = 16) and dopaminergic therapy. Forty-eight models were compared, for each of 90 sessions from 58 subjects. Model-evidences clustered according to sets of structurally similar models, with high correlations over two sessions in healthy older subjects. The same model was identified as most likely in healthy controls on both sessions and in medicated patients. In this most likely network model, the selection of action was associated with enhanced coupling between prefrontal cortex and the pre-supplementary motor area. However, the parameters for intrinsic connectivity and contextual modulation in this model were poorly correlated across sessions. A different model was identified in patients with Parkinson's disease after medication withdrawal. In “off” patients, action selection was associated with enhanced connectivity from prefrontal to lateral premotor cortex. This accords with independent evidence of a dopamine-dependent functional disconnection of the SMA in Parkinson's disease. Together, these results suggest that DCM model selection is robust and sensitive enough to study clinical populations and their pharmacological treatment. For critical inferences, model selection may be sufficient. However, caution is required when comparing groups or drug effects in terms of the connectivity parameter estimates, if there are significant posterior covariances among parameters. PMID:20056151

Voltage-gated sodium channels as targets for pyrethroid insecticides.

PubMed

Field, Linda M; Emyr Davies, T G; O'Reilly, Andrias O; Williamson, Martin S; Wallace, B A

2017-10-01

The pyrethroid insecticides are a very successful group of compounds that have been used extensively for the control of arthropod pests of agricultural crops and vectors of animal and human disease. Unfortunately, this has led to the development of resistance to the compounds in many species. The mode of action of pyrethroids is known to be via interactions with the voltage-gated sodium channel. Understanding how binding to the channel is affected by amino acid substitutions that give rise to resistance has helped to elucidate the mode of action of the compounds and the molecular basis of their selectivity for insects vs mammals and between insects and other arthropods. Modelling of the channel/pyrethroid interactions, coupled with the ability to express mutant channels in oocytes and study function, has led to knowledge of both how the channels function and potentially how to design novel insecticides with greater species selectivity.

Phenotypic and genotypic characterization of influenza virus mutants selected with the sialidase fusion protein DAS181

PubMed Central

Triana-Baltzer, Gallen B.; Sanders, Rebecca L.; Hedlund, Maria; Jensen, Kellie A.; Aschenbrenner, Laura M.; Larson, Jeffrey L.; Fang, Fang

2011-01-01

Background Influenza viruses (IFVs) frequently achieve resistance to antiviral drugs, necessitating the development of compounds with novel mechanisms of action. DAS181 (Fludase®), a sialidase fusion protein, may have a reduced potential for generating drug resistance due to its novel host-targeting mechanism of action. Methods IFV strains B/Maryland/1/59 and A/Victoria/3/75 (H3N2) were subjected to >30 passages under increasing selective pressure with DAS181. The DAS181-selected IFV isolates were characterized in vitro and in mice. Results Despite extensive passaging, DAS181-selected viruses exhibited a very low level of resistance to DAS181, which ranged between 3- and 18-fold increase in EC50. DAS181-selected viruses displayed an attenuated phenotype in vitro, as exhibited by slower growth, smaller plaque size and increased particle to pfu ratios relative to wild-type virus. Further, the DAS181 resistance phenotype was unstable and was substantially reversed over time upon DAS181 withdrawal. In mice, the DAS181-selected viruses exhibited no greater virulence than their wild-type counterparts. Genotypic and phenotypic analysis of DAS181-selected viruses revealed mutations in the haemagglutinin (HA) and neuraminidase (NA) molecules and also changes in HA and NA function. Conclusions Results indicate that resistance to DAS181 is minimal and unstable. The DAS181-selected IFV isolates exhibit reduced fitness in vitro, likely due to altered HA and NA functions. PMID:21097900

Where is the action? Action sentence processing in Parkinson's disease

PubMed Central

Fernandino, Leonardo; Conant, Lisa L.; Binder, Jeffrey R.; Blindauer, Karen; Hiner, Bradley; Spangler, Katie; Desai, Rutvik H.

2013-01-01

According to an influential view of conceptual representation, action concepts are understood through motoric simulations, involving motor networks of the brain. A stronger version of this embodied account suggests that even figurative uses of action words (e.g., grasping the concept) are understood through motoric simulations. We investigated these claims by assessing whether Parkinson's disease (PD), a disorder affecting the motor system, is associated with selective deficits in comprehending action-related sentences. Twenty PD patients and 21 age-matched controls performed a sentence comprehension task, where sentences belonged to one of four conditions: literal action, non-idiomatic metaphoric action, idiomatic action, and abstract. The same verbs (referring to hand/arm actions) were used in the three action-related conditions. Patients, but not controls, were slower to respond to literal and idiomatic action than to abstract sentences. These results indicate that sensory-motor systems play a functional role in semantic processing, including processing of figurative action language. PMID:23624313

Modeling the Value of Strategic Actions in the Superior Colliculus

PubMed Central

Thevarajah, Dhushan; Webb, Ryan; Ferrall, Christopher; Dorris, Michael C.

2009-01-01

In learning models of strategic game play, an agent constructs a valuation (action value) over possible future choices as a function of past actions and rewards. Choices are then stochastic functions of these action values. Our goal is to uncover a neural signal that correlates with the action value posited by behavioral learning models. We measured activity from neurons in the superior colliculus (SC), a midbrain region involved in planning saccadic eye movements, while monkeys performed two saccade tasks. In the strategic task, monkeys competed against a computer in a saccade version of the mixed-strategy game ”matching-pennies”. In the instructed task, saccades were elicited through explicit instruction rather than free choices. In both tasks neuronal activity and behavior were shaped by past actions and rewards with more recent events exerting a larger influence. Further, SC activity predicted upcoming choices during the strategic task and upcoming reaction times during the instructed task. Finally, we found that neuronal activity in both tasks correlated with an established learning model, the Experience Weighted Attraction model of action valuation (Camerer and Ho, 1999). Collectively, our results provide evidence that action values hypothesized by learning models are represented in the motor planning regions of the brain in a manner that could be used to select strategic actions. PMID:20161807

On-board emergent scheduling of autonomous spacecraft payload operations

NASA Technical Reports Server (NTRS)

Lindley, Craig A.

1994-01-01

This paper describes a behavioral competency level concerned with emergent scheduling of spacecraft payload operations. The level is part of a multi-level subsumption architecture model for autonomous spacecraft, and it functions as an action selection system for processing a spacecraft commands that can be considered as 'plans-as-communication'. Several versions of the selection mechanism are described, and their robustness is qualitatively compared.

Investigating category- and shape-selective neural processing in ventral and dorsal visual stream under interocular suppression.

PubMed

Ludwig, Karin; Kathmann, Norbert; Sterzer, Philipp; Hesselmann, Guido

2015-01-01

Recent behavioral and neuroimaging studies using continuous flash suppression (CFS) have suggested that action-related processing in the dorsal visual stream might be independent of perceptual awareness, in line with the "vision-for-perception" versus "vision-for-action" distinction of the influential dual-stream theory. It remains controversial if evidence suggesting exclusive dorsal stream processing of tool stimuli under CFS can be explained by their elongated shape alone or by action-relevant category representations in dorsal visual cortex. To approach this question, we investigated category- and shape-selective functional magnetic resonance imaging-blood-oxygen level-dependent responses in both visual streams using images of faces and tools. Multivariate pattern analysis showed enhanced decoding of elongated relative to non-elongated tools, both in the ventral and dorsal visual stream. The second aim of our study was to investigate whether the depth of interocular suppression might differentially affect processing in dorsal and ventral areas. However, parametric modulation of suppression depth by varying the CFS mask contrast did not yield any evidence for differential modulation of category-selective activity. Together, our data provide evidence for shape-selective processing under CFS in both dorsal and ventral stream areas and, therefore, do not support the notion that dorsal "vision-for-action" processing is exclusively preserved under interocular suppression. © 2014 Wiley Periodicals, Inc.

Pertussis toxin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sekura, R.D.; Moss, J.; Vaughan, M.

1985-01-01

This book contains 13 selections. Some of the titles are: Genetic and Functional Studies of Pertussis Toxin Substrates; Effect of Pertussis Toxin on the Hormonal Responsiveness of Different Tissues; Extracellular Adenylate Cyclase of Bordetella pertussis; and GTP-Regulatory Proteins are Introcellular Messagers: A Model for Hormone Action.

Relative value of managed wetlands and tidal marshlands for wintering northern pintails

USGS Publications Warehouse

Coates, Peter S.; Casazza, Michael L.; Halstead, Brian J.; Fleskes, Joseph P.

2012-01-01

Northern pintail Anas acuta (hereafter, pintail) populations have declined substantially throughout the western US since the 1970s, largely as a result of converting wetlands to cropland. Managed wetlands have been developed throughout the San Francisco Bay estuaries to provide wildlife habitat, particularly for waterfowl. Many of these areas were historically tidal baylands and plans are underway to remove dikes and restore tidal action. The relationship between tidal baylands and waterfowl populations is poorly understood. Our objective was to provide information on selection and avoidance of managed and tidal marshland by pintails. During 1991–1993 and 1998–2000, we radio-marked and relocated 330 female pintails (relocations, n =11,574) at Suisun Marsh, the largest brackish water estuary within San Francisco Bay, to estimate resource selection functions during the nonbreeding months (winter). Using a distance-based modeling approach, we calculated selection functions for different ecological communities (e.g., tidal baylands) and investigated variation explained by time of day (day or night hours) to account for differences in pintail behavior (i.e., foraging vs. roosting). We found strong evidence for selection of managed wetlands. Pintails also avoided tidal marshes and bays and channels. We did not detect differences in selection function between day and night hours for managed wetlands but the degree of avoidance of other habitats varied by time of day. We also found that areas subjected to tidal action did not influence the selection of immediately adjacent managed wetlands. If current management goals include providing habitat for wintering waterfowl populations, particularly pintail, then we recommend wildlife managers focus tidal restoration on areas that are not currently managed wetland and/or improve conditions in areas of managed wetlands to increase local carrying capacities

Mouse Models of Neurodevelopmental Disease of the Basal Ganglia and Associated Circuits

PubMed Central

Pappas, Samuel S.; Leventhal, Daniel K.; Albin, Roger L.; Dauer, William T.

2014-01-01

This chapter focuses on neurodevelopmental diseases that are tightly linked to abnormal function of the striatum and connected structures. We begin with an overview of three representative diseases in which striatal dysfunction plays a key role—Tourette syndrome and obsessive-compulsive disorder, Rett's syndrome, and primary dystonia. These diseases highlight distinct etiologies that disrupt striatal integrity and function during development, and showcase the varied clinical manifestations of striatal dysfunction. We then review striatal organization and function, including evidence for striatal roles in online motor control/action selection, reinforcement learning, habit formation, and action sequencing. A key barrier to progress has been the relative lack of animal models of these diseases, though recently there has been considerable progress. We review these efforts, including their relative merits providing insight into disease pathogenesis, disease symptomatology, and basal ganglia function. PMID:24947237

A computational neural model of goal-directed utterance selection.

PubMed

Klein, Michael; Kamp, Hans; Palm, Guenther; Doya, Kenji

2010-06-01

It is generally agreed that much of human communication is motivated by extra-linguistic goals: we often make utterances in order to get others to do something, or to make them support our cause, or adopt our point of view, etc. However, thus far a computational foundation for this view on language use has been lacking. In this paper we propose such a foundation using Markov Decision Processes. We borrow computational components from the field of action selection and motor control, where a neurobiological basis of these components has been established. In particular, we make use of internal models (i.e., next-state transition functions defined on current state action pairs). The internal model is coupled with reinforcement learning of a value function that is used to assess the desirability of any state that utterances (as well as certain non-verbal actions) can bring about. This cognitive architecture is tested in a number of multi-agent game simulations. In these computational experiments an agent learns to predict the context-dependent effects of utterances by interacting with other agents that are already competent speakers. We show that the cognitive architecture can account for acquiring the capability of deciding when to speak in order to achieve a certain goal (instead of performing a non-verbal action or simply doing nothing), whom to address and what to say. Copyright 2010 Elsevier Ltd. All rights reserved.

The role of selective attention and action selection in the development of multiple action capabilities

NASA Astrophysics Data System (ADS)

Simione, Luca; Nolfi, Stefano

2014-10-01

In this paper we illustrate how the capacity to select the most appropriate actions when handling contexts affording multiple conflicting actions can be solved either through a selective attention strategy (in which the stimuli affording alternative actions are filtered out at the perceptual level through top-down regulation) or at later processing stages through an action selection strategy (through the suppression of the premotor information eliciting alternative actions). By carrying out a series of experiments in which a neuro-robot develops an ability to choose between conflicting actions, we were able to identify the conditions that lead to the development of solutions based on one strategy or another. Overall, the results indicate that the selective attention strategy constitutes the most simple and straightforward mechanism enabling the acquisition of such capacities. Moreover, the characteristics of the adaptive/learning process influence whether the adaptive robot converges towards a selective attention and/or action selection strategy.

Thinking as the control of imagination: a conceptual framework for goal-directed systems.

PubMed

Pezzulo, Giovanni; Castelfranchi, Cristiano

2009-07-01

This paper offers a conceptual framework which (re)integrates goal-directed control, motivational processes, and executive functions, and suggests a developmental pathway from situated action to higher level cognition. We first illustrate a basic computational (control-theoretic) model of goal-directed action that makes use of internal modeling. We then show that by adding the problem of selection among multiple action alternatives motivation enters the scene, and that the basic mechanisms of executive functions such as inhibition, the monitoring of progresses, and working memory, are required for this system to work. Further, we elaborate on the idea that the off-line re-enactment of anticipatory mechanisms used for action control gives rise to (embodied) mental simulations, and propose that thinking consists essentially in controlling mental simulations rather than directly controlling behavior and perceptions. We conclude by sketching an evolutionary perspective of this process, proposing that anticipation leveraged cognition, and by highlighting specific predictions of our model.

Minireview: G Protein-Coupled Estrogen Receptor-1, GPER-1: Its Mechanism of Action and Role in Female Reproductive Cancer, Renal and Vascular Physiology

PubMed Central

Thomas, Peter

2012-01-01

Using cDNA cloning strategies commonly employed for G protein-coupled receptors (GPCR), GPCR-30 (GPR30), was isolated from mammalian cells before knowledge of its cognate ligand. GPR30 is evolutionarily conserved throughout the vertebrates. A broad literature suggests that GPR30 is a Gs-coupled heptahelical transmembrane receptor that promotes specific binding of naturally occurring and man-made estrogens but not cortisol, progesterone, or testosterone. Its “pregenomic” signaling actions are manifested by plasma membrane-associated actions familiar to GPCR, namely, stimulation of adenylyl cyclase and Gβγ-subunit protein-dependent release of membrane-tethered heparan bound epidermal growth factor. These facts regarding its mechanism of action have led to the formal renaming of this receptor to its current functional designate, G protein-coupled estrogen receptor (ER) (GPER)-1. Further insight regarding its biochemical action and physiological functions in vertebrates is derived from receptor knockdown studies and the use of selective agonists/antagonists that discriminate GPER-1 from the nuclear steroid hormone receptors, ERα and ERβ. GPER-1-selective agents have linked GPER-1 to physiological and pathological events regulated by estrogen action, including, but not limited to, the central nervous, immune, renal, reproductive, and cardiovascular systems. Moreover, immunohistochemical studies have shown a positive association between GPER-1 expression and progression of female reproductive cancer, a relationship that is diametrically opposed from ER. Unlike ER knockout mice, GPER-1 knockout mice are fertile and show no overt reproductive anomalies. However, they do exhibit thymic atrophy, impaired glucose tolerance, and altered bone growth. Here, we discuss the role of GPER-1 in female reproductive cancers as well as renal and vascular physiology. PMID:22495674

Minireview: G protein-coupled estrogen receptor-1, GPER-1: its mechanism of action and role in female reproductive cancer, renal and vascular physiology.

PubMed

Filardo, Edward J; Thomas, Peter

2012-07-01

Using cDNA cloning strategies commonly employed for G protein-coupled receptors (GPCR), GPCR-30 (GPR30), was isolated from mammalian cells before knowledge of its cognate ligand. GPR30 is evolutionarily conserved throughout the vertebrates. A broad literature suggests that GPR30 is a Gs-coupled heptahelical transmembrane receptor that promotes specific binding of naturally occurring and man-made estrogens but not cortisol, progesterone, or testosterone. Its "pregenomic" signaling actions are manifested by plasma membrane-associated actions familiar to GPCR, namely, stimulation of adenylyl cyclase and Gβγ-subunit protein-dependent release of membrane-tethered heparan bound epidermal growth factor. These facts regarding its mechanism of action have led to the formal renaming of this receptor to its current functional designate, G protein-coupled estrogen receptor (ER) (GPER)-1. Further insight regarding its biochemical action and physiological functions in vertebrates is derived from receptor knockdown studies and the use of selective agonists/antagonists that discriminate GPER-1 from the nuclear steroid hormone receptors, ERα and ERβ. GPER-1-selective agents have linked GPER-1 to physiological and pathological events regulated by estrogen action, including, but not limited to, the central nervous, immune, renal, reproductive, and cardiovascular systems. Moreover, immunohistochemical studies have shown a positive association between GPER-1 expression and progression of female reproductive cancer, a relationship that is diametrically opposed from ER. Unlike ER knockout mice, GPER-1 knockout mice are fertile and show no overt reproductive anomalies. However, they do exhibit thymic atrophy, impaired glucose tolerance, and altered bone growth. Here, we discuss the role of GPER-1 in female reproductive cancers as well as renal and vascular physiology.

Relating the "mirrorness" of mirror neurons to their origins.

PubMed

Kilner, James M; Friston, Karl J

2014-04-01

Ever since their discovery, mirror neurons have generated much interest and debate. A commonly held view of mirror neuron function is that they transform "visual information into knowledge," thus enabling action understanding and non-verbal social communication between con-specifics (Rizzolatti & Craighero 2004). This functionality is thought to be so important that it has been argued that mirror neurons must be a result of selective pressure.

Hand and Grasp Selection in a Preferential Reaching Task: The Effects of Object Location, Orientation, and Task Intention.

PubMed

Scharoun, Sara M; Scanlan, Kelly A; Bryden, Pamela J

2016-01-01

As numerous movement options are available in reaching and grasping, of particular interest are what factors influence an individual's choice of action. In the current study a preferential reaching task was used to assess the propensity for right handers to select their preferred hand and grasp a coffee mug by the handle in both independent and joint action object manipulation contexts. Mug location (right-space, midline, and left-space) and handle orientation (toward, away, to left, and to right of the participant) varied in four tasks that differed as a function of intention: (1) pick-up (unimanual, independent); (2) pick-up and pour (bimanual, independent); (3) pick-up and pass (unimanual, joint action); and (4) pick-up, pour and pass (bimanual, joint action). In line with previous reports, a right-hand preference for unimanual tasks was observed. Furthermore, extending existing literature to a preferential reaching task, role differentiation between the hands in bimanual tasks (i.e., preferred hand mobilizing, non-preferred hand stabilizing) was displayed. Finally, right-hand selection was greatest in right space, albeit lower in bimanual tasks compared to what is typically reported in unimanual tasks. Findings are attributed to the desire to maximize biomechanical efficiency in reaching. Grasp postures were also observed to reflect consideration of efficiency. More specifically, within independent object manipulation (pick-up; pick-up and pour) participants only grasped the mug by the handle when it afforded a comfortable posture. Furthermore, in joint action (pick-up and pass; pick-up, pour and pass), the confederate was only offered the handle if the intended action of the confederate was similar or required less effort than that of the participant. Together, findings from the current study add to our knowledge of hand and grasp selection in unimanual and bimanual object manipulation, within the context of both independent and joint action tasks.

Beneficial laggards: multilevel selection, cooperative polymorphism and division of labour in threshold public good games

PubMed Central

2010-01-01

Background The origin and stability of cooperation is a hot topic in social and behavioural sciences. A complicated conundrum exists as defectors have an advantage over cooperators, whenever cooperation is costly so consequently, not cooperating pays off. In addition, the discovery that humans and some animal populations, such as lions, are polymorphic, where cooperators and defectors stably live together -- while defectors are not being punished--, is even more puzzling. Here we offer a novel explanation based on a Threshold Public Good Game (PGG) that includes the interaction of individual and group level selection, where individuals can contribute to multiple collective actions, in our model group hunting and group defense. Results Our results show that there are polymorphic equilibria in Threshold PGGs; that multi-level selection does not select for the most cooperators per group but selects those close to the optimum number of cooperators (in terms of the Threshold PGG). In particular for medium cost values division of labour evolves within the group with regard to the two types of cooperative actions (hunting vs. defense). Moreover we show evidence that spatial population structure promotes cooperation in multiple PGGs. We also demonstrate that these results apply for a wide range of non-linear benefit function types. Conclusions We demonstrate that cooperation can be stable in Threshold PGG, even when the proportion of so called free riders is high in the population. A fundamentally new mechanism is proposed how laggards, individuals that have a high tendency to defect during one specific group action can actually contribute to the fitness of the group, by playing part in an optimal resource allocation in Threshold Public Good Games. In general, our results show that acknowledging a multilevel selection process will open up novel explanations for collective actions. PMID:21044340

Untangling Basal Ganglia Network Dynamics and Function: Role of Dopamine Depletion and Inhibition Investigated in a Spiking Network Model.

PubMed

Lindahl, Mikael; Hellgren Kotaleski, Jeanette

2016-01-01

The basal ganglia are a crucial brain system for behavioral selection, and their function is disturbed in Parkinson's disease (PD), where neurons exhibit inappropriate synchronization and oscillations. We present a spiking neural model of basal ganglia including plausible details on synaptic dynamics, connectivity patterns, neuron behavior, and dopamine effects. Recordings of neuronal activity in the subthalamic nucleus and Type A (TA; arkypallidal) and Type I (TI; prototypical) neurons in globus pallidus externa were used to validate the model. Simulation experiments predict that both local inhibition in striatum and the existence of an indirect pathway are important for basal ganglia to function properly over a large range of cortical drives. The dopamine depletion-induced increase of AMPA efficacy in corticostriatal synapses to medium spiny neurons (MSNs) with dopamine receptor D2 synapses (CTX-MSN D2) and the reduction of MSN lateral connectivity (MSN-MSN) were found to contribute significantly to the enhanced synchrony and oscillations seen in PD. Additionally, reversing the dopamine depletion-induced changes to CTX-MSN D1, CTX-MSN D2, TA-MSN, and MSN-MSN couplings could improve or restore basal ganglia action selection ability. In summary, we found multiple changes of parameters for synaptic efficacy and neural excitability that could improve action selection ability and at the same time reduce oscillations. Identification of such targets could potentially generate ideas for treatments of PD and increase our understanding of the relation between network dynamics and network function.

Adaptive constructive processes and memory accuracy: Consequences of counterfactual simulations in young and older adults

PubMed Central

Gerlach, Kathy D.; Dornblaser, David W.; Schacter, Daniel L.

2013-01-01

People frequently engage in counterfactual thinking: mental simulations of alternative outcomes to past events. Like simulations of future events, counterfactual simulations serve adaptive functions. However, future simulation can also result in various kinds of distortions and has thus been characterized as an adaptive constructive process. Here we approach counterfactual thinking as such and examine whether it can distort memory for actual events. In Experiments 1a/b, young and older adults imagined themselves experiencing different scenarios. Participants then imagined the same scenario again, engaged in no further simulation of a scenario, or imagined a counterfactual outcome. On a subsequent recognition test, participants were more likely to make false alarms to counterfactual lures than novel scenarios. Older adults were more prone to these memory errors than younger adults. In Experiment 2, younger and older participants selected and performed different actions, then recalled performing some of those actions, imagined performing alternative actions to some of the selected actions, and did not imagine others. Participants, especially older adults, were more likely to falsely remember counterfactual actions than novel actions as previously performed. The findings suggest that counterfactual thinking can cause source confusion based on internally generated misinformation, consistent with its characterization as an adaptive constructive process. PMID:23560477

Task-Relevant Information Modulates Primary Motor Cortex Activity Before Movement Onset.

PubMed

Calderon, Cristian B; Van Opstal, Filip; Peigneux, Philippe; Verguts, Tom; Gevers, Wim

2018-01-01

Monkey neurophysiology research supports the affordance competition hypothesis (ACH) proposing that cognitive information useful for action selection is integrated in sensorimotor areas. In this view, action selection would emerge from the simultaneous representation of competing action plans, in parallel biased by relevant task factors. This biased competition would take place up to primary motor cortex (M1). Although ACH is plausible in environments affording choices between actions, its relevance for human decision making is less clear. To address this issue, we designed an functional magnetic resonance imaging (fMRI) experiment modeled after monkey neurophysiology studies in which human participants processed cues conveying predictive information about upcoming button presses. Our results demonstrate that, as predicted by the ACH, predictive information (i.e., the relevant task factor) biases activity of primary motor regions. Specifically, first, activity before movement onset in contralateral M1 increases as the competition is biased in favor of a specific button press relative to activity in ipsilateral M1. Second, motor regions were more tightly coupled with fronto-parietal regions when competition between potential actions was high, again suggesting that motor regions are also part of the biased competition network. Our findings support the idea that action planning dynamics as proposed in the ACH are valid both in human and non-human primates.

Adaptive constructive processes and memory accuracy: consequences of counterfactual simulations in young and older adults.

PubMed

Gerlach, Kathy D; Dornblaser, David W; Schacter, Daniel L

2014-01-01

People frequently engage in counterfactual thinking: mental simulations of alternative outcomes to past events. Like simulations of future events, counterfactual simulations serve adaptive functions. However, future simulation can also result in various kinds of distortions and has thus been characterised as an adaptive constructive process. Here we approach counterfactual thinking as such and examine whether it can distort memory for actual events. In Experiments 1a/b young and older adults imagined themselves experiencing different scenarios. Participants then imagined the same scenario again, engaged in no further simulation of a scenario, or imagined a counterfactual outcome. On a subsequent recognition test participants were more likely to make false alarms to counterfactual lures than novel scenarios. Older adults were more prone to these memory errors than younger adults. In Experiment 2 younger and older participants selected and performed different actions, then recalled performing some of those actions, imagined performing alternative actions to some of the selected actions, and did not imagine others. Participants, especially older adults, were more likely to falsely remember counterfactual actions than novel actions as previously performed. The findings suggest that counterfactual thinking can cause source confusion based on internally generated misinformation, consistent with its characterisation as an adaptive constructive process.

Toward sophisticated basal ganglia neuromodulation: Review on basal ganglia deep brain stimulation.

PubMed

Da Cunha, Claudio; Boschen, Suelen L; Gómez-A, Alexander; Ross, Erika K; Gibson, William S J; Min, Hoon-Ki; Lee, Kendall H; Blaha, Charles D

2015-11-01

This review presents state-of-the-art knowledge about the roles of the basal ganglia (BG) in action-selection, cognition, and motivation, and how this knowledge has been used to improve deep brain stimulation (DBS) treatment of neurological and psychiatric disorders. Such pathological conditions include Parkinson's disease, Huntington's disease, Tourette syndrome, depression, and obsessive-compulsive disorder. The first section presents evidence supporting current hypotheses of how the cortico-BG circuitry works to select motor and emotional actions, and how defects in this circuitry can cause symptoms of the BG diseases. Emphasis is given to the role of striatal dopamine on motor performance, motivated behaviors and learning of procedural memories. Next, the use of cutting-edge electrochemical techniques in animal and human studies of BG functioning under normal and disease conditions is discussed. Finally, functional neuroimaging studies are reviewed; these works have shown the relationship between cortico-BG structures activated during DBS and improvement of disease symptoms. Copyright © 2015 Elsevier Ltd. All rights reserved.

Toward sophisiticated basal ganglia neuromodulation: review on basal gaglia deep brain stimulation

PubMed Central

Da Cunha, Claudio; Boschen, Suelen L.; Gómez-A, Alexander; Ross, Erika K.; Gibson, William S. J.; Min, Hoon-Ki; Lee, Kendall H.; Blaha, Charles D.

2015-01-01

This review presents state-of-the-art knowledge about the roles of the basal ganglia (BG) in action-selection, cognition, and motivation, and how this knowledge has been used to improve deep brain stimulation (DBS) treatment of neurological and psychiatric disorders. Such pathological conditions include Parkinson’s disease, Huntington’s disease, Tourette syndrome, depression, and obsessive-compulsive disorder. The first section presents evidence supporting current hypotheses of how the cortico-BG circuitry works to select motor and emotional actions, and how defects in this circuitry can cause symptoms of the BG diseases. Emphasis is given to the role of striatal dopamine on motor performance, motivated behaviors and learning of procedural memories. Next, the use of cutting-edge electrochemical techniques in animal and human studies of BG functioning under normal and disease conditions is discussed. Finally, functional neuroimaging studies are reviewed; these works have shown the relationship between cortico-BG structures activated during DBS and improvement of disease symptoms. PMID:25684727

Visual Power Data Files for Equal Employment Opportunity (EEO)

EPA Pesticide Factsheets

The Visual Powerfiles for EEO is an information management and reporting system designed to meet Federal requirements for the agency's Equal Employment Opportunity (EEO) function in accordance with several civil rights laws and regulations. EPA OCR is responsible for monitoring and evaluating the effectiveness of affirmative programs, conducting workforce ad hoc anlysis and summaries for data related to applicant flow, new hires, promotions, awards, training, disciplinary actions, and selection procedures., and developing plans and actions for an annual Management Directive 715.

Selection and stopping in voluntary action: A meta-analysis and combined fMRI study☆

PubMed Central

Rae, Charlotte L.; Hughes, Laura E.; Weaver, Chelan; Anderson, Michael C.; Rowe, James B.

2014-01-01

Voluntary action control requires selection of appropriate responses and stopping of inappropriate responses. Selection and stopping are often investigated separately, but they appear to recruit similar brain regions, including the pre-supplementary motor area (preSMA) and inferior frontal gyrus. We therefore examined the evidence for overlap of selection and stopping using two approaches: a meta-analysis of existing studies of selection and stopping, and a novel within-subject fMRI study in which action selection and a stop signal task were combined factorially. The novel fMRI study also permitted us to investigate hypotheses regarding a common mechanism for selection and stopping. The preSMA was identified by both methods as common to selection and stopping. However, stopping a selected action did not recruit preSMA more than stopping a specified action, nor did stop signal reaction times differ significantly across the two conditions. These findings suggest that the preSMA supports both action selection and stopping, but the two processes may not require access to a common inhibition mechanism. Instead, the preSMA might represent information about potential actions that is used in both action selection and stopping in order to resolve conflict between competing available responses. PMID:24128740

Patterns of fMRI activity dissociate overlapping functional brain areas that respond to biological motion.

PubMed

Peelen, Marius V; Wiggett, Alison J; Downing, Paul E

2006-03-16

Accurate perception of the actions and intentions of other people is essential for successful interactions in a social environment. Several cortical areas that support this process respond selectively in fMRI to static and dynamic displays of human bodies and faces. Here we apply pattern-analysis techniques to arrive at a new understanding of the neural response to biological motion. Functionally defined body-, face-, and motion-selective visual areas all responded significantly to "point-light" human motion. Strikingly, however, only body selectivity was correlated, on a voxel-by-voxel basis, with biological motion selectivity. We conclude that (1) biological motion, through the process of structure-from-motion, engages areas involved in the analysis of the static human form; (2) body-selective regions in posterior fusiform gyrus and posterior inferior temporal sulcus overlap with, but are distinct from, face- and motion-selective regions; (3) the interpretation of region-of-interest findings may be substantially altered when multiple patterns of selectivity are considered.

Selective attentional enhancement and inhibition of fronto-posterior connectivity by the basal ganglia during attention switching.

PubMed

van Schouwenburg, Martine R; den Ouden, Hanneke E M; Cools, Roshan

2015-06-01

The prefrontal cortex and the basal ganglia interact to selectively gate a desired action. Recent studies have shown that this selective gating mechanism of the basal ganglia extends to the domain of attention. Here, we investigate the nature of this action-like gating mechanism for attention using a spatial attention-switching paradigm in combination with functional neuroimaging and dynamic causal modeling. We show that the basal ganglia guide attention by focally releasing inhibition of task-relevant representations, while simultaneously inhibiting task-irrelevant representations by selectively modulating prefrontal top-down connections. These results strengthen and specify the role of the basal ganglia in attention. Moreover, our findings have implications for psychological theorizing by suggesting that inhibition of unattended sensory regions is not only a consequence of mutual suppression, but is an active process, subserved by the basal ganglia. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Engineered Context-Sensitive Agonism: Tissue-Selective Drug Signaling through a G Protein-Coupled Receptor.

PubMed

Seemann, Wiebke K; Wenzel, Daniela; Schrage, Ramona; Etscheid, Justine; Bödefeld, Theresa; Bartol, Anna; Warnken, Mareille; Sasse, Philipp; Klöckner, Jessica; Holzgrabe, Ulrike; DeAmici, Marco; Schlicker, Eberhard; Racké, Kurt; Kostenis, Evi; Meyer, Rainer; Fleischmann, Bernd K; Mohr, Klaus

2017-02-01

Drug discovery strives for selective ligands to achieve targeted modulation of tissue function. Here we introduce engineered context-sensitive agonism as a postreceptor mechanism for tissue-selective drug action through a G protein-coupled receptor. Acetylcholine M 2 -receptor activation is known to mediate, among other actions, potentially dangerous slowing of the heart rate. This unwanted side effect is one of the main reasons that limit clinical application of muscarinic agonists. Herein we show that dualsteric (orthosteric/allosteric) agonists induce less cardiac depression ex vivo and in vivo than conventional full agonists. Exploration of the underlying mechanism in living cells employing cellular dynamic mass redistribution identified context-sensitive agonism of these dualsteric agonists. They translate elevation of intracellular cAMP into a switch from full to partial agonism. Designed context-sensitive agonism opens an avenue toward postreceptor pharmacologic selectivity, which even works in target tissues operated by the same subtype of pharmacologic receptor. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

The ERP Effects of Combined Cognitive Training on Intention-Based and Stimulus-Based Actions in Older Chinese Adults.

PubMed

Niu, Ya-Nan; Zhu, Xinyi; Li, Juan; Fu, Jiang-Ning

2016-01-01

Age-related decreases in action are caused by neuromuscular weakness and cognitive decline. Although physical interventions have been reported to have beneficial effects on cognitive function in older adults, whether cognitive training improves action-related function remains unclear. In this study, we investigated the effects of combined cognitive training on intention-based and stimulus-based actions in older adults using event-related potentials (ERPs). A total of 26 healthy older adults (16 in the training group and 10 in the control group) participated in the study. The training group received 16 sessions of cognitive training, including eight sessions of executive function training and eight sessions of memory strategy training. Before and after training, both groups of participants underwent cognitive assessments and ERP recordings during both the acquisition and test phases with a motor cognitive paradigm. During the acquisition phase, subjects were asked to press one of two keys, either using a self-selected (intention-based) method or based on the preceding stimulus (stimulus-based). During the test phase, subjects were asked to respond to the pre-cues with either congruent or incongruent tasks. Using ERP indices-including readiness potential, P3 and contingent negative variation to identify motor preparation, stimulus processing and interference effect, respectively-we revealed the effects of training on both intention-based and stimulus-based actions. The correlations were also computed between the improved cognitive performance and the ERP amplitudes. It was shown that the improved executive function might extend substantial benefits to both actions, whereas associative memory may be specifically related to the bidirectional action-effect association of intention-based action, although the training effect of memory was absent during the insufficient training hours. In sum, the present study provided empirical evidence demonstrating that action could benefit from cognitive training. www.chictr.org.cn, identifier: ChiCTR-OON-16007793.

Aberrant supplementary motor complex and limbic activity during motor preparation in motor conversion disorder

PubMed Central

Voon, V; Brezing, C; Gallea, C; Hallett, M

2014-01-01

Background Conversion disorder is characterized by unexplained neurological symptoms presumed related to psychological issues. The main hypotheses to explain conversion paralysis, characterized by a lack of movement, include impairments in either motor intention or disruption of motor execution, and further, that hyperactive self-monitoring, limbic processing or top-down regulation from higher order frontal regions may interfere with motor execution. We have recently shown that conversion disorder with positive abnormal or excessive motor symptoms was associated with greater amygdala activity to arousing stimuli along with greater functional connectivity between the amgydala and supplementary motor area. Here we studied patients with such symptoms focusing on motor initiation. Methods Subjects performed either an internally or externally generated two-button action selection task in a functional MRI study. Results Eleven conversion disorder patients without major depression and 11 age- and gender-matched normal volunteers were assessed. During both internally and externally generated movement, conversion disorder patients relative to normal volunteers had lower left supplementary motor area (SMA) (implicated in motor initiation) and higher right amygdala, left anterior insula and bilateral posterior cingulate activity (implicated in assigning emotional salience). These findings were confirmed in a subgroup analysis of patients with tremor symptoms. During internally versus externally generated action in CD patients, the left SMA had lower functional connectivity with bilateral dorsolateral prefrontal cortices. Conclusion We propose a theory in which previously mapped conversion motor representations may in an arousing context hijack the voluntary action selection system which is both hypoactive and functionally disconnected from prefrontal top-down regulation. PMID:21935985

Aberrant supplementary motor complex and limbic activity during motor preparation in motor conversion disorder.

PubMed

Voon, Valerie; Brezing, Christina; Gallea, Cecile; Hallett, Mark

2011-11-01

Conversion disorder (CD) is characterized by unexplained neurological symptoms presumed related to psychological issues. The main hypotheses to explain conversion paralysis, characterized by a lack of movement, include impairments in either motor intention or disruption of motor execution, and further, that hyperactive self-monitoring, limbic processing or top-down regulation from higher order frontal regions may interfere with motor execution. We have recently shown that CD with positive abnormal or excessive motor symptoms was associated with greater amygdala activity to arousing stimuli along with greater functional connectivity between the amygdala and supplementary motor area. Here we studied patients with such symptoms focusing on motor initiation. Subjects performed either an internally or externally generated 2-button action selection task in a functional MRI study. Eleven CD patients without major depression and 11 age- and gender-matched normal volunteers were assessed. During both internally and externally generated movement, conversion disorder patients relative to normal volunteers had lower left supplementary motor area (SMA) (implicated in motor initiation) and higher right amygdala, left anterior insula, and bilateral posterior cingulate activity (implicated in assigning emotional salience). These findings were confirmed in a subgroup analysis of patients with tremor symptoms. During internally versus externally generated action in CD patients, the left SMA had lower functional connectivity with bilateral dorsolateral prefrontal cortices. We propose a theory in which previously mapped conversion motor representations may in an arousing context hijack the voluntary action selection system, which is both hypoactive and functionally disconnected from prefrontal top-down regulation. Copyright © 2011 Movement Disorder Society.

A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer

PubMed Central

Hu, Qiang; Senapati, Dhirodatta; Venkadakrishnan, Varadha Balaji; Wang, Dan; DePriest, Adam D; Schlanger, Simon E; Ben-Salem, Salma; Valenzuela, Malyn May; Willard, Belinda; Mudambi, Shaila; Swetzig, Wendy M; Das, Gokul M; Shourideh, Mojgan; Koochekpour, Shahriah; Falzarano, Sara Moscovita; Magi-Galluzzi, Cristina; Yadav, Neelu; Chen, Xiwei; Lao, Changshi; Wang, Jianmin; Billaud, Jean-Noel

2017-01-01

Standard treatment for metastatic prostate cancer (CaP) prevents ligand-activation of androgen receptor (AR). Despite initial remission, CaP progresses while relying on AR. AR transcriptional output controls CaP behavior and is an alternative therapeutic target, but its molecular regulation is poorly understood. Here, we show that action of activated AR partitions into fractions that are controlled preferentially by different coregulators. In a 452-AR-target gene panel, each of 18 clinically relevant coregulators mediates androgen-responsiveness of 0–57% genes and acts as a coactivator or corepressor in a gene-specific manner. Selectivity in coregulator-dependent AR action is reflected in differential AR binding site composition and involvement with CaP biology and progression. Isolation of a novel transcriptional mechanism in which WDR77 unites the actions of AR and p53, the major genomic drivers of lethal CaP, to control cell cycle progression provides proof-of-principle for treatment via selective interference with AR action by exploiting AR dependence on coregulators. PMID:28826481

Investigating the Prospective Sense of Agency: Effects of Processing Fluency, Stimulus Ambiguity, and Response Conflict.

PubMed

Sidarus, Nura; Vuorre, Matti; Metcalfe, Janet; Haggard, Patrick

2017-01-01

How do we know how much control we have over our environment? The sense of agency refers to the feeling that we are in control of our actions, and that, through them, we can control our external environment. Thus, agency clearly involves matching intentions, actions, and outcomes. The present studies investigated the possibility that processes of action selection, i.e., choosing what action to make, contribute to the sense of agency. Since selection of action necessarily precedes execution of action, such effects must be prospective. In contrast, most literature on sense of agency has focussed on the retrospective computation whether an outcome fits the action performed or intended. This hypothesis was tested in an ecologically rich, dynamic task based on a computer game. Across three experiments, we manipulated three different aspects of action selection processing: visual processing fluency, categorization ambiguity, and response conflict. Additionally, we measured the relative contributions of prospective, action selection-based cues, and retrospective, outcome-based cues to the sense of agency. Manipulations of action selection were orthogonally combined with discrepancy of visual feedback of action. Fluency of action selection had a small but reliable effect on the sense of agency. Additionally, as expected, sense of agency was strongly reduced when visual feedback was discrepant with the action performed. The effects of discrepant feedback were larger than the effects of action selection fluency, and sometimes suppressed them. The sense of agency is highly sensitive to disruptions of action-outcome relations. However, when motor control is successful, and action-outcome relations are as predicted, fluency or dysfluency of action selection provides an important prospective cue to the sense of agency.

Investigating the Prospective Sense of Agency: Effects of Processing Fluency, Stimulus Ambiguity, and Response Conflict

PubMed Central

Sidarus, Nura; Vuorre, Matti; Metcalfe, Janet; Haggard, Patrick

2017-01-01

How do we know how much control we have over our environment? The sense of agency refers to the feeling that we are in control of our actions, and that, through them, we can control our external environment. Thus, agency clearly involves matching intentions, actions, and outcomes. The present studies investigated the possibility that processes of action selection, i.e., choosing what action to make, contribute to the sense of agency. Since selection of action necessarily precedes execution of action, such effects must be prospective. In contrast, most literature on sense of agency has focussed on the retrospective computation whether an outcome fits the action performed or intended. This hypothesis was tested in an ecologically rich, dynamic task based on a computer game. Across three experiments, we manipulated three different aspects of action selection processing: visual processing fluency, categorization ambiguity, and response conflict. Additionally, we measured the relative contributions of prospective, action selection-based cues, and retrospective, outcome-based cues to the sense of agency. Manipulations of action selection were orthogonally combined with discrepancy of visual feedback of action. Fluency of action selection had a small but reliable effect on the sense of agency. Additionally, as expected, sense of agency was strongly reduced when visual feedback was discrepant with the action performed. The effects of discrepant feedback were larger than the effects of action selection fluency, and sometimes suppressed them. The sense of agency is highly sensitive to disruptions of action-outcome relations. However, when motor control is successful, and action-outcome relations are as predicted, fluency or dysfluency of action selection provides an important prospective cue to the sense of agency. PMID:28450839

Optimum periodicity of repeated contractile actions applied in mass transport

NASA Astrophysics Data System (ADS)

Ahn, Sungsook; Lee, Sang Joon

2015-01-01

Dynamically repeated periodic patterns are abundant in natural and artificial systems, such as tides, heart beats, stock prices, and the like. The characteristic repeatability and periodicity are expected to be optimized in effective system-specific functions. In this study, such optimum periodicity is experimentally evaluated in terms of effective mass transport using one-valve and multi-valve systems working in contractile fluid flows. A set of nanoscale gating functions is utilized, operating in nanocomposite networks through which permeates selectively pass under characteristic contractile actions. Optimized contractile periodicity exists for effective energy impartment to flow in a one-valve system. In the sequential contractile actions for a multi-valve system, synchronization with the fluid flow is critical for effective mass transport. This study provides fundamental understanding on the various repeated periodic patterns and dynamic repeatability occurring in nature and mechanical systems, which are useful for broad applications.

Representation of action in occipito-temporal cortex.

PubMed

Wiggett, Alison J; Downing, Paul E

2011-07-01

A fundamental question for social cognitive neuroscience is how and where in the brain the identities and actions of others are represented. Here we present a replication and extension of a study by Kable and Chatterjee [Kable, J. W., & Chatterjee, A. Specificity of action representations in the lateral occipito-temporal cortex. Journal of Cognitive Neuroscience, 18, 1498-1517, 2006] examining the role of occipito-temporal cortex in these processes. We presented full-cue movies of actors performing whole-body actions and used fMRI to test for action- and identity-specific adaptation effects. We examined a series of functionally defined regions, including the extrastriate and fusiform body areas, the fusiform face area, the parahippocampal place area, the lateral occipital complex, the right posterior superior temporal sulcus, and motion-selective area hMT+. These regions were analyzed with both standard univariate measures as well as multivoxel pattern analyses. Additionally, we performed whole-brain tests for significant adaptation effects. We found significant action-specific adaptation in many areas, but no evidence for identity-specific adaptation. We argue that this finding could be explained by differences in the familiarity of the stimuli presented: The actions shown were familiar but the actors performing the actions were unfamiliar. However, in contrast to previous findings, we found that the action adaptation effect could not be conclusively tied to specific functionally defined regions. Instead, our results suggest that the adaptation to previously seen actions across identities is a widespread effect, evident across lateral and ventral occipito-temporal cortex.

Relative Critical Points

NASA Astrophysics Data System (ADS)

Lewis, Debra

2013-05-01

Relative equilibria of Lagrangian and Hamiltonian systems with symmetry are critical points of appropriate scalar functions parametrized by the Lie algebra (or its dual) of the symmetry group. Setting aside the structures - symplectic, Poisson, or variational - generating dynamical systems from such functions highlights the common features of their construction and analysis, and supports the construction of analogous functions in non-Hamiltonian settings. If the symmetry group is nonabelian, the functions are invariant only with respect to the isotropy subgroup of the given parameter value. Replacing the parametrized family of functions with a single function on the product manifold and extending the action using the (co)adjoint action on the algebra or its dual yields a fully invariant function. An invariant map can be used to reverse the usual perspective: rather than selecting a parametrized family of functions and finding their critical points, conditions under which functions will be critical on specific orbits, typically distinguished by isotropy class, can be derived. This strategy is illustrated using several well-known mechanical systems - the Lagrange top, the double spherical pendulum, the free rigid body, and the Riemann ellipsoids - and generalizations of these systems.

Cobalt-catalysed site-selective intra- and intermolecular dehydrogenative amination of unactivated sp3 carbons

PubMed Central

Wu, Xuesong; Yang, Ke; Zhao, Yan; Sun, Hao; Li, Guigen; Ge, Haibo

2015-01-01

Cobalt-catalysed sp2 C–H bond functionalization has attracted considerable attention in recent years because of the low cost of cobalt complexes and interesting modes of action in the process. In comparison, much less efforts have been devoted to the sp3 carbons. Here we report the cobalt-catalysed site-selective dehydrogenative cyclization of aliphatic amides via a C–H bond functionalization process on unactivated sp3 carbons with the assistance of a bidentate directing group. This method provides a straightforward synthesis of monocyclic and spiro β- or γ-lactams with good to excellent stereoselectivity and functional group tolerance. In addition, a new procedure has been developed to selectively remove the directing group, which enables the synthesis of free β- or γ-lactam compounds. Furthermore, the first cobalt-catalysed intermolecular dehydrogenative amination of unactivated sp3 carbons is also realized. PMID:25753366

The influence of visual training on predicting complex action sequences.

PubMed

Cross, Emily S; Stadler, Waltraud; Parkinson, Jim; Schütz-Bosbach, Simone; Prinz, Wolfgang

2013-02-01

Linking observed and executable actions appears to be achieved by an action observation network (AON), comprising parietal, premotor, and occipitotemporal cortical regions of the human brain. AON engagement during action observation is thought to aid in effortless, efficient prediction of ongoing movements to support action understanding. Here, we investigate how the AON responds when observing and predicting actions we cannot readily reproduce before and after visual training. During pre- and posttraining neuroimaging sessions, participants watched gymnasts and wind-up toys moving behind an occluder and pressed a button when they expected each agent to reappear. Between scanning sessions, participants visually trained to predict when a subset of stimuli would reappear. Posttraining scanning revealed activation of inferior parietal, superior temporal, and cerebellar cortices when predicting occluded actions compared to perceiving them. Greater activity emerged when predicting untrained compared to trained sequences in occipitotemporal cortices and to a lesser degree, premotor cortices. The occipitotemporal responses when predicting untrained agents showed further specialization, with greater responses within body-processing regions when predicting gymnasts' movements and in object-selective cortex when predicting toys' movements. The results suggest that (1) select portions of the AON are recruited to predict the complex movements not easily mapped onto the observer's body and (2) greater recruitment of these AON regions supports prediction of less familiar sequences. We suggest that the findings inform both the premotor model of action prediction and the predictive coding account of AON function. Copyright © 2011 Wiley Periodicals, Inc.

Effects of selected food phytochemicals in reducing the toxic actions of TCDD and p,p′-DDT in U937 macrophages

PubMed Central

Sciullo, Eric M.; Vogel, Christoph F.; Wu, Dalei; Murakami, Akira; Ohigashi, Hajime

2010-01-01

To assess the effectiveness of selected food phytochemicals in reducing the toxic effects of the environmental toxicants, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and p,p′-DDT (DDT), we tested the potencies of auraptene, nobiletin, zerumbone, and (±)-13-hydroxy-10-oxo-trans-11-octadecenoic acid (13-HOA) in reversing the inflammatory action of these toxicants in U937 human macrophages. Using quantitative RT–PCR as the initial screening assay, we identified antagonistic actions of zerumbone and auraptene against the action of TCDD and DDT in up-regulating the mRNA expressions of COX-2 and VEGF. The functional significance of the inhibitory action of zerumbone on COX-2 expression was confirmed by demonstrating its suppression of TCDD-induced activation of COX-2 gene expression in mouse MMDD1 cells. We tested auraptene on DDT-induced reactive oxygen species (ROS) formation in U937 macrophages and found that auraptene is a powerful agent antagonizing this action of DDT. To confirm the significance of these actions of zerumbone and auraptene at the cellular level, we assessed their influence on TCDD-induced apoptosis resistance in intact U937 macrophages and found that they are capable of reversing this action of TCDD. In conclusion, zerumbone and auraptene were identified to be the most effective agents in protecting U937 macrophages from developing these cell toxic effects of TCDD and DDT. PMID:20865247

Idiosyncratic representation of peripersonal space depends on the success of one's own motor actions, but also the successful actions of others!

PubMed Central

Quesque, François; Gigliotti, Maria-Francesca; Ott, Laurent; Bruyelle, Jean-Luc

2018-01-01

Peripersonal space is a multisensory representation of the environment around the body in relation to the motor system, underlying the interactions with the physical and social world. Although changing body properties and social context have been shown to alter the functional processing of space, little is known about how changing the value of objects influences the representation of peripersonal space. In two experiments, we tested the effect of modifying the spatial distribution of reward-yielding targets on manual reaching actions and peripersonal space representation. Before and after performing a target-selection task consisting of manually selecting a set of targets on a touch-screen table, participants performed a two-alternative forced-choice reachability-judgment task. In the target-selection task, half of the targets were associated with a reward (change of colour from grey to green, providing 1 point), the other half being associated with no reward (change of colour from grey to red, providing no point). In Experiment 1, the target-selection task was performed individually with the aim of maximizing the point count, and the distribution of the reward-yielding targets was either 50%, 25% or 75% in the proximal and distal spaces. In Experiment 2, the target-selection task was performed in a social context involving cooperation between two participants to maximize the point count, and the distribution of the reward-yielding targets was 50% in the proximal and distal spaces. Results showed that changing the distribution of the reward-yielding targets or introducing the social context modified concurrently the amplitude of self-generated manual reaching actions and the representation of peripersonal space. Moreover, a decrease of the amplitude of manual reaching actions caused a reduction of peripersonal space when resulting from the distribution of reward-yielding targets, while this effect was not observed in a social interaction context. In that case, the decreased amplitude of manual reaching actions was accompanied by an increase of peripersonal space representation, which was not due to the mere presence of a confederate (control experiment). We conclude that reward-dependent modulation of objects values in the environment modifies the representation of peripersonal space, when resulting from either self-generated motor actions or observation of motor actions performed by a confederate. PMID:29771982

Idiosyncratic representation of peripersonal space depends on the success of one's own motor actions, but also the successful actions of others!

PubMed

Coello, Yann; Quesque, François; Gigliotti, Maria-Francesca; Ott, Laurent; Bruyelle, Jean-Luc

2018-01-01

Peripersonal space is a multisensory representation of the environment around the body in relation to the motor system, underlying the interactions with the physical and social world. Although changing body properties and social context have been shown to alter the functional processing of space, little is known about how changing the value of objects influences the representation of peripersonal space. In two experiments, we tested the effect of modifying the spatial distribution of reward-yielding targets on manual reaching actions and peripersonal space representation. Before and after performing a target-selection task consisting of manually selecting a set of targets on a touch-screen table, participants performed a two-alternative forced-choice reachability-judgment task. In the target-selection task, half of the targets were associated with a reward (change of colour from grey to green, providing 1 point), the other half being associated with no reward (change of colour from grey to red, providing no point). In Experiment 1, the target-selection task was performed individually with the aim of maximizing the point count, and the distribution of the reward-yielding targets was either 50%, 25% or 75% in the proximal and distal spaces. In Experiment 2, the target-selection task was performed in a social context involving cooperation between two participants to maximize the point count, and the distribution of the reward-yielding targets was 50% in the proximal and distal spaces. Results showed that changing the distribution of the reward-yielding targets or introducing the social context modified concurrently the amplitude of self-generated manual reaching actions and the representation of peripersonal space. Moreover, a decrease of the amplitude of manual reaching actions caused a reduction of peripersonal space when resulting from the distribution of reward-yielding targets, while this effect was not observed in a social interaction context. In that case, the decreased amplitude of manual reaching actions was accompanied by an increase of peripersonal space representation, which was not due to the mere presence of a confederate (control experiment). We conclude that reward-dependent modulation of objects values in the environment modifies the representation of peripersonal space, when resulting from either self-generated motor actions or observation of motor actions performed by a confederate.

Thematic knowledge, artifact concepts, and the left posterior temporal lobe: Where action and object semantics converge

PubMed Central

Kalénine, Solène; Buxbaum, Laurel J.

2016-01-01

Converging evidence supports the existence of functionally and neuroanatomically distinct taxonomic (similarity-based; e.g., hammer-screwdriver) and thematic (event-based; e.g., hammer-nail) semantic systems. Processing of thematic relations between objects has been shown to selectively recruit the left posterior temporoparietal cortex. Similar posterior regions have been also been shown to be critical for knowledge of relationships between actions and manipulable human-made objects (artifacts). Based on the hypothesis that thematic relationships for artifacts are based, at least in part, on action relationships, we assessed the prediction that the same regions of the left posterior temporoparietal cortex would be critical for conceptual processing of artifact-related actions and thematic relations for artifacts. To test this hypothesis, we evaluated processing of taxonomic and thematic relations for artifact and natural objects as well as artifact action knowledge (gesture recognition) abilities in a large sample of 48 stroke patients with a range of lesion foci in the left hemisphere. Like control participants, patients identified thematic relations faster than taxonomic relations for artifacts, whereas they identified taxonomic relations faster than thematic relations for natural objects. Moreover, response times for identifying thematic relations for artifacts selectively predicted performance in gesture recognition. Whole brain Voxel Based Lesion-Symptom Mapping (VLSM) analyses and Region of Interest (ROI) regression analyses further demonstrated that lesions to the left posterior temporal cortex, overlapping with LTO and visual motion area hMT+, were associated both with relatively slower response times in identifying thematic relations for artifacts and poorer artifact action knowledge in patients. These findings provide novel insights into the functional role of left posterior temporal cortex in thematic knowledge, and suggest that the close association between thematic relations for artifacts and action representations may reflect their common dependence on visual motion and manipulation information. PMID:27389801

Preferential coding of eye/hand motor actions in the human ventral occipito-temporal cortex.

PubMed

Tosoni, Annalisa; Guidotti, Roberto; Del Gratta, Cosimo; Committeri, Giorgia; Sestieri, Carlo

2016-12-01

The human ventral occipito-temporal cortex (OTC) contains areas specialized for particular perceptual/semantic categories, such as faces (fusiform face area, FFA) and places (parahippocampal place area, PPA). This organization has been interpreted as reflecting the visual structure of the world, i.e. perceptual similarity and/or eccentricity biases. However, recent functional magnetic resonance imaging (fMRI) studies have shown not only that regions of the OTC are modulated by non-visual, action-related object properties but also by motor planning and execution, although the functional role and specificity of this motor-related activity are still unclear. Here, through a reanalysis of previously published data, we tested whether the selectivity for perceptual/semantic categories in the OTC corresponds to a preference for particular motor actions. The results demonstrate for the first time that face- and place-selective regions of the OTC exhibit preferential BOLD response to the execution of hand pointing and saccadic eye movements, respectively. Moreover, multivariate analyses provide novel evidence for the consistency across neural representations of stimulus category and movement effector in OTC. According to a 'spatial hypothesis', this pattern of results originates from the match between the region eccentricity bias and the typical action space of the motor effectors. Alternatively, the double dissociation may be caused by the different effect produced by hand vs. eye movements on regions coding for body representation. Overall, the present findings offer novel insights on the coupling between visual and motor cortical representations. Copyright © 2016. Published by Elsevier Ltd.

Evolutionarily conserved mechanisms for the selection and maintenance of behavioural activity.

PubMed

Fiore, Vincenzo G; Dolan, Raymond J; Strausfeld, Nicholas J; Hirth, Frank

2015-12-19

Survival and reproduction entail the selection of adaptive behavioural repertoires. This selection manifests as phylogenetically acquired activities that depend on evolved nervous system circuitries. Lorenz and Tinbergen already postulated that heritable behaviours and their reliable performance are specified by genetically determined programs. Here we compare the functional anatomy of the insect central complex and vertebrate basal ganglia to illustrate their role in mediating selection and maintenance of adaptive behaviours. Comparative analyses reveal that central complex and basal ganglia circuitries share comparable lineage relationships within clusters of functionally integrated neurons. These clusters are specified by genetic mechanisms that link birth time and order to their neuronal identities and functions. Their subsequent connections and associated functions are characterized by similar mechanisms that implement dimensionality reduction and transition through attractor states, whereby spatially organized parallel-projecting loops integrate and convey sensorimotor representations that select and maintain behavioural activity. In both taxa, these neural systems are modulated by dopamine signalling that also mediates memory-like processes. The multiplicity of similarities between central complex and basal ganglia suggests evolutionarily conserved computational mechanisms for action selection. We speculate that these may have originated from ancestral ground pattern circuitries present in the brain of the last common ancestor of insects and vertebrates. © 2015 The Authors.

Evolutionarily conserved mechanisms for the selection and maintenance of behavioural activity

PubMed Central

Fiore, Vincenzo G.; Dolan, Raymond J.; Strausfeld, Nicholas J.; Hirth, Frank

2015-01-01

Survival and reproduction entail the selection of adaptive behavioural repertoires. This selection manifests as phylogenetically acquired activities that depend on evolved nervous system circuitries. Lorenz and Tinbergen already postulated that heritable behaviours and their reliable performance are specified by genetically determined programs. Here we compare the functional anatomy of the insect central complex and vertebrate basal ganglia to illustrate their role in mediating selection and maintenance of adaptive behaviours. Comparative analyses reveal that central complex and basal ganglia circuitries share comparable lineage relationships within clusters of functionally integrated neurons. These clusters are specified by genetic mechanisms that link birth time and order to their neuronal identities and functions. Their subsequent connections and associated functions are characterized by similar mechanisms that implement dimensionality reduction and transition through attractor states, whereby spatially organized parallel-projecting loops integrate and convey sensorimotor representations that select and maintain behavioural activity. In both taxa, these neural systems are modulated by dopamine signalling that also mediates memory-like processes. The multiplicity of similarities between central complex and basal ganglia suggests evolutionarily conserved computational mechanisms for action selection. We speculate that these may have originated from ancestral ground pattern circuitries present in the brain of the last common ancestor of insects and vertebrates. PMID:26554043

Occult nodal metastasis in solid carcinomata

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moloy, P.J.; Nicolson, G.L.

1987-01-01

This book contains 23 selections. Some of the titles are: Rationale for radiotherapy in subclinical nodal disease; rationale of chemotherapy for nodal disease: The stabilization of topoisomerase II-DNA complexes as a mechanism of antineoplastic drug action; magnetic resonance imaging of malignant cervical adenopathy; and local and regional immune function in cancer patients.

32 CFR 513.3 - Administrative and punitive actions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... with debt complaints will be filed per AR 600-37 and the Army Functional Files System (AR 340-2 and AR... personnel files. (1) The Army requires that all-inclusive information of the qualifications of its soliders be on file. This prevents selection of soldiers for positions of leadership, trust, and...

32 CFR 513.3 - Administrative and punitive actions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... with debt complaints will be filed per AR 600-37 and the Army Functional Files System (AR 340-2 and AR... personnel files. (1) The Army requires that all-inclusive information of the qualifications of its soliders be on file. This prevents selection of soldiers for positions of leadership, trust, and...

32 CFR 513.3 - Administrative and punitive actions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... with debt complaints will be filed per AR 600-37 and the Army Functional Files System (AR 340-2 and AR... personnel files. (1) The Army requires that all-inclusive information of the qualifications of its soliders be on file. This prevents selection of soldiers for positions of leadership, trust, and...

Functional Validation of Virtual Screening for Novel Agents with General Anesthetic Action at Ligand-Gated Ion Channels

PubMed Central

Heusser, Stephanie A.; Howard, Rebecca J.; Borghese, Cecilia M.; Cullins, Madeline A.; Broemstrup, Torben; Lee, Ui S.; Lindahl, Erik; Carlsson, Jens

2013-01-01

GABAA receptors play a crucial role in the actions of general anesthetics. The recently published crystal structure of the general anesthetic propofol bound to Gloeobacter violaceus ligand-gated ion channel (GLIC), a bacterial homolog of GABAA receptors, provided an opportunity to explore structure-based ligand discovery for pentameric ligand-gated ion channels (pLGICs). We used molecular docking of 153,000 commercially available compounds to identify molecules that interact with the propofol binding site in GLIC. In total, 29 compounds were selected for functional testing on recombinant GLIC, and 16 of these compounds modulated GLIC function. Active compounds were also tested on recombinant GABAA receptors, and point mutations around the presumed binding pocket were introduced into GLIC and GABAA receptors to test for binding specificity. The potency of active compounds was only weakly correlated with properties such as lipophilicity or molecular weight. One compound was found to mimic the actions of propofol on GLIC and GABAA, and to be sensitive to mutations that reduce the action of propofol in both receptors. Mutant receptors also provided insight about the position of the binding sites and the relevance of the receptor’s conformation for anesthetic actions. Overall, the findings support the feasibility of the use of virtual screening to discover allosteric modulators of pLGICs, and suggest that GLIC is a valid model system to identify novel GABAA receptor ligands. PMID:23950219

Multi-period response management to contaminated water distribution networks: dynamic programming versus genetic algorithms

NASA Astrophysics Data System (ADS)

Bashi-Azghadi, Seyyed Nasser; Afshar, Abbas; Afshar, Mohammad Hadi

2018-03-01

Previous studies on consequence management assume that the selected response action including valve closure and/or hydrant opening remains unchanged during the entire management period. This study presents a new embedded simulation-optimization methodology for deriving time-varying operational response actions in which the network topology may change from one stage to another. Dynamic programming (DP) and genetic algorithm (GA) are used in order to minimize selected objective functions. Two networks of small and large sizes are used in order to illustrate the performance of the proposed modelling schemes if a time-dependent consequence management strategy is to be implemented. The results show that for a small number of decision variables even in large-scale networks, DP is superior in terms of accuracy and computer runtime. However, as the number of potential actions grows, DP loses its merit over the GA approach. This study clearly proves the priority of the proposed dynamic operation strategy over the commonly used static strategy.

A computational model of Dopamine and Acetylcholine aberrant learning in Basal Ganglia.

PubMed

Baston, Chiara; Ursino, Mauro

2015-01-01

Basal Ganglia (BG) are implied in many motor and cognitive tasks, such as action selection, and have a central role in many pathologies, primarily Parkinson Disease. In the present work, we use a recently developed biologically inspired BG model to analyze how the dopamine (DA) level can affect the temporal response during action selection, and the capacity to learn new actions following rewards and punishments. The model incorporates the 3 main pathways (direct, indirect and hyperdirect) working in BG functioning. The behavior of 2 alternative networks (the first with normal DA levels, the second with reduced DA) is analyzed both in untrained conditions, and during training performed in different epochs. The results show that reduced DA causes delayed temporal responses in the untrained network, and difficult of learning during training, characterized by the necessity of much more epochs. The results provide interesting hints to understand the behavior of healthy and dopamine depleted subjects, such as parkinsonian patients.

Signaling, physiological functions and clinical relevance of the G protein-coupled estrogen receptor GPER.

PubMed

Prossnitz, Eric R; Barton, Matthias

2009-09-01

GPR30, now named GPER1 (G protein-coupled estrogen receptor1) or GPER here, was first identified as an orphan 7-transmembrane G protein-coupled receptor by multiple laboratories using either homology cloning or differential expression and subsequently shown to be required for estrogen-mediated signaling in certain cancer cells. The actions of estrogen are extensive in the body and are thought to be mediated predominantly by classical nuclear estrogen receptors that act as transcription factors/regulators. Nevertheless, certain aspects of estrogen function remain incompatible with the generally accepted mechanisms of classical estrogen receptor action. Many recent studies have revealed that GPER contributes to some of the actions of estrogen, including rapid signaling events and rapid transcriptional activation. With the introduction of GPER-selective ligands and GPER knockout mice, the functions of GPER are becoming more clearly defined. In many cases, there appears to be a complex interplay between the two receptor systems, suggesting that estrogen-mediated physiological responses may be mediated by either receptor or a combination of both receptor types, with important medical implications.

Untangling Basal Ganglia Network Dynamics and Function: Role of Dopamine Depletion and Inhibition Investigated in a Spiking Network Model

PubMed Central

2016-01-01

Abstract The basal ganglia are a crucial brain system for behavioral selection, and their function is disturbed in Parkinson’s disease (PD), where neurons exhibit inappropriate synchronization and oscillations. We present a spiking neural model of basal ganglia including plausible details on synaptic dynamics, connectivity patterns, neuron behavior, and dopamine effects. Recordings of neuronal activity in the subthalamic nucleus and Type A (TA; arkypallidal) and Type I (TI; prototypical) neurons in globus pallidus externa were used to validate the model. Simulation experiments predict that both local inhibition in striatum and the existence of an indirect pathway are important for basal ganglia to function properly over a large range of cortical drives. The dopamine depletion–induced increase of AMPA efficacy in corticostriatal synapses to medium spiny neurons (MSNs) with dopamine receptor D2 synapses (CTX-MSN D2) and the reduction of MSN lateral connectivity (MSN–MSN) were found to contribute significantly to the enhanced synchrony and oscillations seen in PD. Additionally, reversing the dopamine depletion–induced changes to CTX–MSN D1, CTX–MSN D2, TA–MSN, and MSN–MSN couplings could improve or restore basal ganglia action selection ability. In summary, we found multiple changes of parameters for synaptic efficacy and neural excitability that could improve action selection ability and at the same time reduce oscillations. Identification of such targets could potentially generate ideas for treatments of PD and increase our understanding of the relation between network dynamics and network function. PMID:28101525

Selective tuning of the right inferior frontal gyrus during target detection

PubMed Central

Hampshire, Adam; Thompson, Russell; Duncan, John; Owen, Adrian M.

2010-01-01

In the human brain, a network of frontal and parietal regions is commonly recruited during tasks that demand the deliberate, focused control of thought and action. Previously, using a simple target detection task, we reported striking differences in the selectivity of the BOLD response in anatomically distinct subregions of this network. In particular, it was observed that the right inferior frontal gyrus (IFG) followed a tightly tuned function, selectively responding only to the current target object. Here, we examine this functional specialization further, using adapted versions of our original task. Our results demonstrate that the response of the right IFG to targets is a strong and replicable phenomenon. It occurs under increased attentional load, when targets and distractors are equally frequent, and when controlling for inhibitory processes. These findings support the hypothesis that the right IFG responds selectively to those items that are of the most relevance to the currently intended task schema. PMID:19246331

A spiking neural network based on the basal ganglia functional anatomy.

PubMed

Baladron, Javier; Hamker, Fred H

2015-07-01

We introduce a spiking neural network of the basal ganglia capable of learning stimulus-action associations. We model learning in the three major basal ganglia pathways, direct, indirect and hyperdirect, by spike time dependent learning and considering the amount of dopamine available (reward). Moreover, we allow to learn a cortico-thalamic pathway that bypasses the basal ganglia. As a result the system develops new functionalities for the different basal ganglia pathways: The direct pathway selects actions by disinhibiting the thalamus, the hyperdirect one suppresses alternatives and the indirect pathway learns to inhibit common mistakes. Numerical experiments show that the system is capable of learning sets of either deterministic or stochastic rules. Copyright © 2015 Elsevier Ltd. All rights reserved.

Orexin Regulates Bone Remodeling via a Dominant Positive Central Action and a Subordinate Negative Peripheral Action

PubMed Central

Wei, Wei; Motoike, Toshiyuki; Krzeszinski, Jing Y.; Jin, Zixue; Xie, Xian-Jin; Dechow, Paul C.; Yanagisawa, Masashi; Wan, Yihong

2014-01-01

SUMMARY Orexin neuropeptides promote arousal, appetite, reward, and energy expenditure. However, whether orexin affects bone mass accrual is unknown. Here we show that orexin functions centrally through orexin receptor 2 (OX2R) in the brain to enhance bone formation. OX2R-null mice exhibit low-bone-mass owing to elevated circulating leptin; whereas central administration of an OX2R-selective agonist augments bone mass. Conversely, orexin also functions peripherally through orexin receptor 1 (OX1R) in the bone to suppress bone formation. OX1R-null mice exhibit high-bone-mass owing to a mesenchymal stem cell differentiation shift from adipocyte to osteoblast that results from higher osseous ghrelin expression. The central action is dominant over the peripheral action because bone mass is reduced in orexin-null and OX1R2R-double-null mice but enhanced in orexin over-expressing transgenic mice. These findings reveal orexin as a critical rheostat of skeletal homeostasis that exerts a yin-yang dual regulation, and highlight orexin as a therapeutic target for osteoporosis. PMID:24794976

Mesencephalic representations of recent experience influence decision making.

PubMed

Thompson, John A; Costabile, Jamie D; Felsen, Gidon

2016-07-25

Decisions are influenced by recent experience, but the neural basis for this phenomenon is not well understood. Here, we address this question in the context of action selection. We focused on activity in the pedunculopontine tegmental nucleus (PPTg), a mesencephalic region that provides input to several nuclei in the action selection network, in well-trained mice selecting actions based on sensory cues and recent trial history. We found that, at the time of action selection, the activity of many PPTg neurons reflected the action on the previous trial and its outcome, and the strength of this activity predicted the upcoming choice. Further, inactivating the PPTg predictably decreased the influence of recent experience on action selection. These findings suggest that PPTg input to downstream motor regions, where it can be integrated with other relevant information, provides a simple mechanism for incorporating recent experience into the computations underlying action selection.

Accounting for complementarity to maximize monitoring power for species management.

PubMed

Tulloch, Ayesha I T; Chadès, Iadine; Possingham, Hugh P

2013-10-01

To choose among conservation actions that may benefit many species, managers need to monitor the consequences of those actions. Decisions about which species to monitor from a suite of different species being managed are hindered by natural variability in populations and uncertainty in several factors: the ability of the monitoring to detect a change, the likelihood of the management action being successful for a species, and how representative species are of one another. However, the literature provides little guidance about how to account for these uncertainties when deciding which species to monitor to determine whether the management actions are delivering outcomes. We devised an approach that applies decision science and selects the best complementary suite of species to monitor to meet specific conservation objectives. We created an index for indicator selection that accounts for the likelihood of successfully detecting a real trend due to a management action and whether that signal provides information about other species. We illustrated the benefit of our approach by analyzing a monitoring program for invasive predator management aimed at recovering 14 native Australian mammals of conservation concern. Our method selected the species that provided more monitoring power at lower cost relative to the current strategy and traditional approaches that consider only a subset of the important considerations. Our benefit function accounted for natural variability in species growth rates, uncertainty in the responses of species to the prescribed action, and how well species represent others. Monitoring programs that ignore uncertainty, likelihood of detecting change, and complementarity between species will be more costly and less efficient and may waste funding that could otherwise be used for management. © 2013 Society for Conservation Biology.

Epinigericin toxicity towards Tetrahymena pyriformis GL; changes in cell volume and intracellular pH.

PubMed

Bamdad, M; David, L; Grolière, C A

1995-12-01

A study of the toxicity of epinigericin, an antibiotic ionophor, towards the ciliate Tetrahymena pyriformis showed that this molecule stopped cell division, increased cell volume and led to a more basic intracellular pH. The action of epinigericin was probably linked to its function as an ionophor. The ionic selectivity of this molecule is still not known. The raising of the intracellular pH of ciliates by this antibiotic may be linked to its toxic action and its iontransport mechanism in Tetrahymena.

The robust corrective action priority-an improved approach for selecting competing corrective actions in FMEA based on principle of robust design

NASA Astrophysics Data System (ADS)

Sutrisno, Agung; Gunawan, Indra; Vanany, Iwan

2017-11-01

In spite of being integral part in risk - based quality improvement effort, studies improving quality of selection of corrective action priority using FMEA technique are still limited in literature. If any, none is considering robustness and risk in selecting competing improvement initiatives. This study proposed a theoretical model to select risk - based competing corrective action by considering robustness and risk of competing corrective actions. We incorporated the principle of robust design in counting the preference score among corrective action candidates. Along with considering cost and benefit of competing corrective actions, we also incorporate the risk and robustness of corrective actions. An example is provided to represent the applicability of the proposed model.

Using goal- and grip-related information for understanding the correctness of other's actions: an ERP study.

PubMed

van Elk, Michiel; Bousardt, Roel; Bekkering, Harold; van Schie, Hein T

2012-01-01

Detecting errors in other's actions is of pivotal importance for joint action, competitive behavior and observational learning. Although many studies have focused on the neural mechanisms involved in detecting low-level errors, relatively little is known about error-detection in everyday situations. The present study aimed to identify the functional and neural mechanisms whereby we understand the correctness of other's actions involving well-known objects (e.g. pouring coffee in a cup). Participants observed action sequences in which the correctness of the object grasped and the grip applied to a pair of objects were independently manipulated. Observation of object violations (e.g. grasping the empty cup instead of the coffee pot) resulted in a stronger P3-effect than observation of grip errors (e.g. grasping the coffee pot at the upper part instead of the handle), likely reflecting a reorienting response, directing attention to the relevant location. Following the P3-effect, a parietal slow wave positivity was observed that persisted for grip-errors, likely reflecting the detection of an incorrect hand-object interaction. These findings provide new insight in the functional significance of the neurophysiological markers associated with the observation of incorrect actions and suggest that the P3-effect and the subsequent parietal slow wave positivity may reflect the detection of errors at different levels in the action hierarchy. Thereby this study elucidates the cognitive processes that support the detection of action violations in the selection of objects and grips.

Toward an integrated account of object and action selection: A computational analysis and empirical findings from reaching-to-grasp and tool-use

PubMed Central

Botvinick, Matthew M.; Buxbaum, Laurel J.; Bylsma, Lauren M.; Jax, Steven A.

2014-01-01

The act of reaching for and acting upon an object involves two forms of selection: selection of the object as a target, and selection of the action to be performed. While these two forms of selection are logically dissociable, and are evidently subserved by separable neural pathways, they must also be closely coordinated. We examine the nature of this coordination by developing and analyzing a computational model of object and action selection first proposed by Ward [Ward, R. (1999). Interactions between perception and action systems: a model for selective action. In G. W. Humphreys, J. Duncan, & A. Treisman (Eds.), Attention, Space and Action: Studies in Cognitive Neuroscience. Oxford: Oxford University Press]. An interesting tenet of this account, which we explore in detail, is that the interplay between object and action selection depends critically on top-down inputs representing the current task set or plan of action. A concrete manifestation of this, established through a series of simulations, is that the impact of distractor objects on reaching times can vary depending on the nature of the current action plan. In order to test the model's predictions in this regard, we conducted two experiments, one involving direct object manipulation, the other involving tool-use. In both experiments we observed the specific interaction between task set and distractor type predicted by the model. Our findings provide support for the computational model, and more broadly for an interactive account of object and action selection. PMID:19100758

Anterior prefrontal cortex contributes to action selection through tracking of recent reward trends

PubMed Central

Kovach, Christopher K.; Daw, Nathaniel; Rudrauf, David; Tranel, Daniel; O’Doherty, John P.; Adolphs, Ralph

2012-01-01

The functions of prefrontal cortex remain enigmatic, especially so for its anterior sectors, putatively ranging from planning to self-initiated behavior, social cognition, task-switching and memory. A predominant current theory regarding the most anterior sector, frontopolar cortex (FPC), is that it is involved in exploring alternate courses of action, but the detailed causal mechanisms remain unknown. Here we investigated this issue using the lesion method together with a novel model-based analysis. Eight patients with anterior prefrontal brain lesions including the FPC performed a 4-armed bandit task known from neuroimaging studies to activate FPC. Model-based analyses of learning demonstrated a selective deficit in the ability to extrapolate the most recent trend, despite an intact general ability to learn from past rewards. Whereas both brain-damaged and healthy controls used comparisons between the two most recent choice outcomes to infer trends that influenced their decision about the next choice, the group with anterior prefrontal lesions showed a complete absence of this component and instead based their choice entirely on the cumulative reward history. Given that the FPC is thought to be the most evolutionarily recent expansion of primate prefrontal cortex, we suggest that its function may reflect uniquely human adaptations to select and update models of reward contingency in dynamic environments. PMID:22723683

Struggling Readers: An Action Research Project.

ERIC Educational Resources Information Center

Scordias, Margaret

A study focused on designing and implementing a reading program based on modified Reading Recovery programs. The student selected to be worked with made excellent gains and was the second strongest reader of all students observed in the study. Without question, the student functioned at a level equal to the middle of the class and her learning…

Use of genetic algorithm for the selection of EEG features

NASA Astrophysics Data System (ADS)

Asvestas, P.; Korda, A.; Kostopoulos, S.; Karanasiou, I.; Ouzounoglou, A.; Sidiropoulos, K.; Ventouras, E.; Matsopoulos, G.

2015-09-01

Genetic Algorithm (GA) is a popular optimization technique that can detect the global optimum of a multivariable function containing several local optima. GA has been widely used in the field of biomedical informatics, especially in the context of designing decision support systems that classify biomedical signals or images into classes of interest. The aim of this paper is to present a methodology, based on GA, for the selection of the optimal subset of features that can be used for the efficient classification of Event Related Potentials (ERPs), which are recorded during the observation of correct or incorrect actions. In our experiment, ERP recordings were acquired from sixteen (16) healthy volunteers who observed correct or incorrect actions of other subjects. The brain electrical activity was recorded at 47 locations on the scalp. The GA was formulated as a combinatorial optimizer for the selection of the combination of electrodes that maximizes the performance of the Fuzzy C Means (FCM) classification algorithm. In particular, during the evolution of the GA, for each candidate combination of electrodes, the well-known (Σ, Φ, Ω) features were calculated and were evaluated by means of the FCM method. The proposed methodology provided a combination of 8 electrodes, with classification accuracy 93.8%. Thus, GA can be the basis for the selection of features that discriminate ERP recordings of observations of correct or incorrect actions.

The influence of Generalized Anxiety Disorder on Executive Functions in children with ADHD.

PubMed

Menghini, D; Armando, M; Calcagni, M; Napolitano, C; Pasqualetti, P; Sergeant, J A; Pani, P; Vicari, S

2018-06-01

The present study was aimed at verifying whether the presence of generalized anxiety disorder (GAD) affects executive functions in children with attention-deficit hyperactivity disorder (ADHD). Two groups of children with ADHD were selected for the study according to the presence or absence of GAD. The first group of 28 children with ADHD with GAD (mean age: 9 ± 1.2; males/females: 24/4) was matched for gender, age, IQ, psychiatric comorbidity with a second group of 29 children with ADHD without GAD (mean age: 8.8 ± 0.7; males/females: 26/3). The two groups with ADHD were compared to 28 typically developing children (mean age: 8.3 ± 1.3; males/females: 23/5) on different measures involving processes especially important in inhibitory control such as rule maintenance, stimulus detection, action selection and action execution. Our results indicated that, differently from children with ADHD with GAD, only the group with ADHD without GAD showed a deficit in inhibitory control. Comorbid subgroups should be differentiated, especially, to develop specific and efficient therapeutic interventions in ADHD.

ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors.

PubMed

Schmalhofer, William A; Calhoun, Jeffrey; Burrows, Rachel; Bailey, Timothy; Kohler, Martin G; Weinglass, Adam B; Kaczorowski, Gregory J; Garcia, Maria L; Koltzenburg, Martin; Priest, Birgit T

2008-11-01

Voltage-gated sodium (Na(V)1) channels play a critical role in modulating the excitability of sensory neurons, and human genetic evidence points to Na(V)1.7 as an essential contributor to pain signaling. Human loss-of-function mutations in SCN9A, the gene encoding Na(V)1.7, cause channelopathy-associated indifference to pain (CIP), whereas gain-of-function mutations are associated with two inherited painful neuropathies. Although the human genetic data make Na(V)1.7 an attractive target for the development of analgesics, pharmacological proof-of-concept in experimental pain models requires Na(V)1.7-selective channel blockers. Here, we show that the tarantula venom peptide ProTx-II selectively interacts with Na(V)1.7 channels, inhibiting Na(V)1.7 with an IC(50) value of 0.3 nM, compared with IC(50) values of 30 to 150 nM for other heterologously expressed Na(V)1 subtypes. This subtype selectivity was abolished by a point mutation in DIIS3. It is interesting that application of ProTx-II to desheathed cutaneous nerves completely blocked the C-fiber compound action potential at concentrations that had little effect on Abeta-fiber conduction. ProTx-II application had little effect on action potential propagation of the intact nerve, which may explain why ProTx-II was not efficacious in rodent models of acute and inflammatory pain. Mono-iodo-ProTx-II ((125)I-ProTx-II) binds with high affinity (K(d) = 0.3 nM) to recombinant hNa(V)1.7 channels. Binding of (125)I-ProTx-II is insensitive to the presence of other well characterized Na(V)1 channel modulators, suggesting that ProTx-II binds to a novel site, which may be more conducive to conferring subtype selectivity than the site occupied by traditional local anesthetics and anticonvulsants. Thus, the (125)I-ProTx-II binding assay, described here, offers a new tool in the search for novel Na(V)1.7-selective blockers.

Understanding Human Original Actions Directed at Real-World Goals: The Role of the Lateral Prefrontal Cortex

PubMed Central

Sitnikova, Tatiana; Rosen, Bruce R.; Lord, Louis-David; West, W. Caroline

2014-01-01

Adaptive, original actions, which can succeed in multiple contextual situations, require understanding of what is relevant to a goal. Recognizing what is relevant may also help in predicting kinematics of observed, original actions. During action observation, comparisons between sensory input and expected action kinematics have been argued critical to accurate goal inference. Experimental studies with laboratory tasks, both in humans and nonhuman primates, demonstrated that the lateral prefrontal cortex (LPFC) can learn, hierarchically organize, and use goal-relevant information. To determine whether this LPFC capacity is generalizable to real-world cognition, we recorded functional magnetic resonance imaging (fMRI) data in the human brain during comprehension of original and usual object-directed actions embedded in video-depictions of real-life behaviors. We hypothesized that LPFC will contribute to forming goal-relevant representations necessary for kinematic predictions of original actions. Additionally, resting-state fMRI was employed to examine functional connectivity between the brain regions delineated in the video fMRI experiment. According to behavioral data, original videos could be understood by identifying elements relevant to real-life goals at different levels of abstraction. Patterns of enhanced activity in four regions in the left LPFC, evoked by original, relative to usual, video scenes, were consistent with previous neuroimaging findings on representing abstract and concrete stimuli dimensions relevant to laboratory goals. In the anterior left LPFC, the activity increased selectively when representations of broad classes of objects and actions, which could achieve the perceived overall behavioral goal, were likely to bias kinematic predictions of original actions. In contrast, in the more posterior regions, the activity increased even when concrete properties of the target object were more likely to bias the kinematic prediction. Functional connectivity was observed between contiguous regions along the rostro-caudal LPFC axis, but not between the regions that were not immediately adjacent. These findings generalize the representational hierarchy account of LPFC function to diverse core principles that can govern both production and comprehension of flexible real-life behavior. PMID:25224997

Mesencephalic representations of recent experience influence decision making

PubMed Central

Thompson, John A; Costabile, Jamie D; Felsen, Gidon

2016-01-01

Decisions are influenced by recent experience, but the neural basis for this phenomenon is not well understood. Here, we address this question in the context of action selection. We focused on activity in the pedunculopontine tegmental nucleus (PPTg), a mesencephalic region that provides input to several nuclei in the action selection network, in well-trained mice selecting actions based on sensory cues and recent trial history. We found that, at the time of action selection, the activity of many PPTg neurons reflected the action on the previous trial and its outcome, and the strength of this activity predicted the upcoming choice. Further, inactivating the PPTg predictably decreased the influence of recent experience on action selection. These findings suggest that PPTg input to downstream motor regions, where it can be integrated with other relevant information, provides a simple mechanism for incorporating recent experience into the computations underlying action selection. DOI: http://dx.doi.org/10.7554/eLife.16572.001 PMID:27454033

What makes a reach movement effortful? Physical effort discounting supports common minimization principles in decision making and motor control

PubMed Central

Ulbrich, Philipp; Gail, Alexander

2017-01-01

When deciding between alternative options, a rational agent chooses on the basis of the desirability of each outcome, including associated costs. As different options typically result in different actions, the effort associated with each action is an essential cost parameter. How do humans discount physical effort when deciding between movements? We used an action-selection task to characterize how subjective effort depends on the parameters of arm transport movements and controlled for potential confounding factors such as delay discounting and performance. First, by repeatedly asking subjects to choose between 2 arm movements of different amplitudes or durations, performed against different levels of force, we identified parameter combinations that subjects experienced as identical in effort (isoeffort curves). Movements with a long duration were judged more effortful than short-duration movements against the same force, while movement amplitudes did not influence effort. Biomechanics of the movements also affected effort, as movements towards the body midline were preferred to movements away from it. Second, by introducing movement repetitions, we further determined that the cost function for choosing between effortful movements had a quadratic relationship with force, while choices were made on the basis of the logarithm of these costs. Our results show that effort-based action selection during reaching cannot easily be explained by metabolic costs. Instead, force-loaded reaches, a widely occurring natural behavior, imposed an effort cost for decision making similar to cost functions in motor control. Our results thereby support the idea that motor control and economic choice are governed by partly overlapping optimization principles. PMID:28586347

Emulation as an Integrating Principle for Cognition

PubMed Central

Colder, Brian

2011-01-01

Emulations, defined as ongoing internal representations of potential actions and the futures those actions are expected to produce, play a critical role in directing human bodily activities. Studies of gross motor behavior, perception, allocation of attention, response to errors, interoception, and homeostatic activities, and higher cognitive reasoning suggest that the proper execution of all these functions relies on emulations. Further evidence supports the notion that reinforcement learning in humans is aimed at updating emulations, and that action selection occurs via the advancement of preferred emulations toward realization of their action and environmental prediction. Emulations are hypothesized to exist as distributed active networks of neurons in cortical and sub-cortical structures. This manuscript ties together previously unrelated theories of the role of prediction in different aspects of human information processing to create an integrated framework for cognition. PMID:21660288

Differential Effects of Systemic Cholinergic Receptor Blockade on Pavlovian Incentive Motivation and Goal-Directed Action Selection

PubMed Central

Ostlund, Sean B; Kosheleff, Alisa R; Maidment, Nigel T

2014-01-01

Reward-seeking actions can be guided by external cues that signal reward availability. For instance, when confronted with a stimulus that signals sugar, rats will prefer an action that produces sugar over a second action that produces grain pellets. Action selection is also sensitive to changes in the incentive value of potential rewards. Thus, rats that have been prefed a large meal of sucrose will prefer a grain-seeking action to a sucrose-seeking action. The current study investigated the dependence of these different aspects of action selection on cholinergic transmission. Hungry rats were given differential training with two unique stimulus-outcome (S1-O1 and S2-O2) and action-outcome (A1-O1 and A2-O2) contingencies during separate training phases. Rats were then given a series of Pavlovian-to-instrumental transfer tests, an assay of cue-triggered responding. Before each test, rats were injected with scopolamine (0, 0.03, or 0.1 mg/kg, intraperitoneally), a muscarinic receptor antagonist, or mecamylamine (0, 0.75, or 2.25 mg/kg, intraperitoneally), a nicotinic receptor antagonist. Although the reward-paired cues were capable of biasing action selection when rats were tested off-drug, both anticholinergic treatments were effective in disrupting this effect. During a subsequent round of outcome devaluation testing—used to assess the sensitivity of action selection to a change in reward value—we found no effect of either scopolamine or mecamylamine. These results reveal that cholinergic signaling at both muscarinic and nicotinic receptors mediates action selection based on Pavlovian reward expectations, but is not critical for flexibly selecting actions using current reward values. PMID:24370780

Mapping actions to improve access to medicines for mental disorders in low and middle income countries.

PubMed

Barbui, C; Dua, T; Kolappa, K; Saraceno, B; Saxena, S

2017-10-01

In recent years a number of intergovernmental initiatives have been activated in order to enhance the capacity of countries to improve access to essential medicines, particularly for mental disorders. In May 2013 the 66th World Health Assembly adopted the World Health Organization (WHO) Comprehensive Mental Health Action Plan 2013-2020, which builds upon the work of WHO's Mental Health Gap Action Programme. Within this programme, evidence-based guidelines for mental disorders were developed, including recommendations on appropriate use of medicines. Subsequently, the 67th World Health Assembly adopted a resolution on access to essential medicines, which urged Member States to improve national policies for the selection of essential medicines and to promote their availability, affordability and appropriate use. Following the precedent set by these important initiatives, this article presents eleven actions for improving access and appropriate use of psychotropic medicines. A 4 × 4 framework mapping actions as a function of the four components of access - selection, availability, affordability and appropriate use - and across four different health care levels, three of which belong to the supply side and one to the demand side, was developed. The actions are: developing a medicine selection process; promoting information and education activities for staff and end-users; developing a medicine regulation process; implementing a reliable supply system; implementing a reliable quality-control system; developing a community-based system of mental health care and promoting help-seeking behaviours; developing international agreements on medicine affordability; developing pricing policies and a sustainable financing system; developing or adopting evidence-based guidelines; monitoring the use of psychotropic medicines; promoting training initiatives for staff and end-users on critical appraisal of scientific evidence and appropriate use of psychotropic medicines. Activating these actions offers an unique opportunity to address the broader issue of increasing access to treatments and care for mental disorders, as current lack of attention to mental disorders is a central barrier across all domains of the 4 × 4 access framework.

Functional Specificity and Sex Differences in the Neural Circuits Supporting the Inhibition of Automatic Imitation.

PubMed

Darda, Kohinoor M; Butler, Emily E; Ramsey, Richard

2018-06-01

Humans show an involuntary tendency to copy other people's actions. Although automatic imitation builds rapport and affiliation between individuals, we do not copy actions indiscriminately. Instead, copying behaviors are guided by a selection mechanism, which inhibits some actions and prioritizes others. To date, the neural underpinnings of the inhibition of automatic imitation and differences between the sexes in imitation control are not well understood. Previous studies involved small sample sizes and low statistical power, which produced mixed findings regarding the involvement of domain-general and domain-specific neural architectures. Here, we used data from Experiment 1 ( N = 28) to perform a power analysis to determine the sample size required for Experiment 2 ( N = 50; 80% power). Using independent functional localizers and an analysis pipeline that bolsters sensitivity, during imitation control we show clear engagement of the multiple-demand network (domain-general), but no sensitivity in the theory-of-mind network (domain-specific). Weaker effects were observed with regard to sex differences, suggesting that there are more similarities than differences between the sexes in terms of the neural systems engaged during imitation control. In summary, neurocognitive models of imitation require revision to reflect that the inhibition of imitation relies to a greater extent on a domain-general selection system rather than a domain-specific system that supports social cognition.

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products.

PubMed

Shugrue, Christopher R; Miller, Scott J

2017-09-27

The application of small molecules as catalysts for the diversification of natural product scaffolds is reviewed. Specifically, principles that relate to the selectivity challenges intrinsic to complex molecular scaffolds are summarized. The synthesis of analogues of natural products by this approach is then described as a quintessential "late-stage functionalization" exercise wherein natural products serve as the lead scaffolds. Given the historical application of enzymatic catalysts to the site-selective alteration of complex molecules, the focus of this Review is on the recent studies of nonenzymatic catalysts. Reactions involving hydroxyl group derivatization with a variety of electrophilic reagents are discussed. C-H bond functionalizations that lead to oxidations, aminations, and halogenations are also presented. Several examples of site-selective olefin functionalizations and C-C bond formations are also included. Numerous classes of natural products have been subjected to these studies of site-selective alteration including polyketides, glycopeptides, terpenoids, macrolides, alkaloids, carbohydrates, and others. What emerges is a platform for chemical remodeling of naturally occurring scaffolds that targets virtually all known chemical functionalities and microenvironments. However, challenges for the design of very broad classes of catalysts, with even broader selectivity demands (e.g., stereoselectivity, functional group selectivity, and site-selectivity) persist. Yet, a significant spectrum of powerful, catalytic alterations of complex natural products now exists such that expansion of scope seems inevitable. Several instances of biological activity assays of remodeled natural product derivatives are also presented. These reports may foreshadow further interdisciplinary impacts for catalytic remodeling of natural products, including contributions to SAR development, mode of action studies, and eventually medicinal chemistry.

Discovering functional DNA elements using population genomic information: a proof of concept using human mtDNA.

PubMed

Schrider, Daniel R; Kern, Andrew D

2014-06-09

Identifying the complete set of functional elements within the human genome would be a windfall for multiple areas of biological research including medicine, molecular biology, and evolution. Complete knowledge of function would aid in the prioritization of loci when searching for the genetic bases of disease or adaptive phenotypes. Because mutations that disrupt function are disfavored by natural selection, purifying selection leaves a detectable signature within functional elements; accordingly, this signal has been exploited for over a decade through the use of genomic comparisons of distantly related species. While this is so, the functional complement of the genome changes extensively across time and between lineages; therefore, evidence of the current action of purifying selection in humans is essential. Because the removal of deleterious mutations by natural selection also reduces within-species genetic diversity within functional loci, dense population genetic data have the potential to reveal genomic elements that are currently functional. Here, we assess the potential of this approach by examining an ultradeep sample of human mitochondrial genomes (n = 16,411). We show that the high density of polymorphism in this data set precisely delineates regions experiencing purifying selection. Furthermore, we show that the number of segregating alleles at a site is strongly correlated with its divergence across species after accounting for known mutational biases in human mitochondrial DNA (ρ = 0.51; P < 2.2 × 10(-16)). These two measures track one another at a remarkably fine scale across many loci-a correlation that is purely the result of natural selection. Our results demonstrate that genetic variation has the potential to reveal with surprising precision which regions in the genome are currently performing important functions and likely to have deleterious fitness effects when mutated. As more complete human genomes are sequenced, similar power to reveal purifying selection may be achievable in the human nuclear genome. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Acupuncture's Cardiovascular Actions: A Mechanistic Perspective.

PubMed

Longhurst, John

2013-04-01

Over the last several decades, there has been an explosion of articles on acupuncture, including studies that have begun to explore mechanisms underlying its analgesic and cardiovascular actions. Modulation of cardiovascular function is most effective during manual and low-frequency, low-intensity electroacupuncture (EA) at a select set of acupoints situated along meridians located over deep somatic nerves on the upper and lower extremities. Stimulation at these acupoints activates underlying sensory neural pathways that project to a number of regions in the central nervous system (CNS) that ultimately regulate autonomic outflow and hence cardiovascular function. A long-loop pathway involving the hypothalamus, midbrain, and medulla underlies EA modulation of reflex increases in blood pressure (BP). Actions of excitatory and inhibitory neurotransmitters in the supraspinal CNS underlie processing of the somatic input and adjustment of autonomic outflow during EA. Acupuncture also decreases elevated blood pressure through actions in the thoracic spinal cord. Reflexes that lower BP likewise are modulated by EA through its actions on sympathetic and parasympathetic nuclei in the medulla. The autonomic influence of acupuncture is slow in onset but prolonged in duration, typically lasting beyond the period of stimulation. Clinical studies suggest that acupuncture can be used to treat cardiac diseases, such as myocardial ischemia and hypertension, associated with overactivity of the sympathetic nervous system.

Acupuncture's Cardiovascular Actions: A Mechanistic Perspective

PubMed Central

2013-01-01

Abstract Over the last several decades, there has been an explosion of articles on acupuncture, including studies that have begun to explore mechanisms underlying its analgesic and cardiovascular actions. Modulation of cardiovascular function is most effective during manual and low-frequency, low-intensity electroacupuncture (EA) at a select set of acupoints situated along meridians located over deep somatic nerves on the upper and lower extremities. Stimulation at these acupoints activates underlying sensory neural pathways that project to a number of regions in the central nervous system (CNS) that ultimately regulate autonomic outflow and hence cardiovascular function. A long-loop pathway involving the hypothalamus, midbrain, and medulla underlies EA modulation of reflex increases in blood pressure (BP). Actions of excitatory and inhibitory neurotransmitters in the supraspinal CNS underlie processing of the somatic input and adjustment of autonomic outflow during EA. Acupuncture also decreases elevated blood pressure through actions in the thoracic spinal cord. Reflexes that lower BP likewise are modulated by EA through its actions on sympathetic and parasympathetic nuclei in the medulla. The autonomic influence of acupuncture is slow in onset but prolonged in duration, typically lasting beyond the period of stimulation. Clinical studies suggest that acupuncture can be used to treat cardiac diseases, such as myocardial ischemia and hypertension, associated with overactivity of the sympathetic nervous system. PMID:24761168

Speech-associated gestures, Broca’s area, and the human mirror system

PubMed Central

Skipper, Jeremy I.; Goldin-Meadow, Susan; Nusbaum, Howard C.; Small, Steven L

2009-01-01

Speech-associated gestures are hand and arm movements that not only convey semantic information to listeners but are themselves actions. Broca’s area has been assumed to play an important role both in semantic retrieval or selection (as part of a language comprehension system) and in action recognition (as part of a “mirror” or “observation–execution matching” system). We asked whether the role that Broca’s area plays in processing speech-associated gestures is consistent with the semantic retrieval/selection account (predicting relatively weak interactions between Broca’s area and other cortical areas because the meaningful information that speech-associated gestures convey reduces semantic ambiguity and thus reduces the need for semantic retrieval/selection) or the action recognition account (predicting strong interactions between Broca’s area and other cortical areas because speech-associated gestures are goal-direct actions that are “mirrored”). We compared the functional connectivity of Broca’s area with other cortical areas when participants listened to stories while watching meaningful speech-associated gestures, speech-irrelevant self-grooming hand movements, or no hand movements. A network analysis of neuroimaging data showed that interactions involving Broca’s area and other cortical areas were weakest when spoken language was accompanied by meaningful speech-associated gestures, and strongest when spoken language was accompanied by self-grooming hand movements or by no hand movements at all. Results are discussed with respect to the role that the human mirror system plays in processing speech-associated movements. PMID:17533001

Regulator Loss Functions and Hierarchical Modeling for Safety Decision Making.

PubMed

Hatfield, Laura A; Baugh, Christine M; Azzone, Vanessa; Normand, Sharon-Lise T

2017-07-01

Regulators must act to protect the public when evidence indicates safety problems with medical devices. This requires complex tradeoffs among risks and benefits, which conventional safety surveillance methods do not incorporate. To combine explicit regulator loss functions with statistical evidence on medical device safety signals to improve decision making. In the Hospital Cost and Utilization Project National Inpatient Sample, we select pediatric inpatient admissions and identify adverse medical device events (AMDEs). We fit hierarchical Bayesian models to the annual hospital-level AMDE rates, accounting for patient and hospital characteristics. These models produce expected AMDE rates (a safety target), against which we compare the observed rates in a test year to compute a safety signal. We specify a set of loss functions that quantify the costs and benefits of each action as a function of the safety signal. We integrate the loss functions over the posterior distribution of the safety signal to obtain the posterior (Bayes) risk; the preferred action has the smallest Bayes risk. Using simulation and an analysis of AMDE data, we compare our minimum-risk decisions to a conventional Z score approach for classifying safety signals. The 2 rules produced different actions for nearly half of hospitals (45%). In the simulation, decisions that minimize Bayes risk outperform Z score-based decisions, even when the loss functions or hierarchical models are misspecified. Our method is sensitive to the choice of loss functions; eliciting quantitative inputs to the loss functions from regulators is challenging. A decision-theoretic approach to acting on safety signals is potentially promising but requires careful specification of loss functions in consultation with subject matter experts.

Aripiprazole, A Drug that Displays Partial Agonism and Functional Selectivity.

PubMed

Tuplin, Erin W; Holahan, Matthew R

2017-11-14

The treatment of schizophrenia is challenging due to the wide range of symptoms (positive, negative, cognitive) associated with the disease. Typical antipsychotics that antagonize D2 receptors are effective in treating positive symptoms, but extrapyramidal side-effects (EPS) are a common occurrence. Atypical antipsychotics targeting 5-HT2A and D2 receptors are more effective at treating cognitive and negative symptoms compared to typical antipsychotics, but these drugs also result in side-effects such as metabolic syndromes. To identify evidence in the literature that elucidates the pharmacological profile of aripiprazole.s. We searched PubMed for peer reviewed articles on aripiprazole and its clinical efficacy, side-effects, pharmacology, and effects in animal models of schizophrenia symptoms. Aripiprazole is a newer atypical antipsychotic that displays a unique pharmacological profile, including partial D2 agonism and functionally selective properties. Aripiprazole is effective at treating the positive symptoms of schizophrenia and has the potential to treat negative and cognitive symptoms at least as well as other atypical antipsychotics. The drug has a favorable side-effect profile and has a low propensity to result in EPS or metabolic syndromes. Animal models of schizophrenia have been used to determine the efficacy of aripiprazole in symptom management. In these instances, aripiprazole resulted in the reversal of deficits in extinction, pre-pulse inhibition, and social withdrawal. Because aripiprazole requires a greater than 90% occupancy rate at D2 receptors to be clinically active and does not produce EPS, this suggests a functionally selective effect on intracellular signaling pathways. A combination of factors such as dopamine system stabilization via partial agonism, functional selectivity at D2 receptors, and serotonin-dopamine system interaction may contribute to the ability of aripiprazole to successfully manage schizophrenia symptoms. This review examines these mechanisms of action to further clarify the pharmacological actions of aripiprazole. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Mechanisms Underlying Motivational Deficits in Psychopathology: Similarities and Differences in Depression and Schizophrenia.

PubMed

Barch, Deanna M; Pagliaccio, David; Luking, Katherine

2016-01-01

Motivational and hedonic impairments are core aspects of a variety of types of psychopathology. These impairments cut across diagnostic categories and may be critical to understanding major aspects of the functional impairments accompanying psychopathology. Given the centrality of motivational and hedonic systems to psychopathology, the Research Domain Criteria (RDoC) initiative includes a "positive valence" systems domain that outlines a number of constructs that may be key to understanding the nature and mechanisms of motivational and hedonic impairments in psychopathology. These component constructs include initial responsiveness to reward, reward anticipation or expectancy, incentive or reinforcement learning, effort valuation, and action selection. Here, we review behavioral and neuroimaging studies providing evidence for impairments in these constructs in individuals with psychosis versus in individuals with depressive pathology. There are important differences in the nature of reward-related and hedonic deficits associated with psychosis versus depression that have major implications for our understanding of etiology and treatment development. In particular, the literature strongly suggests the presence of impairments in in-the-moment hedonics or "liking" in individuals with depressive pathology, particularly among those who experience anhedonia. Such deficits may propagate forward and contribute to impairments in other constructs that are dependent on hedonic responses, such as anticipation, learning, effort, and action selection. Such hedonic impairments could reflect alterations in dopamine and/or opioid signaling in the striatum related to depression or specifically to anhedonia in depressed populations. In contrast, the literature points to relatively intact in-the-moment hedonic processing in psychosis, but provides much evidence for impairments in other components involved in translating reward to action selection. Particularly, individuals with schizophrenia exhibit altered reward prediction and associated striatal and prefrontal activation, impaired reward learning, and impaired reward-modulated action selection.

Learning Multirobot Hose Transportation and Deployment by Distributed Round-Robin Q-Learning.

PubMed

Fernandez-Gauna, Borja; Etxeberria-Agiriano, Ismael; Graña, Manuel

2015-01-01

Multi-Agent Reinforcement Learning (MARL) algorithms face two main difficulties: the curse of dimensionality, and environment non-stationarity due to the independent learning processes carried out by the agents concurrently. In this paper we formalize and prove the convergence of a Distributed Round Robin Q-learning (D-RR-QL) algorithm for cooperative systems. The computational complexity of this algorithm increases linearly with the number of agents. Moreover, it eliminates environment non sta tionarity by carrying a round-robin scheduling of the action selection and execution. That this learning scheme allows the implementation of Modular State-Action Vetoes (MSAV) in cooperative multi-agent systems, which speeds up learning convergence in over-constrained systems by vetoing state-action pairs which lead to undesired termination states (UTS) in the relevant state-action subspace. Each agent's local state-action value function learning is an independent process, including the MSAV policies. Coordination of locally optimal policies to obtain the global optimal joint policy is achieved by a greedy selection procedure using message passing. We show that D-RR-QL improves over state-of-the-art approaches, such as Distributed Q-Learning, Team Q-Learning and Coordinated Reinforcement Learning in a paradigmatic Linked Multi-Component Robotic System (L-MCRS) control problem: the hose transportation task. L-MCRS are over-constrained systems with many UTS induced by the interaction of the passive linking element and the active mobile robots.

Primacy of Information about Means Selection over Outcome Selection in Goal Attribution by Infants

ERIC Educational Resources Information Center

Verschoor, Stephan; Biro, Szilvia

2012-01-01

It has been shown that, when observing an action, infants can rely on either outcome selection information (i.e., actions that express a choice between potential outcomes) or means selection information (i.e., actions that are causally efficient toward the outcome) in their goal attribution. However, no research has investigated the relationship…

[Modes of action of agrochemicals against plant pathogenic organisms].

PubMed

Leroux, Pierre

2003-01-01

The chemical control of plant pathogens concerns mainly fungal diseases of crops. Most of the available fungicides act directly on essential fungal functions such as respiration, sterol biosynthesis or cell division. Consequently, these compounds can exhibit undesirable toxicological and environmental effects and sometimes select fungal resistant strains. Plant activators are expected to provide sustainable disease management in several crops because the development of resistance is not expected. Considering the future, the discovery of novel antifungal molecules will reap advantage from throughput screening methodologies and functional genomics.

Prefrontal Dopamine D1 and D2 Receptors Regulate Dissociable Aspects of Decision Making via Distinct Ventral Striatal and Amygdalar Circuits.

PubMed

Jenni, Nicole L; Larkin, Joshua D; Floresco, Stan B

2017-06-28

Mesocortical dopamine (DA) regulates a variety of cognitive functions via actions on D 1 and/or D 2 receptors. For example, risk/reward decision making is modulated differentially by these two receptors within the prefrontal cortex (PFC), with D 2 receptors enabling flexible decision making and D 1 receptors promoting persistence in choice biases. However, it is unclear how DA mediates opposing patterns of behavior by acting on different receptors within the same terminal region. We explored the possibility that DA may act on separate networks of PFC neurons that are modulated by D 1 or D 2 receptors and in turn interface with divergent downstream structures such as the basolateral amygdala (BLA) or nucleus accumbens (NAc). Decision making was assessed using a probabilistic discounting task in which well trained male rats chose between small/certain or large/risky rewards, with the odds of obtaining the larger reward changing systematically within a session. Selective disruption of D 1 or D 2 modulation of separate PFC output pathways was achieved using unilateral intra-PFC infusions of DA antagonists combined with contralateral inactivation of the BLA or NAc. Disrupting D 2 (but not D 1 ) modulation of PFC→BLA circuitry impaired adjustments in decision biases in response to changes in reward probabilities. In contrast, disrupting D 1 modulation of PFC→NAc networks reduced risky choice, attenuating reward sensitivity and increasing sensitivity to reward omissions. These findings reveal that mesocortical DA can facilitate dissociable components of reward seeking and action selection by acting on different functional networks of PFC neurons that can be distinguished by the subcortical projection targets with which they interface. SIGNIFICANCE STATEMENT Prefrontal cortical dopamine regulates a variety of executive functions governed by the frontal lobes via actions on D 1 and D 2 receptors. These receptors can in some instances mediate different patterns of behavior, but the mechanisms underlying these dissociable actions are unclear. Using a selective disconnection approach, we reveal that D 1 and D 2 receptors can facilitate diverse aspects of decision making by acting on separate networks of prefrontal neurons that interface with distinct striatal or amygdalar targets. These findings reveal an additional level of complexity in how mesocortical DA regulates different forms of cognition via actions on different receptors, highlighting how it may act upon distinct cortical microcircuits to drive different patterns of behavior. Copyright © 2017 the authors 0270-6474/17/376200-14$15.00/0.

Autonomous power expert system advanced development

NASA Technical Reports Server (NTRS)

Quinn, Todd M.; Walters, Jerry L.

1991-01-01

The autonomous power expert (APEX) system is being developed at Lewis Research Center to function as a fault diagnosis advisor for a space power distribution test bed. APEX is a rule-based system capable of detecting faults and isolating the probable causes. APEX also has a justification facility to provide natural language explanations about conclusions reached during fault isolation. To help maintain the health of the power distribution system, additional capabilities were added to APEX. These capabilities allow detection and isolation of incipient faults and enable the expert system to recommend actions/procedure to correct the suspected fault conditions. New capabilities for incipient fault detection consist of storage and analysis of historical data and new user interface displays. After the cause of a fault is determined, appropriate recommended actions are selected by rule-based inferencing which provides corrective/extended test procedures. Color graphics displays and improved mouse-selectable menus were also added to provide a friendlier user interface. A discussion of APEX in general and a more detailed description of the incipient detection, recommended actions, and user interface developments during the last year are presented.

Using Goal- and Grip-Related Information for Understanding the Correctness of Other’s Actions: An ERP Study

PubMed Central

van Elk, Michiel; Bousardt, Roel; Bekkering, Harold; van Schie, Hein T.

2012-01-01

Detecting errors in other’s actions is of pivotal importance for joint action, competitive behavior and observational learning. Although many studies have focused on the neural mechanisms involved in detecting low-level errors, relatively little is known about error-detection in everyday situations. The present study aimed to identify the functional and neural mechanisms whereby we understand the correctness of other’s actions involving well-known objects (e.g. pouring coffee in a cup). Participants observed action sequences in which the correctness of the object grasped and the grip applied to a pair of objects were independently manipulated. Observation of object violations (e.g. grasping the empty cup instead of the coffee pot) resulted in a stronger P3-effect than observation of grip errors (e.g. grasping the coffee pot at the upper part instead of the handle), likely reflecting a reorienting response, directing attention to the relevant location. Following the P3-effect, a parietal slow wave positivity was observed that persisted for grip-errors, likely reflecting the detection of an incorrect hand-object interaction. These findings provide new insight in the functional significance of the neurophysiological markers associated with the observation of incorrect actions and suggest that the P3-effect and the subsequent parietal slow wave positivity may reflect the detection of errors at different levels in the action hierarchy. Thereby this study elucidates the cognitive processes that support the detection of action violations in the selection of objects and grips. PMID:22606261

Functional differentiation of macaque visual temporal cortical neurons using a parametric action space.

PubMed

Vangeneugden, Joris; Pollick, Frank; Vogels, Rufin

2009-03-01

Neurons in the rostral superior temporal sulcus (STS) are responsive to displays of body movements. We employed a parametric action space to determine how similarities among actions are represented by visual temporal neurons and how form and motion information contributes to their responses. The stimulus space consisted of a stick-plus-point-light figure performing arm actions and their blends. Multidimensional scaling showed that the responses of temporal neurons represented the ordinal similarity between these actions. Further tests distinguished neurons responding equally strongly to static presentations and to actions ("snapshot" neurons), from those responding much less strongly to static presentations, but responding well when motion was present ("motion" neurons). The "motion" neurons were predominantly found in the upper bank/fundus of the STS, and "snapshot" neurons in the lower bank of the STS and inferior temporal convexity. Most "motion" neurons showed strong response modulation during the course of an action, thus responding to action kinematics. "Motion" neurons displayed a greater average selectivity for these simple arm actions than did "snapshot" neurons. We suggest that the "motion" neurons code for visual kinematics, whereas the "snapshot" neurons code for form/posture, and that both can contribute to action recognition, in agreement with computation models of action recognition.

Building a Lego wall: Sequential action selection.

PubMed

Arnold, Amy; Wing, Alan M; Rotshtein, Pia

2017-05-01

The present study draws together two distinct lines of enquiry into the selection and control of sequential action: motor sequence production and action selection in everyday tasks. Participants were asked to build 2 different Lego walls. The walls were designed to have hierarchical structures with shared and dissociated colors and spatial components. Participants built 1 wall at a time, under low and high load cognitive states. Selection times for correctly completed trials were measured using 3-dimensional motion tracking. The paradigm enabled precise measurement of the timing of actions, while using real objects to create an end product. The experiment demonstrated that action selection was slowed at decision boundary points, relative to boundaries where no between-wall decision was required. Decision points also affected selection time prior to the actual selection window. Dual-task conditions increased selection errors. Errors mostly occurred at boundaries between chunks and especially when these required decisions. The data support hierarchical control of sequenced behavior. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Transient stimulation of distinct subpopulations of striatal neurons mimics changes in action value

PubMed Central

Tai, Lung-Hao; Lee, A. Moses; Benavidez, Nora; Bonci, Antonello; Wilbrecht, Linda

2012-01-01

In changing environments animals must adaptively select actions to achieve their goals. In tasks involving goal-directed action selection, striatal neural activity has been shown to represent the value of competing actions. Striatal representations of action value could potentially bias responses toward actions of higher value. However, no study to date has demonstrated the direct impact of distinct striatal pathways in goal-directed action selection. Here we show in mice that transient optogenetic stimulation of dorsal striatal dopamine D1 and D2 receptor-expressing neurons during decision-making introduces opposing biases in the distribution of choices. The effect of stimulation on choice is dependent on recent reward history and mimics an additive change in the action value. While stimulation prior to and during movement initiation produces a robust bias in choice behavior, this bias is significantly diminished when stimulation is delayed after response initiation. Together, our data demonstrate the role of striatal activity in goal-directed action selection. PMID:22902719

Role of Water in the Selection of Stable Proteins at Ambient and Extreme Thermodynamic Conditions

NASA Astrophysics Data System (ADS)

Bianco, Valentino; Franzese, Giancarlo; Dellago, Christoph; Coluzza, Ivan

2017-04-01

Proteins that are functional at ambient conditions do not necessarily work at extreme conditions of temperature T and pressure P . Furthermore, there are limits of T and P above which no protein has a stable functional state. Here, we show that these limits and the selection mechanisms for working proteins depend on how the properties of the surrounding water change with T and P . We find that proteins selected at high T are superstable and are characterized by a nonextreme segregation of a hydrophilic surface and a hydrophobic core. Surprisingly, a larger segregation reduces the stability range in T and P . Our computer simulations, based on a new protein design protocol, explain the hydropathy profile of proteins as a consequence of a selection process influenced by water. Our results, potentially useful for engineering proteins and drugs working far from ambient conditions, offer an alternative rationale to the evolutionary action exerted by the environment in extreme conditions.

Distinct Sources of Deterministic and Stochastic Components of Action Timing Decisions in Rodent Frontal Cortex.

PubMed

Murakami, Masayoshi; Shteingart, Hanan; Loewenstein, Yonatan; Mainen, Zachary F

2017-05-17

The selection and timing of actions are subject to determinate influences such as sensory cues and internal state as well as to effectively stochastic variability. Although stochastic choice mechanisms are assumed by many theoretical models, their origin and mechanisms remain poorly understood. Here we investigated this issue by studying how neural circuits in the frontal cortex determine action timing in rats performing a waiting task. Electrophysiological recordings from two regions necessary for this behavior, medial prefrontal cortex (mPFC) and secondary motor cortex (M2), revealed an unexpected functional dissociation. Both areas encoded deterministic biases in action timing, but only M2 neurons reflected stochastic trial-by-trial fluctuations. This differential coding was reflected in distinct timescales of neural dynamics in the two frontal cortical areas. These results suggest a two-stage model in which stochastic components of action timing decisions are injected by circuits downstream of those carrying deterministic bias signals. Copyright © 2017 Elsevier Inc. All rights reserved.

Subliminal Priming of Actions Influences Sense of Control over Effects of Action

ERIC Educational Resources Information Center

Wenke, Dorit; Fleming, Stephen M.; Haggard, Patrick

2010-01-01

The experience of controlling one's own actions, and through them events in the outside world, is a pervasive feature of human mental life. Two experiments investigated the relation between this sense of control and the internal processes involved in action selection and cognitive control. Action selection was manipulated by subliminally priming…

Mechanisms underlying selecting objects for action

PubMed Central

Wulff, Melanie; Laverick, Rosanna; Humphreys, Glyn W.; Wing, Alan M.; Rotshtein, Pia

2015-01-01

We assessed the factors which affect the selection of objects for action, focusing on the role of action knowledge and its modulation by distracters. Fourteen neuropsychological patients and 10 healthy aged-matched controls selected pairs of objects commonly used together among distracters in two contexts: with real objects and with pictures of the same objects presented sequentially on a computer screen. Across both tasks, semantically related distracters led to slower responses and more errors than unrelated distracters and the object actively used for action was selected prior to the object that would be passively held during the action. We identified a sub-group of patients (N = 6) whose accuracy was 2SDs below the controls performances in the real object task. Interestingly, these impaired patients were more affected by the presence of unrelated distracters during both tasks than intact patients and healthy controls. Note that the impaired patients had lesions to left parietal, right anterior temporal and bilateral pre-motor regions. We conclude that: (1) motor procedures guide object selection for action, (2) semantic knowledge affects action-based selection, (3) impaired action decision making is associated with the inability to ignore distracting information and (4) lesions to either the dorsal or ventral visual stream can lead to deficits in making action decisions. Overall, the data indicate that impairments in everyday tasks can be evaluated using a simulated computer task. The implications for rehabilitation are discussed. PMID:25954177

Looking back (and in)to the future: A personal reflection on 'Serotonin autoreceptor function and antidepressant drug action' (Hjorth et al., 2000).

PubMed

Hjorth, Stephan

2016-11-01

Our article in this journal some 15 years ago focussed on the role of serotonin (5-HT) autoreceptors in the mechanism of action of antidepressant drugs. Specifically in this regard, the results were summarised of rat microdialysis studies carried out to examine: (a) the relative importance of 5-HT 1A and 5-HT 1B autoreceptors, including (b) possible regional variation, and (c) potential changes in autoreceptor responsiveness following chronic selective serotonin reuptake inhibitor administration. In the present reflection piece, I recap some of the key findings against a brief background and provide an account of their bearing within the context of subsequent endeavours in the antidepressant drug research and development field. I conclude by shortly commenting on selected topics relevant to novel, interesting advances and avenues for future research. © The Author(s) 2016.

The Action Mechanism of the Myc Inhibitor Termed Omomyc May Give Clues on How to Target Myc for Cancer Therapy

PubMed Central

Savino, Mauro; Annibali, Daniela; Carucci, Nicoletta; Favuzzi, Emilia; Cole, Michael D.; Evan, Gerard I.; Soucek, Laura; Nasi, Sergio

2011-01-01

Recent evidence points to Myc – a multifaceted bHLHZip transcription factor deregulated in the majority of human cancers – as a priority target for therapy. How to target Myc is less clear, given its involvement in a variety of key functions in healthy cells. Here we report on the action mechanism of the Myc interfering molecule termed Omomyc, which demonstrated astounding therapeutic efficacy in transgenic mouse cancer models in vivo. Omomyc action is different from the one that can be obtained by gene knockout or RNA interference, approaches designed to block all functions of a gene product. This molecule – instead – appears to cause an edge-specific perturbation that destroys some protein interactions of the Myc node and keeps others intact, with the result of reshaping the Myc transcriptome. Omomyc selectively targets Myc protein interactions: it binds c- and N-Myc, Max and Miz-1, but does not bind Mad or select HLH proteins. Specifically, it prevents Myc binding to promoter E-boxes and transactivation of target genes while retaining Miz-1 dependent binding to promoters and transrepression. This is accompanied by broad epigenetic changes such as decreased acetylation and increased methylation at H3 lysine 9. In the presence of Omomyc, the Myc interactome is channeled to repression and its activity appears to switch from a pro-oncogenic to a tumor suppressive one. Given the extraordinary therapeutic impact of Omomyc in animal models, these data suggest that successfully targeting Myc for cancer therapy might require a similar twofold action, in order to prevent Myc/Max binding to E-boxes and, at the same time, keep repressing genes that would be repressed by Myc. PMID:21811581

Adolescent Development of Value-Guided Goal Pursuit.

PubMed

Davidow, Juliet Y; Insel, Catherine; Somerville, Leah H

2018-06-04

Adolescents are challenged to orchestrate goal-directed actions in increasingly independent and consequential ways. In doing so, it is advantageous to use information about value to select which goals to pursue and how much effort to devote to them. Here, we examine age-related changes in how individuals use value signals to orchestrate goal-directed behavior. Drawing on emerging literature on value-guided cognitive control and reinforcement learning, we demonstrate how value and task difficulty modulate the execution of goal-directed action in complex ways across development from childhood to adulthood. We propose that the scope of value-guided goal pursuit expands with age to include increasingly challenging cognitive demands, and scaffolds on the emergence of functional integration within brain networks supporting valuation, cognition, and action. Copyright © 2018 Elsevier Ltd. All rights reserved.

Efficiency in Rule- vs. Plan-Based Movements Is Modulated by Action-Mode.

PubMed

Scheib, Jean P P; Stoll, Sarah; Thürmer, J Lukas; Randerath, Jennifer

2018-01-01

The rule/plan motor cognition (RPMC) paradigm elicits visually indistinguishable motor outputs, resulting from either plan- or rule-based action-selection, using a combination of essentially interchangeable stimuli. Previous implementations of the RPMC paradigm have used pantomimed movements to compare plan- vs. rule-based action-selection. In the present work we attempt to determine the generalizability of previous RPMC findings to real object interaction by use of a grasp-to-rotate task. In the plan task, participants had to use prospective planning to achieve a comfortable post-handle rotation hand posture. The rule task used implementation intentions (if-then rules) leading to the same comfortable end-state. In Experiment A, we compare RPMC performance of 16 healthy participants in pantomime and real object conditions of the experiment, within-subjects. Higher processing efficiency of rule- vs. plan-based action-selection was supported by diffusion model analysis. Results show a significant response-time increase in the pantomime condition compared to the real object condition and a greater response-time advantage of rule-based vs. plan-based actions in the pantomime compared to the real object condition. In Experiment B, 24 healthy participants performed the real object RPMC task in a task switching vs. a blocked condition. Results indicate that plan-based action-selection leads to longer response-times and less efficient information processing than rule-based action-selection in line with previous RPMC findings derived from the pantomime action-mode. Particularly in the task switching mode, responses were faster in the rule compared to the plan task suggesting a modulating influence of cognitive load. Overall, results suggest an advantage of rule-based action-selection over plan-based action-selection; whereby differential mechanisms appear to be involved depending on the action-mode. We propose that cognitive load is a factor that modulates the advantageous effect of implementation intentions in motor cognition on different levels as illustrated by the varying speed advantages and the variation in diffusion parameters per action-mode or condition, respectively.

Conditional Routing of Information to the Cortex: A Model of the Basal Ganglia's Role in Cognitive Coordination

ERIC Educational Resources Information Center

Stocco, Andrea; Lebiere, Christian; Anderson, John R.

2010-01-01

The basal ganglia play a central role in cognition and are involved in such general functions as action selection and reinforcement learning. Here, we present a model exploring the hypothesis that the basal ganglia implement a conditional information-routing system. The system directs the transmission of cortical signals between pairs of regions…

Functional selectivity of GPCR-directed drug action through location bias

PubMed Central

Irannejad, Roshanak; Pessino, Veronica; Mika, Delphine; Huang, Bo; Wedegaertner, Philip B.; Conti, Marco; von Zastrow, Mark

2017-01-01

G protein-coupled receptors (GPCRs) are increasingly recognized to operate from intracellular membranes as well as the plasma membrane. The β2-adrenergic GPCR can activate Gs-linkedcyclic AMP (cAMP) signaling from endosomes. We show here that the homologous human β1-adrenergic receptor initiates an internal Gs-cAMP signal from the Golgi apparatus. By developing a chemical method to acutely squelch G protein coupling at defined membrane locations, we demonstrate that Golgi activation contributes significantly to the overall cellular cAMP response. Golgi signalling utilizes a pre-existing receptor pool rather than receptors delivered from the cell surface, requiring separate access of extracellular ligands. Epinephrine, a hydrophilic endogenous ligand, accesses the Golgi-localized receptor pool by facilitated transport requiring the organic cation transporter 3 (OCT3) whereas drugs can access the Golgi pool by passive diffusion according to hydrophobicity. We demonstrate marked differences among both agonist and antagonist drugs in Golgi-localized receptor access, and show that β-blocker drugs presently used in the clinic differ markedly in ability to antagonize the Golgi signal. We propose ’location bias’ as a new principle for achieving functional selectivity of GPCR-directed drug action. PMID:28553949

Altered brain response to reward and punishment in adolescents with Anorexia Nervosa

PubMed Central

Bischoff-Grethe, Amanda; McCurdy, Danyale; Grenesko-Stevens, Emily; (Zoe) Irvine, Laura E.; Wagner, Angela; Yau, Wai-Ying Wendy; Fennema-Notestine, Christine; Wierenga, Christina E.; Fudge, Julie L.; Delgado, Mauricio R.; Kaye, Walter H.

2013-01-01

Adults recovered from anorexia nervosa (AN) have altered reward modulation within striatal limbic regions associated with the emotional significance of stimuli, and executive regions concerned with planning and consequences. We hypothesized that adolescents with AN would show similar disturbed reward modulation within the striatum and the anterior cingulate cortex, a region connected to the striatum and involved in reward-guided action selection. Using functional magnetic resonance imaging, twenty-two adolescent females (10 restricting-type AN, 12 healthy volunteers) performed a monetary guessing task. Time series data associated with monetary wins and losses within striatal and cingulate regions of interest were subjected to a linear mixed effects analysis. All participants responded more strongly to wins versus losses in limbic and anterior executive striatal territories. However, AN participants exhibited an exaggerated response to losses compared to wins in posterior executive and sensorimotor striatal regions, suggesting altered function in circuitry responsible for coding the affective context of stimuli and action selection based upon these valuations. As AN individuals are particularly sensitive to criticism, failure, and making mistakes, these findings may reflect the neural processes responsible for a bias in those with AN to exaggerate negative consequences. PMID:24148909

Altered brain response to reward and punishment in adolescents with Anorexia nervosa.

PubMed

Bischoff-Grethe, Amanda; McCurdy, Danyale; Grenesko-Stevens, Emily; Irvine, Laura E Zoe; Wagner, Angela; Yau, Wai-Ying Wendy; Fennema-Notestine, Christine; Wierenga, Christina E; Fudge, Julie L; Delgado, Mauricio R; Kaye, Walter H

2013-12-30

Adults recovered from Anorexia nervosa (AN) have altered reward modulation within striatal limbic regions associated with the emotional significance of stimuli, and executive regions concerned with planning and consequences. We hypothesized that adolescents with AN would show similar disturbed reward modulation within the striatum and the anterior cingulate cortex, a region connected to the striatum and involved in reward-guided action selection. Using functional magnetic resonance imaging, twenty-two adolescent females (10 restricting-type AN, 12 healthy volunteers) performed a monetary guessing task. Time series data associated with monetary wins and losses within striatal and cingulate regions of interest were subjected to a linear mixed effects analysis. All participants responded more strongly to wins versus losses in limbic and anterior executive striatal territories. However, AN participants exhibited an exaggerated response to losses compared to wins in posterior executive and sensorimotor striatal regions, suggesting altered function in circuitry responsible for coding the affective context of stimuli and action selection based upon these valuations. As AN individuals are particularly sensitive to criticism, failure, and making mistakes, these findings may reflect the neural processes responsible for a bias in those with AN to exaggerate negative consequences. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

How action selection can be embodied: intracranial gamma band recording shows response competition during the Eriksen flankers test

PubMed Central

Caruana, Fausto; Uithol, Sebo; Cantalupo, Gaetano; Sartori, Ivana; Lo Russo, Giorgio; Avanzini, Pietro

2014-01-01

Recent findings in monkeys suggest that action selection is based on a competition between various action options that are automatically planned by the motor system. Here we discuss data from intracranial EEG recordings in human premotor cortex (PMC) during a bimanual version of the Eriksen flankers test that suggest that the same principles apply to human action decisions. Recording sites in the dorsal PMC show an early but undifferentiated activation, a delayed response that depends on the experimental conditions and, finally, a movement related activation during action execution. Additionally, we found that the medial part of the PMC show a significant increase in response for ipsilateral trials, suggesting a role in inhibiting the wrong response. The ventral PMC seems to be involved in action execution, rather than action selection. Together these findings suggest that the human PMC is part of a network that specifies, selects, and executes actions. PMID:25206328

Alcohol-related biases in selective attention and action tendency make distinct contributions to dysregulated drinking behaviour.

PubMed

Sharbanee, Jason M; Stritzke, Werner G K; Wiers, Reinout W; MacLeod, Colin

2013-10-01

To assess whether alcohol-related biases in selective-attention and action tendency uniquely or concurrently predict the ability to regulate alcohol consumption. Two groups of undergraduate social drinkers (total n = 55) who differed in their ability to regulate their alcohol consumption completed a novel Selective-Attention/Action-Tendency Task (SA/ATT), which assessed separately alcohol-related biases in selective attention and action tendency. University of Western Australia, Australia. Dysregulated drinking was operationalized as a self-reported high level of alcohol consumption on the Alcohol Consumption Questionnaire, and a high desire to reduce consumption on the Brief Readiness to Change Algorithm. Selective attention and action tendency were assessed using the SA/ATT, working memory was assessed using the operation-span task and participant characteristics were assessed using the Alcohol Use Disorders Identification Test (AUDIT) and Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES). Results indicated that (i) there was no significant association between alcohol-related biases in selective attention and action tendency, r = 0.16, P = 0.274, and (ii) biases towards alcohol, in both selective attention, β = 1.01, odds ratio = 2.74, P = 0.022, and action tendency, β = 1.24, odds ratio = 3.45, P = 0.015, predicted independent variance in dysregulated-drinker status. Biases in selective attention and action tendency appear to be distinct mechanisms that contribute independently to difficulty regulating alcohol consumption. Treatment components that could be combined to target both mechanisms could enhance treatment outcomes for alcohol-use disorders. © 2013 Society for the Study of Addiction.

Chapter 4: A policy process and tools for international non-governmental organizations in the health sector using ISPRM as a case in point.

PubMed

Reinhardt, Jan D; von Groote, Per M; DeLisa, Joel A; Melvin, John L; Bickenbach, Jerome E; Stucki, Gerold

2009-09-01

The politics of international non-governmental organizations (NGOs) such as the International Society of Physical and Rehabilitation Medicine (ISPRM) serve the function of selecting and attaining particular socially valued goals. The selection and attainment of goals as the primary function of political action can be structured along a policy process or cycle comprising the stages of strategic goal setting and planning of strategic pathways, agenda setting, resource mobilization, implementation, evaluation and innovation. At the various stages of this policy process different policy tools or instruments, which can be used to influence citizen and organizational behaviour in the light of defined goals, can be applied. The objective of this paper is to introduce and describe policy tools of potential relevance to ISPRM with regard to different policy functions and stages of the policy process.

Computer simulation and evaluation of edge detection algorithms and their application to automatic path selection

NASA Technical Reports Server (NTRS)

Longendorfer, B. A.

1976-01-01

The construction of an autonomous roving vehicle requires the development of complex data-acquisition and processing systems, which determine the path along which the vehicle travels. Thus, a vehicle must possess algorithms which can (1) reliably detect obstacles by processing sensor data, (2) maintain a constantly updated model of its surroundings, and (3) direct its immediate actions to further a long range plan. The first function consisted of obstacle recognition. Obstacles may be identified by the use of edge detection techniques. Therefore, the Kalman Filter was implemented as part of a large scale computer simulation of the Mars Rover. The second function consisted of modeling the environment. The obstacle must be reconstructed from its edges, and the vast amount of data must be organized in a readily retrievable form. Therefore, a Terrain Modeller was developed which assembled and maintained a rectangular grid map of the planet. The third function consisted of directing the vehicle's actions.

40 CFR 300.800 - Establishment of an administrative record.

Code of Federal Regulations, 2011 CFR

2011-07-01

... POLLUTION CONTINGENCY PLAN Administrative Record for Selection of Response Action § 300.800 Establishment of... agency for a federal facility. (3) If EPA is involved in the selection of the response action at a... record that contains the documents that form the basis for the selection of a response action. The lead...

40 CFR 300.800 - Establishment of an administrative record.

Code of Federal Regulations, 2010 CFR

2010-07-01

... POLLUTION CONTINGENCY PLAN Administrative Record for Selection of Response Action § 300.800 Establishment of... agency for a federal facility. (3) If EPA is involved in the selection of the response action at a... record that contains the documents that form the basis for the selection of a response action. The lead...

40 CFR 300.800 - Establishment of an administrative record.

Code of Federal Regulations, 2014 CFR

2014-07-01

... POLLUTION CONTINGENCY PLAN Administrative Record for Selection of Response Action § 300.800 Establishment of... agency for a federal facility. (3) If EPA is involved in the selection of the response action at a... record that contains the documents that form the basis for the selection of a response action. The lead...

40 CFR 300.800 - Establishment of an administrative record.

Code of Federal Regulations, 2012 CFR

2012-07-01

... POLLUTION CONTINGENCY PLAN Administrative Record for Selection of Response Action § 300.800 Establishment of... agency for a federal facility. (3) If EPA is involved in the selection of the response action at a... record that contains the documents that form the basis for the selection of a response action. The lead...

40 CFR 300.800 - Establishment of an administrative record.

Code of Federal Regulations, 2013 CFR

2013-07-01

... POLLUTION CONTINGENCY PLAN Administrative Record for Selection of Response Action § 300.800 Establishment of... agency for a federal facility. (3) If EPA is involved in the selection of the response action at a... record that contains the documents that form the basis for the selection of a response action. The lead...

Neuronal representation of individual heroin choices in the orbitofrontal cortex.

PubMed

Guillem, Karine; Brenot, Viridiana; Durand, Audrey; Ahmed, Serge H

2018-05-01

Drug addiction is a harmful preference for drug use over and at the expense of other non-drug-related activities. We previously identified in the rat orbitofrontal cortex (OFC) a mechanism that influences individual preferences between cocaine use and an alternative action rewarded by a non-drug reward (i.e. sweet water). Here, we sought to test the generality of this mechanism to a different addictive drug, heroin. OFC neuronal activity was recorded while rats responded for heroin or the alternative non-drug reward separately or while they chose between the two. First, we found that heroin-rewarded and sweet water-rewarded actions were encoded by two non-overlapping OFC neuronal populations and that the relative size of the heroin population represented individual drug choices. Second, OFC neurons encoding the preferred action-which was the non-drug action in the large majority of individuals-progressively fired more than non-preferred action-coding neurons 1 second after the onset of choice trials and around 1 second before the preferred action was actually chosen, suggesting a pre-choice neuronal competition for action selection. Together with a previous study on cocaine choice, the present study on heroin choice reveals important commonalities in how OFC neurons encode individual drug choices and preferences across different classes of drugs. It also reveals some drug-specific differences in OFC encoding activity. Notably, the proportion of neurons that non-selectively encode both the drug and the non-drug reward was higher when the drug was heroin (present study) than when it was cocaine (previous study). We will discuss the potential functional significance of these commonalities and differences in OFC neuronal activity across different drugs for understanding drug choice. © 2017 Society for the Study of Addiction.

Broadening the functionality of a J-protein/Hsp70 molecular chaperone system.

PubMed

Schilke, Brenda A; Ciesielski, Szymon J; Ziegelhoffer, Thomas; Kamiya, Erina; Tonelli, Marco; Lee, Woonghee; Cornilescu, Gabriel; Hines, Justin K; Markley, John L; Craig, Elizabeth A

2017-10-01

By binding to a multitude of polypeptide substrates, Hsp70-based molecular chaperone systems perform a range of cellular functions. All J-protein co-chaperones play the essential role, via action of their J-domains, of stimulating the ATPase activity of Hsp70, thereby stabilizing its interaction with substrate. In addition, J-proteins drive the functional diversity of Hsp70 chaperone systems through action of regions outside their J-domains. Targeting to specific locations within a cellular compartment and binding of specific substrates for delivery to Hsp70 have been identified as modes of J-protein specialization. To better understand J-protein specialization, we concentrated on Saccharomyces cerevisiae SIS1, which encodes an essential J-protein of the cytosol/nucleus. We selected suppressors that allowed cells lacking SIS1 to form colonies. Substitutions changing single residues in Ydj1, a J-protein, which, like Sis1, partners with Hsp70 Ssa1, were isolated. These gain-of-function substitutions were located at the end of the J-domain, suggesting that suppression was connected to interaction with its partner Hsp70, rather than substrate binding or subcellular localization. Reasoning that, if YDJ1 suppressors affect Ssa1 function, substitutions in Hsp70 itself might also be able to overcome the cellular requirement for Sis1, we carried out a selection for SSA1 suppressor mutations. Suppressing substitutions were isolated that altered sites in Ssa1 affecting the cycle of substrate interaction. Together, our results point to a third, additional means by which J-proteins can drive Hsp70's ability to function in a wide range of cellular processes-modulating the Hsp70-substrate interaction cycle.

Neural systems for guilt from actions affecting self versus others

PubMed Central

Morey, Rajendra A.; McCarthy, Gregory; Selgrade, Elizabeth S.; Seth, Srishti; Nasser, Jessica D.; LaBar, Kevin S.

2012-01-01

Guilt is a core emotion governing social behavior by promoting compliance with social norms or self-imposed standards. The goal of this study was to contrast guilty responses to actions that affect self versus others, since actions with social consequences are hypothesized to yield greater guilty feelings due to adopting the perspective and subjective emotional experience of others. Sixteen participants were presented with brief hypothetical scenarios in which the participant’s actions resulted in harmful consequences to self (guilt-self) or to others (guilt-other) during functional MRI. Participants felt more intense guilt for guilt-other than guilt-self and guilt-neutral scenarios. Guilt scenarios revealed distinct regions of activity correlated with intensity of guilt, social consequences of actions, and the interaction of guilt by social consequence. Guilt intensity was associated with activation of the dorsomedial PFC, superior frontal gyrus, supramarginal gyrus, and anterior inferior frontal gyrus. Guilt accompanied by social consequences was associated with greater activation than without social consequences in the ventromedial and dorsomedial PFC, precuneus, posterior cingulate, and posterior superior temporal sulcus. Finally, the interaction analysis highlighted select regions that were more strongly correlated with guilt intensity as a function of social consequence, including the left anterior inferior frontal gyrus, left ventromedial PFC, and left anterior inferior parietal cortex. Our results suggest these regions intensify guilt where harm to others may incur a greater social cost. PMID:22230947

Feeling safe in the plane: neural mechanisms underlying superior action control in airplane pilot trainees--a combined EEG/MRS study.

PubMed

Yildiz, Ali; Quetscher, Clara; Dharmadhikari, Shalmali; Chmielewski, Witold; Glaubitz, Benjamin; Schmidt-Wilcke, Tobias; Edden, Richard; Dydak, Ulrike; Beste, Christian

2014-10-01

In day-to-day life, we need to apply strategies to cascade different actions for efficient unfolding of behavior. While deficits in action cascading are examined extensively, almost nothing is known about the neuronal mechanisms mediating superior performance above the normal level. To examine this question, we investigate action control in airplane pilot trainees. We use a stop-change paradigm that is able to estimate the efficiency of action cascading on the basis of mathematical constraints. Behavioral and EEG data is analyzed along these constraints and integrated with neurochemical data obtained using Magnetic Resonance Spectroscopy (MRS) from the striatal gamma-aminobutyric acid (GABA) -ergic system. We show that high performance in action cascading, as exemplified in airplane pilot trainees, can be driven by intensified attentional processes, circumventing response selection processes. The results indicate that the efficiency of action cascading and hence the speed of responding as well as attentional gating functions are modulated by striatal GABA and Glutamate + Glutamine concentrations. In superior performance in action cascading similar increases in the concentrations of GABA and Glutamate + Glutamine lead to stronger neurophysiological and behavioral effects as compared to subjects with normal performance in action cascading. Copyright © 2014 Wiley Periodicals, Inc.

Encoding of human action in Broca's area.

PubMed

Fazio, Patrik; Cantagallo, Anna; Craighero, Laila; D'Ausilio, Alessandro; Roy, Alice C; Pozzo, Thierry; Calzolari, Ferdinando; Granieri, Enrico; Fadiga, Luciano

2009-07-01

Broca's area has been considered, for over a century, as the brain centre responsible for speech production. Modern neuroimaging and neuropsychological evidence have suggested a wider functional role is played by this area. In addition to the evidence that it is involved in syntactical analysis, mathematical calculation and music processing, it has recently been shown that Broca's area may play some role in language comprehension and, more generally, in understanding actions of other individuals. As shown by functional magnetic resonance imaging, Broca's area is one of the cortical areas activated by hand/mouth action observation and it has been proposed that it may form a crucial node of a human mirror-neuron system. If, on the one hand, neuroimaging studies use a correlational approach which cannot offer a final proof for such claims, available neuropsychological data fail to offer a conclusive demonstration for two main reasons: (i) they use tasks taxing both language and action systems; and (ii) they rarely consider the possibility that Broca's aphasics may also be affected by some form of apraxia. We administered a novel action comprehension test--with almost no linguistic requirements--on selected frontal aphasic patients lacking apraxic symptoms. Patients, as well as matched controls, were shown short movies of human actions or of physical events. Their task consisted of ordering, in a temporal sequence, four pictures taken from each movie and randomly presented on the computer screen. Patient's performance showed a specific dissociation in their ability to re-order pictures of human actions (impaired) with respect to physical events (spared). Our study provides a demonstration that frontal aphasics, not affected by apraxia, are specifically impaired in their capability to correctly encode observed human actions.

Using multilevel models to quantify heterogeneity in resource selection

USGS Publications Warehouse

Wagner, Tyler; Diefenbach, Duane R.; Christensen, Sonja; Norton, Andrew S.

2011-01-01

Models of resource selection are being used increasingly to predict or model the effects of management actions rather than simply quantifying habitat selection. Multilevel, or hierarchical, models are an increasingly popular method to analyze animal resource selection because they impose a relatively weak stochastic constraint to model heterogeneity in habitat use and also account for unequal sample sizes among individuals. However, few studies have used multilevel models to model coefficients as a function of predictors that may influence habitat use at different scales or quantify differences in resource selection among groups. We used an example with white-tailed deer (Odocoileus virginianus) to illustrate how to model resource use as a function of distance to road that varies among deer by road density at the home range scale. We found that deer avoidance of roads decreased as road density increased. Also, we used multilevel models with sika deer (Cervus nippon) and white-tailed deer to examine whether resource selection differed between species. We failed to detect differences in resource use between these two species and showed how information-theoretic and graphical measures can be used to assess how resource use may have differed. Multilevel models can improve our understanding of how resource selection varies among individuals and provides an objective, quantifiable approach to assess differences or changes in resource selection.

The processing of actions and action-words in amyotrophic lateral sclerosis patients.

PubMed

Papeo, Liuba; Cecchetto, Cinzia; Mazzon, Giulia; Granello, Giulia; Cattaruzza, Tatiana; Verriello, Lorenzo; Eleopra, Roberto; Rumiati, Raffaella I

2015-03-01

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with prime consequences on the motor function and concomitant cognitive changes, most frequently in the domain of executive functions. Moreover, poorer performance with action-verbs versus object-nouns has been reported in ALS patients, raising the hypothesis that the motor dysfunction deteriorates the semantic representation of actions. Using action-verbs and manipulable-object nouns sharing semantic relationship with the same motor representations, the verb-noun difference was assessed in a group of 21 ALS-patients with severely impaired motor behavior, and compared with a normal sample's performance. ALS-group performed better on nouns than verbs, both in production (action and object naming) and comprehension (word-picture matching). This observation implies that the interpretation of the verb-noun difference in ALS cannot be accounted by the relatedness of verbs to motor representations, but has to consider the role of other semantic and/or morpho-phonological dimensions that distinctively define the two grammatical classes. Moreover, this difference in the ALS-group was not greater than the noun-verb difference in the normal sample. The mental representation of actions also involves an executive-control component to organize, in logical/temporal order, the individual motor events (or sub-goals) that form a purposeful action. We assessed this ability with action sequencing tasks, requiring participants to re-construct a purposeful action from the scrambled presentation of its constitutive motor events, shown in the form of photographs or short sentences. In those tasks, ALS-group's performance was significantly poorer than controls'. Thus, the executive dysfunction manifested in the sequencing deficit -but not the selective verb deficit- appears as a consistent feature of the cognitive profile associated with ALS. We suggest that ALS can offer a valuable model to study the relationship between (frontal) motor centers and the executive-control machinery housed in the frontal brain, and the implications of executive dysfunctions in tasks such as action processing. Copyright © 2014 Elsevier Ltd. All rights reserved.

Moving time: the influence of action on duration perception.

PubMed

Press, Clare; Berlot, Eva; Bird, Geoffrey; Ivry, Richard; Cook, Richard

2014-10-01

Perceiving the sensory consequences of action accurately is essential for appropriate interaction with our physical and social environments. Prediction mechanisms are considered necessary for fine-tuned sensory control of action, yet paradoxically may distort perception. Here, we examine this paradox by addressing how movement influences the perceived duration of sensory outcomes congruent with action. Experiment 1 required participants to make judgments about the duration of vibrations applied to a moving or stationary finger. In Experiments 2 and 3, participants judged observed finger movements that were congruent or incongruent with their own actions. In all experiments, target events were perceived to be longer when congruent with movement. Interestingly, this temporal dilation did not differ as a function of stimulus perspective (1st or 3rd person) or spatial location. We propose that this bias may reflect the operation of an adaptive mechanism for sensorimotor selection and control that preactivates anticipated outcomes of action. The bias itself may have surprising implications for both action control and perception of others: we may be in contact with grasped objects for less time than we realize, and others' reactions to us may be briefer than we believe.

1H-cyclopentapyrimidine-2,4(1H,3H)-dione-related ionotropic glutamate receptors ligands. structure-activity relationships and identification of potent and Selective iGluR5 modulators.

PubMed

Butini, Stefania; Pickering, Darryl S; Morelli, Elena; Coccone, Salvatore Sanna; Trotta, Francesco; De Angelis, Meri; Guarino, Egeria; Fiorini, Isabella; Campiani, Giuseppe; Novellino, Ettore; Schousboe, Arne; Christensen, Jeppe K; Gemma, Sandra

2008-10-23

(S)-CPW399 ((S)-1) is a potent and excitotoxic AMPA receptor partial agonist. Modifying the cyclopentane ring of (S)-1, we developed two of the most potent and selective functional antagonists (5 and 7) for kainate receptor (KA-R) subunit iGluR5. Derivatives 5 and 7, with their unique pharmacological profile, may lead to a better understanding of the different roles and modes of action of iGluR1-5 subunits, paving the way for the synthesis of new potent, subunit selective iGluR5 modulators.

Subjectivity: A Case of Biological Individuation and an Adaptive Response to Informational Overflow

PubMed Central

Jonkisz, Jakub

2016-01-01

The article presents a perspective on the scientific explanation of the subjectivity of conscious experience. It proposes plausible answers for two empirically valid questions: the ‘how’ question concerning the developmental mechanisms of subjectivity, and the ‘why’ question concerning its function. Biological individuation, which is acquired in several different stages, serves as a provisional description of how subjective perspectives may have evolved. To the extent that an individuated informational space seems the most efficient way for a given organism to select biologically valuable information, subjectivity is deemed to constitute an adaptive response to informational overflow. One of the possible consequences of this view is that subjectivity might be (at least functionally) dissociated from consciousness, insofar as the former primarily facilitates selection, the latter action. PMID:27555835

Selective hydrophobic derivatization on the surface of helical silica nanotubes

NASA Astrophysics Data System (ADS)

Jin, Sun-Mi; Sung, Ji Yeong; Sim, Eun-Kyung; Jo, Nam-Ju; Kim, Jong Wook; Lee, Sumin; Jin, Jong Sung

2018-02-01

The chiral 1,2-diphenylethylenediamine derivative that is capable of spontaneous self-assembly was employed as an organogel template to produce a helical mesoporous silica nanotube containing gelators therein by following sol-gel polycondensation of TEOS. The synthesis enabled the successful introduction of the hydrocarbon of octyl silane (hydrophobic functional group) onto the outer surface of the silica nanotube while preserving the hydrophilic silanol (Sisbnd OH) group on internal surface of silica nanotube free from the gelators. This synthetic condition consists of a pre-stage of the introduction of a hydrophobic hydrocarbon functional group onto the outer surface of the silica nanotube selectively, and the post-stage washing of the gelators was presented together with a method analyzing the actions of organogels in the respective experimental processes.

Recent findings and future directions for interpolar mitotic kinesin inhibitors in cancer therapy

PubMed Central

Myers, Stephanie M.; Collins, Ian

2016-01-01

The kinesin class of microtubule-associated motor proteins present attractive anti-cancer targets owing to their roles in key functions in dividing cells. Two interpolar mitotic kinesins Eg5 and HSET have opposing motor functions in mitotic spindle assembly with respect to microtubule movement, but both offer opportunities to develop cancer selective therapeutic agents. Here, we summarize the progress to date in developing inhibitors of Eg5 and HSET, with an emphasis on structural biology insights into the binding modes of allosteric inhibitors, compound selectivity and mechanisms of action of different chemical scaffolds. We discuss translation of preclinical studies to clinical experience with Eg5 inhibitors, recent findings on potential resistance mechanisms, and explore the implications for future anticancer drug development against these targets. PMID:26976726

Recent findings and future directions for interpolar mitotic kinesin inhibitors in cancer therapy.

PubMed

Myers, Stephanie M; Collins, Ian

2016-01-01

The kinesin class of microtubule-associated motor proteins present attractive anticancer targets owing to their roles in key functions in dividing cells. Two interpolar mitotic kinesins Eg5 and HSET have opposing motor functions in mitotic spindle assembly with respect to microtubule movement, but both offer opportunities to develop cancer selective therapeutic agents. Here, we summarize the progress to date in developing inhibitors of Eg5 and HSET, with an emphasis on structural biology insights into the binding modes of allosteric inhibitors, compound selectivity and mechanisms of action of different chemical scaffolds. We discuss translation of preclinical studies to clinical experience with Eg5 inhibitors, recent findings on potential resistance mechanisms and explore the implications for future anticancer drug development against these targets.

miRNAtools: Advanced Training Using the miRNA Web of Knowledge.

PubMed

Stępień, Ewa Ł; Costa, Marina C; Enguita, Francisco J

2018-02-16

Micro-RNAs (miRNAs) are small non-coding RNAs that act as negative regulators of the genomic output. Their intrinsic importance within cell biology and human disease is well known. Their mechanism of action based on the base pairing binding to their cognate targets have helped the development not only of many computer applications for the prediction of miRNA target recognition but also of specific applications for functional assessment and analysis. Learning about miRNA function requires practical training in the use of specific computer and web-based applications that are complementary to wet-lab studies. In order to guide the learning process about miRNAs, we have created miRNAtools (http://mirnatools.eu), a web repository of miRNA tools and tutorials. This article compiles tools with which miRNAs and their regulatory action can be analyzed and that function to collect and organize information dispersed on the web. The miRNAtools website contains a collection of tutorials that can be used by students and tutors engaged in advanced training courses. The tutorials engage in analyses of the functions of selected miRNAs, starting with their nomenclature and genomic localization and finishing with their involvement in specific cellular functions.

Multi-agent Reinforcement Learning Model for Effective Action Selection

NASA Astrophysics Data System (ADS)

Youk, Sang Jo; Lee, Bong Keun

Reinforcement learning is a sub area of machine learning concerned with how an agent ought to take actions in an environment so as to maximize some notion of long-term reward. In the case of multi-agent, especially, which state space and action space gets very enormous in compared to single agent, so it needs to take most effective measure available select the action strategy for effective reinforcement learning. This paper proposes a multi-agent reinforcement learning model based on fuzzy inference system in order to improve learning collect speed and select an effective action in multi-agent. This paper verifies an effective action select strategy through evaluation tests based on Robocop Keep away which is one of useful test-beds for multi-agent. Our proposed model can apply to evaluate efficiency of the various intelligent multi-agents and also can apply to strategy and tactics of robot soccer system.

Central serotonin modulates neural responses to virtual violent actions in emotion regulation networks.

PubMed

Wolf, Dhana; Klasen, Martin; Eisner, Patrick; Zepf, Florian D; Zvyagintsev, Mikhail; Palomero-Gallagher, Nicola; Weber, René; Eisert, Albrecht; Mathiak, Klaus

2018-06-08

Disruptions in the cortico-limbic emotion regulation networks have been linked to depression, anxiety, impulsivity, and aggression. Altered transmission of the central nervous serotonin (5-HT) contributes to dysfunctions in the cognitive control of emotions. To date, studies relating to pharmaco-fMRI challenging of the 5-HT system have focused on emotion processing for facial expressions. We investigated effects of a single-dose selective 5-HT reuptake inhibitor (escitalopram) on emotion regulation during virtual violence. For this purpose, 38 male participants played a violent video game during fMRI scanning. The SSRI reduced neural responses to violent actions in right-hemispheric inferior frontal gyrus and medial prefrontal cortex encompassing the anterior cingulate cortex (ACC), but not to non-violent actions. Within the ACC, the drug effect differentiated areas with high inhibitory 5-HT1A receptor density (subgenual s25) from those with a lower density (pregenual p32, p24). This finding links functional responses during virtual violent actions with 5-HT neurotransmission in emotion regulation networks, underpinning the ecological validity of the 5-HT model in aggressive behavior. Available 5-HT receptor density data suggest that this SSRI effect is only observable when inhibitory and excitatory 5-HT receptors are balanced. The observed early functional changes may impact patient groups receiving SSRI treatment.

Silica-Immobilized Enzyme Reactors (Postprint)

DTIC Science & Technology

2007-09-01

mode of action of drugs such as aspirin and ibuprofen .[61] Serotonin reuptake inhibitors and monoamine oxidase inhibitors can function as...immobilizing PGA onto chromatography supports and using the enantiomeric selectivity of the enzyme to resolve racemic mixtures.[100] Immobilization onto...column. J. Chroma- togr. B. Biomed. Sci. Appl. 2001, 753, 375–383. 37. Jadaud, P.; Wainer, I.W. The stereochemical resolution of the enantiomers of

Method of identification of patent trends based on descriptions of technical functions

NASA Astrophysics Data System (ADS)

Korobkin, D. M.; Fomenkov, S. A.; Golovanchikov, A. B.

2018-05-01

The use of the global patent space to determine the scientific and technological priorities for the technical systems development (identifying patent trends) allows one to forecast the direction of the technical systems development and, accordingly, select patents of priority technical subjects as a source for updating the technical functions database and physical effects database. The authors propose an original method that uses as trend terms not individual unigrams or n-gram (usually for existing methods and systems), but structured descriptions of technical functions in the form “Subject-Action-Object” (SAO), which in the authors’ opinion are the basis of the invention.

C1 domain-targeted isophthalates as protein kinase C modulators: structure-based design, structure-activity relationships and biological activities.

PubMed

Talman, Virpi; Provenzani, Riccardo; Boije af Gennäs, Gustav; Tuominen, Raimo K; Yli-Kauhaluoma, Jari

2014-12-01

Protein kinase C (PKC) is a serine/threonine kinase belonging to the AGC family. PKC isoenzymes are activated by phospholipid-derived second messengers, transmit their signal by phosphorylating specific substrates and play a pivotal role in the regulation of various cell functions, including metabolism, growth, differentiation and apoptosis. Therefore they represent an interesting molecular target for the treatment of several diseases, such as cancer and Alzheimer's disease. Adopting a structure-based approach on the crystal structure of the PKCδ C1B domain, our team has developed isophthalic acid derivatives that are able to modify PKC functions by binding to the C1 domain of the enzyme. Bis[3-(trifluoromethyl)benzyl] 5-(hydroxymethyl)isophthalate (HMI-1a3) and bis(1-ethylpentyl) 5-(hydroxymethyl)isophthalate (HMI-1b11) were selected from a set of compounds for further studies due to their high affinity for the C1 domains of PKCα and PKCδ. HMI-1a3 showed marked antiproliferative activity in HeLa cells whereas HMI-1b11 induced differentiation and supported neurite growth in SH-SY5Y cells. Our aim in the future is to improve the selectivity and potency of isophthalate derivatives, to clarify their mechanism of action in the cellular environment and to assess their efficacy in cell-based and in vivo disease models. HMI-1a3 has already been selected for a further project and redesigned to function as a probe immobilized on an affinity chromatography column. It will be used to identify cellular target proteins from cell lysates, providing new insights into the mechanism of action of HMI-1a3.

A comparison of regression methods for model selection in individual-based landscape genetic analysis.

PubMed

Shirk, Andrew J; Landguth, Erin L; Cushman, Samuel A

2018-01-01

Anthropogenic migration barriers fragment many populations and limit the ability of species to respond to climate-induced biome shifts. Conservation actions designed to conserve habitat connectivity and mitigate barriers are needed to unite fragmented populations into larger, more viable metapopulations, and to allow species to track their climate envelope over time. Landscape genetic analysis provides an empirical means to infer landscape factors influencing gene flow and thereby inform such conservation actions. However, there are currently many methods available for model selection in landscape genetics, and considerable uncertainty as to which provide the greatest accuracy in identifying the true landscape model influencing gene flow among competing alternative hypotheses. In this study, we used population genetic simulations to evaluate the performance of seven regression-based model selection methods on a broad array of landscapes that varied by the number and type of variables contributing to resistance, the magnitude and cohesion of resistance, as well as the functional relationship between variables and resistance. We also assessed the effect of transformations designed to linearize the relationship between genetic and landscape distances. We found that linear mixed effects models had the highest accuracy in every way we evaluated model performance; however, other methods also performed well in many circumstances, particularly when landscape resistance was high and the correlation among competing hypotheses was limited. Our results provide guidance for which regression-based model selection methods provide the most accurate inferences in landscape genetic analysis and thereby best inform connectivity conservation actions. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Impact of post-stroke unilateral spatial neglect on goal-directed arm movements: systematic literature review.

PubMed

Ogourtsova, Tatiana; Archambault, Philippe; Lamontagne, Anouk

2015-12-01

Unilateral spatial neglect (USN), a highly prevalent post-stroke impairment, refers to one's inability to orient or respond to stimuli located in the contralesional visual hemispace. Unilateral spatial neglect has been shown to strongly affect motor performance in functional activities, including non-affected upper extremity (UE) movements. To date, our understanding of the effects of USN on goal-directed UE movements is limited and comparing performance of individuals post-stroke with and without USN is required. To determine, in individuals with stroke, how does the presence of USN, in comparison to the absence of USN, impacts different types of goal-directed movements of the non-affected UE. The present review approach consisted of a comprehensive literature search, an assessment of the quality of the selected studies and qualitative data analysis. A total of 20 studies of moderate to high quality were selected. The USN-specific impairments were found in tasks that required a perceptual, memory-guided or delayed actions, and fewer impairments were found in tasks that required an immediate action to a predefined target. The results indicate that USN contributes to deficits observed in action execution with the non-effected UE that requires greater perceptual demands.

Efficiency in Rule- vs. Plan-Based Movements Is Modulated by Action-Mode

PubMed Central

Scheib, Jean P. P.; Stoll, Sarah; Thürmer, J. Lukas; Randerath, Jennifer

2018-01-01

The rule/plan motor cognition (RPMC) paradigm elicits visually indistinguishable motor outputs, resulting from either plan- or rule-based action-selection, using a combination of essentially interchangeable stimuli. Previous implementations of the RPMC paradigm have used pantomimed movements to compare plan- vs. rule-based action-selection. In the present work we attempt to determine the generalizability of previous RPMC findings to real object interaction by use of a grasp-to-rotate task. In the plan task, participants had to use prospective planning to achieve a comfortable post-handle rotation hand posture. The rule task used implementation intentions (if-then rules) leading to the same comfortable end-state. In Experiment A, we compare RPMC performance of 16 healthy participants in pantomime and real object conditions of the experiment, within-subjects. Higher processing efficiency of rule- vs. plan-based action-selection was supported by diffusion model analysis. Results show a significant response-time increase in the pantomime condition compared to the real object condition and a greater response-time advantage of rule-based vs. plan-based actions in the pantomime compared to the real object condition. In Experiment B, 24 healthy participants performed the real object RPMC task in a task switching vs. a blocked condition. Results indicate that plan-based action-selection leads to longer response-times and less efficient information processing than rule-based action-selection in line with previous RPMC findings derived from the pantomime action-mode. Particularly in the task switching mode, responses were faster in the rule compared to the plan task suggesting a modulating influence of cognitive load. Overall, results suggest an advantage of rule-based action-selection over plan-based action-selection; whereby differential mechanisms appear to be involved depending on the action-mode. We propose that cognitive load is a factor that modulates the advantageous effect of implementation intentions in motor cognition on different levels as illustrated by the varying speed advantages and the variation in diffusion parameters per action-mode or condition, respectively. PMID:29593612

The effects of freedom of choice in action selection on perceived mental effort and the sense of agency.

PubMed

Barlas, Zeynep; Hockley, William E; Obhi, Sukhvinder S

2017-10-01

Previous research showed that increasing the number of action alternatives enhances the sense of agency (SoA). Here, we investigated whether choice space could affect subjective judgments of mental effort experienced during action selection and examined the link between subjective effort and the SoA. Participants performed freely selected (among two, three, or four options) and instructed actions that produced pleasant or unpleasant tones. We obtained action-effect interval estimates to quantify intentional binding - the perceived interval compression between actions and outcomes and feeling of control (FoC) ratings. Additionally, participants reported the degree of mental effort they experienced during action selection. We found that both binding and FoC were systematically enhanced with increasing choice-level. Outcome valence did not influence binding, while FoC was stronger for pleasant than unpleasant outcomes. Finally, freely chosen actions were associated with low subjective effort and slow responses (i.e., higher reaction times), and instructed actions were associated with high effort and fast responses. Although the conditions that yielded the greatest and least subjective effort also yielded the greatest and least binding and FoC, there was no significant correlation between subjective effort and SoA measures. Overall, our results raise interesting questions about how agency may be influenced by response selection demands (i.e., indexed by speed of responding) and subjective mental effort. Our work also highlights the importance of understanding how subjective mental effort and response speed are related to popular notions of fluency in response selection. Copyright © 2017 Elsevier B.V. All rights reserved.

Adipokines and insulin action: A sensitive issue.

PubMed

Knights, Alexander J; Funnell, Alister Pw; Pearson, Richard Cm; Crossley, Merlin; Bell-Anderson, Kim S

2014-04-01

Obesity is a major public health concern and a strong risk factor for insulin resistance, type 2 diabetes mellitus (T2DM), and cardiovascular disease. The last two decades have seen a reconsideration of the role of white adipose tissue (WAT) in whole body metabolism and insulin action. Adipose tissue-derived cytokines and hormones, or adipokines, are likely mediators of metabolic function and dysfunction. While several adipokines have been associated with obese and insulin-resistant phenotypes, a select group has been linked with insulin sensitivity, namely leptin, adiponectin, and more recently, adipolin. What is known about these insulin-sensitizing molecules and their effects in healthy and insulin resistant states is the subject of this review. There remains a significant amount of research to do to fully elucidate the mechanisms of action of these adipokines for development of therapeutics in metabolic disease.

Adipokines and insulin action

PubMed Central

Knights, Alexander J; Funnell, Alister PW; Pearson, Richard CM; Crossley, Merlin; Bell-Anderson, Kim S

2014-01-01

Obesity is a major public health concern and a strong risk factor for insulin resistance, type 2 diabetes mellitus (T2DM), and cardiovascular disease. The last two decades have seen a reconsideration of the role of white adipose tissue (WAT) in whole body metabolism and insulin action. Adipose tissue-derived cytokines and hormones, or adipokines, are likely mediators of metabolic function and dysfunction. While several adipokines have been associated with obese and insulin-resistant phenotypes, a select group has been linked with insulin sensitivity, namely leptin, adiponectin, and more recently, adipolin. What is known about these insulin-sensitizing molecules and their effects in healthy and insulin resistant states is the subject of this review. There remains a significant amount of research to do to fully elucidate the mechanisms of action of these adipokines for development of therapeutics in metabolic disease. PMID:24719781

Brain evolution and development: adaptation, allometry and constraint

PubMed Central

Barton, Robert A.

2016-01-01

Phenotypic traits are products of two processes: evolution and development. But how do these processes combine to produce integrated phenotypes? Comparative studies identify consistent patterns of covariation, or allometries, between brain and body size, and between brain components, indicating the presence of significant constraints limiting independent evolution of separate parts. These constraints are poorly understood, but in principle could be either developmental or functional. The developmental constraints hypothesis suggests that individual components (brain and body size, or individual brain components) tend to evolve together because natural selection operates on relatively simple developmental mechanisms that affect the growth of all parts in a concerted manner. The functional constraints hypothesis suggests that correlated change reflects the action of selection on distributed functional systems connecting the different sub-components, predicting more complex patterns of mosaic change at the level of the functional systems and more complex genetic and developmental mechanisms. These hypotheses are not mutually exclusive but make different predictions. We review recent genetic and neurodevelopmental evidence, concluding that functional rather than developmental constraints are the main cause of the observed patterns. PMID:27629025

Diversity in the glucose transporter-4 gene (SLC2A4) in humans reflects the action of natural selection along the old-world primates evolution.

PubMed

Tarazona-Santos, Eduardo; Fabbri, Cristina; Yeager, Meredith; Magalhaes, Wagner C; Burdett, Laurie; Crenshaw, Andrew; Pettener, Davide; Chanock, Stephen J

2010-03-23

Glucose is an important source of energy for living organisms. In vertebrates it is ingested with the diet and transported into the cells by conserved mechanisms and molecules, such as the trans-membrane Glucose Transporters (GLUTs). Members of this family have tissue specific expression, biochemical properties and physiologic functions that together regulate glucose levels and distribution. GLUT4 -coded by SLC2A4 (17p13) is an insulin-sensitive transporter with a critical role in glucose homeostasis and diabetes pathogenesis, preferentially expressed in the adipose tissue, heart muscle and skeletal muscle. We tested the hypothesis that natural selection acted on SLC2A4. We re-sequenced SLC2A4 and genotyped 104 SNPs along a approximately 1 Mb region flanking this gene in 102 ethnically diverse individuals. Across the studied populations (African, European, Asian and Latin-American), all the eight common SNPs are concentrated in the N-terminal region upstream of exon 7 ( approximately 3700 bp), while the C-terminal region downstream of intron 6 ( approximately 2600 bp) harbors only 6 singletons, a pattern that is not compatible with neutrality for this part of the gene. Tests of neutrality based on comparative genomics suggest that: (1) episodes of natural selection (likely a selective sweep) predating the coalescent of human lineages, within the last 25 million years, account for the observed reduced diversity downstream of intron 6 and, (2) the target of natural selection may not be in the SLC2A4 coding sequence. We propose that the contrast in the pattern of genetic variation between the N-terminal and C-terminal regions are signatures of the action of natural selection and thus follow-up studies should investigate the functional importance of different regions of the SLC2A4 gene.

Effects of co-administration of fluoxetine and risperidone on properties of peritoneal and pleural macrophages in rats subjected to the forced swimming test.

PubMed

Roman, Adam; Kuśmierczyk, Justyna; Klimek, Ewa; Rogóż, Zofia; Nalepa, Irena

2012-01-01

Literature data show that administration of atypical antipsychotic drug, risperidone (RIS), enhances antidepressive action of fluoxetine (FLU). As antidepressive treatments also regulate immune functions, we examined whether combined administration of FLU and RIS to rats subsequently subjected to a forced swimming test (FST) modifies parameters of macrophage activity that are directly related to their immunomodulatory functions, i.e., arginase (ARG) activity and nitric oxide (NO) synthesis. Antidepressive action of the drugs was assessed with FST. Peritoneal and pleural cells were eluted and selected parameters of immunoreactivity were assessed colorimetrically. We found that the concomitant administration of FLU (10 mg/kg) and RIS (0.1 mg/kg) produced antidepressive-like effects in the FST,whereas the drugs were ineffective if administered separately. Stress related to the FST affected immune cell redistribution and changed some of the metabolic and immunomodulatory properties of macrophages. FLU administered to rats at a suboptimal dose for antidepressive action potently influenced macrophage immunomodulatory properties and redirected their activity toward anti-inflammatory M2 functional phenotype, as manifested by changes in the ARG/NO ratio. These effects resulted from a direct cellular influence of the drug, as well as its action via neuroendocrine pathways, as evidenced in peritoneal and pleural cells. Addition of RIS did not augment immunomodulatory action of FLU, though the combination showed antidepressant-like activity in the FST. Our results suggest that when the drugs were administered together, FLU was potent enough to redirect macrophages toward M2 activity. It is also postulated that drug-induced changes in the immune system are not so closely related to antidepressant-like effects or might be secondary to those produced in the neuroendocrine system.

Ebselen has lithium-like effects on central 5-HT2A receptor function.

PubMed

Antoniadou, I; Kouskou, M; Arsiwala, T; Singh, N; Vasudevan, S R; Fowler, T; Cadirci, E; Churchill, G C; Sharp, T

2018-02-27

Lithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in G q protein coupled receptor signalling. Recently, the antioxidant agent ebselen was identified as an IMPase inhibitor. Here we investigated both ebselen and lithium in models of the 5-HT 2A receptor, a G q protein coupled receptor implicated in lithium's actions. 5-HT 2A receptor function was modelled in mice by measuring the behavioural (head-twitches) and cortical immediate early gene (IEG; Arc, c-fos and Erg2 mRNA) responses to 5-HT 2A receptor agonist administration. Ebselen and lithium were administered either acutely or chronically prior to assessment of 5-HT 2A receptor function. Given the SSRI augmenting action of lithium and 5-HT 2A antagonists, ebselen was also tested for this action by co-administration with the SSRI citalopram in microdialysis (extracellular 5-HT) experiments. Acute and repeated administration of ebselen inhibited behavioural and IEG responses to the 5-HT 2A receptor agonist DOI. Repeated lithium also inhibited DOI-evoked behavioural and IEG responses. In comparison, a selective IMPase inhibitor (L-690,330) attenuated the behavioural response to DOI whereas glycogen synthase kinase inhibitor (AR-A014418) did not. Finally, ebselen increased regional brain 5-HT synthesis and enhanced the increase in extracellular 5-HT induced by citalopram. The current data demonstrate lithium-mimetic effects of ebselen in different experimental models of 5-HT 2A receptor function, likely mediated by IMPase inhibition. This evidence of lithium-like neuropharmacological effects of ebselen adds further support for the clinical testing of ebselen in mood disorder, including as an antidepressant augmenting agent. This article is protected by copyright. All rights reserved.

Clinical benefit of drugs targeting mitochondrial function as an adjunct to reperfusion in ST-segment elevation myocardial infarction: A meta-analysis of randomized clinical trials.

PubMed

Campo, Gianluca; Pavasini, Rita; Morciano, Giampaolo; Lincoff, A Michael; Gibson, C Michael; Kitakaze, Masafumi; Lonborg, Jacob; Ahluwalia, Amrita; Ishii, Hideki; Frenneaux, Michael; Ovize, Michel; Galvani, Marcello; Atar, Dan; Ibanez, Borja; Cerisano, Giampaolo; Biscaglia, Simone; Neil, Brandon J; Asakura, Masanori; Engstrom, Thomas; Jones, Daniel A; Dawson, Dana; Ferrari, Roberto; Pinton, Paolo; Ottani, Filippo

2017-10-01

To perform a systematic review and meta-analysis of randomized clinical trials (RCT) comparing the effectiveness of drugs targeting mitochondrial function vs. placebo in patients with ST-segment elevation myocardial infarction (STEMI) undergoing mechanical coronary reperfusion. Inclusion criteria: RCTs enrolling STEMI patients treated with primary percutaneous coronary intervention (PCI) and comparing drugs targeting mitochondrial function vs. placebo. Odds ratios (OR) were computed from individual studies and pooled with random-effect meta-analysis. Fifteen studies were identified involving 5680 patients. When compared with placebo, drugs targeting mitochondrial component/pathway were not associated with significant reduction of cardiovascular and all-cause mortality (OR 0.9, 95% CI 0.7-1.17 and OR 0.92, 95% CI 0.69-1.23, respectively). However, these agents significantly reduced hospital admission for heart failure (HF) (OR 0.64; 95% CI 0.45-0.92) and increased left ventricular ejection fraction (LVEF) (OR 1.44; 95% CI 1.15-1.82). After analysis for subgroups according to the mechanism of action, drugs with direct/selective action did not reduce any outcome. Conversely, those with indirect/unspecific action showed a significant effect on cardiovascular mortality (0.65, 95% CI 0.46-0.92), all-cause mortality (OR 0.69, 95% CI 0.52-0.92), hospital readmission for HF (OR 0.41, 95% CI 0.28-0.6) and LVEF (OR 1.49, 95% CI 1.09-2.05). Administration of drugs targeting mitochondrial function in STEMI patients undergoing primary PCI appear to have no effect on mortality, but may reduce hospital readmission for HF. The drugs with a broad-spectrum mechanism of action seem to be more effective in reducing adverse events. Copyright © 2017 Elsevier B.V. All rights reserved.

Modulation of attention network activation under antidepressant agents in healthy subjects.

PubMed

Graf, Heiko; Abler, Birgit; Hartmann, Antonie; Metzger, Coraline D; Walter, Martin

2013-07-01

While antidepressants are supposed to exert similar effects on mood and drive via various mechanisms of action, diverging effects are observed regarding side-effects and accordingly on neural correlates of motivation, emotion, reward and salient stimuli processing as a function of the drugs impact on neurotransmission. In the context of erotic stimulation, a unidirectional modulation of attentional functioning despite opposite effects on sexual arousal has been suggested for the selective serotonin reuptake-inhibitor (SSRI) paroxetine and the selective dopamine and noradrenaline reuptake-inhibitor (SDNRI) bupropion. To further elucidate the effects of antidepressant-related alterations of neural attention networks, we investigated 18 healthy males under subchronic administration (7 d) of paroxetine (20 mg), bupropion (150 mg) and placebo within a randomized placebo-controlled cross-over double-blind functional magnetic resonance imaging (fMRI) design during an established preceding attention task. Neuropsychological effects beyond the fMRI-paradigm were assessed by measuring alertness and divided attention. Comparing preceding attention periods of salient vs. neutral pictures, we revealed congruent effects of both drugs vs. placebo within the anterior midcingulate cortex, dorsolateral prefrontal cortex, anterior prefrontal cortex, superior temporal gyrus, anterior insula and the thalamus. Relatively decreased activation in this network was paralleled by slower reaction times in the divided attention task in both verum conditions compared to placebo. Our results suggest similar effects of antidepressant treatments on behavioural and neural attentional functioning by diverging neurochemical pathways. Concurrent alterations of brain regions within a fronto-parietal and cingulo-opercular attention network for top-down control could point to basic neural mechanisms of antidepressant action irrespective of receptor profiles.

Molecular population genetics of the insulin/TOR signal transduction pathway: a network-level analysis in Drosophila melanogaster.

PubMed

Alvarez-Ponce, David; Guirao-Rico, Sara; Orengo, Dorcas J; Segarra, Carmen; Rozas, Julio; Aguadé, Montserrat

2012-01-01

The IT-insulin/target of rapamycin (TOR)-signal transduction pathway is a relatively well-characterized pathway that plays a central role in fundamental biological processes. Network-level analyses of DNA divergence in Drosophila and vertebrates have revealed a clear gradient in the levels of purifying selection along this pathway, with the downstream genes being the most constrained. Remarkably, this feature does not result from factors known to affect selective constraint such as gene expression, codon bias, protein length, and connectivity. The present work aims to establish whether the selective constraint gradient detected along the IT pathway at the between-species level can also be observed at a shorter time scale. With this purpose, we have surveyed DNA polymorphism in Drosophila melanogaster and divergence from D. simulans along the IT pathway. Our network-level analysis shows that DNA polymorphism exhibits the same polarity in the strength of purifying selection as previously detected at the divergence level. This equivalent feature detected both within species and between closely and distantly related species points to the action of a general mechanism, whose action is neither organism specific nor evolutionary time dependent. The detected polarity would be, therefore, intrinsic to the IT pathway architecture and function.

Defining the Molecular Actions of Dietary Fatty Acids in Breast Cancer: Selective Modulation of Peroxisome Proliferator-Activated Receptor Gamma

DTIC Science & Technology

2005-05-01

Maximum 200 Words) Stark differences in the actions of lenoleic acid (LAA), an omega-6 fatty acid , and eicosapentaenoic acid (EPA), an omega-3 fatty acid ...AD_ Award Number: W81XWH-04-1-0532 TITLE: Defining the Molecular Actions of Dietary Fatty acids in Breast Cancer: Selective Modulation of Peroxisome...TITLE AND SUBTITLE 5. FUNDING NUMBERS Defining the Molecular Actions of Dietary Fatty acids in W81XWH-04-1-0532 Breast Cancer: Selective Modulation of

Sensorimotor Learning Biases Choice Behavior: A Learning Neural Field Model for Decision Making

PubMed Central

Schöner, Gregor; Gail, Alexander

2012-01-01

According to a prominent view of sensorimotor processing in primates, selection and specification of possible actions are not sequential operations. Rather, a decision for an action emerges from competition between different movement plans, which are specified and selected in parallel. For action choices which are based on ambiguous sensory input, the frontoparietal sensorimotor areas are considered part of the common underlying neural substrate for selection and specification of action. These areas have been shown capable of encoding alternative spatial motor goals in parallel during movement planning, and show signatures of competitive value-based selection among these goals. Since the same network is also involved in learning sensorimotor associations, competitive action selection (decision making) should not only be driven by the sensory evidence and expected reward in favor of either action, but also by the subject's learning history of different sensorimotor associations. Previous computational models of competitive neural decision making used predefined associations between sensory input and corresponding motor output. Such hard-wiring does not allow modeling of how decisions are influenced by sensorimotor learning or by changing reward contingencies. We present a dynamic neural field model which learns arbitrary sensorimotor associations with a reward-driven Hebbian learning algorithm. We show that the model accurately simulates the dynamics of action selection with different reward contingencies, as observed in monkey cortical recordings, and that it correctly predicted the pattern of choice errors in a control experiment. With our adaptive model we demonstrate how network plasticity, which is required for association learning and adaptation to new reward contingencies, can influence choice behavior. The field model provides an integrated and dynamic account for the operations of sensorimotor integration, working memory and action selection required for decision making in ambiguous choice situations. PMID:23166483

Acotiamide hydrochloride (Z-338), a new selective acetylcholinesterase inhibitor, enhances gastric motility without prolonging QT interval in dogs: comparison with cisapride, itopride, and mosapride.

PubMed

Matsunaga, Yugo; Tanaka, Takao; Yoshinaga, Koji; Ueki, Shigeru; Hori, Yuko; Eta, Runa; Kawabata, Yoshihiro; Yoshii, Kazuyoshi; Yoshida, Kenji; Matsumura, Toshihiro; Furuta, Shigeru; Takei, Mineo; Tack, Jan; Itoh, Zen

2011-03-01

Acotiamide hydrochloride (acotiamide; N-[2-[bis(1-methylethyl) amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole-4-carboxamide monohydrochloride trihydrate, Z-338) has been reported to improve meal-related symptoms of functional dyspepsia in clinical studies. Here, we examined the gastroprokinetic effects of acotiamide and its antiacetylcholinesterase activity as a possible mechanism of action in conscious dogs. Acotiamide increased postprandial gastric motor activity in conscious dogs with chronically implanted force transducers and, like itopride, mosapride, and cisapride, exhibited gastroprokinetic activity in these dogs. Furthermore, acotiamide improved clonidine-induced hypomotility and delayed gastric emptying. Acotiamide-enhanced postprandial gastroduodenal motility was suppressed completely by pretreatment with atropine, a muscarinic receptor antagonist. In in vitro studies, acotiamide enhanced acetylcholine- but not carbachol-induced contractile responses of guinea pig gastric antrum strips. Moreover, like itopride and neostigmine, acotiamide inhibited recombinant human and canine stomach-derived acetylcholinesterase (AChE) activity in vitro. The mode of the AChE inhibitory action of acotiamide was selective and reversible. Unlike itopride or mosapride, acotiamide showed no affinity for dopamine D(2) or serotonin 5-HT(4) receptors. With regard to cardiovascular side effects, unlike cisapride, acotiamide did not affect myocardial monophasic action potential duration, QT interval, or corrected QT interval in anesthetized dogs. These results suggest that acotiamide stimulates gastric motility in vivo by inhibiting AChE activity without affecting QT interval. Acotiamide thus represents a beneficial new drug for the treatment of functional dyspepsia involving gastric motility dysfunction, with differences from other prokinetic agents.

Directional selection has shaped the oral jaws of Lake Malawi cichlid fishes.

PubMed

Albertson, R Craig; Streelman, J Todd; Kocher, Thomas D

2003-04-29

East African cichlid fishes represent one of the most striking examples of rapid and convergent evolutionary radiation among vertebrates. Models of ecological speciation would suggest that functional divergence in feeding morphology has contributed to the origin and maintenance of cichlid species diversity. However, definitive evidence for the action of natural selection has been missing. Here we use quantitative genetics to identify regions of the cichlid genome responsible for functionally important shape differences in the oral jaw apparatus. The consistent direction of effects for individual quantitative trait loci suggest that cichlid jaws and teeth evolved in response to strong, divergent selection. Moreover, several chromosomal regions contain a disproportionate number of quantitative trait loci, indicating a prominent role for pleiotropy or genetic linkage in the divergence of this character complex. Of particular interest are genomic intervals with concerted effects on both the length and height of the lower jaw. Coordinated changes in this area of the oral jaw apparatus are predicted to have direct consequences for the speed and strength of jaw movement. Taken together, our results imply that the rapid and replicative nature of cichlid trophic evolution is the result of directional selection on chromosomal packages that encode functionally linked aspects of the craniofacial skeleton.

Implications of the new EEOC guidelines.

PubMed

Dhanens, T P

1979-01-01

How can employers exercise their right to select employees without running afoul of the new guidelines? Are interviews best? Pencil and paper tests? "Nonrandom selection procedures are inevitable for most jobs," says Dr. Thomas Dhanens, a management psychologist. "Therefore, employers will always be open to charges of discrimination or favoritism from some quarter. Organizations that avoid their responsibility for examining and validating their selection procedures will be forced into a costly catch-up effort before long." The author shows employers how to collect data systematically, analyze job functions, evaluate applicants, record data, handle performance appraisals, maintain records, and identify priorities. Since a lack of data is no defense in an EEOC action, Dhanens suggests that these are the minimum steps wise employers should follow.

Immediate movement history influences reach-to-grasp action selection in children and adults.

PubMed

Kent, Samuel W; Wilson, Andrew D; Plumb, Mandy S; Williams, Justin H G; Mon-Williams, Mark

2009-01-01

Action selection is subject to many biases. Immediate movement history is one such bias seen in young infants. Is this bias strong enough to affect adult behavior? Adult participants reached and grasped a cylinder positioned to require either pronation or supination of the hand. Successive cylinder positions changed either randomly or systematically between trials. Random positioning led to optimized economy of movement. In contrast, systematic changes in position biased action selection toward previously selected actions at the expense of movement economy. Thus, one switches to a new movement only when the savings outweigh the costs of the switch. Immediate movement history had an even larger influence on children aged 7-15 years. This suggests that switching costs are greater in children, which is consistent with their reduced grasping experience. The presence of this effect in adults suggests that immediate movement history exerts a more widespread and pervasive influence on patterns of action selection than researchers had previously recognized.

Metastasis Suppressor Genes: At the Interface Between the Environment and Tumor Cell Growth

PubMed Central

Hurst, Douglas R.; Welch, Danny R.

2013-01-01

The molecular mechanisms and genetic programs required for cancer metastasis are sometimes overlapping, but components are clearly distinct from those promoting growth of a primary tumor. Every sequential, rate-limiting step in the sequence of events leading to metastasis requires coordinated expression of multiple genes, necessary signaling events, and favorable environmental conditions or the ability to escape negative selection pressures. Metastasis suppressors are molecules that inhibit the process of metastasis without preventing growth of the primary tumor. The cellular processes regulated by metastasis suppressors are diverse and function at every step in the metastatic cascade. As we gain knowledge into the molecular mechanisms of metastasis suppressors and cofactors with which they interact, we learn more about the process, including appreciation that some are potential targets for therapy of metastasis, the most lethal aspect of cancer. Until now, metastasis suppressors have been described largely by their function. With greater appreciation of their biochemical mechanisms of action, the importance of context is increasingly recognized especially since tumor cells exist in myriad microenvironments. In this review, we assemble the evidence that selected molecules are indeed suppressors of metastasis, collate the data defining the biochemical mechanisms of action, and glean insights regarding how metastasis suppressors regulate tumor cell communication to–from microenvironments. PMID:21199781

Voltage-Gated Potassium Channels: A Structural Examination of Selectivity and Gating

PubMed Central

Kim, Dorothy M.; Nimigean, Crina M.

2016-01-01

Voltage-gated potassium channels play a fundamental role in the generation and propagation of the action potential. The discovery of these channels began with predictions made by early pioneers, and has culminated in their extensive functional and structural characterization by electrophysiological, spectroscopic, and crystallographic studies. With the aid of a variety of crystal structures of these channels, a highly detailed picture emerges of how the voltage-sensing domain reports changes in the membrane electric field and couples this to conformational changes in the activation gate. In addition, high-resolution structural and functional studies of K+ channel pores, such as KcsA and MthK, offer a comprehensive picture on how selectivity is achieved in K+ channels. Here, we illustrate the remarkable features of voltage-gated potassium channels and explain the mechanisms used by these machines with experimental data. PMID:27141052

Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin★

PubMed Central

Wang, Qian; Liu, Chen; Uchida, Aki; Chuang, Jen-Chieh; Walker, Angela; Liu, Tiemin; Osborne-Lawrence, Sherri; Mason, Brittany L.; Mosher, Christina; Berglund, Eric D.; Elmquist, Joel K.; Zigman, Jeffrey M.

2013-01-01

The hormone ghrelin stimulates eating and helps maintain blood glucose upon caloric restriction. While previous studies have demonstrated that hypothalamic arcuate AgRP neurons are targets of ghrelin, the overall relevance of ghrelin signaling within intact AgRP neurons is unclear. Here, we tested the functional significance of ghrelin action on AgRP neurons using a new, tamoxifen-inducible AgRP-CreERT2 transgenic mouse model that allows spatiotemporally-controlled re-expression of physiological levels of ghrelin receptors (GHSRs) specifically in AgRP neurons of adult GHSR-null mice that otherwise lack GHSR expression. AgRP neuron-selective GHSR re-expression partially restored the orexigenic response to administered ghrelin and fully restored the lowered blood glucose levels observed upon caloric restriction. The normalizing glucoregulatory effect of AgRP neuron-selective GHSR expression was linked to glucagon rises and hepatic gluconeogenesis induction. Thus, our data indicate that GHSR-containing AgRP neurons are not solely responsible for ghrelin's orexigenic effects but are sufficient to mediate ghrelin's effects on glycemia. PMID:24567905

Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin.

PubMed

Wang, Qian; Liu, Chen; Uchida, Aki; Chuang, Jen-Chieh; Walker, Angela; Liu, Tiemin; Osborne-Lawrence, Sherri; Mason, Brittany L; Mosher, Christina; Berglund, Eric D; Elmquist, Joel K; Zigman, Jeffrey M

2014-02-01

The hormone ghrelin stimulates eating and helps maintain blood glucose upon caloric restriction. While previous studies have demonstrated that hypothalamic arcuate AgRP neurons are targets of ghrelin, the overall relevance of ghrelin signaling within intact AgRP neurons is unclear. Here, we tested the functional significance of ghrelin action on AgRP neurons using a new, tamoxifen-inducible AgRP-CreER(T2) transgenic mouse model that allows spatiotemporally-controlled re-expression of physiological levels of ghrelin receptors (GHSRs) specifically in AgRP neurons of adult GHSR-null mice that otherwise lack GHSR expression. AgRP neuron-selective GHSR re-expression partially restored the orexigenic response to administered ghrelin and fully restored the lowered blood glucose levels observed upon caloric restriction. The normalizing glucoregulatory effect of AgRP neuron-selective GHSR expression was linked to glucagon rises and hepatic gluconeogenesis induction. Thus, our data indicate that GHSR-containing AgRP neurons are not solely responsible for ghrelin's orexigenic effects but are sufficient to mediate ghrelin's effects on glycemia.

The thing that should not be: predictive coding and the uncanny valley in perceiving human and humanoid robot actions

PubMed Central

Chaminade, Thierry; Ishiguro, Hiroshi; Driver, Jon; Frith, Chris

2012-01-01

Using functional magnetic resonance imaging (fMRI) repetition suppression, we explored the selectivity of the human action perception system (APS), which consists of temporal, parietal and frontal areas, for the appearance and/or motion of the perceived agent. Participants watched body movements of a human (biological appearance and movement), a robot (mechanical appearance and movement) or an android (biological appearance, mechanical movement). With the exception of extrastriate body area, which showed more suppression for human like appearance, the APS was not selective for appearance or motion per se. Instead, distinctive responses were found to the mismatch between appearance and motion: whereas suppression effects for the human and robot were similar to each other, they were stronger for the android, notably in bilateral anterior intraparietal sulcus, a key node in the APS. These results could reflect increased prediction error as the brain negotiates an agent that appears human, but does not move biologically, and help explain the ‘uncanny valley’ phenomenon. PMID:21515639

Brain activation associated with eccentric movement: A narrative review of the literature.

PubMed

Perrey, Stéphane

2018-02-01

The movement occurring when a muscle exerts tension while lengthening is known as eccentric muscle action. Literature contains limited evidence on how our brain controls eccentric movement. However, how the cortical regions in the motor network are activated during eccentric muscle actions may be critical for understanding the underlying control mechanism of eccentric movements encountered in daily tasks. This is a novel topic that has only recently begun to be investigated through advancements in neuroimaging methods (electroencephalography, EEG; functional magnetic resonance imaging, fMRI). This review summarizes a selection of seven studies indicating mainly: longer time and higher cortical signal amplitude (EEG) for eccentric movement preparation and execution, greater magnitude of cortical signals with wider activated brain area (EEG, fMRI), and weaker brain functional connectivity (fMRI) between primary motor cortex (M1) and other cortical areas involved in the motor network during eccentric muscle actions. Only some differences among studies due to the forms of movement with overload were observed in the contralateral (to the active hand) M1 activity during eccentric movement. Altogether, the findings indicate an important challenge to the brain for controlling the eccentric movement. However, our understanding remains limited regarding the acute effects of eccentric exercise on cortical regions and their cooperation as functional networks that support motor functions. Further analysis and standardized protocols will provide deeper insights into how different cortical regions of the underlying motor network interplay with each other in increasingly demanding muscle exertions in eccentric mode.

Being selective at the plate: processing dependence between perceptual variables relates to hitting goals and performance.

PubMed

Gray, Rob

2013-08-01

Performance of a skill that involves acting on a goal object (e.g., a ball to be hit) can influence one's judgment of the size and speed of that object. The present study examined how these action-specific effects are affected when the goal of the actor is varied and they are free to choose between alternative actions. In Experiment 1, expert baseball players were asked to perform three different directional hitting tasks in a batting simulation and make interleaved perceptual judgments about three ball parameters (speed, plate crossing location, and size). Perceived ball size was largest (and perceived speed was slowest) when the ball crossing location was optimal for the particular hitting task the batter was performing (e.g., an "outside" pitch for opposite-field hitting). The magnitude of processing dependency between variables (speed vs. location and size vs. location) was positively correlated with batting performance. In Experiment 2, the action-specific effects observed in Experiment 1 were mimicked by systematically changing the ball diameter in the simulation as a function of plate crossing location. The number of swing initiations was greater when ball size was larger, and batters were more successful in the hitting task for which the larger pitches were optimal (e.g., greater number of pull hits than opposite-field hits when "inside" pitches were larger). These findings suggest attentional accentuation of goal-relevant targets underlies action-related changes in perception and are consistent with an action selection role for these effects. 2013 APA, all rights reserved

Genome-wide detection of selection signatures in Chinese indigenous Laiwu pigs revealed candidate genes regulating fat deposition in muscle.

PubMed

Chen, Minhui; Wang, Jiying; Wang, Yanping; Wu, Ying; Fu, Jinluan; Liu, Jian-Feng

2018-05-18

Currently, genome-wide scans for positive selection signatures in commercial breed have been investigated. However, few studies have focused on selection footprints of indigenous breeds. Laiwu pig is an invaluable Chinese indigenous pig breed with extremely high proportion of intramuscular fat (IMF), and an excellent model to detect footprint as the result of natural and artificial selection for fat deposition in muscle. In this study, based on GeneSeek Genomic profiler Porcine HD data, three complementary methods, F ST , iHS (integrated haplotype homozygosity score) and CLR (composite likelihood ratio), were implemented to detect selection signatures in the whole genome of Laiwu pigs. Totally, 175 candidate selected regions were obtained by at least two of the three methods, which covered 43.75 Mb genomic regions and corresponded to 1.79% of the genome sequence. Gene annotation of the selected regions revealed a list of functionally important genes for feed intake and fat deposition, reproduction, and immune response. Especially, in accordance to the phenotypic features of Laiwu pigs, among the candidate genes, we identified several genes, NPY1R, NPY5R, PIK3R1 and JAKMIP1, involved in the actions of two sets of neurons, which are central regulators in maintaining the balance between food intake and energy expenditure. Our results identified a number of regions showing signatures of selection, as well as a list of functionally candidate genes with potential effect on phenotypic traits, especially fat deposition in muscle. Our findings provide insights into the mechanisms of artificial selection of fat deposition and further facilitate follow-up functional studies.

Nonuniform Changes in the Distribution of Visual Attention from Visual Complexity and Action: A Driving Simulation Study.

PubMed

Park, George D; Reed, Catherine L

2015-02-01

Researchers acknowledge the interplay between action and attention, but typically consider action as a response to successful attentional selection or the correlation of performance on separate action and attention tasks. We investigated how concurrent action with spatial monitoring affects the distribution of attention across the visual field. We embedded a functional field of view (FFOV) paradigm with concurrent central object recognition and peripheral target localization tasks in a simulated driving environment. Peripheral targets varied across 20-60 deg eccentricity at 11 radial spokes. Three conditions assessed the effects of visual complexity and concurrent action on the size and shape of the FFOV: (1) with no background, (2) with driving background, and (3) with driving background and vehicle steering. The addition of visual complexity slowed task performance and reduced the FFOV size but did not change the baseline shape. In contrast, the addition of steering produced not only shrinkage of the FFOV, but also changes in the FFOV shape. Nonuniform performance decrements occurred in proximal regions used for the central task and for steering, independent of interference from context elements. Multifocal attention models should consider the role of action and account for nonhomogeneities in the distribution of attention. © 2015 SAGE Publications.

Using a Simple Neural Network to Delineate Some Principles of Distributed Economic Choice.

PubMed

Balasubramani, Pragathi P; Moreno-Bote, Rubén; Hayden, Benjamin Y

2018-01-01

The brain uses a mixture of distributed and modular organization to perform computations and generate appropriate actions. While the principles under which the brain might perform computations using modular systems have been more amenable to modeling, the principles by which the brain might make choices using distributed principles have not been explored. Our goal in this perspective is to delineate some of those distributed principles using a neural network method and use its results as a lens through which to reconsider some previously published neurophysiological data. To allow for direct comparison with our own data, we trained the neural network to perform binary risky choices. We find that value correlates are ubiquitous and are always accompanied by non-value information, including spatial information (i.e., no pure value signals). Evaluation, comparison, and selection were not distinct processes; indeed, value signals even in the earliest stages contributed directly, albeit weakly, to action selection. There was no place, other than at the level of action selection, at which dimensions were fully integrated. No units were specialized for specific offers; rather, all units encoded the values of both offers in an anti-correlated format, thus contributing to comparison. Individual network layers corresponded to stages in a continuous rotation from input to output space rather than to functionally distinct modules. While our network is likely to not be a direct reflection of brain processes, we propose that these principles should serve as hypotheses to be tested and evaluated for future studies.

Using a Simple Neural Network to Delineate Some Principles of Distributed Economic Choice

PubMed Central

Balasubramani, Pragathi P.; Moreno-Bote, Rubén; Hayden, Benjamin Y.

2018-01-01

The brain uses a mixture of distributed and modular organization to perform computations and generate appropriate actions. While the principles under which the brain might perform computations using modular systems have been more amenable to modeling, the principles by which the brain might make choices using distributed principles have not been explored. Our goal in this perspective is to delineate some of those distributed principles using a neural network method and use its results as a lens through which to reconsider some previously published neurophysiological data. To allow for direct comparison with our own data, we trained the neural network to perform binary risky choices. We find that value correlates are ubiquitous and are always accompanied by non-value information, including spatial information (i.e., no pure value signals). Evaluation, comparison, and selection were not distinct processes; indeed, value signals even in the earliest stages contributed directly, albeit weakly, to action selection. There was no place, other than at the level of action selection, at which dimensions were fully integrated. No units were specialized for specific offers; rather, all units encoded the values of both offers in an anti-correlated format, thus contributing to comparison. Individual network layers corresponded to stages in a continuous rotation from input to output space rather than to functionally distinct modules. While our network is likely to not be a direct reflection of brain processes, we propose that these principles should serve as hypotheses to be tested and evaluated for future studies. PMID:29643773

Covalent immobilization of molecularly imprinted polymer nanoparticles using an epoxy silane.

PubMed

Kamra, Tripta; Chaudhary, Shilpi; Xu, Changgang; Johansson, Niclas; Montelius, Lars; Schnadt, Joachim; Ye, Lei

2015-05-01

Molecularly imprinted polymers (MIPs) can be used as antibody mimics to develop robust chemical sensors. One challenging problem in using MIPs for sensor development is the lack of reliable conjugation chemistry that allows MIPs to be fixed on transducer surface. In this work, we study the use of epoxy silane to immobilize MIP nanoparticles on model transducer surfaces without impairing the function of the immobilized nanoparticles. The MIP nanoparticles with a core-shell structure have selective molecular binding sites in the core and multiple amino groups in the shell. The model transducer surface is functionalized with a self-assembled monolayer of epoxy silane, which reacts with the core-shell MIP particles to enable straightforward immobilization. The whole process is characterized by studying the treated surfaces after each preparation step using atomic force microscopy, scanning electron microscopy, fluorescence microscopy, contact angle measurements and X-ray photoelectron spectroscopy. The microscopy results show that the MIP particles are immobilized uniformly on surface. The photoelectron spectroscopy results further confirm the action of each functionalization step. The molecular selectivity of the MIP-functionalized surface is verified by radioligand binding analysis. The particle immobilization approach described here has a general applicability for constructing selective chemical sensors in different formats. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Targeted estrogen delivery reverses the metabolic syndrome

PubMed Central

Finan, Brian; Yang, Bin; Ottaway, Nickki; Stemmer, Kerstin; Müller, Timo D; Yi, Chun-Xia; Habegger, Kirk; Schriever, Sonja C; García-Cáceres, Cristina; Kabra, Dhiraj G; Hembree, Jazzminn; Holland, Jenna; Raver, Christine; Seeley, Randy J; Hans, Wolfgang; Irmler, Martin; Beckers, Johannes; de Angelis, Martin Hrabě; Tiano, Joseph P; Mauvais-Jarvis, Franck; Perez-Tilve, Diego; Pfluger, Paul; Zhang, Lianshan; Gelfanov, Vasily; DiMarchi, Richard D; Tschöp, Matthias H

2013-01-01

We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1–targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1–estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases. PMID:23142820

Priority scheme planning for the robust SSM/PMAD testbed

NASA Technical Reports Server (NTRS)

Elges, Michael R.; Ashworth, Barry R.

1991-01-01

Whenever mixing priorities of manually controlled resources with those of autonomously controlled resources, the space station module power management and distribution (SSM/PMAD) environment requires cooperating expert system interaction between the planning function and the priority manager. The elements and interactions of the SSM/PMAD planning and priority management functions are presented. Their adherence to cooperating for common achievement are described. In the SSM/PMAD testbed these actions are guided by having a system planning function, KANT, which has insight to the executing system and its automated database. First, the user must be given access to all information which may have an effect on the desired outcome. Second, the fault manager element, FRAMES, must be informed as to the change so that correct diagnoses and operations take place if and when faults occur. Third, some element must engage as mediator for selection of resources and actions to be added or removed at the user's request. This is performed by the priority manager, LPLMS. Lastly, the scheduling mechanism, MAESTRO, must provide future schedules adhering to the user modified resource base.

Research & market strategy: how choice of drug discovery approach can affect market position.

PubMed

Sams-Dodd, Frank

2007-04-01

In principal, drug discovery approaches can be grouped into target- and function-based, with the respective aims of developing either a target-selective drug or a drug that produces a specific biological effect irrespective of its mode of action. Most analyses of drug discovery approaches focus on productivity, whereas the strategic implications of the choice of drug discovery approach on market position and ability to maintain market exclusivity are rarely considered. However, a comparison of approaches from the perspective of market position indicates that the functional approach is superior for the development of novel, innovative treatments.

Learning, remembering, and predicting how to use tools: Distributed neurocognitive mechanisms

PubMed Central

Buxbaum, Laurel J.

2016-01-01

The reasoning-based approach championed by Francois Osiurak and Arnaud Badets (Osiurak & Badets, 2016) denies the existence of sensory-motor memories of tool use except in limited circumstances, and suggests instead that most tool use is subserved solely by online technical reasoning about tool properties. In this commentary, I highlight the strengths and limitations of the reasoning-based approach and review a number of lines of evidence that manipulation knowledge is in fact used in tool action tasks. In addition, I present a “two route” neurocognitive model of tool use called the “Two Action Systems Plus (2AS+)” framework that posits a complementary role for online and stored information and specifies the neurocognitive substrates of task-relevant action selection. This framework, unlike the reasoning based approach, has the potential to integrate the existing psychological and functional neuroanatomic data in the tool use domain. PMID:28358565

4-Nitro styrylquinoline is an antimalarial inhibiting multiple stages of Plasmodium falciparum asexual life cycle.

PubMed

Roberts, Bracken F; Zheng, Yongsheng; Cleaveleand, Jacob; Lee, Sukjun; Lee, Eunyoung; Ayong, Lawrence; Yuan, Yu; Chakrabarti, Debopam

2017-04-01

Drugs against malaria are losing their effectiveness because of emerging drug resistance. This underscores the need for novel therapeutic options for malaria with mechanism of actions distinct from current antimalarials. To identify novel pharmacophores against malaria we have screened compounds containing structural features of natural products that are pharmacologically relevant. This screening has identified a 4-nitro styrylquinoline (SQ) compound with submicromolar antiplasmodial activity and excellent selectivity. SQ exhibits a cellular action distinct from current antimalarials, acting early on malaria parasite's intraerythrocytic life cycle including merozoite invasion. The compound is a fast-acting parasitocidal agent and also exhibits curative property in the rodent malaria model when administered orally. In this report, we describe the synthesis, preliminary structure-function analysis, and the parasite developmental stage specific action of the SQ scaffold. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

I control therefore I do: judgments of agency influence action selection.

PubMed

Karsh, N; Eitam, B

2015-05-01

Our sense of being agents, that is of willingly controlling both our own bodies and the external environment is ubiquitous if thin. Empirical and theoretical work on this 'sense of agency' has documented motivational, cognitive and neural influences on implicit (out of awareness) and explicit (conscious) judgments of agency. For example, fluency of action selection processes has been recently shown to affect judgments of one's degree of control over an external event. However, it is an open question whether and how such judgments of agency act as input to other processes. In this study we demonstrate that the opposite relationship between action selection and judgment of agency also exists. Specifically, we show that manipulating one's objective control over the environment influences both the speed and the frequency of performing an action associated with that control. This pattern bears a striking resemblance to the effect that tangible rewards have on action selection and suggests that positive control feedback is rewarding to the organism, consequently affecting action selection. If further corroborated this 'reward from control' may explain everyday addictions such as prolonged engagement in arcade games and pathological behaviors, such as stereotypy. Copyright © 2015 Elsevier B.V. All rights reserved.

Emotion in Action: A Predictive Processing Perspective and Theoretical Synthesis

PubMed Central

Ridderinkhof, K. Richard

2017-01-01

Starting from a decidedly Frijdian perspective on emotion in action, we adopt neurocognitive theories of action control to analyze the mechanisms through which emotional action arises. Appraisal of events vis-à-vis concerns gives rise to a determinate motive to establish a specific state of the world; the pragmatic idea of the action’s effects incurs the valuation of action options and a change in action readiness in the form of incipient ideomotor capture of the selected action. Forward modeling of the sensory consequences of the selected action option allows for the evaluation and fine-tuning of anticipated action effects, which renders the emotional action impulsive yet purposive. This novel theoretical synthesis depicts the cornerstone principles for a mechanistic view on emotion in action. PMID:29098017

Distinct contributions of functional and deep neural network features to representational similarity of scenes in human brain and behavior

PubMed Central

Greene, Michelle R; Baldassano, Christopher; Fei-Fei, Li; Beck, Diane M; Baker, Chris I

2018-01-01

Inherent correlations between visual and semantic features in real-world scenes make it difficult to determine how different scene properties contribute to neural representations. Here, we assessed the contributions of multiple properties to scene representation by partitioning the variance explained in human behavioral and brain measurements by three feature models whose inter-correlations were minimized a priori through stimulus preselection. Behavioral assessments of scene similarity reflected unique contributions from a functional feature model indicating potential actions in scenes as well as high-level visual features from a deep neural network (DNN). In contrast, similarity of cortical responses in scene-selective areas was uniquely explained by mid- and high-level DNN features only, while an object label model did not contribute uniquely to either domain. The striking dissociation between functional and DNN features in their contribution to behavioral and brain representations of scenes indicates that scene-selective cortex represents only a subset of behaviorally relevant scene information. PMID:29513219

Distinct contributions of functional and deep neural network features to representational similarity of scenes in human brain and behavior.

PubMed

Groen, Iris Ia; Greene, Michelle R; Baldassano, Christopher; Fei-Fei, Li; Beck, Diane M; Baker, Chris I

2018-03-07

Inherent correlations between visual and semantic features in real-world scenes make it difficult to determine how different scene properties contribute to neural representations. Here, we assessed the contributions of multiple properties to scene representation by partitioning the variance explained in human behavioral and brain measurements by three feature models whose inter-correlations were minimized a priori through stimulus preselection. Behavioral assessments of scene similarity reflected unique contributions from a functional feature model indicating potential actions in scenes as well as high-level visual features from a deep neural network (DNN). In contrast, similarity of cortical responses in scene-selective areas was uniquely explained by mid- and high-level DNN features only, while an object label model did not contribute uniquely to either domain. The striking dissociation between functional and DNN features in their contribution to behavioral and brain representations of scenes indicates that scene-selective cortex represents only a subset of behaviorally relevant scene information.

Lactosamine-Based Derivatives as Tools to Delineate the Biological Functions of Galectins: Application to Skin Tissue Repair.

PubMed

Dion, Johann; Deshayes, Frédérique; Storozhylova, Nataliya; Advedissian, Tamara; Lambert, Annie; Viguier, Mireille; Tellier, Charles; Dussouy, Christophe; Poirier, Françoise; Grandjean, Cyrille

2017-04-18

Galectins have been recognized as potential novel therapeutic targets for the numerous fundamental biological processes in which they are involved. Galectins are key players in homeostasis, and as such their expression and function are finely tuned in vivo. Thus, their modes of action are complex and remain largely unexplored, partly because of the lack of dedicated tools. We thus designed galectin inhibitors from a lactosamine core, functionalized at key C2 and C3' positions by aromatic substituents to ensure both high affinity and selectivity, and equipped with a spacer that can be modified on demand to further modulate their physico-chemical properties. As a proof-of-concept, galectin-3 was selectively targeted. The efficacy of the synthesized di-aromatic lactosamine tools was shown in cellular assays to modulate collective epithelial cell migration and to interfere with actin/cortactin localization. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evolution of an intricate J-protein network driving protein disaggregation in eukaryotes.

PubMed

Nillegoda, Nadinath B; Stank, Antonia; Malinverni, Duccio; Alberts, Niels; Szlachcic, Anna; Barducci, Alessandro; De Los Rios, Paolo; Wade, Rebecca C; Bukau, Bernd

2017-05-15

Hsp70 participates in a broad spectrum of protein folding processes extending from nascent chain folding to protein disaggregation. This versatility in function is achieved through a diverse family of J-protein cochaperones that select substrates for Hsp70. Substrate selection is further tuned by transient complexation between different classes of J-proteins, which expands the range of protein aggregates targeted by metazoan Hsp70 for disaggregation. We assessed the prevalence and evolutionary conservation of J-protein complexation and cooperation in disaggregation. We find the emergence of a eukaryote-specific signature for interclass complexation of canonical J-proteins. Consistently, complexes exist in yeast and human cells, but not in bacteria, and correlate with cooperative action in disaggregation in vitro. Signature alterations exclude some J-proteins from networking, which ensures correct J-protein pairing, functional network integrity and J-protein specialization. This fundamental change in J-protein biology during the prokaryote-to-eukaryote transition allows for increased fine-tuning and broadening of Hsp70 function in eukaryotes.

The Adaptation for Conservation Targets (ACT) framework: a tool for incorporating climate change into natural resource management.

PubMed

Cross, Molly S; Zavaleta, Erika S; Bachelet, Dominique; Brooks, Marjorie L; Enquist, Carolyn A F; Fleishman, Erica; Graumlich, Lisa J; Groves, Craig R; Hannah, Lee; Hansen, Lara; Hayward, Greg; Koopman, Marni; Lawler, Joshua J; Malcolm, Jay; Nordgren, John; Petersen, Brian; Rowland, Erika L; Scott, Daniel; Shafer, Sarah L; Shaw, M Rebecca; Tabor, Gary M

2012-09-01

As natural resource management agencies and conservation organizations seek guidance on responding to climate change, myriad potential actions and strategies have been proposed for increasing the long-term viability of some attributes of natural systems. Managers need practical tools for selecting among these actions and strategies to develop a tailored management approach for specific targets at a given location. We developed and present one such tool, the participatory Adaptation for Conservation Targets (ACT) framework, which considers the effects of climate change in the development of management actions for particular species, ecosystems and ecological functions. Our framework is based on the premise that effective adaptation of management to climate change can rely on local knowledge of an ecosystem and does not necessarily require detailed projections of climate change or its effects. We illustrate the ACT framework by applying it to an ecological function in the Greater Yellowstone Ecosystem (Montana, Wyoming, and Idaho, USA)--water flows in the upper Yellowstone River. We suggest that the ACT framework is a practical tool for initiating adaptation planning, and for generating and communicating specific management interventions given an increasingly altered, yet uncertain, climate.

The Adaptation for Conservation Targets (ACT) Framework: A tool for incorporating climate change into natural resource management

USGS Publications Warehouse

Cross, Molly S.; Zavaleta, Erika S.; Bachelet, Dominique; Brooks, Marjorie L.; Enquist, Carolyn A.F.; Fleishman, Erica; Graumlich, Lisa J.; Groves, Craig R.; Hannah, Lee; Hansen, Lara J.; Hayward, Gregory D.; Koopman, Marni; Lawler, Joshua J.; Malcolm, Jay; Nordgren, John R.; Petersen, Brian; Rowland, Erika; Scott, Daniel; Shafer, Sarah L.; Shaw, M. Rebecca; Tabor, Gary

2012-01-01

As natural resource management agencies and conservation organizations seek guidance on responding to climate change, myriad potential actions and strategies have been proposed for increasing the long-term viability of some attributes of natural systems. Managers need practical tools for selecting among these actions and strategies to develop a tailored management approach for specific targets at a given location. We developed and present one such tool, the participatory Adaptation for Conservation Targets (ACT) framework, which considers the effects of climate change in the development of management actions for particular species, ecosystems and ecological functions. Our framework is based on the premise that effective adaptation of management to climate change can rely on local knowledge of an ecosystem and does not necessarily require detailed projections of climate change or its effects. We illustrate the ACT framework by applying it to an ecological function in the Greater Yellowstone Ecosystem (Montana, Wyoming, and Idaho, USA)—water flows in the upper Yellowstone River. We suggest that the ACT framework is a practical tool for initiating adaptation planning, and for generating and communicating specific management interventions given an increasingly altered, yet uncertain, climate.

Prostaglandin E2 modulates dendritic cell function via EP2 and EP4 receptor subtypes.

PubMed

Harizi, Hedi; Grosset, Christophe; Gualde, Norbert

2003-06-01

We have reported previously that PGE(2) inhibits dendritic cells (DC) functions. Because E prostanoid receptor (EPR) subtypes involved in this action are unknown, expression and functions of these receptors were examined in DC. Western blot and flow cytometry analyses showed that all EPRs were coexpressed in DC. In a dose-dependent manner, lipopolysaccharide (LPS) enhanced EP(2)R/EP(4)R but not EP(1)R/EP(3)R expressions. NS-398, a cyclooxygenase (COX)-2-selective inhibitor, suppressed LPS-enhanced EP(2)R/EP(4)R expression, suggesting that COX-2-issued prostaglandin E(2) (PGE(2)) modulates DC function through stimulation of specific EPR subtypes. Using selective agonists, we found that butaprost, an EP(2)R agonist, and PGE(1) alcohol, an EP(2)R and EP(2)R/EP(4)R agonist, inhibited major histocompatibility complex class II expression and enhanced interleukin-10 production from DC. However, no effect was observed with sulprostone and 17-phenyl-omega-trinor-PGE(2), selective agonists for EP(1)R and EP(1)R/EP(3)R, respectively. Treatment of DC with dibutyryl cyclic adenosine monophosphate (cAMP), an analog of cAMP, mimics PGE(2)-induced, inhibitory effects. Taken together, our data demonstrate that EP(2)R/EP(4)R are efficient for mediating PGE(2)-induced modulation of DC functions.

Early-Life Cocaine Interferes with BDNF-Mediated Behavioral Plasticity

ERIC Educational Resources Information Center

Hinton, Elizabeth A.; Wheeler, Marina G.; Gourley, Shannon L.

2014-01-01

An important aspect of goal-directed action selection is differentiating between actions that are more or less likely to be reinforced. With repeated performance or psychostimulant exposure, however, actions can assume stimulus-elicited--or "habitual"--qualities that are resistant to change. We show that selective knockdown of prelimbic…

Seven Transmembrane Receptors as Shapeshifting Proteins: The Impact of Allosteric Modulation and Functional Selectivity on New Drug Discovery

PubMed Central

Miller, Laurence J.

2010-01-01

It is useful to consider seven transmembrane receptors (7TMRs) as disordered proteins able to allosterically respond to a number of binding partners. Considering 7TMRs as allosteric systems, affinity and efficacy can be thought of in terms of energy flow between a modulator, conduit (the receptor protein), and a number of guests. These guests can be other molecules, receptors, membrane-bound proteins, or signaling proteins in the cytosol. These vectorial flows of energy can yield standard canonical guest allostery (allosteric modification of drug effect), effects along the plane of the cell membrane (receptor oligomerization), or effects directed into the cytosol (differential signaling as functional selectivity). This review discusses these apparently diverse pharmacological effects in terms of molecular dynamics and protein ensemble theory, which tends to unify 7TMR behavior toward cells. Special consideration will be given to functional selectivity (biased agonism and biased antagonism) in terms of mechanism of action and potential therapeutic application. The explosion of technology that has enabled observation of diverse 7TMR behavior has also shown how drugs can have multiple (pluridimensional) efficacies and how this can cause paradoxical drug classification and nomenclatures. PMID:20392808

Independent losses of function in a polyphenol oxidase in rice: differentiation in grain discoloration between subspecies and the role of positive selection under domestication.

PubMed

Yu, Yanchun; Tang, Tian; Qian, Qian; Wang, Yonghong; Yan, Meixian; Zeng, Dali; Han, Bin; Wu, Chung-I; Shi, Suhua; Li, Jiayang

2008-11-01

Asian rice (Oryza sativa) cultivars originated from wild rice and can be divided into two subspecies by several criteria, one of which is the phenol reaction (PHR) phenotype. Grains of indica cultivars turn brown in a phenol solution that accelerates a similar process that occurs during prolonged storage. By contrast, the grains of japonica do not discolor. This distinction may reflect the divergent domestication of these two subspecies. The PHR is controlled by a single gene, Phr1; here, we report the cloning of Phr1, which encodes a polyphenol oxidase. The Phr1 gene is indeed responsible for the PHR phenotype, as transformation with a functional Phr1 can complement a PHR negative cultivar. Phr1 is defective in all japonica lines but functional in nearly all indica and wild strains. Phylogenetic analysis showed that the defects in Phr1 arose independently three times. The multiple recent origins and rapid spread of phr1 in japonica suggest the action of positive selection, which is further supported by several population genetic tests. This case may hence represent an example of artificial selection driving the differentiation among domesticated varieties.

Enzymes in human milk

PubMed Central

Dallas, David C.; German, J. Bruce

2017-01-01

Milk proteins are a complex and diverse source of biological activities. Beyond their function intact, milk proteins also act as carriers of encrypted functional sequences that when released as peptides exert biological functions, including antimicrobial and immunomodulatory, which could contribute to the infant’s competitive success. Research has now revealed that the release of these functional peptides begins within the mammary gland itself. A complex array of proteases produced in mother’s milk have been shown to be active in the milk, releasing these peptides. Moreover, our recent research demonstrates that these milk proteases continue to digest milk proteins within the infant’s stomach, possibly even to a larger extent than the infant’s own proteases. As the neonate has relatively low digestive capacity, the activity of milk proteases in the infant may provide important assistance to digesting milk proteins. The coordinated release of these encrypted sequences is accomplished by selective proteolytic action provided by an array of native milk proteases and infant-produced enzymes. The task for scientists is now to discover the selective advantages of this protein-protease based peptide release system. PMID:28346930

Enzymes in Human Milk.

PubMed

Dallas, David C; German, J Bruce

2017-01-01

Milk proteins are a complex and diverse source of biological activities. Beyond their function, intact milk proteins also act as carriers of encrypted functional sequences that, when released as peptides, exert biological functions, including antimicrobial and immunomodulatory activity, which could contribute to the infant's competitive success. Research has now revealed that the release of these functional peptides begins within the mammary gland itself. A complex array of proteases produced in mother's milk has been shown to be active in the milk, releasing these peptides. Moreover, our recent research demonstrates that these milk proteases continue to digest milk proteins within the infant's stomach, possibly even to a larger extent than the infant's own proteases. As the neonate has relatively low digestive capacity, the activity of milk proteases in the infant may provide important assistance to digesting milk proteins. The coordinated release of these encrypted sequences is accomplished by selective proteolytic action provided by an array of native milk proteases and infant-produced enzymes. The task for scientists is now to discover the selective advantages of this protein-protease-based peptide release system. © 2017 Nestec Ltd., Vevey/S. Karger AG, Basel.

The dissociation between command following and communication in disorders of consciousness: an fMRI study in healthy subjects.

PubMed

Osborne, Natalie R; Owen, Adrian M; Fernández-Espejo, Davinia

2015-01-01

Neuroimaging studies have identified a subgroup of patients with a Disorder of Consciousness (DOC) who, while being behaviorally non-responsive, are nevertheless able to follow commands by modulating their brain activity in motor imagery (MI) tasks. These techniques have even allowed for binary communication in a small number of DOC patients. However, the majority of patients who can follow commands are unable to use their responses to communicate. A similar dissociation between present command following (CF) and absent communication abilities has been reported in overt behavioral assessments. However, the neural correlates of this dissociation in both overt and covert modalities are unknown. Here, we used functional magnetic resonance imaging (fMRI) to explore the neural mechanisms underlying CF and selection of responses for binary communication using either executed or imagined movements. Fifteen healthy participants executed or imagined two different types of arm movements that were either pre-determined by the experimenters (CF) or decided by them (action selection, AS). Action selection involved greater activity in high-level associative areas in frontal and parietal regions than CF. Additionally, motor execution (ME), as compared to MI, activated contralateral motor cortex, while the opposite contrast revealed activation in the ipsilateral sensorimotor cortex and the left inferior frontal gyrus. Importantly, there was no interaction between the task (CF/AS) and modality (MI/ME). Our results suggest that the neural processes involved in following a motor command or selecting between two motor actions are not dependent on how the response is expressed (via ME/MI). They also suggest a potential neural basis for the distinction in cognitive abilities seen in DOC patients.

The dissociation between command following and communication in disorders of consciousness: an fMRI study in healthy subjects

PubMed Central

Osborne, Natalie R.; Owen, Adrian M.; Fernández-Espejo, Davinia

2015-01-01

Neuroimaging studies have identified a subgroup of patients with a Disorder of Consciousness (DOC) who, while being behaviorally non-responsive, are nevertheless able to follow commands by modulating their brain activity in motor imagery (MI) tasks. These techniques have even allowed for binary communication in a small number of DOC patients. However, the majority of patients who can follow commands are unable to use their responses to communicate. A similar dissociation between present command following (CF) and absent communication abilities has been reported in overt behavioral assessments. However, the neural correlates of this dissociation in both overt and covert modalities are unknown. Here, we used functional magnetic resonance imaging (fMRI) to explore the neural mechanisms underlying CF and selection of responses for binary communication using either executed or imagined movements. Fifteen healthy participants executed or imagined two different types of arm movements that were either pre-determined by the experimenters (CF) or decided by them (action selection, AS). Action selection involved greater activity in high-level associative areas in frontal and parietal regions than CF. Additionally, motor execution (ME), as compared to MI, activated contralateral motor cortex, while the opposite contrast revealed activation in the ipsilateral sensorimotor cortex and the left inferior frontal gyrus. Importantly, there was no interaction between the task (CF/AS) and modality (MI/ME). Our results suggest that the neural processes involved in following a motor command or selecting between two motor actions are not dependent on how the response is expressed (via ME/MI). They also suggest a potential neural basis for the distinction in cognitive abilities seen in DOC patients. PMID:26441593

(3) Development of composite adsorbents for high decontamination and their selective adsorption properties

NASA Astrophysics Data System (ADS)

Mimura, Hitoshi; Yamagishi, Isao

In an action for the convergence of the Fukushima Daiichi Nuclear Power Plant accident, the completion of Step 2 was declared in last December, 2011. As for the circulating cooling system supporting the cold shutdown of nuclear reactor, the temporary treatment equipment operation maintains stability. On the other hand, the establishment of permanent equipments, safety storage, treatment and disposal for the secondary solid wastes are urgent subjects. This special issue deals with the development of highly functional composite adsorbents and the evaluation of selective adsorption properties. The technical issues for the stable treatment and disposal of solid wastes are further discussed.

R-type Ca(2+) channels contribute to fast synaptic excitation and action potentials in subsets of myenteric neurons in the guinea pig intestine.

PubMed

Naidoo, V; Dai, X; Galligan, J J

2010-12-01

R-type Ca(2+) channels are expressed by myenteric neurons in the guinea pig ileum but the specific function of these channels is unknown. In the present study, we used intracellular electrophysiological techniques to determine the function of R-type Ca(2+) channels in myenteric neurons in the acutely isolated longitudinal musclemyenteric plexus. We used immunohistochemical methods to localize the Ca(V)2.3 subunit of the R-type Ca(2+) channel in myenteric neurons. We also studied the effects of the non-selective Ca(2+) channel antagonist, CdCl₂ (100 μmol L⁻¹), the R-type Ca(2+) channel blockers NiCl₂ (50 μmol L⁻¹) and SNX-482 (0.1 μmol L⁻¹), and the N-type Ca(2+) channel blocker x-conotoxin GVIA (CTX 0.1 μmol L⁻¹) on action potentials and fast and slow excitatory postsynaptic potentials (fEPSPs and sEPSPs) in S and AH neurons in vitro. Ca(V)2.3 co-localized with calretinin and calbindin in myenteric neurons. NiCl₂ and SNX-482 reduced the duration and amplitude of action potentials in AH but not S neurons. NiCl₂ inhibited the afterhyperpolarization in AH neurons. x-conotoxin GVIA, but not NiCl₂, blocked sEPSPs in AH neurons. NiCl₂ and SNX-482 inhibited cholinergic, but not cholinergic/purinergic, fEPSPs in S neurons. These data show that R-type Ca(2+) channels contribute to action potentials, but not slow synaptic transmission, in AH neurons. R-type Ca(2+) channels contribute to release of acetylcholine as the mediator of fEPSPs in some S neurons. These data indicate that R-type Ca(2+) channels may be a target for drugs that selectively modulate activity of AH neurons or could alter fast synaptic excitation in specific pathways in the myenteric plexus.

Deep brain stimulation of the subthalamic nucleus modulates reward processing and action selection in Parkinson patients.

PubMed

Wagenbreth, Caroline; Zaehle, Tino; Galazky, Imke; Voges, Jürgen; Guitart-Masip, Marc; Heinze, Hans-Jochen; Düzel, Emrah

2015-06-01

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for motor impairments in Parkinson's disease (PD) but its effect on the motivational regulation of action control is still not fully understood. We investigated whether DBS of the STN influences the ability of PD patients to act for anticipated reward or loss, or whether DBS improves action execution independent of motivational valence. 16 PD patients (12 male, mean age = 58.5 ± 10.17 years) treated with bilateral STN-DBS and an age- and gender-matched group of healthy controls (HC) performed a go/no-go task whose contingencies explicitly decouple valence and action. Patients were tested with (ON) and without (OFF) active STN stimulation. For HC, there was a benefit in performing rewarded actions when compared to actions that avoided punishment. PD patients showed such a benefit reliably only when STN stimulation was ON. In fact, the relative behavioral benefit for go for reward over go to avoid losing was stronger in the PD patients under DBS ON than in HC. In PD patients, rather than generally improving motor functions independent of motivational valence, modulation of the STN by DBS improves action execution specifically when rewards are anticipated. Thus, STN-DBS establishes a reliable congruency between action and reward ("Pavlovian congruency") and remarkably enhances it over the level observed in HC.

STN1 OB Fold Mutation Alters DNA Binding and Affects Selective Aspects of CST Function

PubMed Central

Bhattacharjee, Anukana; Stewart, Jason; Chaiken, Mary; Price, Carolyn M.

2016-01-01

Mammalian CST (CTC1-STN1-TEN1) participates in multiple aspects of telomere replication and genome-wide recovery from replication stress. CST resembles Replication Protein A (RPA) in that it binds ssDNA and STN1 and TEN1 are structurally similar to RPA2 and RPA3. Conservation between CTC1 and RPA1 is less apparent. Currently the mechanism underlying CST action is largely unknown. Here we address CST mechanism by using a DNA-binding mutant, (STN1 OB-fold mutant, STN1-OBM) to examine the relationship between DNA binding and CST function. In vivo, STN1-OBM affects resolution of endogenous replication stress and telomere duplex replication but telomeric C-strand fill-in and new origin firing after exogenous replication stress are unaffected. These selective effects indicate mechanistic differences in CST action during resolution of different replication problems. In vitro binding studies show that STN1 directly engages both short and long ssDNA oligonucleotides, however STN1-OBM preferentially destabilizes binding to short substrates. The finding that STN1-OBM affects binding to only certain substrates starts to explain the in vivo separation of function observed in STN1-OBM expressing cells. CST is expected to engage DNA substrates of varied length and structure as it acts to resolve different replication problems. Since STN1-OBM will alter CST binding to only some of these substrates, the mutant should affect resolution of only a subset of replication problems, as was observed in the STN1-OBM cells. The in vitro studies also provide insight into CST binding mechanism. Like RPA, CST likely contacts DNA via multiple OB folds. However, the importance of STN1 for binding short substrates indicates differences in the architecture of CST and RPA DNA-protein complexes. Based on our results, we propose a dynamic DNA binding model that provides a general mechanism for CST action at diverse forms of replication stress. PMID:27690379

Where neuroscience and dynamic system theory meet autonomous robotics: a contracting basal ganglia model for action selection.

PubMed

Girard, B; Tabareau, N; Pham, Q C; Berthoz, A; Slotine, J-J

2008-05-01

Action selection, the problem of choosing what to do next, is central to any autonomous agent architecture. We use here a multi-disciplinary approach at the convergence of neuroscience, dynamical system theory and autonomous robotics, in order to propose an efficient action selection mechanism based on a new model of the basal ganglia. We first describe new developments of contraction theory regarding locally projected dynamical systems. We exploit these results to design a stable computational model of the cortico-baso-thalamo-cortical loops. Based on recent anatomical data, we include usually neglected neural projections, which participate in performing accurate selection. Finally, the efficiency of this model as an autonomous robot action selection mechanism is assessed in a standard survival task. The model exhibits valuable dithering avoidance and energy-saving properties, when compared with a simple if-then-else decision rule.

Infants Show Stability of Goal-Directed Imitation

ERIC Educational Resources Information Center

Sakkalou, Elena; Ellis-Davies, Kate; Fowler, Nia C.; Hilbrink, Elma E.; Gattis, Merideth

2013-01-01

Previous studies have reported that infants selectively reproduce observed actions and have argued that this selectivity reflects understanding of intentions and goals, or goal-directed imitation. We reasoned that if selective imitation of goal-directed actions reflects understanding of intentions, infants should demonstrate stability across…

Demystifying Probiotics: Use in the Elderly.

PubMed

Martin, Caren McHenry; Bryan, Gianna

2017-08-01

Pharmacists and other health care professionals can be perplexed by the growing body of literature regarding the use of probiotics for a variety of symptoms and conditions and by an increasing number of probiotic products available to consumers. Understanding the functions of the intestinal microbiome, the possible mechanisms of actions of probiotics, the research supporting or refuting probiotic use, and criteria for selecting a probiotic product is essential to making a rational recommendation for patients.

Automated Author Aiding System Conference

DTIC Science & Technology

1985-07-01

fraie. Most selections lead to other frames , but some have " actions ", which perform a procedural function such as running a particular program. Finally...S. Army L=J Research Institute for thie Behavioral and Social Sciences..- j July 1985 APProved for public release; distribullon unlimited. ,8 6 .. U...Repotf) Approved for public release; distribution unlimited 17. GISTRIOUTION STATEMENT (.o UI. sba’,ect tr.,.d i. Block 20, t diff.,ret from Repoar) Is

TRPM4 non-selective cation channels influence action potentials in rabbit Purkinje fibres.

PubMed

Hof, Thomas; Sallé, Laurent; Coulbault, Laurent; Richer, Romain; Alexandre, Joachim; Rouet, René; Manrique, Alain; Guinamard, Romain

2016-01-15

The transient receptor potential melastatin 4 (TRPM4) inhibitor 9-phenanthrol reduces action potential duration in rabbit Purkinje fibres but not in ventricle. TRPM4-like single channel activity is observed in isolated rabbit Purkinje cells but not in ventricular cells. The TRPM4-like current develops during the notch and early repolarization phases of the action potential in Purkinje cells. Transient receptor potential melastatin 4 (TRPM4) Ca(2+)-activated non-selective cation channel activity has been recorded in cardiomyocytes and sinus node cells from mammals. In addition, TRPM4 gene mutations are associated with human diseases of cardiac conduction, suggesting that TRPM4 plays a role in this aspect of cardiac function. Here we evaluate the TRPM4 contribution to cardiac electrophysiology of Purkinje fibres. Ventricular strips with Purkinje fibres were isolated from rabbit hearts. Intracellular microelectrodes recorded Purkinje fibre activity and the TRPM4 inhibitor 9-phenanthrol was applied to unmask potential TRPM4 contributions to the action potential. 9-Phenanthrol reduced action potential duration measured at the point of 50 and 90% repolarization with an EC50 of 32.8 and 36.1×10(-6) mol l(-1), respectively, but did not modulate ventricular action potentials. Inside-out patch-clamp recordings were used to monitor TRPM4 activity in isolated Purkinje cells. TRPM4-like single channel activity (conductance = 23.8 pS; equal permeability for Na(+) and K(+); sensitivity to voltage, Ca(2+) and 9-phenanthrol) was observed in 43% of patches from Purkinje cells but not from ventricular cells (0/16). Action potential clamp experiments performed in the whole-cell configuration revealed a transient inward 9-phenanthrol-sensitive current (peak density = -0.65 ± 0.15 pA pF(-1); n = 5) during the plateau phases of the Purkinje fibre action potential. These results show that TRPM4 influences action potential characteristics in rabbit Purkinje fibres and thus could modulate cardiac conduction and be involved in triggering arrhythmias. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Functional neuroanatomy of intuitive physical inference

PubMed Central

Mikhael, John G.; Tenenbaum, Joshua B.; Kanwisher, Nancy

2016-01-01

To engage with the world—to understand the scene in front of us, plan actions, and predict what will happen next—we must have an intuitive grasp of the world’s physical structure and dynamics. How do the objects in front of us rest on and support each other, how much force would be required to move them, and how will they behave when they fall, roll, or collide? Despite the centrality of physical inferences in daily life, little is known about the brain mechanisms recruited to interpret the physical structure of a scene and predict how physical events will unfold. Here, in a series of fMRI experiments, we identified a set of cortical regions that are selectively engaged when people watch and predict the unfolding of physical events—a “physics engine” in the brain. These brain regions are selective to physical inferences relative to nonphysical but otherwise highly similar scenes and tasks. However, these regions are not exclusively engaged in physical inferences per se or, indeed, even in scene understanding; they overlap with the domain-general “multiple demand” system, especially the parts of that system involved in action planning and tool use, pointing to a close relationship between the cognitive and neural mechanisms involved in parsing the physical content of a scene and preparing an appropriate action. PMID:27503892

Functional neuroanatomy of intuitive physical inference.

PubMed

Fischer, Jason; Mikhael, John G; Tenenbaum, Joshua B; Kanwisher, Nancy

2016-08-23

To engage with the world-to understand the scene in front of us, plan actions, and predict what will happen next-we must have an intuitive grasp of the world's physical structure and dynamics. How do the objects in front of us rest on and support each other, how much force would be required to move them, and how will they behave when they fall, roll, or collide? Despite the centrality of physical inferences in daily life, little is known about the brain mechanisms recruited to interpret the physical structure of a scene and predict how physical events will unfold. Here, in a series of fMRI experiments, we identified a set of cortical regions that are selectively engaged when people watch and predict the unfolding of physical events-a "physics engine" in the brain. These brain regions are selective to physical inferences relative to nonphysical but otherwise highly similar scenes and tasks. However, these regions are not exclusively engaged in physical inferences per se or, indeed, even in scene understanding; they overlap with the domain-general "multiple demand" system, especially the parts of that system involved in action planning and tool use, pointing to a close relationship between the cognitive and neural mechanisms involved in parsing the physical content of a scene and preparing an appropriate action.

Serotonin and Blood Pressure Regulation

PubMed Central

Morrison, Shaun F.; Davis, Robert Patrick; Barman, Susan M.

2012-01-01

5-Hydroxytryptamine (5-HT; serotonin) was discovered more than 60 years ago as a substance isolated from blood. The neural effects of 5-HT have been well investigated and understood, thanks in part to the pharmacological tools available to dissect the serotonergic system and the development of the frequently prescribed selective serotonin-reuptake inhibitors. By contrast, our understanding of the role of 5-HT in the control and modification of blood pressure pales in comparison. Here we focus on the role of 5-HT in systemic blood pressure control. This review provides an in-depth study of the function and pharmacology of 5-HT in those tissues that can modify blood pressure (blood, vasculature, heart, adrenal gland, kidney, brain), with a focus on the autonomic nervous system that includes mechanisms of action and pharmacology of 5-HT within each system. We compare the change in blood pressure produced in different species by short- and long-term administration of 5-HT or selective serotonin receptor agonists. To further our understanding of the mechanisms through which 5-HT modifies blood pressure, we also describe the blood pressure effects of commonly used drugs that modify the actions of 5-HT. The pharmacology and physiological actions of 5-HT in modifying blood pressure are important, given its involvement in circulatory shock, orthostatic hypotension, serotonin syndrome and hypertension. PMID:22407614

Dose Dependent Dopaminergic Modulation of Reward-Based Learning in Parkinson's Disease

ERIC Educational Resources Information Center

van Wouwe, N. C.; Ridderinkhof, K. R.; Band, G. P. H.; van den Wildenberg, W. P. M.; Wylie, S. A.

2012-01-01

Learning to select optimal behavior in new and uncertain situations is a crucial aspect of living and requires the ability to quickly associate stimuli with actions that lead to rewarding outcomes. Mathematical models of reinforcement-based learning to select rewarding actions distinguish between (1) the formation of stimulus-action-reward…

Nuclear and Membrane Actions of Estrogen Receptor Alpha: Contribution to the Regulation of Energy and Glucose Homeostasis.

PubMed

Guillaume, Maeva; Montagner, Alexandra; Fontaine, Coralie; Lenfant, Françoise; Arnal, Jean-François; Gourdy, Pierre

2017-01-01

Estrogen receptor alpha (ERα) has been demonstrated to play a key role in reproduction but also to exert numerous functions in nonreproductive tissues. Accordingly, ERα is now recognized as a key regulator of energy homeostasis and glucose metabolism and mediates the protective effects of estrogens against obesity and type 2 diabetes. This chapter attempts to summarize our current understanding of the mechanisms of ERα activation and their involvement in the modulation of energy balance and glucose metabolism. We first focus on the experimental studies that constitute the basis of the understanding of ERα as a nuclear receptor and more specifically on the key roles played by its two activation functions (AFs). We depict the consequences of the selective inactivation of these AFs in mouse models, which further underline the prominent role of nuclear ERα in the prevention of obesity and diabetes, as on the reproductive tract and the vascular system. Besides these nuclear actions, a fraction of ERα is associated with the plasma membrane and activates nonnuclear signaling from this site. Such rapid effects, called membrane-initiated steroid signals (MISS), have been characterized in a variety of cell lines and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS as well as the generation of mice expressing an ERα protein impeded for membrane localization has just begun to unravel the physiological role of MISS in vivo and their contribution to ERα-mediated metabolic protection. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators.

Socio-Economic Status (SES) Affects Infants' Selective Exploration

ERIC Educational Resources Information Center

Tacke, Nicholas F.; Bailey, Lillian S.; Clearfield, Melissa W.

2015-01-01

Infants change their behaviours in accordance with the objects they are exploring. They also tailor their exploratory actions to the physical context. This selectivity of exploratory actions represents a foundational cognitive skill that underlies higher-level cognitive processes. The present study compared the development of selective exploratory…

Closure Report for Corrective Action Unit 568: Area 3 Plutonium Dispersion Sites Nevada National Security Site, Nevada, Revision 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matthews, Patrick

The purpose of this CR is to provide documentation and justification that no further corrective action is needed for the closure of CAU 568 based on the implementation of corrective actions. This includes a description of closure activities that were performed and an evaluation of the verification data. The CAP (NNSA/NFO, 2016a) and ROTC-1 (NNSA/NFO, 2016c) provide information relating to the selection of CAAs and the reasoning behind their selection. The CADD (NNSA/NFO, 2015) identifies the release sites that require additional corrective action and presents information supporting the selection of CAAs.

Design and Characterization of a Multifunctional pH-Triggered Peptide C8 for Selective Anticancer Activity.

PubMed

Lu, Sheng; Bennett, W F Drew; Ding, Yong; Zhang, Lei; Fan, Helen Y; Zhao, Danyang; Zheng, Tao; Ouyang, Ping-Kai; Li, Jason; Wu, Yan; Xu, Wen; Chu, Dafeng; Yuan, Yongfang; Heerklotz, Heiko; Karttunen, Mikko; Chen, P

2015-12-09

Most drug delivery systems have been developed for efficient delivery to tumor sites via targeting and on-demand strategies, but the carriers rarely execute synergistic therapeutic actions. In this work, C8, a cationic, pH-triggered anticancer peptide, is developed by incorporating histidine-mediated pH-sensitivity, amphipathic helix, and amino acid pairing self-assembly design. We designed C8 to function as a pH-responsive nanostructure whose cytotoxicity can be switched on and off by its self-assembly: Noncytotoxic β-sheet fibers at high pH with neutral histidines, and positively charged monomers with membrane lytic activity at low pH. The selective activity of C8, tested for three different cancer cell lines and two noncancerous cell lines, is shown. Based on liposome leakage assays and multiscale computer simulations, its physical mechanisms of pore-forming action and selectivity are proposed, which originate from differences in the lipid composition of the cellular membrane and changes in hydrogen bonding. C8 is then investigated for its potential as a drug carrier. C8 forms a nanocomplex with ellipticine, a nonselective model anticancer drug. It selectively targets cancer cells in a pH-responsive manner, demonstrating enhanced efficacy and selectivity. This study provides a novel powerful strategy for the design and development of multifunctional self-assembling peptides for therapeutic and drug delivery applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

P2X and P2Y nucleotide receptors as targets in cardiovascular disease.

PubMed

Kennedy, Charles; Chootip, Krongkarn; Mitchell, Callum; Syed, Nawazish-i-Husain; Tengah, Asrin

2013-03-01

Endogenous nucleotides have widespread actions in the cardiovascular system, but it is only recently that the P2X and P2Y receptor subtypes, at which they act, have been identified and subtype-selective agonists and antagonists developed. These advances have greatly increased our understanding of the physiological and pathophysiological functions of P2X and P2Y receptors, but investigation of the clinical usefulness of selective ligands is at an early stage. Nonetheless, the evidence considered in this review demonstrates clearly that various cardiovascular disorders, including vasospasm, hypertension, congestive heart failure and cardiac damage during ischemic episodes, may be viable targets. With further development of novel, selective agonists and antagonists, our understanding will continue to improve and further therapeutic applications are likely to be discovered.

Select Dietary Phytochemicals Function as Inhibitors of COX-1 but Not COX-2

PubMed Central

Li, Haitao; Zhu, Feng; Sun, Yanwen; Li, Bing; Oi, Naomi; Chen, Hanyong; Lubet, Ronald A.; Bode, Ann M.; Dong, Zigang

2013-01-01

Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors. Many active dietary factors are reported to suppress carcinogenesis by targeting COX-2. A major question was accordingly raised: why has the lifelong use of phytochemicals that likely inhibit COX-2 presumably not been associated with adverse cardiovascular side effects. To answer this question, we selected a library of dietary-derived phytochemicals and evaluated their potential cardiovascular toxicity in human umbilical vein endothelial cells. Our data indicated that the possibility of cardiovascular toxicity of these dietary phytochemicals was low. Further mechanistic studies revealed that the actions of these phytochemicals were similar to aspirin in that they mainly inhibited COX-1 rather than COX-2, especially at low doses. PMID:24098505

Chemoselective Hydroxyl Group Transformation: An Elusive Target‡

PubMed Central

Trader, Darci J.; Carlson, Erin E.

2012-01-01

The selective reaction of one functional group in the presence of others is not a trivial task. A noteworthy amount of research has been dedicated to the chemoselective reaction of the hydroxyl moiety. This group is prevalent in many biologically important molecules including natural products and proteins. However, targeting the hydroxyl group is difficult for many reasons including its relatively low nucleophilicity in comparison to other ubiquitous functional groups such as amines and thiols. Additionally, many of the developed chemoselective reactions cannot be used in the presence of water. Despite these complications, chemoselective transformation of the hydroxyl moiety has been utilized in the synthesis of complex natural product derivatives, the reaction of tyrosine residues in proteins, the isolation of natural products and is the mechanism of action of myriad drugs. Here, methods for selective targeting of this group, as well as applications of several devised methods, are described. PMID:22695722

Rational action selection in 1½- to 3-year-olds following an extended training experience.

PubMed

Klossek, Ulrike M H; Dickinson, Anthony

2012-02-01

Previous studies failed to find evidence for rational action selection in children under 2 years of age. The current study investigated whether younger children required more training to encode the relevant causal relationships. Children between 1½ and 3 years of age were trained over two sessions to perform actions on a touch-sensitive screen to obtain video clips as outcomes. Subsequently, a visual habituation procedure was employed to devalue one of the training outcomes. As in previous studies, 2- and 3-year-olds chose actions associated with an expected valued outcome significantly more often during a subsequent choice test. Moreover, analysis of children's first responses in the post-devaluation test revealed evidence of rational action selection even in the youngest age group (18-23 months). Consistent with dual-process accounts of action control, the findings support the view that the ability to make rational action choices develops gradually. 2011 Elsevier Inc. All rights reserved.

Uncovering effects of self-control and stimulus-driven action selection on the sense of agency.

PubMed

Wang, Yuru; Damen, Tom G E; Aarts, Henk

2017-10-01

The sense of agency refers to feelings of causing one's own action and resulting effect. Previous research indicates that voluntary action selection is an important factor in shaping the sense of agency. Whereas the volitional nature of the sense of agency is well documented, the present study examined whether agency is modulated when action selection shifts from self-control to a more automatic stimulus-driven process. Seventy-two participants performed an auditory Simon task including congruent and incongruent trials to generate automatic stimulus-driven vs. more self-control driven action, respectively. Responses in the Simon task produced a tone and agency was assessed with the intentional binding task - an implicit measure of agency. Results showed a Simon effect and temporal binding effect. However, temporal binding was independent of congruency. These findings suggest that temporal binding, a window to the sense of agency, emerges for both automatic stimulus-driven actions and self-controlled actions. Copyright © 2017 Elsevier Inc. All rights reserved.

Point specificity in acupuncture

PubMed Central

2012-01-01

The existence of point specificity in acupuncture is controversial, because many acupuncture studies using this principle to select control points have found that sham acupoints have similar effects to those of verum acupoints. Furthermore, the results of pain-related studies based on visual analogue scales have not supported the concept of point specificity. In contrast, hemodynamic, functional magnetic resonance imaging and neurophysiological studies evaluating the responses to stimulation of multiple points on the body surface have shown that point-specific actions are present. This review article focuses on clinical and laboratory studies supporting the existence of point specificity in acupuncture and also addresses studies that do not support this concept. Further research is needed to elucidate the point-specific actions of acupuncture. PMID:22373514

7 CFR 246.18 - Administrative review of State agency actions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... actions: (A) Denial of authorization based on the application of the vendor selection criteria for minimum...) Denial of authorization based on the vendor selection criteria for business integrity or for a current...)(iii)); (B) Denial of authorization based on the application of the vendor selection criteria for...

The Role, Involvement and Function(s) of Interleukin-35 and Interleukin-37 in Disease Pathogenesis.

PubMed

Bello, Ramatu Omenesa; Chin, Voon Kin; Abd Rachman Isnadi, Mohammad Faruq; Abd Majid, Roslaini; Atmadini Abdullah, Maizaton; Lee, Tze Yan; Amiruddin Zakaria, Zainul; Hussain, Mohd Khairi; Basir, Rusliza

2018-04-11

The recently identified cytokines-interleukin (IL)-35 and interleukin (IL)-37-have been described for their anti-inflammatory and immune-modulating actions in numerous inflammatory diseases, auto-immune disorders, malignancies, infectious diseases and sepsis. Either cytokine has been reported to be reduced and in some cases elevated and consequently contributed towards disease pathogenesis. In view of the recent advances in utilizing cytokine profiles for the development of biological macromolecules, beneficial in the management of certain intractable immune-mediated disorders, these recently characterized cytokines (IL-35 and IL-37) offer potential as reasonable targets for the discovery of novel immune-modulating anti-inflammatory therapies. A detailed comprehension of their sophisticated regulatory mechanisms and patterns of expression may provide unique opportunities for clinical application as highly selective and target specific therapeutic agents. This review seeks to summarize the recent advancements in discerning the dynamics, mechanisms, immunoregulatory and anti-inflammatory actions of IL-35 and IL-37 as they relate to disease pathogenesis.

A tachykinin-like neuroendocrine signalling axis couples central serotonin action and nutrient sensing with peripheral lipid metabolism

PubMed Central

Palamiuc, Lavinia; Noble, Tallie; Witham, Emily; Ratanpal, Harkaranveer; Vaughan, Megan; Srinivasan, Supriya

2017-01-01

Serotonin, a central neuromodulator with ancient ties to feeding and metabolism, is a major driver of body fat loss. However, mechanisms by which central serotonin action leads to fat loss remain unknown. Here, we report that the FLP-7 neuropeptide and its cognate receptor, NPR-22, function as the ligand-receptor pair that defines the neuroendocrine axis of serotonergic body fat loss in Caenorhabditis elegans. FLP-7 is secreted as a neuroendocrine peptide in proportion to fluctuations in neural serotonin circuit functions, and its release is regulated from secretory neurons via the nutrient sensor AMPK. FLP-7 acts via the NPR-22/Tachykinin2 receptor in the intestine and drives fat loss via the adipocyte triglyceride lipase ATGL-1. Importantly, this ligand-receptor pair does not alter other serotonin-dependent behaviours including food intake. For global modulators such as serotonin, the use of distinct neuroendocrine peptides for each output may be one means to achieve phenotypic selectivity. PMID:28128367

Software development to support decision making in the selection of nursing diagnoses and interventions for children and adolescents1

PubMed Central

Silva, Kenya de Lima; Évora, Yolanda Dora Martinez; Cintra, Camila Santana Justo

2015-01-01

Objective: to report the development of a software to support decision-making for the selection of nursing diagnoses and interventions for children and adolescents, based on the nomenclature of nursing diagnoses, outcomes and interventions of a university hospital in Paraiba. Method: a methodological applied study based on software engineering, as proposed by Pressman, developed in three cycles, namely: flow chart construction, development of the navigation interface, and construction of functional expressions and programming development. Result: the software consists of administrative and nursing process screens. The assessment is automatically selected according to age group, the nursing diagnoses are suggested by the system after information is inserted, and can be indicated by the nurse. The interventions for the chosen diagnosis are selected by structuring the care plan. Conclusion: the development of this tool used to document the nursing actions will contribute to decision-making and quality of care. PMID:26487144

Software development to support decision making in the selection of nursing diagnoses and interventions for children and adolescents.

PubMed

Silva, Kenya de Lima; Évora, Yolanda Dora Martinez; Cintra, Camila Santana Justo

2015-01-01

to report the development of a software to support decision-making for the selection of nursing diagnoses and interventions for children and adolescents, based on the nomenclature of nursing diagnoses, outcomes and interventions of a university hospital in Paraiba. a methodological applied study based on software engineering, as proposed by Pressman, developed in three cycles, namely: flow chart construction, development of the navigation interface, and construction of functional expressions and programming development. the software consists of administrative and nursing process screens. The assessment is automatically selected according to age group, the nursing diagnoses are suggested by the system after information is inserted, and can be indicated by the nurse. The interventions for the chosen diagnosis are selected by structuring the care plan. the development of this tool used to document the nursing actions will contribute to decision-making and quality of care.

The Innovation Paradox: A Selective Review of the Literature on Action Learning and Innovation

ERIC Educational Resources Information Center

Pedler, Mike; Brook, Cheryl

2017-01-01

This paper explores selective literatures in the two fields of action learning and innovation, and seeks insights into the processes of, and connections between, innovation, engagement and implementation. We searched the action learning articles for references to innovation, beginning with the work of Revans, who highlights the innovation paradox,…

Specialization of the Motor System in Infancy: From Broad Tuning to Selectively Specialized Purposeful Actions

ERIC Educational Resources Information Center

D'Souza, Hana; Cowie, Dorothy; Karmiloff-Smith, Annette; Bremner, Andrew J.

2017-01-01

In executing purposeful actions, adults select sufficient and necessary limbs. But infants often move goal-irrelevant limbs, suggesting a developmental process of motor specialization. Two experiments with 9- and 12-month-olds revealed gradual decreases in extraneous movements in non-acting limbs during unimanual actions. In Experiment 1,…

76 FR 41454 - Caribbean Fishery Management Council; Scoping Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-14

... based on alternative selected in Action 3(a) and time series of landings data as defined in Action 1(a...., Puerto Rico, St. Thomas/St. John, St. Croix) based on the preferred management reference point time series selected by the Council in Actions 1(a) and 2(a). Alternative 2A. Use a mid-point or equidistant...

Immune-Mediated Mechanisms of Action of Probiotics and Synbiotics in Treating Pediatric Intestinal Diseases

PubMed Central

Gil-Campos, Mercedes

2018-01-01

The pediatric population is continually at risk of developing infectious and inflammatory diseases. The treatment for infections, particularly gastrointestinal conditions, focuses on oral or intravenous rehydration, nutritional support and, in certain case, antibiotics. Over the past decade, the probiotics and synbiotics administration for the prevention and treatment of different acute and chronic infectious diseases has dramatically increased. Probiotic microorganisms are primarily used as treatments because they can stimulate changes in the intestinal microbial ecosystem and improve the immunological status of the host. The beneficial impact of probiotics is mediated by different mechanisms. These mechanisms include the probiotics’ capacity to increase the intestinal barrier function, to prevent bacterial transferation and to modulate inflammation through immune receptor cascade signaling, as well as their ability to regulate the expression of selected host intestinal genes. Nevertheless, with respect to pediatric intestinal diseases, information pertaining to these key mechanisms of action is scarce, particularly for immune-mediated mechanisms of action. In the present work, we review the biochemical and molecular mechanisms of action of probiotics and synbiotics that affect the immune system. PMID:29303974

Combining UV photodissociation action spectroscopy with electron transfer dissociation for structure analysis of gas-phase peptide cation-radicals.

PubMed

Shaffer, Christopher J; Pepin, Robert; Tureček, František

2015-12-01

We report the first example of using ultraviolet (UV) photodissociation action spectroscopy for the investigation of gas-phase peptide cation-radicals produced by electron transfer dissociation. z-Type fragment ions (●) Gly-Gly-Lys(+), coordinated to 18-crown-6-ether (CE), are generated, selected by mass and photodissociated in the 200-400 nm region. The UVPD action spectra indicate the presence of valence-bond isomers differing in the position of the Cα radical defect, (α-Gly)-Gly-Lys(+) (CE), Gly-(α-Gly)-Lys(+) (CE) and Gly-Gly-(α-Lys(+))(CE). The isomers are readily distinguishable by UV absorption spectra obtained by time-dependent density functional theory (TD-DFT) calculations. In contrast, conformational isomers of these radical types are calculated to have similar UV spectra. UV photodissociation action spectroscopy represents a new tool for the investigation of transient intermediates of ion-electron reactions. Specifically, z-type cation radicals are shown to undergo spontaneous hydrogen atom migrations upon electron transfer dissociation. Copyright © 2015 John Wiley & Sons, Ltd.

'Proactive' use of cue-context congruence for building reinforcement learning's reward function.

PubMed

Zsuga, Judit; Biro, Klara; Tajti, Gabor; Szilasi, Magdolna Emma; Papp, Csaba; Juhasz, Bela; Gesztelyi, Rudolf

2016-10-28

Reinforcement learning is a fundamental form of learning that may be formalized using the Bellman equation. Accordingly an agent determines the state value as the sum of immediate reward and of the discounted value of future states. Thus the value of state is determined by agent related attributes (action set, policy, discount factor) and the agent's knowledge of the environment embodied by the reward function and hidden environmental factors given by the transition probability. The central objective of reinforcement learning is to solve these two functions outside the agent's control either using, or not using a model. In the present paper, using the proactive model of reinforcement learning we offer insight on how the brain creates simplified representations of the environment, and how these representations are organized to support the identification of relevant stimuli and action. Furthermore, we identify neurobiological correlates of our model by suggesting that the reward and policy functions, attributes of the Bellman equitation, are built by the orbitofrontal cortex (OFC) and the anterior cingulate cortex (ACC), respectively. Based on this we propose that the OFC assesses cue-context congruence to activate the most context frame. Furthermore given the bidirectional neuroanatomical link between the OFC and model-free structures, we suggest that model-based input is incorporated into the reward prediction error (RPE) signal, and conversely RPE signal may be used to update the reward-related information of context frames and the policy underlying action selection in the OFC and ACC, respectively. Furthermore clinical implications for cognitive behavioral interventions are discussed.

Models of morality

PubMed Central

Crockett, Molly J.

2013-01-01

Moral dilemmas engender conflicts between two traditions: consequentialism, which evaluates actions based on their outcomes, and deontology, which evaluates actions themselves. These strikingly resemble two distinct decision-making architectures: a model-based system that selects actions based on inferences about their consequences; and a model-free system that selects actions based on their reinforcement history. Here, I consider how these systems, along with a Pavlovian system that responds reflexively to rewards and punishments, can illuminate puzzles in moral psychology. PMID:23845564

Information processing in decision-making systems.

PubMed

van der Meer, Matthijs; Kurth-Nelson, Zeb; Redish, A David

2012-08-01

Decisions result from an interaction between multiple functional systems acting in parallel to process information in very different ways, each with strengths and weaknesses. In this review, the authors address three action-selection components of decision-making: The Pavlovian system releases an action from a limited repertoire of potential actions, such as approaching learned stimuli. Like the Pavlovian system, the habit system is computationally fast but, unlike the Pavlovian system permits arbitrary stimulus-action pairings. These associations are a "forward'' mechanism; when a situation is recognized, the action is released. In contrast, the deliberative system is flexible but takes time to process. The deliberative system uses knowledge of the causal structure of the world to search into the future, planning actions to maximize expected rewards. Deliberation depends on the ability to imagine future possibilities, including novel situations, and it allows decisions to be taken without having previously experienced the options. Various anatomical structures have been identified that carry out the information processing of each of these systems: hippocampus constitutes a map of the world that can be used for searching/imagining the future; dorsal striatal neurons represent situation-action associations; and ventral striatum maintains value representations for all three systems. Each system presents vulnerabilities to pathologies that can manifest as psychiatric disorders. Understanding these systems and their relation to neuroanatomy opens up a deeper way to treat the structural problems underlying various disorders.

Indoxacarb, Metaflumizone, and Other Sodium Channel Inhibitor Insecticides: Mechanism and Site of Action on Mammalian Voltage-Gated Sodium Channels

PubMed Central

von Stein, Richard T.; Silver, Kristopher S.; Soderlund, David M.

2013-01-01

Sodium channel inhibitor (SCI) insecticides were discovered almost four decades ago but have only recently yielded important commercial products (eg., indoxacarb and metaflumizone). SCI insecticides inhibit sodium channel function by binding selectively to slow-inactivated (non-conducting) sodium channel states. Characterization of the action of SCI insecticides on mammalian sodium channels using both biochemical and electrophysiological approaches demonstrates that they bind at or near a drug receptor site, the "local anesthetic (LA) receptor." This mechanism and site of action on sodium channels differentiates SCI insecticides from other insecticidal agents that act on sodium channels. However, SCI insecticides share a common mode of action with drugs currently under investigation as anticonvulsants and treatments for neuropathic pain. In this paper we summarize the development of the SCI insecticide class and the evidence that this structurally diverse group of compounds have a common mode of action on sodium channels. We then review research that has used site-directed mutagenesis and heterologous expression of cloned mammalian sodium channels in Xenopus laevis oocytes to further elucidate the site and mechanism of action of SCI insecticides. The results of these studies provide new insight into the mechanism of action of SCI insecticides on voltage-gated sodium channels, the location of the SCI insecticide receptor, and its relationship to the LA receptor that binds therapeutic SCI agents. PMID:24072940

Information Processing in Decision-Making Systems

PubMed Central

van der Meer, Matthijs; Kurth-Nelson, Zeb; Redish, A. David

2015-01-01

Decisions result from an interaction between multiple functional systems acting in parallel to process information in very different ways, each with strengths and weaknesses. In this review, the authors address three action-selection components of decision-making: The Pavlovian system releases an action from a limited repertoire of potential actions, such as approaching learned stimuli. Like the Pavlovian system, the habit system is computationally fast but, unlike the Pavlovian system permits arbitrary stimulus-action pairings. These associations are a “forward” mechanism; when a situation is recognized, the action is released. In contrast, the deliberative system is flexible but takes time to process. The deliberative system uses knowledge of the causal structure of the world to search into the future, planning actions to maximize expected rewards. Deliberation depends on the ability to imagine future possibilities, including novel situations, and it allows decisions to be taken without having previously experienced the options. Various anatomical structures have been identified that carry out the information processing of each of these systems: hippocampus constitutes a map of the world that can be used for searching/imagining the future; dorsal striatal neurons represent situation-action associations; and ventral striatum maintains value representations for all three systems. Each system presents vulnerabilities to pathologies that can manifest as psychiatric disorders. Understanding these systems and their relation to neuroanatomy opens up a deeper way to treat the structural problems underlying various disorders. PMID:22492194

In Vitro Effects of Cognitives and Nootropics on Mitochondrial Respiration and Monoamine Oxidase Activity.

PubMed

Singh, Namrata; Hroudová, Jana; Fišar, Zdeněk

2017-10-01

Impairment of mitochondrial metabolism, particularly the electron transport chain (ETC), as well as increased oxidative stress might play a significant role in pathogenesis of Alzheimer's disease (AD). Some effects of drugs used for symptomatic AD treatment may be related to their direct action on mitochondrial function. In vitro effects of pharmacologically different cognitives (galantamine, donepezil, rivastigmine, 7-MEOTA, memantine) and nootropic drugs (latrepirdine, piracetam) were investigated on selected mitochondrial parameters: activities of ETC complexes I, II + III, and IV, citrate synthase, monoamine oxidase (MAO), oxygen consumption rate, and hydrogen peroxide production of pig brain mitochondria. Complex I activity was decreased by galantamine, donepezil, and memantine; complex II + III activity was increased by galantamine. None of the tested drugs caused significant changes in the rate of mitochondrial oxygen consumption, even at high concentrations. Except galantamine, all tested drugs were selective MAO-A inhibitors. Latrepirdine, donepezil, and 7-MEOTA were found to be the most potent MAO-A inhibitors. Succinate-induced mitochondrial hydrogen peroxide production was not significantly affected by the drugs tested. The direct effect of cognitives and nootropics used in the treatment of AD on mitochondrial respiration is relatively small. The safest drugs in terms of disturbing mitochondrial function appear to be piracetam and rivastigmine. The MAO-A inhibition by cognitives and nootropics may also participate in mitochondrial neuroprotection. The results support the future research aimed at measuring the effects of currently used drugs or newly synthesized drugs on mitochondrial functioning in order to understand their mechanism of action.

Critical elements in the development of cell therapy potency assays for ischemic conditions.

PubMed

Porat, Yael; Abraham, Eytan; Karnieli, Ohad; Nahum, Sagi; Woda, Juliana; Zylberberg, Claudia

2015-07-01

A successful potency assay for a cell therapy product (CTP) used in the treatment of ischemic conditions should quantitatively measure relevant biological properties that predict therapeutic activity. This is especially challenging because of numerous degrees of complexity stemming from factors that include a multifactorial complex mechanism of action, cell source, inherent cell characteristics, culture method, administration mode and the in vivo conditions to which the cells are exposed. The expected biological function of a CTP encompasses complex interactions that range from a biochemical, metabolic or immunological activity to structural replacement of damaged tissue or organ. Therefore, the requirements for full characterization of the active substance with respect to biological function could be taxing. Moreover, the specific mechanism of action is often difficult to pinpoint to a specific molecular entity; rather, it is more dependent on the functionality of the cellular components acting in a in a multifactorial fashion. In the case of ischemic conditions, the cell therapy mechanism of action can vary from angiogenesis, vasculogenesis and arteriogenesis that may activate different pathways and clinical outcomes. The CTP cellular attributes with relation to the suggested mechanism of action can be used for the development of quantitative and reproducible analytical potency assays. CTPs selected and released on the basis of such potency assays should have the highest probability of providing meaningful clinical benefit for patients. This White Paper will discuss and give examples for key elements in the development of a potency assay for treatment of ischemic disorders treated by the use of CTPs. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Western Juniper Field Guide: Asking the Right Questions to Select Appropriate Management Actions

USGS Publications Warehouse

Miller, R.F.; Bates, J.D.; Svejcar, T.J.; Pierson, F.B.; Eddleman, L.E.

2007-01-01

Introduction Strong evidence indicates that western juniper has significantly expanded its range since the late 1800s by encroaching into landscapes once dominated by shrubs and herbaceous vegetation (fig. 1). Woodland expansion affects soil resources, plant community structure and composition, water, nutrient and fire cycles, forage production, wildlife habitat, and biodiversity. Goals of juniper management include an attempt to restore ecosystem function and a more balanced plant community that includes shrubs, grasses, and forbs, and to increase ecosystem resilience to disturbances. Developing a management strategy can be a difficult task due to uncertainty about how vegetation, soils, hydrologic function, and wildlife will respond to treatments.

Prostaglandins and Inflammation

PubMed Central

Ricciotti, Emanuela; FitzGerald, Garret A.

2011-01-01

Prostaglandins are lipid autacoids derived from arachidonic acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. They are generated from arachidonate by the action of cyclooxygenase (COX) isoenzymes and their biosynthesis is blocked by nonsteroidal anti-inflammatory drugs (NSAIDs), including those selective for inhibition of COX-2. Despite the clinical efficacy of NSAIDs, prostaglandins may function in both the promotion and resolution of inflammation. This review summarizes insights into the mechanisms of prostaglandin generation and the roles of individual mediators and their receptors in modulating the inflammatory response. Prostaglandin biology has potential clinical relevance for atherosclerosis, the response to vascular injury and aortic aneurysm. PMID:21508345

Rhomboid protease inhibitors: Emerging tools and future therapeutics.

PubMed

Strisovsky, Kvido

2016-12-01

Rhomboid-family intramembrane serine proteases are evolutionarily widespread. Their functions in different organisms are gradually being uncovered and already suggest medical relevance for infectious diseases and cancer. In contrast to these advances, selective inhibitors that could serve as efficient tools for investigation of physiological functions of rhomboids, validation of their disease relevance or as templates for drug development are lacking. In this review I extract what is known about rhomboid protease mechanism and specificity, examine the currently used inhibitors, their mechanism of action and limitations, and conclude by proposing routes for future development of rhomboid protease inhibitors. Copyright © 2016 The Author. Published by Elsevier Ltd.. All rights reserved.

Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release

PubMed Central

Estacion, Mark; Turner, Jamie; Mis, Malgorzata A.; Wilbrey, Anna; Payne, Elizabeth C.; Gutteridge, Alex; Cox, Peter J.; Doyle, Rachel; Printzenhoff, David; Lin, Zhixin; Marron, Brian E.; West, Christopher; Swain, Nigel A.; Storer, R. Ian; Stupple, Paul A.; Castle, Neil A.; Hounshell, James A.; Rivara, Mirko; Randall, Andrew; Dib-Hajj, Sulayman D.; Krafte, Douglas; Waxman, Stephen G.; Patel, Manoj K.; Butt, Richard P.; Stevens, Edward B.

2016-01-01

Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Nav1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Nav1.7’s role in nociceptor physiology. We report that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential. Moreover, we confirm a role for Nav1.7 in influencing synaptic transmission in the dorsal horn of the spinal cord as well as peripheral neuropeptide release in the skin. These findings demonstrate multiple contributions of Nav1.7 to nociceptor signalling and shed new light on the relative functional contribution of this channel to peripheral and central noxious signal transmission. PMID:27050761

Semiosis in self-producing systems

NASA Astrophysics Data System (ADS)

Sharov, Alexei

2000-05-01

Cybernetic methodology has reached its limits in the study of life because it ignores the meaning of biological information. Thus it should be augmented by semiotics that studies the meaning and value of signs. According to the pragmatic definition, a sign is a biological adaptation, i.e. a persistent useful function. Usefulness of an action can be measured by its contribution to the reproductive value of an organism in a particular quasi-species. Reproductive values are equal to the components of the left eigenvector of the linearized model of system dynamics. Every organism is a sign, and its life cycle is a continuous process of self-interpretation. Organisms use receptors to predict changing environments. Natural selection is functionally equivalent to perception at the level of lineages. Selective survival and reproduction is analogous to selective excitation of photoreceptors in the eye. Lineages learn how to avoid harmful variation by using developmental constraints, proofreading, dominance, and other mechanisms. If intelligence is defined as the ability to learn, then lineages are intelligent systems, which we did not recognize simply because they are too slow.

Selectivity Mechanism of the Nuclear Pore Complex Characterized by Single Cargo Tracking

PubMed Central

Lowe, Alan R.; Siegel, Jake J.; Kalab, Petr; Siu, Merek; Weis, Karsten; Liphardt, Jan T.

2010-01-01

The Nuclear Pore Complex (NPC) mediates all exchange between the cytoplasm and the nucleus. Small molecules can passively diffuse through the NPC, while larger cargos require transport receptors to translocate1. How the NPC facilitates the translocation of transport receptor/cargo complexes remains unclear. Here, we track single protein-functionalized Quantum Dot (QD) cargos as they translocate the NPC. Import proceeds by successive sub-steps comprising cargo capture, filtering and translocation, and release into the nucleus. The majority of QDs are rejected at one of these steps and return to the cytoplasm including very large cargos that abort at a size-selective barrier. Cargo movement in the central channel is subdiffusive and cargos that can bind more transport receptors diffuse more freely. Without Ran, cargos still explore the entire NPC, but have a markedly reduced probability of exit into the nucleus, suggesting that NPC entry and exit steps are not equivalent and that the pore is functionally asymmetric to importing cargos. The overall selectivity of the NPC appears to arise from the cumulative action of multiple reversible sub-steps and a final irreversible exit step. PMID:20811366

Influence of verbal instructions on effect-based action control.

PubMed

Eder, Andreas B; Dignath, David

2017-03-01

According to ideomotor theory, people use bidirectional associations between movements and their effects for action selection and initiation. Our experiments examined how verbal instructions of action effects influence response selection without prior experience of action effects in a separate acquisition phase. Instructions for different groups of participants specified whether they should ignore, attend, learn, or intentionally produce acoustic effects produced by button presses. Results showed that explicit instructions of action-effect relations trigger effect-congruent action tendencies in the first trials following the instruction; in contrast, no evidence for effect-based action control was observed in these trials when instructions were to ignore or to attend to the action effects. These findings show that action-effect knowledge acquired through verbal instruction and direct experience is similarly effective for effect-based action control as long as the relation between the movement and the effect is clearly spelled out in the instruction.

Bridging the Divide: The Role of Motivation and Self-Regulation in Explaining the Judgment-Action Gap Related to Academic Dishonesty.

PubMed

Stephens, Jason M

2018-01-01

There is often a divide between moral judgment and moral action; between what we believe we ought to do (or not do) and what we do. Knowledge of this divide is not new, and numerous theories have attempted to offer more robust accounts of ethical decision-making and moral functioning. Knowledge of widespread academic dishonesty among students is also not new, and several studies have revealed that many students report cheating despite believing it is wrong. The present study, involving cross-sectional survey data from a sample of secondary students ( N = 380) in the United States, contributes to the literature on this important area of theory and research by fulfilling three broad purposes. The first purpose concerned the assessment of students' judgments related to academic dishonesty, and offered evidence for the utility of a new instrument that measures what domain (personal, conventional, or moral) students use to categorize various types of cheating behavior rather than how much they believe it to be wrong. The second purpose involved exploring the relations between domain judgments and engagement in academic dishonesty, and results provided evidence for the hypothesis that students who believed an action to be morally wrong would be less likely to report doing it. Finally, the third and most important purpose of the study involved bridging the divide between moral judgment and action of academic dishonesty by testing competing theoretical models of moral functioning. Results indicated that the data demonstrated the best fit to a modified version of the hypothesized four-component model, whereby self-regulation (in the form of selective moral disengagement) played a significant mediating role in the relations between moral judgment and academic dishonesty, and that moral judgment also affected self-regulation indirectly through moral motivation (i.e., responsibility judgments). In brief, findings from this study offer support for the contention that moral functioning is both multi-component and effortful. Moral judgment is important, but only one of several components needed for effective moral functioning, and motivation and self-regulation play critical mediating roles in helping to bridge the divide between judgment and action.

Bridging the Divide: The Role of Motivation and Self-Regulation in Explaining the Judgment-Action Gap Related to Academic Dishonesty

PubMed Central

Stephens, Jason M.

2018-01-01

There is often a divide between moral judgment and moral action; between what we believe we ought to do (or not do) and what we do. Knowledge of this divide is not new, and numerous theories have attempted to offer more robust accounts of ethical decision-making and moral functioning. Knowledge of widespread academic dishonesty among students is also not new, and several studies have revealed that many students report cheating despite believing it is wrong. The present study, involving cross-sectional survey data from a sample of secondary students (N = 380) in the United States, contributes to the literature on this important area of theory and research by fulfilling three broad purposes. The first purpose concerned the assessment of students' judgments related to academic dishonesty, and offered evidence for the utility of a new instrument that measures what domain (personal, conventional, or moral) students use to categorize various types of cheating behavior rather than how much they believe it to be wrong. The second purpose involved exploring the relations between domain judgments and engagement in academic dishonesty, and results provided evidence for the hypothesis that students who believed an action to be morally wrong would be less likely to report doing it. Finally, the third and most important purpose of the study involved bridging the divide between moral judgment and action of academic dishonesty by testing competing theoretical models of moral functioning. Results indicated that the data demonstrated the best fit to a modified version of the hypothesized four-component model, whereby self-regulation (in the form of selective moral disengagement) played a significant mediating role in the relations between moral judgment and academic dishonesty, and that moral judgment also affected self-regulation indirectly through moral motivation (i.e., responsibility judgments). In brief, findings from this study offer support for the contention that moral functioning is both multi-component and effortful. Moral judgment is important, but only one of several components needed for effective moral functioning, and motivation and self-regulation play critical mediating roles in helping to bridge the divide between judgment and action. PMID:29545762

Neuronal plasticity and antidepressant actions

PubMed Central

Castrén, Eero; Hen, René

2013-01-01

Antidepressant treatments enhance plasticity and increase neurogenesis in the adult brain, but it has been unclear how these effects influence mood. We propose that like environmental enrichment and exercise, antidepressant treatments enhance adaptability by increasing structural variability within the nervous system at many levels, from proliferating precursors to immature synaptic contacts. Conversely, sensory deprivation and chronic stress reduce this structural variability. Activity-dependent competition within the mood-related circuits, guided by rehabilitation, then selects for the survival and stabilization of those structures that best represent the internal or external milieu. Increased variability together with competition-mediated selection facilitates normal function, such as pattern separation within the dentate gyrus and other mood-related circuits, thereby enhancing adaptability towards novel experiences. PMID:23380665

Evolutionary constraints or opportunities?

PubMed

Sharov, Alexei A

2014-09-01

Natural selection is traditionally viewed as a leading factor of evolution, whereas variation is assumed to be random and non-directional. Any order in variation is attributed to epigenetic or developmental constraints that can hinder the action of natural selection. In contrast I consider the positive role of epigenetic mechanisms in evolution because they provide organisms with opportunities for rapid adaptive change. Because the term "constraint" has negative connotations, I use the term "regulated variation" to emphasize the adaptive nature of phenotypic variation, which helps populations and species to survive and evolve in changing environments. The capacity to produce regulated variation is a phenotypic property, which is not described in the genome. Instead, the genome acts as a switchboard, where mostly random mutations switch "on" or "off" preexisting functional capacities of organism components. Thus, there are two channels of heredity: informational (genomic) and structure-functional (phenotypic). Functional capacities of organisms most likely emerged in a chain of modifications and combinations of more simple ancestral functions. The role of DNA has been to keep records of these changes (without describing the result) so that they can be reproduced in the following generations. Evolutionary opportunities include adjustments of individual functions, multitasking, connection between various components of an organism, and interaction between organisms. The adaptive nature of regulated variation can be explained by the differential success of lineages in macro-evolution. Lineages with more advantageous patterns of regulated variation are likely to produce more species and secure more resources (i.e., long-term lineage selection). Published by Elsevier Ireland Ltd.

Loss of function of Saccharomyces cerevisiae kinesin-related CIN8 and KIP1 is suppressed by KAR3 motor domain mutations.

PubMed

Hoyt, M A; He, L; Totis, L; Saunders, W S

1993-09-01

The kinesin-related products of the CIN8 and KIP1 genes of Saccharomyces cerevisiae redundantly perform an essential function in mitosis. The action of either gene-product is required for an outwardly directed force that acts upon the spindle poles. We have selected mutations that suppress the temperature-sensitivity of a cin8-temperature-sensitive kip1-delta strain. The extragenic suppressors analyzed were all found to be alleles of the KAR3 gene. KAR3 encodes a distinct kinesin-related protein whose action antagonizes Cin8p/Kip1p function. All seven alleles analyzed were altered within the region of KAR3 that encodes the putative force-generating (or "motor") domain. These mutations also suppressed the inviability associated with the cin8-delta kip1-delta genotype, a property not shared by a deletion of KAR3. Other properties of the suppressing alleles revealed that they were not null for function. Six of the seven were unaffected for the essential karyogamy and meiosis properties of KAR3 and the seventh was dominant for the suppressing trait. Our findings suggest that despite an antagonistic relationship between Cin8p/Kip1p and Kar3p, aspects of their mitotic roles may be similar.

Supporting awareness through collaborative brushing and linking of tabular data.

PubMed

Hajizadeh, Amir Hossein; Tory, Melanie; Leung, Rock

2013-12-01

Maintaining an awareness of collaborators' actions is critical during collaborative work, including during collaborative visualization activities. Particularly when collaborators are located at a distance, it is important to know what everyone is working on in order to avoid duplication of effort, share relevant results in a timely manner and build upon each other's results. Can a person's brushing actions provide an indication of their queries and interests in a data set? Can these actions be revealed to a collaborator without substantially disrupting their own independent work? We designed a study to answer these questions in the context of distributed collaborative visualization of tabular data. Participants in our study worked independently to answer questions about a tabular data set, while simultaneously viewing brushing actions of a fictitious collaborator, shown directly within a shared workspace. We compared three methods of presenting the collaborator's actions: brushing & linking (i.e. highlighting exactly what the collaborator would see), selection (i.e. showing only a selected item), and persistent selection (i.e. showing only selected items but having them persist for some time). Our results demonstrated that persistent selection enabled some awareness of the collaborator's activities while causing minimal interference with independent work. Other techniques were less effective at providing awareness, and brushing & linking caused substantial interference. These findings suggest promise for the idea of exploiting natural brushing actions to provide awareness in collaborative work.

Structural basis for selective targeting of leishmanial ribosomes: Aminoglycoside derivatives as promising therapeutics

DOE PAGES

Shalev, Moran; Rozenberg, Haim; Smolkin, Boris; ...

2015-08-11

Leishmaniasis comprises an array of diseases caused by pathogenic species of Leishmania, resulting in a spectrum of mild to life-threatening pathologies. Currently available therapies for leishmaniasis include a limited selection of drugs. This coupled with the rather fast emergence of parasite resistance, presents a dire public health concern. Paromomycin (PAR), a broad-spectrum aminoglycoside antibiotic, has been shown in recent years to be highly efficient in treating visceral leishmaniasis (VL)—the life-threatening form of the disease. While much focus has been given to exploration of PAR activities in bacteria, its mechanism of action in Leishmania has received relatively little scrutiny and hasmore » yet to be fully deciphered. In the present study we present an X-ray structure of PAR bound to rRNA model mimicking its leishmanial binding target, the ribosomal A-site. We evaluate PAR inhibitory actions on leishmanial growth and ribosome function, as well as effects on auditory sensory cells, by comparing several structurally related natural and synthetic aminoglycoside derivatives. The results provide insights into the structural elements important for aminoglycoside inhibitory activities and selectivity for leishmanial cytosolic ribosomes, highlighting a novel synthetic derivative, compound 3, as a prospective therapeutic candidate for the treatment of VL.« less

Dopamine receptor blockade attenuates the general incentive motivational effects of noncontingently delivered rewards and reward-paired cues without affecting their ability to bias action selection.

PubMed

Ostlund, Sean B; Maidment, Nigel T

2012-01-01

Environmental cues affect our behavior in a variety of ways. Despite playing an invaluable role in guiding our daily activities, such cues also appear to trigger the harmful, compulsive behaviors that characterize addiction and other disorders of behavioral control. In instrumental conditioning, rewards and reward-paired cues bias action selection and invigorate reward-seeking behaviors, and appear to do so through distinct neurobehavioral processes. Although reward-paired cues are known to invigorate performance through a dopamine-dependent incentive motivational process, it is not known if dopamine also mediates the influence of rewards and reward-paired cues over action selection. The current study contrasted the effects of systemic administration of the nonspecific dopamine receptor antagonist flupentixol on response invigoration and action bias in Pavlovian-instrumental transfer, a test of cue-elicited responding, and in instrumental reinstatement, a test of noncontingent reward-elicited responding. Hungry rats were trained on two different stimulus-outcome relationships (eg, tone-grain pellets and noise-sucrose solution) and two different action-outcome relationships (eg, left press-grain and right press-sucrose). At test, we found that flupentixol pretreatment blocked the response invigoration generated by the cues but spared their ability to bias action selection to favor the action whose outcome was signaled by the cue being presented. The response-biasing influence of noncontingent reward deliveries was also unaffected by flupentixol. Interestingly, although flupentixol had a modest effect on the immediate response invigoration produced by those rewards, it was particularly potent in countering the lingering enhancement of responding produced by multiple reward deliveries. These findings indicate that dopamine mediates the general incentive motivational effects of noncontingent rewards and reward-paired cues but does not support their ability to bias action selection.

Generation of novel motor sequences: the neural correlates of musical improvisation.

PubMed

Berkowitz, Aaron L; Ansari, Daniel

2008-06-01

While some motor behavior is instinctive and stereotyped or learned and re-executed, much action is a spontaneous response to a novel set of environmental conditions. The neural correlates of both pre-learned and cued motor sequences have been previously studied, but novel motor behavior has thus far not been examined through brain imaging. In this paper, we report a study of musical improvisation in trained pianists with functional magnetic resonance imaging (fMRI), using improvisation as a case study of novel action generation. We demonstrate that both rhythmic (temporal) and melodic (ordinal) motor sequence creation modulate activity in a network of brain regions comprised of the dorsal premotor cortex, the rostral cingulate zone of the anterior cingulate cortex, and the inferior frontal gyrus. These findings are consistent with a role for the dorsal premotor cortex in movement coordination, the rostral cingulate zone in voluntary selection, and the inferior frontal gyrus in sequence generation. Thus, the invention of novel motor sequences in musical improvisation recruits a network of brain regions coordinated to generate possible sequences, select among them, and execute the decided-upon sequence.

Design, synthesis, and action of oxotremorine-related hybrid-type allosteric modulators of muscarinic acetylcholine receptors.

PubMed

Disingrini, Teresa; Muth, Mathias; Dallanoce, Clelia; Barocelli, Elisabetta; Bertoni, Simona; Kellershohn, Kerstin; Mohr, Klaus; De Amici, Marco; Holzgrabe, Ulrike

2006-01-12

A novel series of muscarinic receptor ligands of the hexamethonio-type was prepared which contained, on one side, the phthalimidopropane or 1,8-naphthalimido-2,2-dimethylpropane moiety typical for subtype selective allosteric antagonists and, on the other, the acetylenic fragment typical for the nonselective orthosteric muscarinic agonists oxotremorine, oxotremorine-M, and related muscarinic agonists. Binding experiments in M(2) receptors using [(3)H]N-methylscopolamine as an orthosteric probe proved an allosteric action of both groups of hybrids, 7a-10a and 8b-10b. The difference in activity between a-group and b-group hybrids corresponded with the activity difference between the allosteric parent compounds. In M(1)-M(3) muscarinic isolated organ preparations, most of the hybrids behaved as subtype selective antagonists. [(35)S]GTPgammaS binding assays using human M(2) receptors overexpressed in CHO cells revealed that a weak intrinsic efficacy was preserved in 8b-10b. Thus, attaching muscarinic allosteric antagonist moieties to orthosteric muscarinic agonists may lead to hybrid compounds in which functions of both components are mixed.

Functions of Aggression and Disciplinary Actions among Elementary School-Age Youth

ERIC Educational Resources Information Center

Fite, Paula J.; Evans, Spencer C.; Pederson, Casey A.; Tampke, Elizabeth C.

2017-01-01

Background: A link between aggression and disciplinary actions has been established; however, specific associations between reactive and proactive functions of aggression and disciplinary actions in the elementary school setting have not been evaluated. A better understanding of links between functions of aggression and disciplinary actions could…

Probiotics as an Immune Modulator.

PubMed

Kang, Hye-Ji; Im, Sin-Hyeog

2015-01-01

Probiotics are nonpathogenic live microorganism that can provide a diverse health benefits on the host when consumed in adequate amounts. Probiotics are consumed in diverse ways including dairy product, food supplements and functional foods with specific health claims. Recently, many reports suggest that certain probiotic strains or multi strain mixture have potent immunomodulatory activity in diverse disorders including allergic asthma, atopic dermatitis and rheumatoid arthritis. However, underlying mechanism of action is still unclear and efficacy of probiotic administration is quite different depending on the type of strains and the amounts of doses. We and others have suggested that live probiotics or their metabolites could interact with diverse immune cells (antigen presenting cells and T cells) and confer them to have immunoregulatory functions. Through this interaction, probiotics could contribute to maintaining immune homeostasis by balancing pro-inflammatory and anti-inflammatory immune responses. However, the effect of probiotics in prevention or modulation of ongoing disease is quite diverse even within a same species. Therefore, identification of functional probiotics with specific immune regulatory property is a certainly important issue. Herein, we briefly review selection methods for immunomodulatory probiotic strains and the mechanism of action of probiotics in immune modulation.

Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities

PubMed Central

2009-01-01

Abstract Redox dysregulation originating from metabolic alterations and dependence on mitogenic and survival signaling through reactive oxygen species represents a specific vulnerability of malignant cells that can be selectively targeted by redox chemotherapeutics. This review will present an update on drug discovery, target identification, and mechanisms of action of experimental redox chemotherapeutics with a focus on pro- and antioxidant redox modulators now in advanced phases of preclinal and clinical development. Recent research indicates that numerous oncogenes and tumor suppressor genes exert their functions in part through redox mechanisms amenable to pharmacological intervention by redox chemotherapeutics. The pleiotropic action of many redox chemotherapeutics that involves simultaneous modulation of multiple redox sensitive targets can overcome cancer cell drug resistance originating from redundancy of oncogenic signaling and rapid mutation. Moreover, some redox chemotherapeutics may function according to the concept of synthetic lethality (i.e., drug cytotoxicity is confined to cancer cells that display loss of function mutations in tumor suppressor genes or upregulation of oncogene expression). The impressive number of ongoing clinical trials that examine therapeutic performance of novel redox drugs in cancer patients demonstrates that redox chemotherapy has made the crucial transition from bench to bedside. Antioxid. Redox Signal. 11, 3013–3069. PMID:19496700

Caltech campus executive LDRD.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shepodd, Timothy J.; Knudsen, Tamara

2013-01-01

The environment most brain systems of humans and other animals are almost constantly confronted with is complex and continuously changing, with each time step updating a potentially bewildering set of opportunities and demands for action. Far from the controlled, discrete trials used in most neuro- and psychological investigations, behavior outside the lab at Caltech is a seamless and continuous process of monitoring (and error correction) of ongoing action, and of evaluating persistence in the current activity with respect to opportunities to switch tasks as alternatives become available. Prior work on frontopolar and prefrontal task switching, use tasks within the samemore » modality (View a stream of symbols on a screen and perform certain response mappings depending on task rules). However, in these task switches the effector is constant: only the mapping of visual symbols to the specific button changes. In this task, the subjects are choosing what kinds of future action decisions they want to perform, where they can control either which body part will act, or which direction they will orient an instructed body action. An effector choice task presents a single target and the subject selects which effector to use to reach the target (eye or hand). While the techniques available for humans can be less spatially resolved compared to non-human primate neural data, they do allow for experimentation on multiple brain areas with relative ease. Thus, we address a broader network of areas involved in motor decisions. We aim to resolve a current dispute regarding the specific functional roles of brain areas that are often co-activated in studies of decision tasks, dorsal premotor cortex(PMd) and posterior parietal cortex(PPC). In one model, the PPC distinctly drives intentions for action selection, whereas PMd stimulation results in complex multi-joint movements without any awareness of, nor subjective feeling of, willing the elicited movement, thus seems to merely help execute the chosen action.« less

Selective Attention and Control of Action: Comparative Psychology of an Artificial, Evolved Agent and People

ERIC Educational Resources Information Center

Ward, Robert; Ward, Ronnie

2008-01-01

This study examined the selective attention abilities of a simple, artificial, evolved agent and considered implications of the agent's performance for theories of selective attention and action. The agent processed two targets in continuous time, catching one and then the other. This task required many cognitive operations, including prioritizing…

76 FR 5611 - Notice of Availability of the Environmental Assessment for the Short Term Sentences Acquisition

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-01

... action alternatives and the No Action Alternative. Natural, cultural, and socioeconomic resource impacts.... Cohn, Chief, or Issac J. Gaston, Site Selection Specialist, Capacity Planning and Site Selection Branch..., Capacity Planning and Site Selection Branch. [FR Doc. 2011-1817 Filed 1-31-11; 8:45 am] BILLING CODE P ...

Bupropion Administration Increases Resting-State Functional Connectivity in Dorso-Medial Prefrontal Cortex.

PubMed

Rzepa, Ewelina; Dean, Zola; McCabe, Ciara

2017-06-01

Patients on the selective serotonergic reuptake inhibitors like citalopram report emotional blunting. We showed previously that citalopram reduces resting-state functional connectivity in healthy volunteers in a number of brain regions, including the dorso-medial prefrontal cortex, which may be related to its clinical effects. Bupropion is a dopaminergic and noradrenergic reuptake inhibitor and is not reported to cause emotional blunting. However, how bupropion affects resting-state functional connectivity in healthy controls remains unknown. Using a within-subjects, repeated-measures, double-blind, crossover design, we examined 17 healthy volunteers (9 female, 8 male). Volunteers received 7 days of bupropion (150 mg/d) and 7 days of placebo treatment and underwent resting-state functional Magnetic Resonance Imaging. We selected seed regions in the salience network (amygdala and pregenual anterior cingulate cortex) and the central executive network (dorsal medial prefrontal cortex). Mood and anhedonia measures were also recorded and examined in relation to resting-state functional connectivity. Relative to placebo, bupropion increased resting-state functional connectivity in healthy volunteers between the dorsal medial prefrontal cortex seed region and the posterior cingulate cortex and the precuneus cortex, key parts of the default mode network. These results are opposite to that which we found with 7 days treatment of citalopram in healthy volunteers. These results reflect a different mechanism of action of bupropion compared with selective serotonergic reuptake inhibitors. These results help explain the apparent lack of emotional blunting caused by bupropion in depressed patients. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Neural correlates of the divergence of instrumental probability distributions.

PubMed

Liljeholm, Mimi; Wang, Shuo; Zhang, June; O'Doherty, John P

2013-07-24

Flexible action selection requires knowledge about how alternative actions impact the environment: a "cognitive map" of instrumental contingencies. Reinforcement learning theories formalize this map as a set of stochastic relationships between actions and states, such that for any given action considered in a current state, a probability distribution is specified over possible outcome states. Here, we show that activity in the human inferior parietal lobule correlates with the divergence of such outcome distributions-a measure that reflects whether discrimination between alternative actions increases the controllability of the future-and, further, that this effect is dissociable from those of other information theoretic and motivational variables, such as outcome entropy, action values, and outcome utilities. Our results suggest that, although ultimately combined with reward estimates to generate action values, outcome probability distributions associated with alternative actions may be contrasted independently of valence computations, to narrow the scope of the action selection problem.

Neural Correlates of the Divergence of Instrumental Probability Distributions

PubMed Central

Wang, Shuo; Zhang, June; O'Doherty, John P.

2013-01-01

Flexible action selection requires knowledge about how alternative actions impact the environment: a “cognitive map” of instrumental contingencies. Reinforcement learning theories formalize this map as a set of stochastic relationships between actions and states, such that for any given action considered in a current state, a probability distribution is specified over possible outcome states. Here, we show that activity in the human inferior parietal lobule correlates with the divergence of such outcome distributions–a measure that reflects whether discrimination between alternative actions increases the controllability of the future–and, further, that this effect is dissociable from those of other information theoretic and motivational variables, such as outcome entropy, action values, and outcome utilities. Our results suggest that, although ultimately combined with reward estimates to generate action values, outcome probability distributions associated with alternative actions may be contrasted independently of valence computations, to narrow the scope of the action selection problem. PMID:23884955

Psychological issues relevant to astronaut selection for long-duration space flight: a review of the literature.

PubMed

Collins, Daniel L

2003-01-01

This technical paper reviews the current literature on psychological issues relevant to astronaut selection for long-duration space flights. Interpersonal problems have been and remain a recurring problem for both short and long-duration space flights. Even after completion of the space mission, intense psychological aftereffects are reported. The specific behavioral problems experienced during United States and Soviet Union space flights are reviewed, specifically addressing contentious episodes and impaired judgments that occurred during the Mercury, Apollo, and Skylab missions. Psychological tests used in the selection process for the space program have focused primarily on the detection of gross psychopathologies in potential candidates. Although these psychological instruments excluded some people from becoming astronauts, the battery of tests failed to predict which individuals would manifest behavioral aberrations in judgment, cooperative functioning, overt irritability, or destructive interpersonal actions.

Rational Action Selection in 1 1/2- to 3-Year-Olds Following an Extended Training Experience

ERIC Educational Resources Information Center

Klossek, Ulrike M. H.; Dickinson, Anthony

2012-01-01

Previous studies failed to find evidence for rational action selection in children under 2 years of age. The current study investigated whether younger children required more training to encode the relevant causal relationships. Children between 1 1/2 and 3 years of age were trained over two sessions to perform actions on a touch-sensitive screen…

Report on Action Research: An Analysis of the Effects of Selected Instructional Strategies on Student Achievement at Terre Haute North Vigo High School

ERIC Educational Resources Information Center

Haystead, Mark W.

2010-01-01

This report describes the findings of an analysis of a series of action research projects conducted by Vigo County School Corporation at Terre Haute North Vigo High School. During the 2009-2010 school year, 17 teachers participated in independent action research studies regarding the extent to which selected instructional strategies enhanced the…

Introduction: understanding mechanisms of the actions of rifaximin in selected gastrointestinal diseases.

PubMed

DuPont, H L

2016-01-01

Historically, the beneficial effects of the nonsystemic oral agent rifaximin on various gastrointestinal (GI) disorders have been attributed to direct antibiotic activity on gut microbiota. However, data are accumulating to suggest that other nonantibacterial effects may be involved in rifaximin efficacy. To explore the mechanisms of action of rifaximin that may underlie its clinical benefits in travellers' diarrhoea, hepatic encephalopathy and other cirrhosis complications, inflammatory bowel diseases, and irritable bowel syndrome with diarrhoea. Gastroenterology experts convened a round-table discussion to address clinical and pre-clinical rifaximin data pertaining to select GI diseases and the potential mechanisms of action that underlie rifaximin efficacy profiles. As preparation, the literature was searched for publications related to rifaximin, its mechanisms of action, and its efficacy in travellers' diarrhoea, hepatic encephalopathy and other cirrhosis-related complications, inflammatory bowel diseases and irritable bowel syndrome. Gut microbiota dysbiosis and proinflammatory activities are thought to significantly contribute to disease pathophysiology of these conditions. Rifaximin may resolve gut microbiota dysbiosis by promoting GI colonisation of beneficial bacterial species without drastic alterations in overall diversity. Rifaximin-induced changes in the production and metabolism of bacteria-produced agents (e.g. deoxycholic acid, lipopolysaccharides) also may help preserve normal gut microbiota. Rifaximin may suppress local and systemic inflammatory processes by preserving epithelial function (e.g. limiting bacterial translocation), modulating bacterial virulence and reducing proinflammatory cytokine production. The commonality of pathological mechanisms underlying multiple GI diseases and the ability of rifaximin to modulate the gut microenvironment (i.e. gut microenvironment modulator) may explain its diverse efficacy profile. © 2015 John Wiley & Sons Ltd.

Thalamic Control of Dorsomedial Striatum Regulates Internal State to Guide Goal-Directed Action Selection.

PubMed

Bradfield, Laura A; Balleine, Bernard W

2017-03-29

We (Bradfield et al., 2013) have demonstrated previously that parafascicular thalamic nucleus (PF)-controlled neurons in the posterior dorsomedial striatum (pDMS) are critical for interlacing new and existing action-outcome contingencies to control goal-directed action. Based on these findings, it was suggested that animals with a dysfunctional PF-pDMS pathway might suffer a deficit in creating or retrieving internal contexts or "states" on which such information could become conditional. To assess this hypothesis more directly, rats were given a disconnection treatment using contralateral cytotoxic lesions of the PF and pDMS (Group CONTRA) or ipsilateral control lesions (Group IPSI) and trained to press a right and left lever for sucrose and pellet outcomes, after which these contingencies were reversed. The rats were then given an outcome devaluation test (all experiments) and a test of outcome-specific reinstatement (Experiments 1 and 3). We found that devaluation performance was intact for both groups after training of initial contingencies, but impaired for Group CONTRA after reversal. However, performance was restored by additional reversal training. Furthermore, when tested a second time after reversal training, rats in both groups demonstrated responding in accordance with the original contingencies, providing direct evidence of modulation of action selection by state. Finally, we found that external context could substitute for internal state and so could rescue responding in Group CONTRA, but only in the reinstatement test. Together, these findings suggest that animals use internal state information to guide action selection and that this information is modulated by the PF-pDMS pathway. SIGNIFICANCE STATEMENT Individuals with Parkinson's disease dementia often suffer a characteristic deficit in "cognitive flexibility." It has been suggested that neurodegeneration in the pathway between the centromedian/parafascicular thalalmic nucleus (PF) and striatum might underlie such deficits (Smith et al., 2014). In rats, we have similarly observed that a functional disconnection of the PF-posterior dorsomedial striatal pathway produces a specific impairment in the ability to alter goal-directed actions (Bradfield et al., 2013). It was suggested that this impairment could be a result of a deficit in state modulation. Here, we present four experiments that provide evidence for this hypothesis and suggest several ways (e.g., extended practice, providing external cues) in which this state modulation can be rescued. Copyright © 2017 the authors 0270-6474/17/373721-13$15.00/0.

Rare Neural Correlations Implement Robotic Conditioning with Delayed Rewards and Disturbances

PubMed Central

Soltoggio, Andrea; Lemme, Andre; Reinhart, Felix; Steil, Jochen J.

2013-01-01

Neural conditioning associates cues and actions with following rewards. The environments in which robots operate, however, are pervaded by a variety of disturbing stimuli and uncertain timing. In particular, variable reward delays make it difficult to reconstruct which previous actions are responsible for following rewards. Such an uncertainty is handled by biological neural networks, but represents a challenge for computational models, suggesting the lack of a satisfactory theory for robotic neural conditioning. The present study demonstrates the use of rare neural correlations in making correct associations between rewards and previous cues or actions. Rare correlations are functional in selecting sparse synapses to be eligible for later weight updates if a reward occurs. The repetition of this process singles out the associating and reward-triggering pathways, and thereby copes with distal rewards. The neural network displays macro-level classical and operant conditioning, which is demonstrated in an interactive real-life human-robot interaction. The proposed mechanism models realistic conditioning in humans and animals and implements similar behaviors in neuro-robotic platforms. PMID:23565092

Ecological Modeling Guide for Ecosystem Restoration and Management

DTIC Science & Technology

2012-08-01

may result from proposed restoration and management actions. This report provides information to guide environmental planers in selection, development...actions. This report provides information to guide environmental planers in selection, development, evaluation and documentation of ecological models. A

Selective Activation of M4 Muscarinic Acetylcholine Receptors Reverses MK-801-Induced Behavioral Impairments and Enhances Associative Learning in Rodents

PubMed Central

2015-01-01

Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for the treatment of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that the selective M4 PAM VU0152100 produced an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) in the central nervous system. Prior to this study, the M1 mAChR subtype was viewed as the primary candidate for these actions relative to the other mAChR subtypes. Here we describe the discovery of a novel M4 PAM, VU0467154, with enhanced in vitro potency and improved pharmacokinetic properties relative to other M4 PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801. VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task in wild-type mice, but failed to reverse these stimulant-induced deficits in M4 KO mice. VU0467154 also enhanced the acquisition of both contextual and cue-mediated fear conditioning when administered alone in wild-type mice. These novel findings suggest that M4 PAMs may provide a strategy for addressing the more complex affective and cognitive disruptions associated with schizophrenia and other neuropsychiatric disorders. PMID:25137629

The Representation of Object-Directed Action and Function Knowledge in the Human Brain

PubMed Central

Chen, Quanjing; Garcea, Frank E.; Mahon, Bradford Z.

2016-01-01

The appropriate use of everyday objects requires the integration of action and function knowledge. Previous research suggests that action knowledge is represented in frontoparietal areas while function knowledge is represented in temporal lobe regions. Here we used multivoxel pattern analysis to investigate the representation of object-directed action and function knowledge while participants executed pantomimes of familiar tool actions. A novel approach for decoding object knowledge was used in which classifiers were trained on one pair of objects and then tested on a distinct pair; this permitted a measurement of classification accuracy over and above object-specific information. Region of interest (ROI) analyses showed that object-directed actions could be decoded in tool-preferring regions of both parietal and temporal cortex, while no independently defined tool-preferring ROI showed successful decoding of object function. However, a whole-brain searchlight analysis revealed that while frontoparietal motor and peri-motor regions are engaged in the representation of object-directed actions, medial temporal lobe areas in the left hemisphere are involved in the representation of function knowledge. These results indicate that both action and function knowledge are represented in a topographically coherent manner that is amenable to study with multivariate approaches, and that the left medial temporal cortex represents knowledge of object function. PMID:25595179

The attentive brain: insights from developmental cognitive neuroscience.

PubMed

Amso, Dima; Scerif, Gaia

2015-10-01

Visual attention functions as a filter to select environmental information for learning and memory, making it the first step in the eventual cascade of thought and action systems. Here, we review studies of typical and atypical visual attention development and explain how they offer insights into the mechanisms of adult visual attention. We detail interactions between visual processing and visual attention, as well as the contribution of visual attention to memory. Finally, we discuss genetic mechanisms underlying attention disorders and how attention may be modified by training.

Anatomically selective serotonergic type 1A and serotonergic type 2A therapies for Parkinson's disease: an approach to reducing dyskinesia without exacerbating parkinsonism?

PubMed

Huot, Philippe; Fox, Susan H; Newman-Tancredi, Adrian; Brotchie, Jonathan M

2011-10-01

L-DOPA remains the most effective treatment for Parkinson's disease (PD). However, long-term administration of L-DOPA is compromised by complications, particularly dyskinesia. Serotonergic type 1A (5-HT(1A)) receptor agonists and serotonergic type 2A (5-HT(2A)) receptor antagonists were, until recently, considered to be promising therapies against dyskinesia. However, there have been some recent high-profile failures in clinical trials, notably with sarizotan, and it seems that these classes of drugs may also impair l-DOPA antiparkinsonian efficacy. A simple explanation for the loss of antiparkinsonian benefit might be lack of good selectivity of these compounds for their respective targets, particularly with respect to off-target actions on dopaminergic receptors or poor dose selection in clinical studies. However, such explanations do not hold broadly when considering the actions of all compounds studied to date, whether in animal models or clinical trials. Here, we review 5-HT(1A) and 5-HT(2A) receptor function in PD and provide an anatomically based rationale as to why in some instances 5-HT(1A)- and 5-HT(2A)-modulating drugs might worsen parkinsonism, in addition to reducing dyskinesia. We propose that, in addition to selectivity for specific receptor subtypes, to target 5-HT(1A) and 5-HT(2A) receptors to alleviate dyskinesia, without worsening parkinsonism, it will be necessary to develop compounds that display anatomical selectivity, targeting corticostriatal transmission, while avoiding 5-HT receptors on ascending serotonergic and dopaminergic inputs from the raphe and substantia nigra, respectively.

Reward Sensitivity and Waiting Impulsivity: Shift towards Reward Valuation away from Action Control

PubMed Central

Mechelmans, Daisy J; Strelchuk, Daniela; Doñamayor, Nuria; Banca, Paula; Robbins, Trevor W; Baek, Kwangyeol

2017-01-01

Abstract Background Impulsivity and reward expectancy are commonly interrelated. Waiting impulsivity, measured using the rodent 5-Choice Serial Reaction Time task, predicts compulsive cocaine seeking and sign (or cue) tracking. Here, we assess human waiting impulsivity using a novel translational task, the 4-Choice Serial Reaction Time task, and the relationship with reward cues. Methods Healthy volunteers (n=29) performed the monetary incentive delay task as a functional MRI study where subjects observe a cue predicting reward (cue) and wait to respond for high (£5), low (£1), or no reward. Waiting impulsivity was tested with the 4-Choice Serial Reaction Time task. Results For high reward prospects (£5, no reward), greater waiting impulsivity on the 4-CSRT correlated with greater medial orbitofrontal cortex and lower supplementary motor area activity to cues. In response to high reward cues, greater waiting impulsivity was associated with greater subthalamic nucleus connectivity with orbitofrontal cortex and greater subgenual cingulate connectivity with anterior insula, but decreased connectivity with regions implicated in action selection and preparation. Conclusion These findings highlight a shift towards regions implicated in reward valuation and a shift towards compulsivity away from higher level motor preparation and action selection and response. We highlight the role of reward sensitivity and impulsivity, mechanisms potentially linking human waiting impulsivity with incentive approach and compulsivity, theories highly relevant to disorders of addiction. PMID:29020291

From action intentions to action effects: how does the sense of agency come about?

PubMed Central

Chambon, Valérian; Sidarus, Nura; Haggard, Patrick

2014-01-01

Sense of agency refers to the feeling of controlling an external event through one’s own action. On one influential view, agency depends on how predictable the consequences of one’s action are, getting stronger as the match between predicted and actual effect of an action gets closer. Thus, sense of agency arises when external events that follow our action are consistent with predictions of action effects made by the motor system while we perform or simply intend to perform an action. According to this view, agency is inferred retrospectively, after an action has been performed and its consequences are known. In contrast, little is known about whether and how internal processes involved in the selection of actions may influence subjective sense of control, in advance of the action itself, and irrespective of effect predictability. In this article, we review several classes of behavioral and neuroimaging data suggesting that earlier processes, linked to fluency of action selection, prospectively contribute to sense of agency. These findings have important implications for better understanding human volition and abnormalities of action experience. PMID:24860486

Sensitivity to biomechanical limitations during postural decision-making depends on the integrity of posterior superior parietal cortex.

PubMed

Wood, Daniel K; Chouinard, Philippe A; Major, Alex J; Goodale, Melvyn A

2017-12-01

Most object-directed limb movements can be carried out with a comfortable grasp posture. However, the orientation of an object relative to our bodies can sometimes lead us to select an uncomfortable or awkward grasp posture due to limitations imposed by the biomechanics of the arm. In a series of experiments, we identified a network of cortical areas that are engaged during the selection of movement strategies. Neurologically intact participants and two brain-damaged patients with overlapping lesions in the right posterior superior parietal lobule (pSPL) performed a grasp posture selection task in which biomechanical constraints were the primary consideration for selecting an action. The task induced states of bistable actions whereby the same stimulus gave rise to categorically different grasp postures. In a behavioral experiment, the two patients displayed a large range of manual bistability with the contralesional hand, resulting in a higher incidence of awkward grasping postures. In neurologically intact participants, a separate functional magnetic resonance imaging (fMRI) experiment revealed activation of a parieto-frontal network, which included the posterior intraparietal sulcus (pIPS) along the banks of the pSPL that was parametrically modulated by the degree of bistability in grasp posture selection. Superimposing this activation over the patients' structural MRIs revealed that the pIPS/pSPL activation in the neurologically intact participants overlapped with lesioned cortical tissue in both patients; all other areas of activation overlapped with intact cortical tissue in the patients. These results provide converging evidence that the posterior parietal cortex plays a critical role in selecting biomechanically appropriate postures during reach-to-grasp behaviors. Copyright © 2016 Elsevier Ltd. All rights reserved.

Depletion of the cellular levels of Bag-1 proteins attenuates phorbol ester-induced downregulation of I{kappa}B{alpha} and nuclear accumulation of NF-{kappa}B

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maier, Jana V., E-mail: Jana.maier@kit.edu; Volz, Yvonne; Berger, Caroline

2010-10-22

Research highlights: {yields}Bag-1 depletion only marginally affects the action of the glucocorticoid receptor but strongly regulates the activity of NF-{kappa}B. {yields}Bag-1 depletion attenuates phosphorylation and degradation of I{kappa}B{alpha} and nuclear accumulation of NF-{kappa}B p65 and p50. {yields}Bag-1 interacts with I{kappa}B{alpha} and partially restores I{kappa}B{alpha} and NF-{kappa}B activation in Bag-1 depleted cells. -- Abstract: Bag-1 consists in humans of four isoforms generated from the same RNA by alternative translation. Overexpression of single Bag-1 isoforms has identified Bag-1 as a negative regulator of action of many proteins including the glucocorticoid receptor (GR). Here we have analysed the ability of Bag-1 to regulatemore » the transrepression function of the GR. Silencing Bag-1 expression only marginally affects the transrepression action of the GR but decreased the action of the transcription factor NF-{kappa}B. Furthermore phosphorylation and degradation of the inhibitor protein I{kappa}B{alpha} and nuclear accumulation of p65 and p50 NF-{kappa}B proteins in response to phorbol ester was attenuated following Bag-1 depletion in HeLa cells. Reconstitution of Bag-1 in depleted cells partially restored I{kappa}B{alpha} and NF-{kappa}B activation. Knock-down of Bag-1 expression also did not significantly alter GR-mediated transactivation but affected the basal transcription of some of the target genes. Thus Bag-1 proteins function as regulators of the action of selective transcription factors.« less

New insights into the acute actions from a high dosage of fluoxetine on neuronal and cardiac function: Drosophila, crayfish and rodent models.

PubMed

Majeed, Zana R; Ritter, Kyle; Robinson, Jonathan; Blümich, Sandra L E; Brailoiu, Eugen; Cooper, Robin L

2015-01-01

The commonly used mood altering drug fluoxetine (Prozac) in humans has a low occurrence in reports of harmful effects from overdose; however, individuals with altered metabolism of the drug and accidental overdose have led to critical conditions and even death. We addressed direct actions of high concentrations on synaptic transmission at neuromuscular junctions (NMJs), neural properties, and cardiac function unrelated to fluoxetine's action as a selective 5-HT reuptake inhibitor. There appears to be action in blocking action potentials in crayfish axons, enhanced occurrences of spontaneous synaptic vesicle fusion events in the presynaptic terminals at NMJs of both Drosophila and crayfish. In rodent neurons, cytoplasmic Ca(2+) rises by fluoxetine and is thapsigargin dependent. The Drosophila larval heart showed a dose dependent effect in cardiac arrest. Acute paralytic behavior in crayfish occurred at a systemic concentration of 2mM. A high percentage of death as well as slowed development occurred in Drosophila larvae consuming food containing 100μM fluoxetine. The release of Ca(2+) from the endoplasmic reticulum in neurons and the cardiac tissue as well as blockage of voltage-gated Na(+) channels in neurons could explain the effects on the whole animal as well as the isolated tissues. The use of various animal models in demonstrating the potential mechanisms for the toxic effects with high doses of fluoxetine maybe beneficial for acute treatments in humans. Future studies in determining how fluoxetine is internalized in cells and if there are subtle effects of these mentioned mechanisms presented with chronic therapeutic doses are of general interest. Copyright © 2015 Elsevier Inc. All rights reserved.

COMBINE genetics study: the pharmacogenetics of alcoholism treatment response: genes and mechanisms.

PubMed

Goldman, David; Oroszi, Gabor; O'Malley, Stephanie; Anton, Raymond

2005-07-01

Partial efficacy of treatment and differences in adverse events across individuals are a challenge and an opportunity in the treatment of alcoholism. Individuation of therapy and understanding origins of differential treatment response may require identification of inherited functional variants of genes. The neurobiology of reward, executive cognitive function, anxiety and dysphoria have been identified as critical domains that may have a genetic basis that could predict treatment response. The COMBINE Study presents a unique opportunity to evaluate specific genetic loci (markers) that affect neurobiology central to addiction and extended withdrawal. The study also addresses variation in drug metabolism and action. Candidate genetic markers are selected for study based on functionality and abundance. COMT Vall58Met is a common (minor allele frequency 0.42), functional, catecholamine-metabolizing enzyme polymorphism with threefold relevance. Vall58Met alters executive cognitive function, stress and anxiety responses and brain endogenous opioid function. OPRM1 Asn40Asp is a common (minor allele frequency 0.10), functional polymorphism of the mu-opioid receptor, which may serve as a gatekeeper molecule in naltrexone's actions and was recently reported to affect naltrexone response. HTTLPR (minor allele frequency 0.40) alters serotonin transporter function to affect anxiety, dysphoria and obsessional behavior, which are assessed in COMBINE and may be related to relapse and addictive behavior. All genetic testing is consented through a separate human research protocol, and the testing is conducted nonclinically, confidentially and apart from the clinical record to protect human research participants who have volunteered for this aspect of COMBINE.

Selective inhibition of a multicomponent response can be achieved without cost

PubMed Central

Westrick, Zachary; Ivry, Richard B.

2014-01-01

Behavioral flexibility frequently requires the ability to modify an on-going action. In some situations, optimal performance requires modifying some components of an on-going action without interrupting other components of that action. This form of control has been studied with the selective stop-signal task, in which participants are instructed to abort only one movement of a multicomponent response. Previous studies have shown a transient disruption of the nonaborted component, suggesting limitations in our ability to use selective inhibition. This cost has been attributed to a structural limitation associated with the recruitment of a cortico-basal ganglia pathway that allows for the rapid inhibition of action but operates in a relatively generic manner. Using a model-based approach, we demonstrate that, with a modest amount of training and highly compatible stimulus-response mappings, people can perform a selective-stop task without any cost on the nonaborted component. Prior reports of behavioral costs in selective-stop tasks reflect, at least in part, a sampling bias in the method commonly used to estimate such costs. These results suggest that inhibition can be selectively controlled and present a challenge for models of inhibitory control that posit the operation of generic processes. PMID:25339712

Superfund Record of Decision (EPA Region 4): Milan Army Ammunition Plant, Milan, TN, March 11, 1998

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1998-09-01

This decision document presents the selected action for the Salvage Yard, Former Ammunition Burnout Area (ABA), and Sanitary Landfill at MLAAP, located in Gibson and Carroll Counties, TN. This ROD addresses the final response action planned for the Salvage Yard, Former ABA, and Sanitary Landfill, including soil and groundwater. NFA is the selected remedy for soil and groundwater at the Salvage Yard, Former ABA, and Sanitary landfill. The selected remedy manages the risk to acceptable levels for both human health and the environment and is the final action planned.

Learning Spatio-Temporal Representations for Action Recognition: A Genetic Programming Approach.

PubMed

Liu, Li; Shao, Ling; Li, Xuelong; Lu, Ke

2016-01-01

Extracting discriminative and robust features from video sequences is the first and most critical step in human action recognition. In this paper, instead of using handcrafted features, we automatically learn spatio-temporal motion features for action recognition. This is achieved via an evolutionary method, i.e., genetic programming (GP), which evolves the motion feature descriptor on a population of primitive 3D operators (e.g., 3D-Gabor and wavelet). In this way, the scale and shift invariant features can be effectively extracted from both color and optical flow sequences. We intend to learn data adaptive descriptors for different datasets with multiple layers, which makes fully use of the knowledge to mimic the physical structure of the human visual cortex for action recognition and simultaneously reduce the GP searching space to effectively accelerate the convergence of optimal solutions. In our evolutionary architecture, the average cross-validation classification error, which is calculated by an support-vector-machine classifier on the training set, is adopted as the evaluation criterion for the GP fitness function. After the entire evolution procedure finishes, the best-so-far solution selected by GP is regarded as the (near-)optimal action descriptor obtained. The GP-evolving feature extraction method is evaluated on four popular action datasets, namely KTH, HMDB51, UCF YouTube, and Hollywood2. Experimental results show that our method significantly outperforms other types of features, either hand-designed or machine-learned.

Time course of action representations evoked during sentence comprehension.

PubMed

Heard, Alison W; Masson, Michael E J; Bub, Daniel N

2015-03-01

The nature of hand-action representations evoked during language comprehension was investigated using a variant of the visual-world paradigm in which eye fixations were monitored while subjects viewed a screen displaying four hand postures and listened to sentences describing an actor using or lifting a manipulable object. Displayed postures were related to either a functional (using) or volumetric (lifting) interaction with an object that matched or did not match the object mentioned in the sentence. Subjects were instructed to select the hand posture that matched the action described in the sentence. Even before the manipulable object was mentioned in the sentence, some sentence contexts allowed subjects to infer the object's identity and the type of action performed with it and eye fixations immediately favored the corresponding hand posture. This effect was assumed to be the result of ongoing motor or perceptual imagery in which the action described in the sentence was mentally simulated. In addition, the hand posture related to the manipulable object mentioned in a sentence, but not related to the described action (e.g., a writing posture in the context of a sentence that describes lifting, but not using, a pencil), was favored over other hand postures not related to the object. This effect was attributed to motor resonance arising from conceptual processing of the manipulable object, without regard to the remainder of the sentence context. Copyright © 2014 Elsevier B.V. All rights reserved.

Differentiating neural systems mediating the acquisition versus expression of goal-directed and habitual behavioral control

PubMed Central

Liljeholm, Mimi; Dunne, Simon; O'Doherty, John P.

2015-01-01

Considerable behavioral data indicates that operant actions can become habitual, as evidenced by insensitivity to changes in the action-outcome contingency and in subjective outcome values. Notably, although several studies have investigated the neural substrates of habits, none has clearly differentiated the areas of the human brain that support habit formation from those that implement habitual control. We scanned participants with fMRI as they learned and performed an operant task in which the conditional structure of the environment encouraged either goal-directed encoding of the consequences of actions, or a habit-like mapping of actions to antecedent cues. Participants were also scanned during a subsequent assessment of insensitivity to outcome devaluation. We identified dissociable roles of the cerebellum and ventral striatum, across learning and test performance, in behavioral insensitivity to outcome devaluation. We also show that the inferior parietal lobule – an area previously implicated in several aspects of goal-directed action selection, including the attribution of intent and awareness of agency – predicts sensitivity to outcome devaluation. Finally, we reveal a potential functional homology between the human subgenual cortex and rodent infralimbic cortex in the implementation of habitual control. In summary, our findings suggest a broad systems division, at the cortical and subcortical levels, between brain areas mediating the encoding and expression of action-outcome and stimulus-response associations. PMID:25892332

Superfund Record of Decision (EPA Region 9): El Toro Marine Corps Air Station, Operable Units 2A and 3A (no action sites), El Toro, CA, September 29, 1997

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

This decision document presents the selected remedial action for Sites 4, 6, 9, 10, 13, 15, 19, 20, 21, 22, and 25 at MCAS El Toro in Orange County, California. The selected remedy for Sites, 4, 6, 9, 19, 13, 15, 19, 20, 21, 22, and 25 is no action.

Excitatory and inhibitory effects of opiates in the rat vas deferens: a dual mechanism of opiate action.

PubMed

Jacquet, Y F

1980-10-03

Both natural (-)-morphine and its unnatural enantiomer (+)-morphine exert an excitatory action on electrically stimulated contractions of rat vas deferens. Preexposure to (-)-morphine results in cross-tolerance to the inhibitory action of beta-endorphin. (-)-Naloxone and its stereoisomer (+)-naloxone also exert an excitatory action, but only (-)-naloxone bocks the inhibtory action of beta-endorphin. Thus morphine exerts a dual action on a peripheral organ: one an inhibitory action mediated by the stereospecific endorphin receptor that is blocked stereospecifically by naloxone, the other an excitatory action mediated by a nonstereospecific receptor that is not blocked by naloxone. The opiate abstinence syndrome is seen as due to the unmasking of the excitatory action of opiates when its concomitant inhibitory influence is removed by selective blockade by naloxone or weakened by selective tolerance. The view that the rat vas deferens is devoid of morphine receptors is now seen as arising from a reverse example of morphine's dual action: the masking of the inhibitory action of morphine by its concomitant and more potent excitatory action.

Neural theory for the perception of causal actions.

PubMed

Fleischer, Falk; Christensen, Andrea; Caggiano, Vittorio; Thier, Peter; Giese, Martin A

2012-07-01

The efficient prediction of the behavior of others requires the recognition of their actions and an understanding of their action goals. In humans, this process is fast and extremely robust, as demonstrated by classical experiments showing that human observers reliably judge causal relationships and attribute interactive social behavior to strongly simplified stimuli consisting of simple moving geometrical shapes. While psychophysical experiments have identified critical visual features that determine the perception of causality and agency from such stimuli, the underlying detailed neural mechanisms remain largely unclear, and it is an open question why humans developed this advanced visual capability at all. We created pairs of naturalistic and abstract stimuli of hand actions that were exactly matched in terms of their motion parameters. We show that varying critical stimulus parameters for both stimulus types leads to very similar modulations of the perception of causality. However, the additional form information about the hand shape and its relationship with the object supports more fine-grained distinctions for the naturalistic stimuli. Moreover, we show that a physiologically plausible model for the recognition of goal-directed hand actions reproduces the observed dependencies of causality perception on critical stimulus parameters. These results support the hypothesis that selectivity for abstract action stimuli might emerge from the same neural mechanisms that underlie the visual processing of natural goal-directed action stimuli. Furthermore, the model proposes specific detailed neural circuits underlying this visual function, which can be evaluated in future experiments.

Metal ion-dependent DNAzymes and their applications as biosensors.

PubMed

Lan, Tian; Lu, Yi

2012-01-01

Long considered to serve solely as the genetic information carrier, DNA has been shown in 1994 to be able to act as DNA catalysts capable of catalyzing a trans-esterification reaction similar to the action of ribozymes and protein enzymes. Although not yet found in nature, numerous DNAzymes have been isolated through in vitro selection for catalyzing many different types of reactions in the presence of different metal ions and thus become a new class of metalloenzymes. What remains unclear is how DNA can carry out catalysis with simpler building blocks and fewer functional groups than ribozymes and protein enzymes and how DNA can bind metal ions specifically to perform these functions. In the past two decades, many biochemical and biophysical studies have been carried out on DNAzymes, especially RNA-cleaving DNAzymes. Important insights have been gained regarding their metal-dependent activity, global folding, metal binding sites, and catalytic mechanisms for these DNAzymes. Because of their high metal ion selectivity, one of the most important practical applications for DNAzymes is metal ion detection, resulting in highly sensitive and selective fluorescent, colorimetric, and electrochemical sensors for a wide range of metal ions such as Pb(2+), UO2 2 +,[Formula: see text] including paramagnetic metal ions such as Cu(2+). This chapter summarizes recent progresses in in vitro selection of metal ion-selective DNAzymes, their biochemical and biophysical studies and sensing applications.

Evaluation of high-density, multi-contact nerve cuffs for activation of grasp muscles in monkeys

NASA Astrophysics Data System (ADS)

Brill, N. A.; Naufel, S. N.; Polasek, K.; Ethier, C.; Cheesborough, J.; Agnew, S.; Miller, L. E.; Tyler, D. J.

2018-06-01

Objective. The objective of this work was to evaluate whether nerve cuffs can selectively activate hand muscles for functional electrical stimulation (FES). FES typically involves identifying and implanting electrodes in many individual muscles, but nerve cuffs only require implantation at a single site around the nerve. This method is surgically more attractive. Nerve cuffs may also more effectively stimulate intrinsic hand muscles, which are difficult to implant and stimulate without spillover to adjacent muscles. Approach. To evaluate its ability to selectively activate muscles, we implanted and tested the flat interface nerve electrode (FINE), which is designed to selectively stimulate peripheral nerves that innervate multiple muscles (Tyler and Durand 2002 IEEE Trans. Neural Syst. Rehabil. Eng. 10 294-303). We implanted FINEs on the nerves and bipolar intramuscular wires for recording compound muscle action potentials (CMAPs) from up to 20 muscles in each arm of six monkeys. We then collected recruitment curves while the animals were anesthetized. Main result. A single FINE implanted on an upper extremity nerve in the monkey can selectively activate muscles or small groups of muscles to produce multiple, independent hand functions. Significance. FINE cuffs can serve as a viable supplement to intramuscular electrodes in FES systems, where they can better activate intrinsic and extrinsic muscles with lower currents and less extensive surgery.

Mechanisms and Evidence of Genital Coevolution: The Roles of Natural Selection, Mate Choice, and Sexual Conflict

PubMed Central

Brennan, Patricia L.R.; Prum, Richard O.

2015-01-01

Genital coevolution between the sexes is expected to be common because of the direct interaction between male and female genitalia during copulation. Here we review the diverse mechanisms of genital coevolution that include natural selection, female mate choice, male–male competition, and how their interactions generate sexual conflict that can lead to sexually antagonistic coevolution. Natural selection on genital morphology will result in size coevolution to allow for copulation to be mechanically possible, even as other features of genitalia may reflect the action of other mechanisms of selection. Genital coevolution is explicitly predicted by at least three mechanisms of genital evolution: lock and key to prevent hybridization, female choice, and sexual conflict. Although some good examples exist in support of each of these mechanisms, more data on quantitative female genital variation and studies of functional morphology during copulation are needed to understand more general patterns. A combination of different approaches is required to continue to advance our understanding of genital coevolution. Knowledge of the ecology and behavior of the studied species combined with functional morphology, quantitative morphological tools, experimental manipulation, and experimental evolution have been provided in the best-studied species, all of which are invertebrates. Therefore, attention to vertebrates in any of these areas is badly needed. PMID:26134314

Selective reaching in macaques: evidence for action-centred attention.

PubMed

Bulgheroni, Maria; Camperio-Ciani, Andrea; Straulino, Elisa; Sartori, Luisa; D'Amico, Enrico; Castiello, Umberto

2017-03-01

When a monkey selects a piece of food lying on the ground from among other viable objects in the near vicinity, only the desired item governs the particular pattern and direction of the animal's reaching action. It would seem then that selection is an important component controlling the animal's action. But, we may ask, is the selection process in such cases impervious to the presence of other objects that could constitute potential obstacles to or constraints on movement execution? And if it is, in fact, pervious to other objects, do they have a direct influence on the organization of the response? The kinematics of macaques' reaching movements were examined by the current study that analysed some exemplars as they selectively reached to grasp a food item in the absence as well as in the presence of potential obstacles (i.e., stones) that could affect the arm trajectory. Changes in movement parameterization were noted in temporal measures, such as movement time, as well as in spatial ones, such as paths of trajectory. Generally speaking, the presence of stones in the vicinity of the acting hand stalled the reaching movement and affected the arm trajectory as the hand veered away from the stone even when it was not a physical obstacle. We concluded that nearby objects evoke a motor response in macaques, and the attentional mechanisms that allow for a successful action selection are revealed in the reaching path. The data outlined here concur with human studies indicating that potential obstacles are internally represented, a finding implying basic cognitive operations allowing for action selection in macaques.

29 CFR 1607.13 - Affirmative action.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 4 2011-07-01 2011-07-01 false Affirmative action. 1607.13 Section 1607.13 Labor... EMPLOYEE SELECTION PROCEDURES (1978) General Principles § 1607.13 Affirmative action. A. Affirmative action... relieve users of any obligations they may have to undertake affirmative action to assure equal employment...

41 CFR 60-3.13 - Affirmative action.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 41 Public Contracts and Property Management 1 2010-07-01 2010-07-01 true Affirmative action. 60-3... Affirmative action. A. Affirmative action obligations. The use of selection procedures which have been... affirmative action to assure equal employment opportunity. Nothing in these guidelines is intended to preclude...

29 CFR 1607.13 - Affirmative action.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 4 2010-07-01 2010-07-01 false Affirmative action. 1607.13 Section 1607.13 Labor... EMPLOYEE SELECTION PROCEDURES (1978) General Principles § 1607.13 Affirmative action. A. Affirmative action... relieve users of any obligations they may have to undertake affirmative action to assure equal employment...

41 CFR 60-3.13 - Affirmative action.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 41 Public Contracts and Property Management 1 2011-07-01 2009-07-01 true Affirmative action. 60-3... Affirmative action. A. Affirmative action obligations. The use of selection procedures which have been... affirmative action to assure equal employment opportunity. Nothing in these guidelines is intended to preclude...

Corticostriatal circuit mechanisms of value-based action selection: Implementation of reinforcement learning algorithms and beyond.

PubMed

Morita, Kenji; Jitsev, Jenia; Morrison, Abigail

2016-09-15

Value-based action selection has been suggested to be realized in the corticostriatal local circuits through competition among neural populations. In this article, we review theoretical and experimental studies that have constructed and verified this notion, and provide new perspectives on how the local-circuit selection mechanisms implement reinforcement learning (RL) algorithms and computations beyond them. The striatal neurons are mostly inhibitory, and lateral inhibition among them has been classically proposed to realize "Winner-Take-All (WTA)" selection of the maximum-valued action (i.e., 'max' operation). Although this view has been challenged by the revealed weakness, sparseness, and asymmetry of lateral inhibition, which suggest more complex dynamics, WTA-like competition could still occur on short time scales. Unlike the striatal circuit, the cortical circuit contains recurrent excitation, which may enable retention or temporal integration of information and probabilistic "soft-max" selection. The striatal "max" circuit and the cortical "soft-max" circuit might co-implement an RL algorithm called Q-learning; the cortical circuit might also similarly serve for other algorithms such as SARSA. In these implementations, the cortical circuit presumably sustains activity representing the executed action, which negatively impacts dopamine neurons so that they can calculate reward-prediction-error. Regarding the suggested more complex dynamics of striatal, as well as cortical, circuits on long time scales, which could be viewed as a sequence of short WTA fragments, computational roles remain open: such a sequence might represent (1) sequential state-action-state transitions, constituting replay or simulation of the internal model, (2) a single state/action by the whole trajectory, or (3) probabilistic sampling of state/action. Copyright © 2016. Published by Elsevier B.V.

The endocrine disruptor bisphenol A increases the expression of HSP70 and ecdysone receptor genes in the aquatic larvae of Chironomus riparius.

PubMed

Planelló, R; Martínez-Guitarte, J L; Morcillo, G

2008-05-01

Bisphenol A (BPA) is an endocrine disruptor that can mimic the action of estrogens by interacting with hormone receptors and is, therefore, potentially able to influence reproductive functions in vertebrates. Although information about the interaction with the endocrine systems in invertebrates is limited, it has also been shown its effect on reproductive and developmental parameters in these organisms. As little is known about its mechanism of action in aquatic invertebrates, we have examined the effects of BPA on the expression of some selected genes, including housekeeping, stress-induced and hormone-related genes in Chironomus riparius larvae, a widely used organism in aquatic ecotoxicology. The levels of different gene transcripts were measured by Northern blot or by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Exposure to BPA (3 mgl(-1), 12-24h) did not affect the levels of rRNA or those of mRNAs for both L11 or L13 ribosomal proteins, selected as examples of housekeeping genes involved in ribosome biogenesis. Nevertheless, BPA treatment induced the expression of the HSP70 gene. Interestingly, it was found that BPA significantly increases the mRNA level of the ecdysone receptor (EcR). These results show for the first time that exposure to endocrine disrupting chemicals, such as BPA, can selectively affect the expression of the ecdysone receptor gene suggesting a direct interaction with the insect endocrine system. Furthermore, this finding suggests a common way of BPA action, shared by vertebrates and invertebrates, through interaction with steroid hormone receptors. Our study adds a new element, the EcR, which may be a useful tool for the screening of environmental xenoestrogens in insects.

Profile of neuronal excitation following selective activation of the neurokinin-1 receptor in rat deep dorsal horn in vitro.

PubMed

King, A E; Ackley, M A; Slack, J R

1997-08-29

The excitatory actions of the selective neurokinin-1 receptor (NK1R) agonist [Sar9,Met(O2)11]substance P (SP) were tested on a sample (n = 50) of deep dorsal horn neurones in the isolated and hemisected young rat spinal cord. Superfusion of the NK1R agonist (2 microM) elicited a prolonged membrane depolarisation (6.6 +/- 0.5 mV) and an increase in action potential firing in 41/50 (82%) neurones. These [Sar9,Met(O2)11]SP-induced depolarisations were attenuated by the selective NK1R antagonist GR82334 (1 microM). An increased neuronal excitability after [Sar9,Met(O2)11]SP application was indicated by an augmented spike frequency generated in response to long duration, step depolarisations. In order to assess whether a direct excitatory action existed, [Sar9,Met(O2)11]SP was re-tested on a sample of TTX-treated neurones (n = 14). The majority (9/14) retained agonist sensitivity although the amplitude of the depolarisation was reduced to 48% of the control value. A sample of neurones (n = 7) that responded to the NK1R agonist were morphologically characterised after filling with the intracellular dye, biocytin. Dorsal dendrites that clearly penetrated lamina II and that could receive a direct C-afferent input, were identified in only 2/7 neurones. These electrophysiological and neuroanatomical data demonstrate that deep dorsal horn neurones possess functional NK1Rs. The implications of the existence of these NK1Rs in the context of spinal somatosensory systems and SP is considered.

Identification of yeast DNA topoisomerase II mutants resistant to the antitumor drug doxorubicin: implications for the mechanisms of doxorubicin action and cytotoxicity.

PubMed

Patel, S; Sprung, A U; Keller, B A; Heaton, V J; Fisher, L M

1997-10-01

Doxorubicin is a therapeutically useful anticancer drug that exerts multiple biological effects. Its antitumor and cardiotoxic properties have been ascribed to anthracycline-mediated free radical damage to DNA and membranes. Evidence for this idea comes in part from the selection by doxorubicin from stationary phase yeast cells of mutants (petites) deficient in mitochondrial respiration and therefore defective in free radical generation. However, doxorubicin also binds to DNA topoisomerase II, converting the enzyme into a DNA damaging agent through the trapping of a covalent enzyme-DNA complex termed the 'cleavable complex.' We have used yeast to determine whether stabilization of cleavable complexes plays a role in doxorubicin action and cytotoxicity. A plasmid-borne yeast TOP2 gene was mutagenized with hydroxylamine and used to transform drug-permeable yeast strain JN394t2-4, which carries a temperature-sensitive top2-4 mutation in its chromosomal TOP2 gene. Selection in growth medium at the nonpermissive temperature of 35 degrees in the presence of doxorubicin resulted in the isolation of plasmid-borne top2 mutants specifying functional doxorubicin-resistant DNA topoisomerase II. Single-point changes of Gly748 to Glu or Ala642 to Ser in yeast topoisomerase II, which lie in and adjacent to the CAP-like DNA binding domain, respectively, were identified as responsible for resistance to doxorubicin, implicating these regions in drug action. None of the mutants selected in JN394t2-4, which has a rad52 defect in double-strand DNA break repair, was respiration-deficient. We conclude that topoisomerase II is an intracellular target for doxorubicin and that the genetic background and/or cell proliferation status can determine the relative importance of topoisomerase II- versus free radical-killing.

A behavioral task for investigating action discovery, selection and switching: comparison between types of reinforcer

PubMed Central

Fisher, Simon D.; Gray, Jason P.; Black, Melony J.; Davies, Jennifer R.; Bednark, Jeffery G.; Redgrave, Peter; Franz, Elizabeth A.; Abraham, Wickliffe C.; Reynolds, John N. J.

2014-01-01

Action discovery and selection are critical cognitive processes that are understudied at the cellular and systems neuroscience levels. Presented here is a new rodent joystick task suitable to test these processes due to the range of action possibilities that can be learnt while performing the task. Rats learned to manipulate a joystick while progressing through task milestones that required increasing degrees of movement accuracy. In a switching phase designed to measure action discovery, rats were repeatedly required to discover new target positions to meet changing task demands. Behavior was compared using both food and electrical brain stimulation reward (BSR) of the substantia nigra as reinforcement. Rats reinforced with food and those with BSR performed similarly overall, although BSR-treated rats exhibited greater vigor in responding. In the switching phase, rats learnt new actions to adapt to changing task demands, reflecting action discovery processes. Because subjects are required to learn different goal-directed actions, this task could be employed in further investigations of the cellular mechanisms of action discovery and selection. Additionally, this task could be used to assess the behavioral flexibility impairments seen in conditions such as Parkinson's disease and obsessive-compulsive disorder. The versatility of the task will enable cross-species investigations of these impairments. PMID:25477795

The Representation of Object-Directed Action and Function Knowledge in the Human Brain.

PubMed

Chen, Quanjing; Garcea, Frank E; Mahon, Bradford Z

2016-04-01

The appropriate use of everyday objects requires the integration of action and function knowledge. Previous research suggests that action knowledge is represented in frontoparietal areas while function knowledge is represented in temporal lobe regions. Here we used multivoxel pattern analysis to investigate the representation of object-directed action and function knowledge while participants executed pantomimes of familiar tool actions. A novel approach for decoding object knowledge was used in which classifiers were trained on one pair of objects and then tested on a distinct pair; this permitted a measurement of classification accuracy over and above object-specific information. Region of interest (ROI) analyses showed that object-directed actions could be decoded in tool-preferring regions of both parietal and temporal cortex, while no independently defined tool-preferring ROI showed successful decoding of object function. However, a whole-brain searchlight analysis revealed that while frontoparietal motor and peri-motor regions are engaged in the representation of object-directed actions, medial temporal lobe areas in the left hemisphere are involved in the representation of function knowledge. These results indicate that both action and function knowledge are represented in a topographically coherent manner that is amenable to study with multivariate approaches, and that the left medial temporal cortex represents knowledge of object function. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Elucidating Duramycin's Bacterial Selectivity and Mode of Action on the Bacterial Cell Envelope.

PubMed

Hasim, Sahar; Allison, David P; Mendez, Berlin; Farmer, Abigail T; Pelletier, Dale A; Retterer, Scott T; Campagna, Shawn R; Reynolds, Todd B; Doktycz, Mitchel J

2018-01-01

The use of naturally occurring antimicrobial peptides provides a promising route to selectively target pathogenic agents and to shape microbiome structure. Lantibiotics, such as duramycin, are one class of bacterially produced peptidic natural products that can selectively inhibit the growth of other bacteria. However, despite longstanding characterization efforts, the microbial selectivity and mode of action of duramycin are still obscure. We describe here a suite of biological, chemical, and physical characterizations that shed new light on the selective and mechanistic aspects of duramycin activity. Bacterial screening assays have been performed using duramycin and Populus -derived bacterial isolates to determine species selectivity. Lipidomic profiles of selected resistant and sensitive strains show that the sensitivity of Gram-positive bacteria depends on the presence of phosphatidylethanolamine (PE) in the cell membrane. Further the surface and interface morphology were studied by high resolution atomic force microscopy and showed a progression of cellular changes in the cell envelope after treatment with duramycin for the susceptible bacterial strains. Together, these molecular and cellular level analyses provide insight into duramycin's mode of action and a better understanding of its selectivity.

Functional Requirements and the Theory of Action.

ERIC Educational Resources Information Center

Hills, R. Jean

1982-01-01

Responding to Willower's earlier questioning of the concept of systems' functional requirements, the author outlines the Parsonian theory of action, discussing action systems' components (values, norms, organizations, and facilities) and their functional imperatives or requirements (pattern maintenance, integration, goal attainment, and…

Logic-Gate Functions in Chemomechanical Materials.

PubMed

Schneider, Hans-Jörg

2017-09-06

Chemomechanical polymers that change their shape or volume on stimulation by multiple external chemical signals, particularly on the basis of selective molecular recognition, are discussed. Several examples illustrate how such materials, usually in the form of hydrogels, can be used for the design of chemically triggered valves or artificial muscles and applied, for example, in self-healing materials or drug delivery. The most attractive feature of such materials is that they can combine sensor and actuator within single units, from nano- to macrosize. Simultaneous action of a cofactor allows selective response in the sense of AND logic gates by, for example, amino acids and peptides, which without the presence of a second effector do not induce any changes. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Selective androgen receptor modulators in preclinical and clinical development.

PubMed

Narayanan, Ramesh; Mohler, Michael L; Bohl, Casey E; Miller, Duane D; Dalton, James T

2008-01-01

Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and hypogonadism. This review summarizes the current standing of research and development of SARMs, crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic indications for this emerging class of drugs.

Safinamide in the treatment of Parkinson's disease.

PubMed

Schapira, Anthony H V

2010-09-01

Current therapy for Parkinson's disease (PD) is primarily directed at reversing the motor symptoms that are the consequence of dopamine deficiency and includes levodopa, dopamine agonists and monoamine oxidase (MAO) B inhibitors. New drugs offering both dopaminergic and non-dopaminergic actions could offer a significant advantage. This review surveys the current treatment strategies for PD. Defining unmet needs and how a new compound - safinamide, which has both dopaminergic and non-dopaminergic actions - might address these. The reader will gain an understanding of safinamide and its mechanisms of action, including reversible MAOB inhibition and reduced dopamine reuptake with antiglutamatergic effects, and how it may potentially provide improvement of PD motor symptoms with an antidyskinetic effect through its effect on glutamate release. The clinical trial profile of safinamide is reviewed. Early results are promising in terms of improved motor function and reduced 'OFF' time. Additional Phase III trials are now in progress for this adjunctive indication. Finally, the reader will understand the potential role for safinamide in the selection and sequencing of drugs for PD. safinamide combines both dopaminergic and non-dopaminergic actions that may add a new dimension to PD treatment options as an adjunct to current drugs. Its efficacy is under active evaluation in Phase III clinical trials.

Bacterial cell wall composition and the influence of antibiotics by cell-wall and whole-cell NMR

PubMed Central

Romaniuk, Joseph A. H.; Cegelski, Lynette

2015-01-01

The ability to characterize bacterial cell-wall composition and structure is crucial to understanding the function of the bacterial cell wall, determining drug modes of action and developing new-generation therapeutics. Solid-state NMR has emerged as a powerful tool to quantify chemical composition and to map cell-wall architecture in bacteria and plants, even in the context of unperturbed intact whole cells. In this review, we discuss solid-state NMR approaches to define peptidoglycan composition and to characterize the modes of action of old and new antibiotics, focusing on examples in Staphylococcus aureus. We provide perspectives regarding the selected NMR strategies as we describe the exciting and still-developing cell-wall and whole-cell NMR toolkit. We also discuss specific discoveries regarding the modes of action of vancomycin analogues, including oritavancin, and briefly address the reconsideration of the killing action of β-lactam antibiotics. In such chemical genetics approaches, there is still much to be learned from perturbations enacted by cell-wall assembly inhibitors, and solid-state NMR approaches are poised to address questions of cell-wall composition and assembly in S. aureus and other organisms. PMID:26370936

Grasping with the Press of a Button: Grasp-selective Responses in the Human Anterior Intraparietal Sulcus Depend on Nonarbitrary Causal Relationships between Hand Movements and End-effector Actions

PubMed Central

Frey, Scott H.; Hansen, Marc; Marchal, Noah

2016-01-01

Evidence implicates ventral parieto-premotor cortices in representing the goal of grasping independent of the movements or effectors involved [Umilta, M. A., Escola, L., Intskirveli, I., Grammont, F., Rochat, M., Caruana, F., et al. When pliers become fingers in the monkey motor system. Proceedings of the National Academy of Sciences, U.S.A., 105, 2209–2213, 2008; Tunik, E., Frey, S. H., & Grafton, S. T. Virtual lesions of the anterior intraparietal area disrupt goal-dependent on-line adjustments of grasp. Nature Neuroscience, 8, 505–511, 2005]. Modern technologies that enable arbitrary causal relationships between hand movements and tool actions provide a strong test of this hypothesis. We capitalized on this unique opportunity by recording activity with fMRI during tasks in which healthy adults performed goal-directed reach and grasp actions manually or by depressing buttons to initiate these same behaviors in a remotely located robotic arm (arbitrary causal relationship). As shown previously [Binkofski, F., Dohle, C., Posse, S., Stephan, K. M., Hefter, H., Seitz, R. J., et al. Human anterior intraparietal area subserves prehension: A combined lesion and functional MRI activation study. Neurology, 50, 1253–1259, 1998], we detected greater activity in the vicinity of the anterior intraparietal sulcus (aIPS) during manual grasp versus reach. In contrast to prior studies involving tools controlled by nonarbitrarily related hand movements [Gallivan, J. P., McLean, D. A., Valyear, K. F., & Culham, J. C. Decoding the neural mechanisms of human tool use. Elife, 2, e00425, 2013; Jacobs, S., Danielmeier, C., & Frey, S. H. Human anterior intraparietal and ventral premotor cortices support representations of grasping with the hand or a novel tool. Journal of Cognitive Neuroscience, 22, 2594–2608, 2010], however, responses within the aIPS and premotor cortex exhibited no evidence of selectivity for grasp when participants employed the robot. Instead, these regions showed comparable increases in activity during both the reach and grasp conditions. Despite equivalent sensorimotor demands, the right cerebellar hemisphere displayed greater activity when participants initiated the robot’s actions versus when they pressed a button known to be nonfunctional and watched the very same actions undertaken autonomously. This supports the hypothesis that the cerebellum predicts the forthcoming sensory consequences of volitional actions [Blakemore, S. J., Frith, C. D., & Wolpert, D. M. The cerebellum is involved in predicting the sensory consequences of action. NeuroReport, 12, 1879–1884, 2001]. We conclude that grasp-selective responses in the human aIPS and premotor cortex depend on the existence of nonarbitrary causal relationships between hand movements and end-effector actions. PMID:25436672

Selective leptin resistance revisited

PubMed Central

2013-01-01

In addition to effects on appetite and metabolism, leptin influences many neuroendocrine and physiological systems, including the sympathetic nervous system. Building on my Carl Ludwig Lecture of the American Physiological Society, I review the sympathetic and cardiovascular actions of leptin. The review focuses on a critical analysis of the concept of selective leptin resistance (SLR) and the role of leptin in the pathogenesis of obesity-induced hypertension in both experimental animals and humans. We introduced the concept of SLR in 2002 to explain how leptin might increase blood pressure (BP) in obese states, such as diet-induced obesity (DIO), that are accompanied by partial leptin resistance. This concept, analogous to selective insulin resistance in the metabolic syndrome, holds that in several genetic and acquired models of obesity, there is preservation of the renal sympathetic and pressor actions of leptin despite attenuation of the appetite and weight-reducing actions. Two potential overlapping mechanisms of SLR are reviewed: 1) differential leptin molecular signaling pathways that mediate selective as opposed to universal leptin action and 2) brain site-specific leptin action and resistance. Although the phenomenon of SLR in DIO has so far focused on preservation of sympathetic and BP actions of leptin, consideration should be given to the possibility that this concept may extend to preservation of other actions of leptin. Finally, I review perplexing data on the effects of leptin on sympathetic activity and BP in humans and its role in human obesity-induced hypertension. PMID:23883674

Using Functional Signature Ontology (FUSION) to Identify Mechanisms of Action for Natural Products

PubMed Central

Potts, Malia B.; Kim, Hyun Seok; Fisher, Kurt W.; Hu, Youcai; Carrasco, Yazmin P.; Bulut, Gamze Betul; Ou, Yi-Hung; Herrera-Herrera, Mireya L.; Cubillos, Federico; Mendiratta, Saurabh; Xiao, Guanghua; Hofree, Matan; Ideker, Trey; Xie, Yang; Huang, Lily Jun-shen; Lewis, Robert E.; MacMillan, John B.; White, Michael A.

2014-01-01

A challenge for biomedical research is the development of pharmaceuticals that appropriately target disease mechanisms. Natural products can be a rich source of bioactive chemicals for medicinal applications but can act through unknown mechanisms and can be difficult to produce or obtain. To address these challenges, we developed a new marine-derived, renewable natural products resource and a method for linking bioactive derivatives of this library to the proteins and biological processes that they target in cells. We used cell-based screening and computational analysis to match gene expression signatures produced by natural products to those produced by siRNA and synthetic microRNA libraries. With this strategy, we matched proteins and microRNAs with diverse biological processes and also identified putative protein targets and mechanisms of action for several previously undescribed marine-derived natural products. We confirmed mechanistic relationships for selected short-interfering RNAs, microRNAs, and compounds with functional roles in autophagy, chemotaxis mediated by discoidin domain receptor 2, or activation of the kinase AKT. Thus, this approach may be an effective method for screening new drugs while simultaneously identifying their targets. PMID:24129700

Multifunctional mesoporous silica nanoparticles for combined therapeutic, diagnostic and targeted action in cancer treatment.

PubMed

Rosenholm, Jessica M; Sahlgren, Cecilia; Lindén, Mika

2011-07-01

The main objective in the development of nanomedicine is to obtain delivery platforms for targeted delivery of drugs or imaging agents for improved therapeutic efficacy, reduced side effects and increased diagnostic sensitivity. A (nano)material class that has been recognized for its controllable properties on many levels is ordered mesoporous inorganic materials, typically in the form of amorphous silica (SiO2). Characteristics for this class of materials include mesoscopic order, tunable pore dimensions in the (macro)molecular size range, a high pore volume and surface area, the possibility for selective surface functionality as well as morphology control. The robust but biodegradable ceramic matrix moreover provides shelter for incorporated agents (drugs, proteins, imaging agents, photosensitizers) leaving the outer particle surface free for further modification. The unique features make these materials particularly amenable to modular design, whereby functional moieties and features may be interchanged or combined to produce multifunctional nanodelivery systems combining targeting, diagnostic, and therapeutic actions. This review covers the latest developments related to the use of mesoporous silica nanoparticles (MSNs) as nanocarriers in biomedical applications, with special focus on cancer therapy and diagnostics.

Multi-criteria evaluation methods in the production scheduling

NASA Astrophysics Data System (ADS)

Kalinowski, K.; Krenczyk, D.; Paprocka, I.; Kempa, W.; Grabowik, C.

2016-08-01

The paper presents a discussion on the practical application of different methods of multi-criteria evaluation in the process of scheduling in manufacturing systems. Among the methods two main groups are specified: methods based on the distance function (using metacriterion) and methods that create a Pareto set of possible solutions. The basic criteria used for scheduling were also described. The overall procedure of evaluation process in production scheduling was presented. It takes into account the actions in the whole scheduling process and human decision maker (HDM) participation. The specified HDM decisions are related to creating and editing a set of evaluation criteria, selection of multi-criteria evaluation method, interaction in the searching process, using informal criteria and making final changes in the schedule for implementation. According to need, process scheduling may be completely or partially automated. Full automatization is possible in case of metacriterion based objective function and if Pareto set is selected - the final decision has to be done by HDM.

Hormones and the blood-brain barrier.

PubMed

Hampl, Richard; Bičíková, Marie; Sosvorová, Lucie

2015-03-01

Hormones exert many actions in the brain, and brain cells are also hormonally active. To reach their targets in brain structures, hormones must overcome the blood-brain barrier (BBB). The BBB is a unique device selecting desired/undesired molecules to reach or leave the brain, and it is composed of endothelial cells forming the brain vasculature. These cells differ from other endothelial cells in their almost impermeable tight junctions and in possessing several membrane structures such as receptors, transporters, and metabolically active molecules, ensuring their selection function. The main ways how compounds pass through the BBB are briefly outlined in this review. The main part concerns the transport of major classes of hormones: steroids, including neurosteroids, thyroid hormones, insulin, and other peptide hormones regulating energy homeostasis, growth hormone, and also various cytokines. Peptide transporters mediating the saturable transport of individual classes of hormones are reviewed. The last paragraph provides examples of how hormones affect the permeability and function of the BBB either at the level of tight junctions or by various transporters.

From Outcome Prediction to Action Selection: Developmental Change in the Role of Action-Effect Bindings

ERIC Educational Resources Information Center

Verschoor, Stephan A.; Spapé, Michiel; Biro, Szilvia; Hommel, Bernhard

2013-01-01

Ideomotor theory considers bidirectional action-effect associations to be the fundamental building blocks for intentional action. The present study employed a novel pupillometric and oculomotor paradigm to study developmental changes in the role of action-effects in the acquisition of voluntary action. Our findings suggest that both 7- and…

Evolutionary constraints or opportunities?

PubMed

Sharov, Alexei A

2014-04-22

Natural selection is traditionally viewed as a leading factor of evolution, whereas variation is assumed to be random and non-directional. Any order in variation is attributed to epigenetic or developmental constraints that can hinder the action of natural selection. In contrast I consider the positive role of epigenetic mechanisms in evolution because they provide organisms with opportunities for rapid adaptive change. Because the term "constraint" has negative connotations, I use the term "regulated variation" to emphasize the adaptive nature of phenotypic variation, which helps populations and species to survive and evolve in changing environments. The capacity to produce regulated variation is a phenotypic property, which is not described in the genome. Instead, the genome acts as a switchboard, where mostly random mutations switch "on" or "off" preexisting functional capacities of organism components. Thus, there are two channels of heredity: informational (genomic) and structure-functional (phenotypic). Functional capacities of organisms most likely emerged in a chain of modifications and combinations of more simple ancestral functions. The role of DNA has been to keep records of these changes (without describing the result) so that they can be reproduced in the following generations. Evolutionary opportunities include adjustments of individual functions, multitasking, connection between various components of an organism, and interaction between organisms. The adaptive nature of regulated variation can be explained by the differential success of lineages in macro-evolution. Lineages with more advantageous patterns of regulated variation are likely to produce more species and secure more resources (i.e., long-term lineage selection). Copyright © 2014. Published by Elsevier Ireland Ltd.

Probing the reaching-grasping network in humans through multivoxel pattern decoding.

PubMed

Di Bono, Maria Grazia; Begliomini, Chiara; Castiello, Umberto; Zorzi, Marco

2015-11-01

The quest for a putative human homolog of the reaching-grasping network identified in monkeys has been the focus of many neuropsychological and neuroimaging studies in recent years. These studies have shown that the network underlying reaching-only and reach-to-grasp movements includes the superior parieto-occipital cortex (SPOC), the anterior part of the human intraparietal sulcus (hAIP), the ventral and the dorsal portion of the premotor cortex, and the primary motor cortex (M1). Recent evidence for a wider frontoparietal network coding for different aspects of reaching-only and reach-to-grasp actions calls for a more fine-grained assessment of the reaching-grasping network in humans by exploiting pattern decoding methods (multivoxel pattern analysis--MVPA). Here, we used MPVA on functional magnetic resonance imaging (fMRI) data to assess whether regions of the frontoparietal network discriminate between reaching-only and reach-to-grasp actions, natural and constrained grasping, different grasp types, and object sizes. Participants were required to perform either reaching-only movements or two reach-to-grasp types (precision or whole hand grasp) upon spherical objects of different sizes. Multivoxel pattern analysis highlighted that, independently from the object size, all the selected regions of both hemispheres contribute in coding for grasp type, with the exception of SPOC and the right hAIP. Consistent with recent neurophysiological findings on monkeys, there was no evidence for a clear-cut distinction between a dorsomedial and a dorsolateral pathway that would be specialized for reaching-only and reach-to-grasp actions, respectively. Nevertheless, the comparison of decoding accuracy across brain areas highlighted their different contributions to reaching-only and grasping actions. Altogether, our findings enrich the current knowledge regarding the functional role of key brain areas involved in the cortical control of reaching-only and reach-to-grasp actions in humans, by revealing novel fine-grained distinctions among action types within a wide frontoparietal network.

Emergent biological properties of arrestin pathway-selective biased agonism.

PubMed

Appleton, Kathryn M; Luttrell, Louis M

2013-06-01

Our growing appreciation of the pluridimensionality of G protein-coupled receptor (GPCR) signaling, combined with the phenomenon of orthosteric ligand "bias", has created the possibility of drugs that selectively modulate different aspects of GPCR function for therapeutic benefit. When viewed from the short-term perspective, e.g. changes in receptor conformation, effector coupling or second messenger generation, biased ligands appear to activate a subset of the response profile produced by a conventional agonist. Yet when examined in vivo, the limited data available suggest that biased ligand effects can diverge from their conventional counterparts in ways that cannot be predicted from their in vitro efficacy profile. What is currently missing, at least with respect to G protein and arrestin pathway-selective ligands, is a rational framework for relating the in vitro efficacy of a "biased" agonist to its in vivo actions that will enable drug screening programs to identify ligands with the desired biological effects.

Monitoring Ion Activities In and Around Cells Using Ion-Selective Liquid-Membrane Microelectrodes

PubMed Central

Lee, Seong-Ki; Boron, Walter F.; Parker, Mark D.

2013-01-01

Determining the effective concentration (i.e., activity) of ions in and around living cells is important to our understanding of the contribution of those ions to cellular function. Moreover, monitoring changes in ion activities in and around cells is informative about the actions of the transporters and/or channels operating in the cell membrane. The activity of an ion can be measured using a glass microelectrode that includes in its tip a liquid-membrane doped with an ion-selective ionophore. Because these electrodes can be fabricated with tip diameters that are less than 1 μm, they can be used to impale single cells in order to monitor the activities of intracellular ions. This review summarizes the history, theory, and practice of ion-selective microelectrode use and brings together a number of classic and recent examples of their usefulness in the realm of physiological study. PMID:23322102

40 CFR 304.32 - Arbitral hearing.

Code of Federal Regulations, 2010 CFR

2010-07-01

... hearing not later than twenty days in advance of the hearing, unless the parties by mutual agreement waive... issues, except for any disputed issues concerning the selection or adequacy of the response action, which... the documents which formed the basis for the selection of the response action (with additional...

40 CFR 304.32 - Arbitral hearing.

Code of Federal Regulations, 2011 CFR

2011-07-01

... hearing not later than twenty days in advance of the hearing, unless the parties by mutual agreement waive... issues, except for any disputed issues concerning the selection or adequacy of the response action, which... the documents which formed the basis for the selection of the response action (with additional...

Selective activation of heteromeric SK channels contributes to action potential repolarization in mouse atrial myocytes.

PubMed

Hancock, Jane M; Weatherall, Kate L; Choisy, Stéphanie C; James, Andrew F; Hancox, Jules C; Marrion, Neil V

2015-05-01

Activation of small conductance calcium-activated potassium (SK) channels is proposed to contribute to repolarization of the action potential in atrial myocytes. This role is controversial, as these cardiac SK channels appear to exhibit an uncharacteristic pharmacology. The objectives of this study were to resolve whether activation of SK channels contributes to atrial action potential repolarization and to determine the likely subunit composition of the channel. The effect of 2 SK channel inhibitors was assessed on outward current evoked in voltage clamp and on action potential duration in perforated patch and whole-cell current clamp recording from acutely isolated mouse atrial myocytes. The presence of SK channel subunits was assessed using immunocytochemistry. A significant component of outward current was reduced by the SK channel blockers apamin and UCL1684. Block by apamin displayed a sensitivity indicating that this current was carried by homomeric SK2 channels. Action potential duration was significantly prolonged by UCL1684, but not by apamin. This effect was accompanied by an increase in beat-to-beat variability and action potential triangulation. This pharmacology was matched by that of expressed heteromeric SK2-SK3 channels in HEK293 cells. Immunocytochemistry showed that atrial myocytes express both SK2 and SK3 channels with an overlapping expression pattern. Only proposed heteromeric SK2-SK3 channels are physiologically activated to contribute to action potential repolarization, which is indicated by the difference in pharmacology of evoked outward current and prolongation of atrial action potential duration. The effect of blocking this channel on the action potential suggests that SK channel inhibition during cardiac function has the potential to be proarrhythmic. Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Testing the physiological plausibility of conflicting psychological models of response inhibition: A forward inference fMRI study.

PubMed

Criaud, Marion; Longcamp, Marieke; Anton, Jean-Luc; Nazarian, Bruno; Roth, Muriel; Sescousse, Guillaume; Strafella, Antonio P; Ballanger, Bénédicte; Boulinguez, Philippe

2017-08-30

The neural mechanisms underlying response inhibition and related disorders are unclear and controversial for several reasons. First, it is a major challenge to assess the psychological bases of behaviour, and ultimately brain-behaviour relationships, of a function which is precisely intended to suppress overt measurable behaviours. Second, response inhibition is difficult to disentangle from other parallel processes involved in more general aspects of cognitive control. Consequently, different psychological and anatomo-functional models coexist, which often appear in conflict with each other even though they are not necessarily mutually exclusive. The standard model of response inhibition in go/no-go tasks assumes that inhibitory processes are reactively and selectively triggered by the stimulus that participants must refrain from reacting to. Recent alternative models suggest that action restraint could instead rely on reactive but non-selective mechanisms (all automatic responses are automatically inhibited in uncertain contexts) or on proactive and non-selective mechanisms (a gating function by which reaction to any stimulus is prevented in anticipation of stimulation when the situation is unpredictable). Here, we assessed the physiological plausibility of these different models by testing their respective predictions regarding event-related BOLD modulations (forward inference using fMRI). We set up a single fMRI design which allowed for us to record simultaneously the different possible forms of inhibition while limiting confounds between response inhibition and parallel cognitive processes. We found BOLD dynamics consistent with non-selective models. These results provide new theoretical and methodological lines of inquiry for the study of basic functions involved in behavioural control and related disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

Spatial attention improves the quality of population codes in human visual cortex.

PubMed

Saproo, Sameer; Serences, John T

2010-08-01

Selective attention enables sensory input from behaviorally relevant stimuli to be processed in greater detail, so that these stimuli can more accurately influence thoughts, actions, and future goals. Attention has been shown to modulate the spiking activity of single feature-selective neurons that encode basic stimulus properties (color, orientation, etc.). However, the combined output from many such neurons is required to form stable representations of relevant objects and little empirical work has formally investigated the relationship between attentional modulations on population responses and improvements in encoding precision. Here, we used functional MRI and voxel-based feature tuning functions to show that spatial attention induces a multiplicative scaling in orientation-selective population response profiles in early visual cortex. In turn, this multiplicative scaling correlates with an improvement in encoding precision, as evidenced by a concurrent increase in the mutual information between population responses and the orientation of attended stimuli. These data therefore demonstrate how multiplicative scaling of neural responses provides at least one mechanism by which spatial attention may improve the encoding precision of population codes. Increased encoding precision in early visual areas may then enhance the speed and accuracy of perceptual decisions computed by higher-order neural mechanisms.

Monoaminergic Modulation of Motor Cortex Function

PubMed Central

Vitrac, Clément; Benoit-Marand, Marianne

2017-01-01

Elaboration of appropriate responses to behavioral situations rests on the ability of selecting appropriate motor outcomes in accordance to specific environmental inputs. To this end, the primary motor cortex (M1) is a key structure for the control of voluntary movements and motor skills learning. Subcortical loops regulate the activity of the motor cortex and thus contribute to the selection of appropriate motor plans. Monoamines are key mediators of arousal, attention and motivation. Their firing pattern enables a direct encoding of different states thus promoting or repressing the selection of actions adapted to the behavioral context. Monoaminergic modulation of motor systems has been extensively studied in subcortical circuits. Despite evidence of converging projections of multiple neurotransmitters systems in the motor cortex pointing to a direct modulation of local circuits, their contribution to the execution and learning of motor skills is still poorly understood. Monoaminergic dysregulation leads to impaired plasticity and motor function in several neurological and psychiatric conditions, thus it is critical to better understand how monoamines modulate neural activity in the motor cortex. This review aims to provide an update of our current understanding on the monoaminergic modulation of the motor cortex with an emphasis on motor skill learning and execution under physiological conditions. PMID:29062274

Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S-22, regulate androgen receptor function through distinct genomic and nongenomic signaling pathways.

PubMed

Narayanan, Ramesh; Coss, Christopher C; Yepuru, Muralimohan; Kearbey, Jeffrey D; Miller, Duane D; Dalton, James T

2008-11-01

Androgen receptor (AR) ligands are important for the development and function of several tissues and organs. However, the poor oral bioavailability, pharmacokinetic properties, and receptor cross-reactivity of testosterone, coupled with side effects, place limits on its clinical use. Selective AR modulators (SARMs) elicit anabolic effects in muscle and bone, sparing reproductive organs like the prostate. However, molecular mechanisms underlying the tissue selectivity remain ambiguous. We performed a variety of in vitro studies to compare and define the molecular mechanisms of an aryl propionamide SARM, S-22, as compared with dihydrotestosterone (DHT). Studies indicated that S-22 increased levator ani muscle weight but decreased the size of prostate in rats. Analysis of the upstream intracellular signaling events indicated that S-22 and DHT mediated their actions through distinct pathways. Modulation of these pathways altered the recruitment of AR and its cofactors to the PSA enhancer in a ligand-dependent fashion. In addition, S-22 induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases, through pathways distinct from steroids. These studies reveal novel differences in the molecular mechanisms by which S-22, a nonsteroidal SARM, and DHT mediate their pharmacological effects.

Towards mapping the brain connectome in depression: functional connectivity by perfusion SPECT.

PubMed

Gardner, Ann; Åstrand, Disa; Öberg, Johanna; Jacobsson, Hans; Jonsson, Cathrine; Larsson, Stig; Pagani, Marco

2014-08-30

Several studies have demonstrated altered brain functional connectivity in the resting state in depression. However, no study has investigated interregional networking in patients with persistent depressive disorder (PDD). The aim of this study was to assess differences in brain perfusion distribution and connectivity between large groups of patients and healthy controls. Participants comprised 91 patients with PDD and 65 age- and sex-matched healthy controls. Resting state perfusion was investigated by single photon emission computed tomography, and group differences were assessed by Statistical Parametric Mapping. Brain connectivity was explored through a voxel-wise interregional correlation analysis using as covariate of interest the normalized values of clusters of voxels in which perfusion differences were found in group analysis. Significantly increased regional brain perfusion distribution covering a large part of the cerebellum was observed in patients as compared with controls. Patients showed a significant negative functional connectivity between the cerebellar cluster and caudate, bilaterally. This study demonstrated inverse relative perfusion between the cerebellum and the caudate in PDD. Functional uncoupling may be associated with a dysregulation between the role of the cerebellum in action control and of the caudate in action selection, initiation and decision making in the patients. The potential impact of the resting state condition and the possibility of mitochondrial impairment are discussed. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

What is the function of hippocampal theta rhythm?--Linking behavioral data to phasic properties of field potential and unit recording data.

PubMed

Hasselmo, Michael E

2005-01-01

The extensive physiological data on hippocampal theta rhythm provide an opportunity to evaluate hypotheses about the role of theta rhythm for hippocampal network function. Computational models based on these hypotheses help to link behavioral data with physiological measurements of different variables during theta rhythm. This paper reviews work on network models in which theta rhythm contributes to the following functions: (1) separating the dynamics of encoding and retrieval, (2) enhancing the context-dependent retrieval of sequences, (3) buffering of novel information in entorhinal cortex (EC) for episodic encoding, and (4) timing interactions between prefrontal cortex and hippocampus for memory-guided action selection. Modeling shows how these functional mechanisms are related to physiological data from the hippocampal formation, including (1) the phase relationships of synaptic currents during theta rhythm measured by current source density analysis of electroencephalographic data from region CA1 and dentate gyrus, (2) the timing of action potentials, including the theta phase precession of single place cells during running on a linear track, the context-dependent changes in theta phase precession across trials on each day, and the context-dependent firing properties of hippocampal neurons in spatial alternation (e.g., "splitter cells"), (3) the cholinergic regulation of sustained activity in entorhinal cortical neurons, and (4) the phasic timing of prefrontal cortical neurons relative to hippocampal theta rhythm. Copyright 2005 Wiley-Liss, Inc.

[Automation in surgery: a systematical approach].

PubMed

Strauss, G; Meixensberger, J; Dietz, A; Manzey, D

2007-04-01

Surgical assistance systems permit a misalignment from the purely manual to an assisted activity of the surgeon (automation). Automation defines a system, that partly or totally fulfils function, those was carried out before totally or partly by the user. The organization of surgical assistance systems following application (planning, simulation, intraoperative navigation and visualization) or technical configuration of the system (manipulator, robot) is not suitable for a description of the interaction between user (surgeon) and the system. The available work has the goal of providing a classification for the degree of the automation of surgical interventions and describing by examples. The presented classification orients itself at pre-working from the Human-Factors-Sciences. As a condition for an automation of a surgical intervention applies that an assumption of a task, which was alone assigned so far to the surgeon takes place via the system. For both reference objects (humans and machine) the condition passively or actively comes into consideration. Besides can be classified according to which functions are taken over during a selected function division by humans and/or the surgical assistance system. Three functional areas were differentiated: "information acquisition and -analysis", "decision making and action planning" as well as "execution of the surgical action". From this results a classification of pre- and intraoperative surgical assist systems in six categories, which represent different automation degrees. The classification pattern is described and illustrated on the basis of surgical of examples.

Impact of Pilot Delay and Non-Responsiveness on the Safety Performance of Airborne Separation

NASA Technical Reports Server (NTRS)

Consiglio, Maria; Hoadley, Sherwood; Wing, David; Baxley, Brian; Allen, Bonnie Danette

2008-01-01

Assessing the safety effects of prediction errors and uncertainty on automationsupported functions in the Next Generation Air Transportation System concept of operations is of foremost importance, particularly safety critical functions such as separation that involve human decision-making. Both ground-based and airborne, the automation of separation functions must be designed to account for, and mitigate the impact of, information uncertainty and varying human response. This paper describes an experiment that addresses the potential impact of operator delay when interacting with separation support systems. In this study, we evaluated an airborne separation capability operated by a simulated pilot. The experimental runs are part of the Safety Performance of Airborne Separation (SPAS) experiment suite that examines the safety implications of prediction errors and system uncertainties on airborne separation assistance systems. Pilot actions required by the airborne separation automation to resolve traffic conflicts were delayed within a wide range, varying from five to 240 seconds while a percentage of randomly selected pilots were programmed to completely miss the conflict alerts and therefore take no action. Results indicate that the strategicAirborne Separation Assistance System (ASAS) functions exercised in the experiment can sustain pilot response delays of up to 90 seconds and more, depending on the traffic density. However, when pilots or operators fail to respond to conflict alerts the safety effects are substantial, particularly at higher traffic densities.

Thoughts turned into high-level commands: Proof-of-concept study of a vision-guided robot arm driven by functional MRI (fMRI) signals.

PubMed

Minati, Ludovico; Nigri, Anna; Rosazza, Cristina; Bruzzone, Maria Grazia

2012-06-01

Previous studies have demonstrated the possibility of using functional MRI to control a robot arm through a brain-machine interface by directly coupling haemodynamic activity in the sensory-motor cortex to the position of two axes. Here, we extend this work by implementing interaction at a more abstract level, whereby imagined actions deliver structured commands to a robot arm guided by a machine vision system. Rather than extracting signals from a small number of pre-selected regions, the proposed system adaptively determines at individual level how to map representative brain areas to the input nodes of a classifier network. In this initial study, a median action recognition accuracy of 90% was attained on five volunteers performing a game consisting of collecting randomly positioned coloured pawns and placing them into cups. The "pawn" and "cup" instructions were imparted through four mental imaginery tasks, linked to robot arm actions by a state machine. With the current implementation in MatLab language the median action recognition time was 24.3s and the robot execution time was 17.7s. We demonstrate the notion of combining haemodynamic brain-machine interfacing with computer vision to implement interaction at the level of high-level commands rather than individual movements, which may find application in future fMRI approaches relevant to brain-lesioned patients, and provide source code supporting further work on larger command sets and real-time processing. Copyright © 2012 IPEM. Published by Elsevier Ltd. All rights reserved.

Cortical and subcortical interactions during action reprogramming and their related white matter pathways

PubMed Central

Neubert, Franz-Xaver; Mars, Rogier B.; Buch, Ethan R.; Olivier, Etienne; Rushworth, Matthew F. S.

2010-01-01

The right inferior frontal gyrus (rIFG) and the presupplementary motor area (pre-SMA) have been identified with cognitive control—the top-down influence on other brain areas when nonroutine behavior is required. It has been argued that they “inhibit” habitual motor responses when environmental changes mean a different response should be made. However, whether such “inhibition” can be equated with inhibitory physiological interactions has been unclear, as has the areas’ relationship with each other and the anatomical routes by which they influence movement execution. Paired-pulse transcranial magnetic stimulation (ppTMS) was applied over rIFG and primary motor cortex (M1) or over pre-SMA and M1 to measure their interactions, at a subsecond scale, during either inhibition and reprogramming of actions or during routine action selection. Distinct patterns of functional interaction between pre-SMA and M1 and between rIFG and M1 were found that were specific to action reprogramming trials; at a physiological level, direct influences of pre-SMA and rIFG on M1 were predominantly facilitatory and inhibitory, respectively. In a subsequent experiment, it was shown that the rIFG's inhibitory influence was dependent on pre-SMA. A third experiment showed that pre-SMA and rIFG influenced M1 at two time scales. By regressing white matter fractional anisotropy from diffusion-weighted magnetic resonance images against TMS-measured functional connectivity, it was shown that short-latency (6 ms) and longer latency (12 ms) influences were mediated by cortico-cortical and subcortical pathways, respectively, with the latter passing close to the subthalamic nucleus. PMID:20622155

Cortical and subcortical interactions during action reprogramming and their related white matter pathways.

PubMed

Neubert, Franz-Xaver; Mars, Rogier B; Buch, Ethan R; Olivier, Etienne; Rushworth, Matthew F S

2010-07-27

The right inferior frontal gyrus (rIFG) and the presupplementary motor area (pre-SMA) have been identified with cognitive control-the top-down influence on other brain areas when nonroutine behavior is required. It has been argued that they "inhibit" habitual motor responses when environmental changes mean a different response should be made. However, whether such "inhibition" can be equated with inhibitory physiological interactions has been unclear, as has the areas' relationship with each other and the anatomical routes by which they influence movement execution. Paired-pulse transcranial magnetic stimulation (ppTMS) was applied over rIFG and primary motor cortex (M1) or over pre-SMA and M1 to measure their interactions, at a subsecond scale, during either inhibition and reprogramming of actions or during routine action selection. Distinct patterns of functional interaction between pre-SMA and M1 and between rIFG and M1 were found that were specific to action reprogramming trials; at a physiological level, direct influences of pre-SMA and rIFG on M1 were predominantly facilitatory and inhibitory, respectively. In a subsequent experiment, it was shown that the rIFG's inhibitory influence was dependent on pre-SMA. A third experiment showed that pre-SMA and rIFG influenced M1 at two time scales. By regressing white matter fractional anisotropy from diffusion-weighted magnetic resonance images against TMS-measured functional connectivity, it was shown that short-latency (6 ms) and longer latency (12 ms) influences were mediated by cortico-cortical and subcortical pathways, respectively, with the latter passing close to the subthalamic nucleus.

Simulation Models of the Effects of Race- and Socioeconomic-Based Affirmative Action Policies on Elite College Enrollment Patterns

ERIC Educational Resources Information Center

Reardon, Sean; Baker, Rachel; Kasman, Matt; Townsend, Joe; Klasik, Daniel

2014-01-01

The creation of racially diverse colleges at all levels of selectivity has proven to be no small task, even with the legal use of race-conscious affirmative action. As evidenced in the postsecondary destinations of the high school class of 2004, very selective schools (those with Barron's Selectivity rankings of 1, 2 or 3) have many more White,…

Functional screening of selective mitochondrial inhibitors of Plasmodium.

PubMed

Gomez-Lorenzo, Maria G; Rodríguez-Alejandre, Ane; Moliner-Cubel, Sonia; Martínez-Hoyos, María; Bahamontes-Rosa, Noemí; Gonzalez Del Rio, Rubén; Ródenas, Carolina; Fuente, Jesús de la; Lavandera, Jose Luis; García-Bustos, Jose F; Mendoza-Losana, Alfonso

2018-05-09

Phenotypic screening has produced most of the new chemical entities currently in clinical development for malaria, plus many lead compounds active against Plasmodium falciparum asexual stages. However, lack of knowledge about the mode of action of these compounds delays and may even hamper their future development. Identifying the mode of action of the inhibitors greatly helps to prioritise compounds for further development as novel antimalarials. Here we describe a whole-cell method to detect inhibitors of the mitochondrial electron transport chain, using oxygen consumption as high throughput readout in 384-well plate format. The usefulness of the method has been confirmed with the Tres Cantos Antimalarial Compound Set (TCAMS). The assay identified 124 respiratory inhibitors in TCAMS, seven of which were novel anti-plasmodial chemical structures never before described as mitochondrial inhibitors. Copyright © 2018. Published by Elsevier Ltd.

[Pharmacological action and clinical aspects of salmeterol].

PubMed

Oguri, Kojiro

2003-09-01

Previous systemic beta(2) agonists such as procatrol tablets and tulobuterol patch were developed in Japan to address nocturnal symptoms and maintenance of lung function in asthmatic patients. Salmeterol, a potent and highly selective in beta(2) adrenocepter agonist with a duration of action greater than 12 h, was developed to provide long duration of bronchodilation with binding to a non-active site in the beta(2)-adrenocepter. Salmeterol is administrated via dry power inhalation and clinical studies have showed it has a good efficacy and a good safety profile, similar to inhaled steroids. Indeed, many clinical studies showed that salmeterol demonstrated better efficacy than long-acting beta(2)-agonist oral bronchodilators, theophyllines, and leukotriene-receptor antagonists in asthmatic patients and anticholinergic agents and theophyllines in COPD patients. Salmeterol will provide clinical benefits for Japanese asthma and COPD patients.

Information theory of adaptation in neurons, behavior, and mood.

PubMed

Sharpee, Tatyana O; Calhoun, Adam J; Chalasani, Sreekanth H

2014-04-01

The ability to make accurate predictions of future stimuli and consequences of one's actions are crucial for the survival and appropriate decision-making. These predictions are constantly being made at different levels of the nervous system. This is evidenced by adaptation to stimulus parameters in sensory coding, and in learning of an up-to-date model of the environment at the behavioral level. This review will discuss recent findings that actions of neurons and animals are selected based on detailed stimulus history in such a way as to maximize information for achieving the task at hand. Information maximization dictates not only how sensory coding should adapt to various statistical aspects of stimuli, but also that reward function should adapt to match the predictive information from past to future. Copyright © 2013 Elsevier Ltd. All rights reserved.

Antinociceptive action of NOP and opioid receptor agonists in the mouse orofacial formalin test.

PubMed

Rizzi, A; Ruzza, C; Bianco, S; Trapella, C; Calo', G

2017-08-01

Nociceptin/orphanin FQ (N/OFQ) modulates several biological functions, including pain transmission via selective activation of a specific receptor named NOP. The aim of this study was the investigation of the antinociceptive properties of NOP agonists and their interaction with opioids in the trigeminal territory. The orofacial formalin (OFF) test in mice was used to investigate the antinociceptive potential associated to the activation of NOP and opioid receptors. Mice subjected to OFF test displayed the typical biphasic nociceptive response and sensitivity to opioid and NSAID drugs. Mice knockout for the NOP gene displayed a robust pronociceptive phenotype. The NOP selective agonist Ro 65-6570 (0.1-1mgkg -1 ) and morphine (0.1-10mgkg -1 ) elicited dose dependent antinociceptive effects in the OFF with the alkaloid showing larger effects; the isobologram analysis of their actions demonstrated an additive type of interaction. The mixed NOP/opioid receptor agonist cebranopadol elicited potent (0.01-0.1mgkg -1 ) and robust antinociceptive effects. In the investigated dose range, all drugs did not modify the motor performance of the mice in the rotarod test. Collectively the results of this study demonstrated that selective NOP agonists and particularly mixed NOP/opioid agonists are worthy of development as innovative drugs to treat painful conditions of the trigeminal territory. Copyright © 2017 Elsevier Inc. All rights reserved.

The influence of salinity on the toxicity of selected sulfonamides and trimethoprim towards the green algae Chlorella vulgaris.

PubMed

Borecka, Marta; Białk-Bielińska, Anna; Haliński, Łukasz P; Pazdro, Ksenia; Stepnowski, Piotr; Stolte, Stefan

2016-05-05

This paper presents the investigation of the influence of salinity variations on the toxicity of sulfapyridine, sulfamethoxazole, sulfadimethoxine and trimethoprim towards the green algae Chlorella vulgaris after exposure times of 48 and 72 h. In freshwater the EC50 values ranged from 0.98 to 123.22 mg L(-1) depending on the compound. The obtained results revealed that sulfamethoxazole and sulfapyridine were the most toxic, while trimethoprim was the least toxic pharmaceutical to the selected organism. Deviations between the nominal and real test concentrations were determined via instrumental analysis to support the interpretation of ecotoxicological data. The toxicity effects were also tested in saline water (3, 6 and 9 PSU). The tendency that the toxicity of selected pharmaceuticals decreases with increasing salinity was observed. Higher salinity implies an elevated concentration of inorganic monovalent cations that are capable of binding with countercharges available on algal surfaces (hydroxyl functional groups). Hence it can reduce the permeability of pharmaceuticals through the algal cell walls, which could be the probable reason for the observed effect. Moreover, for the classification of the mode of toxic action, the toxic ratio concept was applied, which indicated that the effects of the investigated drugs towards algae are caused by the specific mode of toxic action. Copyright © 2016 Elsevier B.V. All rights reserved.

A complicated complex: Ion channels, voltage sensing, cell membranes and peptide inhibitors.

PubMed

Zhang, Alan H; Sharma, Gagan; Undheim, Eivind A B; Jia, Xinying; Mobli, Mehdi

2018-04-21

Voltage-gated ion channels (VGICs) are specialised ion channels that have a voltage dependent mode of action, where ion conduction, or gating, is controlled by a voltage-sensing mechanism. VGICs are critical for electrical signalling and are therefore important pharmacological targets. Among these, voltage-gated sodium channels (Na V s) have attracted particular attention as potential analgesic targets. Na V s, however, comprise several structurally similar subtypes with unique localisations and distinct functions, ranging from amplification of action potentials in nociception (e.g. Na V 1.7) to controlling electrical signalling in cardiac function (Na V 1.5). Understanding the structural basis of Na V function is therefore of great significance, both to our knowledge of electrical signalling and in development of subtype and state selective drugs. An important tool in this pursuit has been the use of peptides from animal venoms as selective Na V modulators. In this review, we look at peptides, particularly from spider venoms, that inhibit Na V s by binding to the voltage sensing domain (VSD) of this channel, known as gating modifier toxins (GMT). In the first part of the review, we look at the structural determinants of voltage sensing in VGICs, the gating cycle and the conformational changes that accompany VSD movement. Next, the modulation of the analgesic target Na V 1.7 by GMTs is reviewed to develop bioinformatic tools that, based on sequence information alone, can identify toxins that are likely to inhibit this channel. The same approach is also used to define VSD sequences, other than that from Na V 1.7, which are likely to be sensitive to this class of toxins. The final section of the review focuses on the important role of the cellular membrane in channel modulation and also how the lipid composition affects measurements of peptide-channel interactions both in binding kinetics measurements in solution and in cell-based functional assays. Copyright © 2018 Elsevier B.V. All rights reserved.

Hallucinogen-like effects of N,N-dipropyltryptamine (DPT): possible mediation by serotonin 5-HT1A and 5-HT2A receptors in rodents

PubMed Central

Fantegrossi, William E.; Reissig, Chad J.; Katz, Elyse B.; Yarosh, Haley L.; Rice, Kenner C.; Winter, Jerrold C.

2008-01-01

N,N-dipropyltryptamine (DPT) is a synthetic tryptamine hallucinogen which has been used psychotherapeutically in humans, but has been studied preclinically only rarely. In the present studies, DPT was tested in a drug-elicited head twitch assay in mice, and in rats trained to discriminate lysergic acid diethylamide (LSD), N,N-dimethyl-4-phosphoryloxytryptamine (psilocybin), or 3,4-methylenedioxymethamphetamine (MDMA). A separate group of rats was also trained to recognize DPT itself as a discriminative stimulus, and in all cases, the behavioral effects of DPT were challenged with the selective serotonin (5-HT)2A antagonist M100907, the 5-HT1A selective antagonist WAY-100635, or their combination. In the head twitch assay, DPT elicited dose-dependent effects, producing a biphasic dose-effect curve. WAY-100635 produced a parallel rightward shift in the dose-effect curve for head twitches, indicative of surmountable antagonism, but the antagonist effects of M100907 were functionally insurmountable. DPT produced partial to full substitution when tested in rats trained to discriminate LSD, psilocybin or MDMA, and served as a discriminative stimulus. In all cases, the antagonist effects of M100907 were more profound than were those of WAY-100635. DPT is thus active in two rodent models relevant to 5-HT2 agonist activity. The effectiveness with which M100907 antagonizes the behavioral actions of this compound strongly suggests that the 5-HT2A receptor is an important site of action for DPT, but the modulatory actions of WAY-100635 also imply a 5-HT1A-mediated component to the actions of this compound. PMID:17905422

A mathematical model of embodied consciousness.

PubMed

Rudrauf, David; Bennequin, Daniel; Granic, Isabela; Landini, Gregory; Friston, Karl; Williford, Kenneth

2017-09-07

We introduce a mathematical model of embodied consciousness, the Projective Consciousness Model (PCM), which is based on the hypothesis that the spatial field of consciousness (FoC) is structured by a projective geometry and under the control of a process of active inference. The FoC in the PCM combines multisensory evidence with prior beliefs in memory and frames them by selecting points of view and perspectives according to preferences. The choice of projective frames governs how expectations are transformed by consciousness. Violations of expectation are encoded as free energy. Free energy minimization drives perspective taking, and controls the switch between perception, imagination and action. In the PCM, consciousness functions as an algorithm for the maximization of resilience, using projective perspective taking and imagination in order to escape local minima of free energy. The PCM can account for a variety of psychological phenomena: the characteristic spatial phenomenology of subjective experience, the distinctions and integral relationships between perception, imagination and action, the role of affective processes in intentionality, but also perceptual phenomena such as the dynamics of bistable figures and body swap illusions in virtual reality. It relates phenomenology to function, showing the computational advantages of consciousness. It suggests that changes of brain states from unconscious to conscious reflect the action of projective transformations and suggests specific neurophenomenological hypotheses about the brain, guidelines for designing artificial systems, and formal principles for psychology. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of Message Type on the Visual Attention of Adults With Traumatic Brain Injury.

PubMed

Thiessen, Amber; Brown, Jessica; Beukelman, David; Hux, Karen; Myers, Angela

2017-05-17

The purpose of this investigation was to measure the effect of message type (i.e., action, naming) on the visual attention patterns of individuals with and without traumatic brain injury (TBI) when viewing grids composed of 3 types of images (i.e., icons, decontextualized photographs, and contextualized photographs). Fourteen adults with TBI and 14 without TBI-assigned either to an action or naming message condition-viewed grids composed of 3 different image types. Participants' task was to select/sustain visual fixation on the image they felt best represented a stated message (i.e., action or naming). With final fixation location serving as a proxy for selection, participants in the naming message condition selected decontextualized photographs significantly more often than the other 2 image types. Participants in the action message condition selected contextualized photographs significantly more frequently than the other 2 image types. Minimal differences were noted between participant groups. This investigation provides preliminary evidence of the relationship between image and message type. Clinicians involved in the selection of images used for message representation should consider the message being represented when designing supports for people with TBI. Further research is necessary to fully understand the relationship between images and message type.

New-generation 5-HT4 receptor agonists: potential for treatment of gastrointestinal motility disorders.

PubMed

Manabe, Noriaki; Wong, Banny S; Camilleri, Michael

2010-06-01

Gastrointestinal (GI) dysmotility is an important mechanism in functional GI disorders (FGIDs) including constipation, irritable bowel syndrome, functional dyspepsia, and gastroparesis. 5-hydroxytryptamine(4) (5-HT(4)) receptors are targets for the treatment of GI motility disorders. However, older 5-HT(4) receptor agonists had limited clinical success because they were associated with changes in the function of the cardiac HERG potassium channel. We conducted a PubMed search using the following key words alone or in combination: 5-HT(4), safety, toxicity, pharmacokinetics, pharmacodynamics, clinical trial, cardiac, hERG, arrhythmia, potassium current, elderly, prucalopride, ATI-7505, and velusetrag (TD-5108), to review mechanisms of action, clinical efficacy, safety and tolerability of three new-generation 5-HT(4) receptor agonists. Prucalopride, ATI-7505, and velusetrag (TD-5108) are highly selective, high-affinity 5-HT(4) receptor agonists that are devoid of action on other receptors within their therapeutic range. Their efficacy has been demonstrated in pharmacodynamic studies which demonstrate acceleration of colonic transit and, to a variable degree, in clinical trials that significantly relieve chronic constipation. Currently available evidence shows that the new 5-HT(4) receptor agonists have safe cardiac profiles. New-generation 5-HT(4) receptor agonists and future drugs targeting organ-specific splice variants are promising approaches to treat GI dysmotility, particularly colonic diseases.

Immune cell impact of three differently coated lipid nanocapsules: pluronic, chitosan and polyethylene glycol

PubMed Central

Farace, Cristiano; Sánchez-Moreno, Paola; Orecchioni, Marco; Manetti, Roberto; Sgarrella, Francesco; Asara, Yolande; Peula-García, José M.; Marchal, Juan A.; Madeddu, Roberto; Delogu, Lucia G.

2016-01-01

Lipid nanocapsules (NCs) represent promising tools in clinical practice for diagnosis and therapy applications. However, the NC appropriate functionalization is essential to guarantee high biocompatibility and molecule loading ability. In any medical application, the immune system-impact of differently functionalized NCs still remains to be fully understood. A comprehensive study on the action exerted on human peripheral blood mononuclear cells (PBMCs) and major immune subpopulations by three different NC coatings: pluronic, chitosan and polyethylene glycol-polylactic acid (PEG) is reported. After a deep particle characterization, the uptake was assessed by flow-cytometry and confocal microscopy, focusing then on apoptosis, necrosis and proliferation impact in T cells and monocytes. Cell functionality by cell diameter variations, different activation marker analysis and cytokine assays were performed. We demonstrated that the NCs impact on the immune cell response is strongly correlated to their coating. Pluronic-NCs were able to induce immunomodulation of innate immunity inducing monocyte activations. Immunomodulation was observed in monocytes and T lymphocytes treated with Chitosan-NCs. Conversely, PEG-NCs were completely inert. These findings are of particular value towards a pre-selection of specific NC coatings depending on biomedical purposes for pre-clinical investigations; i.e. the immune-specific action of particular NC coating can be excellent for immunotherapy applications. PMID:26728491

Immune cell impact of three differently coated lipid nanocapsules: pluronic, chitosan and polyethylene glycol.

PubMed

Farace, Cristiano; Sánchez-Moreno, Paola; Orecchioni, Marco; Manetti, Roberto; Sgarrella, Francesco; Asara, Yolande; Peula-García, José M; Marchal, Juan A; Madeddu, Roberto; Delogu, Lucia G

2016-01-05

Lipid nanocapsules (NCs) represent promising tools in clinical practice for diagnosis and therapy applications. However, the NC appropriate functionalization is essential to guarantee high biocompatibility and molecule loading ability. In any medical application, the immune system-impact of differently functionalized NCs still remains to be fully understood. A comprehensive study on the action exerted on human peripheral blood mononuclear cells (PBMCs) and major immune subpopulations by three different NC coatings: pluronic, chitosan and polyethylene glycol-polylactic acid (PEG) is reported. After a deep particle characterization, the uptake was assessed by flow-cytometry and confocal microscopy, focusing then on apoptosis, necrosis and proliferation impact in T cells and monocytes. Cell functionality by cell diameter variations, different activation marker analysis and cytokine assays were performed. We demonstrated that the NCs impact on the immune cell response is strongly correlated to their coating. Pluronic-NCs were able to induce immunomodulation of innate immunity inducing monocyte activations. Immunomodulation was observed in monocytes and T lymphocytes treated with Chitosan-NCs. Conversely, PEG-NCs were completely inert. These findings are of particular value towards a pre-selection of specific NC coatings depending on biomedical purposes for pre-clinical investigations; i.e. the immune-specific action of particular NC coating can be excellent for immunotherapy applications.

From genes to brain development to phenotypic behavior: "dorsal-stream vulnerability" in relation to spatial cognition, attention, and planning of actions in Williams syndrome (WS) and other developmental disorders.

PubMed

Atkinson, Janette; Braddick, Oliver

2011-01-01

Visual information is believed to be processed through two distinct, yet interacting cortical streams. The ventral stream performs the computations needed for recognition of objects and faces ("what" and "who"?) and the dorsal stream the computations for registering spatial relationships and for controlling visually guided actions ("where" and "how"?). We initially proposed a model of spatial deficits in Williams syndrome (WS) in which visual abilities subserved by the ventral stream, such as face recognition, are relatively well developed (although not necessarily in exactly the same way as in typical development), whereas dorsal-stream functions, such as visuospatial actions, are markedly impaired. Since these initial findings in WS, deficits of motion coherence sensitivity, a dorsal-stream function has been found in other genetic disorders such as Fragile X and autism, and as a consequence of perinatal events (in hemiplegia, perinatal brain anomalies following very premature birth), leading to the proposal of a general "dorsal-stream vulnerability" in many different conditions of abnormal human development. In addition, dorsal-stream systems provide information used in tasks of visuospatial memory and locomotor planning, and these systems are closely coupled to networks for attentional control. We and several other research groups have previously shown deficits of frontal and parietal lobe function in WS individuals for specific attention tasks [e.g., Atkinson, J., Braddick, O., Anker, S., Curran, W., & Andrew, R. (2003). Neurobiological models of visuospatial cognition in children with Williams Syndrome: Measures of dorsal-stream and frontal function. Developmental Neuropsychology, 23(1/2), 141-174.]. We have used the Test of Everyday Attention for Children (TEA-Ch) which aims to attempt to separate components of attention with distinct brain networks (selective attention, sustained attention, and attention control-executive function) testing a group of older children with WS, but this test battery is too demanding for many children and adults with WS. Consequently, we have devised a new set of tests of attention, the Early Childhood Attention Battery (ECAB). This uses similar principles to the TEA-Ch, but adapted for mental ages younger than 6 years. The ECAB shows a distinctive attention profile for WS individuals relative to their overall cognitive development, with relative strength in tasks of sustained attention and poorer performance on tasks of selective attention and executive control. These profiles, and the characteristic developmental courses, also show differences between children with Down's syndrome and WS. This chapter briefly reviews new research findings on WS in these areas, relating the development of brain systems in WS to evidence from neuroimaging in typically developing infants, children born very preterm, and normal adults. The hypothesis of "dorsal-stream(s) vulnerability" which will be discussed includes a number of interlinked brain networks, subserving not only global visual processing and formulation of visuomotor actions but interlinked networks of attention. Copyright © 2011 Elsevier B.V. All rights reserved.

Accessing biological actions of Ganoderma secondary metabolites by in silico profiling

PubMed Central

Grienke, Ulrike; Kaserer, Teresa; Pfluger, Florian; Mair, Christina E.; Langer, Thierry; Schuster, Daniela; Rollinger, Judith M.

2016-01-01

The species complex around the medicinal fungus Ganoderma lucidum Karst. (Ganodermataceae) is widely known in traditional medicines as well as in modern applications such as functional food or nutraceuticals. A considerable number of publications reflects its abundance and variety in biological actions either provoked by primary metabolites such as polysaccharides or secondary metabolites such as lanostane-type triterpenes. However, due to this remarkable amount of information, a rationalization of the individual Ganoderma constituents to biological actions on a molecular level is quite challenging. To overcome this issue, a database was generated containing meta-information, i.e. chemical structures and biological actions of hitherto identified Ganoderma constituents (279). This was followed by a computational approach subjecting this 3D multi-conformational molecular dataset to in silico parallel screening against an in-house collection of validated structure- and ligand-based 3D pharmacophore models. The predictive power of the evaluated in silico tools and hints from traditional application fields served as criteria for the model selection. Thus, we focused on representative druggable targets in the field of viral infections (5) and diseases related to the metabolic syndrome (22). The results obtained from this in silico approach were compared to bioactivity data available from the literature to distinguish between true and false positives or negatives. 89 and 197 Ganoderma compounds were predicted as ligands of at least one of the selected pharmacological targets in the antiviral and the metabolic syndrome screening, respectively. Among them only a minority of individual compounds (around 10%) has ever been investigated on these targets or for the associated biological activity. Accordingly, this study discloses putative ligand target interactions for a plethora of Ganoderma constituents in the empirically manifested field of viral diseases and metabolic syndrome which serve as a basis for future applications to access yet undiscovered biological actions of Ganoderma secondary metabolites on a molecular level. PMID:25457486

In and out of control: brain mechanisms linking fluency of action selection to self-agency in patients with schizophrenia.

PubMed

Voss, Martin; Chambon, Valérian; Wenke, Dorit; Kühn, Simone; Haggard, Patrick

2017-08-01

Sense of agency refers to the feeling of control over one's actions, and their consequences. It involves both predictive processes linked to action control, and retrospective 'sense-making' causal inferences. Schizophrenia has been associated with impaired predictive processing, but the underlying mechanisms that impair patients' sense of agency remain unclear. We introduce a new 'prospective' aspect of agency and show that subliminally priming an action not only influences response times, but also influences reported sense of agency over subsequent action outcomes. This effect of priming was associated with altered connectivity between frontal areas and the angular gyrus. The effects on response times and on frontal action selection mechanisms were similar in patients with schizophrenia and in healthy volunteers. However, patients showed no effects of priming on sense of agency, no priming-related activation of angular gyrus, and no priming-related changes in fronto-parietal connectivity. We suggest angular gyrus activation reflects the experiences of agency, or non-agency, in part by processing action selection signals generated in the frontal lobes. The altered action awareness that characterizes schizophrenia may be due to impaired communication between these areas. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

SALGOT - Stroke Arm Longitudinal study at the University of Gothenburg, prospective cohort study protocol

PubMed Central

2011-01-01

Background Recovery patterns of upper extremity motor function have been described in several longitudinal studies, but most of these studies have had selected samples, short follow up times or insufficient outcomes on motor function. The general understanding is that improvements in upper extremity occur mainly during the first month after the stroke incident and little if any, significant recovery can be gained after 3-6 months. The purpose of this study is to describe the recovery of upper extremity function longitudinally in a non-selected sample initially admitted to a stroke unit with first ever stroke, living in Gothenburg urban area. Methods/Design A sample of 120 participants with a first-ever stroke and impaired upper extremity function will be consecutively included from an acute stroke unit and followed longitudinally for one year. Assessments are performed at eight occasions: at day 3 and 10, week 3, 4 and 6, month 3, 6 and 12 after onset of stroke. The primary clinical outcome measures are Action Research Arm Test and Fugl-Meyer Assessment for Upper Extremity. As additional measures, two new computer based objective methods with kinematic analysis of arm movements are used. The ABILHAND questionnaire of manual ability, Stroke Impact Scale, grip strength, spasticity, pain, passive range of motion and cognitive function will be assessed as well. At one year follow up, two patient reported outcomes, Impact on Participation and Autonomy and EuroQol Quality of Life Scale, will be added to cover the status of participation and aspects of health related quality of life. Discussion This study comprises a non-selected population with first ever stroke and impaired arm function. Measurements are performed both using traditional clinical assessments as well as computer based measurement systems providing objective kinematic data. The ICF classification of functioning, disability and health is used as framework for the selection of assessment measures. The study design with several repeated measurements on motor function will give us more confident information about the recovery patterns after stroke. This knowledge is essential both for optimizing rehabilitation planning as well as providing important information to the patient about the recovery perspectives. Trial registration ClinicalTrials.gov: NCT01115348 PMID:21612620

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shalev, Moran; Rozenberg, Haim; Smolkin, Boris

Leishmaniasis comprises an array of diseases caused by pathogenic species of Leishmania, resulting in a spectrum of mild to life-threatening pathologies. Currently available therapies for leishmaniasis include a limited selection of drugs. This coupled with the rather fast emergence of parasite resistance, presents a dire public health concern. Paromomycin (PAR), a broad-spectrum aminoglycoside antibiotic, has been shown in recent years to be highly efficient in treating visceral leishmaniasis (VL)—the life-threatening form of the disease. While much focus has been given to exploration of PAR activities in bacteria, its mechanism of action in Leishmania has received relatively little scrutiny and hasmore » yet to be fully deciphered. In the present study we present an X-ray structure of PAR bound to rRNA model mimicking its leishmanial binding target, the ribosomal A-site. We evaluate PAR inhibitory actions on leishmanial growth and ribosome function, as well as effects on auditory sensory cells, by comparing several structurally related natural and synthetic aminoglycoside derivatives. The results provide insights into the structural elements important for aminoglycoside inhibitory activities and selectivity for leishmanial cytosolic ribosomes, highlighting a novel synthetic derivative, compound 3, as a prospective therapeutic candidate for the treatment of VL.« less

The Ion Permeability Induced in Thin Lipid Membranes by the Polyene Antibiotics Nystatin and Amphotericin B

PubMed Central

Cass, Albert; Finkelstein, Alan; Krespi, Vivian

1970-01-01

Characteristics of nystatin and amphotericin B action on thin (<100 A) lipid membranes are: (a) micromolar amounts increase membrane conductance from 10-8 to over 10-2 Ω-1 cm-2; (b) such membranes are (non-ideally) anion selective and discriminate among anions on the basis of size; (c) membrane sterol is required for action; (d) antibiotic presence on both sides of membrane strongly favors action; (e) conductance is proportional to a large power of antibiotic concentration; (f) conductance decreases ∼104 times for a 10°C temperature rise; (g) kinetics of antibiotic action are also very temperature sensitive; (h) ion selectivity is pH independent between 3 and 10, but (i) activity is reversibly lost at high pH; (j) methyl ester derivatives are fully active; N-acetyl and N-succinyl derivatives are inactive; (k) current-voltage characteristic is nonlinear when membrane separates nonidentical salt solutions. These characteristics are contrasted with those of valinomycin. Observations (a)–(g) suggest that aggregates of polyene and sterol from opposite sides of the membrane interact to create aqueous pores; these pores are not static, but break up (melt) and reform continuously. Mechanism of anion selectivity is obscure. Observations (h)–(j) suggest—NH3 + is important for activity; it is probably not responsible for selectivity, particularly since four polyene antibiotics, each containing two—NH3 + groups, induce ideal cation selectivity. Possibly the many hydroxyl groups in nystatin and amphotericin B are responsible for anion selectivity. The effects of polyene antibiotics on thin lipid membranes are consistent with their action on biological membranes. PMID:5514157

Use of an action-selection framework for human-carnivore conflict in the Bangladesh Sundarbans.

PubMed

Barlow, Adam C D; Greenwood, Christina J; Ahmad, Ishtiaq U; Smith, James L D

2010-10-01

Human-carnivore conflict is manifested in the death of humans, livestock, and carnivores. The resulting negative local attitudes and retribution killings imperil the future of many endangered carnivores. We tailored existing management tools to create a framework to facilitate the selection of actions to alleviate human-carnivore conflict and applied the framework to the human-tiger conflict in the Bangladesh Sundarbans. We identified potential actions that consider previous management efforts, local knowledge, cost-effectiveness, fieldwork experience of authors and project staff, previous research on tiger ecology by the authors, and recommendations from human-carnivore conflict studies in other countries. Our framework includes creation of a profile to improve understanding of the nature of the conflict and its underlying causality. Identified actions include deterrents, education, direct tiger management, and response teams. We ranked actions by their potential to reduce conflict and the monetary cost of their implementation. We ranked tiger-response teams and monitoring problem tigers as the two best actions because both had relatively high impact and cost-effectiveness. We believe this framework could be used under a wide range of human-wildlife conflict situations because it provides a structured approach to selection of mitigating actions. © 2010 Society for Conservation Biology.

In silico Interrogation of Insect Central Complex Suggests Computational Roles for the Ellipsoid Body in Spatial Navigation.

PubMed

Fiore, Vincenzo G; Kottler, Benjamin; Gu, Xiaosi; Hirth, Frank

2017-01-01

The central complex in the insect brain is a composite of midline neuropils involved in processing sensory cues and mediating behavioral outputs to orchestrate spatial navigation. Despite recent advances, however, the neural mechanisms underlying sensory integration and motor action selections have remained largely elusive. In particular, it is not yet understood how the central complex exploits sensory inputs to realize motor functions associated with spatial navigation. Here we report an in silico interrogation of central complex-mediated spatial navigation with a special emphasis on the ellipsoid body. Based on known connectivity and function, we developed a computational model to test how the local connectome of the central complex can mediate sensorimotor integration to guide different forms of behavioral outputs. Our simulations show integration of multiple sensory sources can be effectively performed in the ellipsoid body. This processed information is used to trigger continuous sequences of action selections resulting in self-motion, obstacle avoidance and the navigation of simulated environments of varying complexity. The motor responses to perceived sensory stimuli can be stored in the neural structure of the central complex to simulate navigation relying on a collective of guidance cues, akin to sensory-driven innate or habitual behaviors. By comparing behaviors under different conditions of accessible sources of input information, we show the simulated insect computes visual inputs and body posture to estimate its position in space. Finally, we tested whether the local connectome of the central complex might also allow the flexibility required to recall an intentional behavioral sequence, among different courses of actions. Our simulations suggest that the central complex can encode combined representations of motor and spatial information to pursue a goal and thus successfully guide orientation behavior. Together, the observed computational features identify central complex circuitry, and especially the ellipsoid body, as a key neural correlate involved in spatial navigation.

Tamoxifen regulation of bone growth and endocrine function in the ovariectomized rat: discrimination of responses involving estrogen receptor α/estrogen receptor β, G protein-coupled estrogen receptor, or estrogen-related receptor γ using fulvestrant (ICI 182780).

PubMed

Fitts, James M; Klein, Robert M; Powers, C Andrew

2011-07-01

Tamoxifen is a selective estrogen receptor (ER) modulator, but it is also a deactivating ligand for estrogen-related receptor-γ (ERRγ) and a full agonist for the G protein-coupled estrogen receptor (GPER). Fulvestrant is a selective ER down-regulator that lacks agonist effects on ERα/ERβ, is inactive on ERRγ, but acts as a full agonist on GPER. Fulvestrant effects on tamoxifen actions on uterine and somatic growth, bone, the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis, and pituitary prolactin were analyzed to pharmacologically discriminate tamoxifen effects that may be mediated by ERα/ERβ versus ERRγ versus GPER. Ovariectomized rats received tamoxifen (0.6 mg/kg/daily) plus fulvestrant at 0, 3, 6, or 12 mg/kg/daily for 5 weeks; controls received vehicle or 6 mg/kg fulvestrant daily. Tamoxifen effects to increase uterine weight, decrease serum IGF-I, increase pituitary prolactin, and increase bone mineral density could be fully blocked by fulvestrant, indicating mediation by ERα/ERβ. Tamoxifen effects to decrease pituitary GH, tibia length, and body weight were only partially blocked by fulvestrant, indicating involvement of mechanisms unrelated to ERα/ERβ. Fulvestrant did not inhibit tamoxifen actions to reduce total pituitary protein, again indicating effects not mediated by ERα/ERβ. Tamoxifen actions to reduce serum GH were mimicked rather than inhibited by fulvestrant, pharmacological features consistent with GPER involvement. However, fulvestrant alone increased IGF-I and also blocked tamoxifen-evoked IGF-I decreases; thus fulvestrant effects on serum GH might reflect increased IGF-I feedback inhibition. Fulvestrant alone had no effect on the other parameters. The findings indicate that mechanisms unrelated to ERα/ERβ contribute to tamoxifen effects on body weight, bone growth, and pituitary function.

Impact of streptozotocin on altering normal glucose homeostasis during insulin testing in diabetic rats compared to normoglycemic rats

PubMed Central

Qinna, Nidal A; Badwan, Adnan A

2015-01-01

Streptozotocin (STZ) is currently the most used diabetogenic agent in testing insulin and new antidiabetic drugs in animals. Due to the toxic and disruptive nature of STZ on organs, apart from pancreas, involved in preserving the body’s normal glucose homeostasis, this study aims to reassess the action of STZ in inducing different glucose response states in diabetic rats while testing insulin. Diabetic Sprague-Dawley rats induced with STZ were classified according to their initial blood glucose levels into stages. The effect of randomizing rats in such a manner was investigated for the severity of interrupting normal liver, pancreas, and kidney functions. Pharmacokinetic and pharmacodynamic actions of subcutaneously injected insulin in diabetic and nondiabetic rats were compared. Interruption of glucose homeostasis by STZ was challenged by single and repeated administrations of injected insulin and oral glucose to diabetic rats. In diabetic rats with high glucose (451–750 mg/dL), noticeable changes were seen in the liver and kidney functions compared to rats with lower basal glucose levels. Increased serum levels of recombinant human insulin were clearly indicated by a significant increase in the calculated maximum serum concentration and area under the concentration–time curve. Reversion of serum glucose levels to normal levels pre- and postinsulin and oral glucose administrations to STZ diabetic rats were found to be variable. In conclusion, diabetic animals were more responsive to insulin than nondiabetic animals. STZ was capable of inducing different levels of normal glucose homeostasis disruption in rats. Both pharmacokinetic and pharmacodynamic actions of insulin were altered when different initial blood glucose levels of STZ diabetic rats were selected for testing. Such findings emphasize the importance of selecting predefined and unified glucose levels when using STZ as a diabetogenic agent in experimental protocols evaluating new antidiabetic agents and insulin delivery systems. PMID:26005328

In silico Interrogation of Insect Central Complex Suggests Computational Roles for the Ellipsoid Body in Spatial Navigation

PubMed Central

Fiore, Vincenzo G.; Kottler, Benjamin; Gu, Xiaosi; Hirth, Frank

2017-01-01

The central complex in the insect brain is a composite of midline neuropils involved in processing sensory cues and mediating behavioral outputs to orchestrate spatial navigation. Despite recent advances, however, the neural mechanisms underlying sensory integration and motor action selections have remained largely elusive. In particular, it is not yet understood how the central complex exploits sensory inputs to realize motor functions associated with spatial navigation. Here we report an in silico interrogation of central complex-mediated spatial navigation with a special emphasis on the ellipsoid body. Based on known connectivity and function, we developed a computational model to test how the local connectome of the central complex can mediate sensorimotor integration to guide different forms of behavioral outputs. Our simulations show integration of multiple sensory sources can be effectively performed in the ellipsoid body. This processed information is used to trigger continuous sequences of action selections resulting in self-motion, obstacle avoidance and the navigation of simulated environments of varying complexity. The motor responses to perceived sensory stimuli can be stored in the neural structure of the central complex to simulate navigation relying on a collective of guidance cues, akin to sensory-driven innate or habitual behaviors. By comparing behaviors under different conditions of accessible sources of input information, we show the simulated insect computes visual inputs and body posture to estimate its position in space. Finally, we tested whether the local connectome of the central complex might also allow the flexibility required to recall an intentional behavioral sequence, among different courses of actions. Our simulations suggest that the central complex can encode combined representations of motor and spatial information to pursue a goal and thus successfully guide orientation behavior. Together, the observed computational features identify central complex circuitry, and especially the ellipsoid body, as a key neural correlate involved in spatial navigation. PMID:28824390

Characterization of Structure and Function of ZS-9, a K+ Selective Ion Trap

PubMed Central

Stavros, Fiona; Yang, Alex; Leon, Alejandro; Nuttall, Mark; Rasmussen, Henrik S.

2014-01-01

Hyperkalemia, a condition in which serum potassium ions (K+) exceed 5.0 mmol/L, is a common electrolyte disorder associated with substantial morbidity. Current methods of managing hyperkalemia, including organic polymer resins such as sodium polystyrene sulfonate (SPS), are poorly tolerated and/or not effective. Sodium zirconium cyclosilicate (ZS-9) is under clinical development as an orally administered, non-absorbed, novel, inorganic microporous zirconium silicate compound that selectively removes excess K+ in vivo. The development, structure and ion exchange properties of ZS-9 and its hypothesized mechanism of action are described. Based on calculation of the interatomic distances between the atoms forming the ZS-9 micropores, the size of the pore opening was determined to be ∼3 Å (∼diameter of unhydrated K+). Unlike nonspecific organic polymer resins like SPS, the ZS-9 K+ exchange capacity (KEC) was unaffected by the presence of calcium (Ca2+) or magnesium ions (Mg2+) and showed>25-fold selectivity for K+ over either Ca2+ or Mg2+. Conversely, the selectivity of SPS for K+ was only 0.2–0.3 times its selectivity for Ca2+ or Mg2+in mixed ionic media. It is hypothesized that the high K+ specificity of ZS-9 is attributable to the chemical composition and diameter of the micropores, which possibly act in an analogous manner to the selectivity filter utilized by physiologic K+ channels. This hypothesized mechanism of action is supported by the multi-ion exchange studies. The effect of pH on the KEC of ZS-9 was tested in different media buffered to mimic different portions of the human gastrointestinal tract. Rapid K+ uptake was observed within 5 minutes - mainly in the simulated small intestinal and large intestinal fluids, an effect that was sustained for up to 1 hour. If approved, ZS-9 will represent a novel, first-in-class therapy for hyperkalemia with improved capacity, selectivity, and speed for entrapping K+ when compared to currently available options. PMID:25531770

Characterization of structure and function of ZS-9, a K+ selective ion trap.

PubMed

Stavros, Fiona; Yang, Alex; Leon, Alejandro; Nuttall, Mark; Rasmussen, Henrik S

2014-01-01

Hyperkalemia, a condition in which serum potassium ions (K+) exceed 5.0 mmol/L, is a common electrolyte disorder associated with substantial morbidity. Current methods of managing hyperkalemia, including organic polymer resins such as sodium polystyrene sulfonate (SPS), are poorly tolerated and/or not effective. Sodium zirconium cyclosilicate (ZS-9) is under clinical development as an orally administered, non-absorbed, novel, inorganic microporous zirconium silicate compound that selectively removes excess K+ in vivo. The development, structure and ion exchange properties of ZS-9 and its hypothesized mechanism of action are described. Based on calculation of the interatomic distances between the atoms forming the ZS-9 micropores, the size of the pore opening was determined to be ∼ 3 Å (∼ diameter of unhydrated K+). Unlike nonspecific organic polymer resins like SPS, the ZS-9 K+ exchange capacity (KEC) was unaffected by the presence of calcium (Ca2+) or magnesium ions (Mg2+) and showed>25-fold selectivity for K+ over either Ca2+ or Mg2+. Conversely, the selectivity of SPS for K+ was only 0.2-0.3 times its selectivity for Ca2+ or Mg2+in mixed ionic media. It is hypothesized that the high K+ specificity of ZS-9 is attributable to the chemical composition and diameter of the micropores, which possibly act in an analogous manner to the selectivity filter utilized by physiologic K+ channels. This hypothesized mechanism of action is supported by the multi-ion exchange studies. The effect of pH on the KEC of ZS-9 was tested in different media buffered to mimic different portions of the human gastrointestinal tract. Rapid K+ uptake was observed within 5 minutes - mainly in the simulated small intestinal and large intestinal fluids, an effect that was sustained for up to 1 hour. If approved, ZS-9 will represent a novel, first-in-class therapy for hyperkalemia with improved capacity, selectivity, and speed for entrapping K+ when compared to currently available options.

Functional neuroimaging of emotional learning and autonomic reactions.

PubMed

Peper, Martin; Herpers, Martin; Spreer, Joachim; Hennig, Jürgen; Zentner, Josef

2006-06-01

This article provides a selective overview of the functional neuroimaging literature with an emphasis on emotional activation processes. Emotions are fast and flexible response systems that provide basic tendencies for adaptive action. From the range of involved component functions, we first discuss selected automatic mechanisms that control basic adaptational changes. Second, we illustrate how neuroimaging work has contributed to the mapping of the network components associated with basic emotion families (fear, anger, disgust, happiness), and secondary dimensional concepts that organise the meaning space for subjective experience and verbal labels (emotional valence, activity/intensity, approach/withdrawal, etc.). Third, results and methodological difficulties are discussed in view of own neuroimaging experiments that investigated the component functions involved in emotional learning. The amygdala, prefrontal cortex, and striatum form a network of reciprocal connections that show topographically distinct patterns of activity as a correlate of up and down regulation processes during an emotional episode. Emotional modulations of other brain systems have attracted recent research interests. Emotional neuroimaging calls for more representative designs that highlight the modulatory influences of regulation strategies and socio-cultural factors responsible for inhibitory control and extinction. We conclude by emphasising the relevance of the temporal process dynamics of emotional activations that may provide improved prediction of individual differences in emotionality.

Dynamic Modulation of Human Motor Activity When Observing Actions

PubMed Central

Press, Clare; Cook, Jennifer; Blakemore, Sarah-Jayne; Kilner, James

2012-01-01

Previous studies have demonstrated that when we observe somebody else executing an action many areas of our own motor systems are active. It has been argued that these motor activations are evidence that we motorically simulate observed actions; this motoric simulation may support various functions such as imitation and action understanding. However, whether motoric simulation is indeed the function of motor activations during action observation is controversial, due to inconsistency in findings. Previous studies have demonstrated dynamic modulations in motor activity when we execute actions. Therefore, if we do motorically simulate observed actions, our motor systems should also be modulated dynamically, and in a corresponding fashion, during action observation. Using magnetoencephalography, we recorded the cortical activity of human participants while they observed actions performed by another person. Here, we show that activity in the human motor system is indeed modulated dynamically during action observation. The finding that activity in the motor system is modulated dynamically when observing actions can explain why studies of action observation using functional magnetic resonance imaging have reported conflicting results, and is consistent with the hypothesis that we motorically simulate observed actions. PMID:21414901

Whole-Genome Positive Selection and Habitat-Driven Evolution in a Shallow and a Deep-Sea Urchin

PubMed Central

Oliver, Thomas A.; Garfield, David A.; Manier, Mollie K.; Haygood, Ralph; Wray, Gregory A.; Palumbi, Stephen R.

2010-01-01

Comparisons of genomic sequence between divergent species can provide insight into the action of natural selection across many distinct classes of proteins. Here, we examine the extent of positive selection as a function of tissue-specific and stage-specific gene expression in two closely-related sea urchins, the shallow-water Strongylocentrotus purpuratus and the deep-sea Allocentrotus fragilis, which have diverged greatly in their adult but not larval habitats. Genes that are expressed specifically in adult somatic tissue have significantly higher dN/dS ratios than the genome-wide average, whereas those in larvae are indistinguishable from the genome-wide average. Testis-specific genes have the highest dN/dS values, whereas ovary-specific have the lowest. Branch-site models involving the outgroup S. franciscanus indicate greater selection (ωFG) along the A. fragilis branch than along the S. purpuratus branch. The A. fragilis branch also shows a higher proportion of genes under positive selection, including those involved in skeletal development, endocytosis, and sulfur metabolism. Both lineages are approximately equal in enrichment for positive selection of genes involved in immunity, development, and cell–cell communication. The branch-site models further suggest that adult-specific genes have experienced greater positive selection than those expressed in larvae and that ovary-specific genes are more conserved (i.e., experienced greater negative selection) than those expressed specifically in adult somatic tissues and testis. Our results chart the patterns of protein change that have occurred after habitat divergence in these two species and show that the developmental or functional context in which a gene acts can play an important role in how divergent species adapt to new environments. PMID:20935062

Preschoolers' encoding of rational actions: the role of task features and verbal information.

PubMed

Pfeifer, Caroline; Elsner, Birgit

2013-10-01

In the current study, we first investigated whether preschoolers imitate selectively across three imitation tasks. Second, we examined whether preschoolers' selective imitation is influenced by differences in the modeled actions and/or by the situational context. Finally, we investigated how verbal cues given by the model affect preschoolers' imitation. Participants (3- to 5-year-olds) watched an adult performing an unusual action in three imitation tasks (touch light, house, and obstacle). In two conditions, the model either was or was not restricted by situational constraints. In addition, the model verbalized either the goal that was to be achieved, the movement, or none of the action components. Preschoolers always acted on the objects without constraints. Results revealed differences in preschoolers' selective imitation across the tasks. In the house task, they showed the selective imitation pattern that has been interpreted as rational, imitating the unusual action more often in the no-constraint condition than in the constraint condition. In contrast, in the touch light task, preschoolers imitated the unusual head touch irrespective of the model's constraints or of the verbal cues that had been presented. Finally, in the obstacle task, children mostly emulated the observed goal irrespective of the presence of the constraint, but they increased their imitation of the unusual action when the movement had been emphasized. Overall, our data suggest that preschoolers adjust their imitative behavior to context-specific information about objects, actions, and their interpretations of the model's intention to teach something. Copyright © 2012 Elsevier Inc. All rights reserved.

Peripheral μ-opioid receptor mediated inhibition of calcium signaling and action potential-evoked calcium fluorescent transients in primary afferent CGRP nociceptive terminals.

PubMed

Baillie, Landon D; Schmidhammer, Helmut; Mulligan, Sean J

2015-06-01

While μ-opioid receptor (MOR) agonists remain the most powerful analgesics for the treatment of severe pain, serious adverse side effects that are secondary to their central nervous system actions pose substantial barriers to therapeutic use. Preclinical and clinical evidence suggest that peripheral MORs play an important role in opioid analgesia, particularly under inflammatory conditions. However, the mechanisms of peripheral MOR signaling in primary afferent pain fibres remain to be established. We have recently introduced a novel ex vivo optical imaging approach that, for the first time, allows the study of physiological functioning within individual peripheral nociceptive fibre free nerve endings in mice. In the present study, we found that MOR activation in selectively identified, primary afferent CGRP nociceptive terminals caused inhibition of N-type Ca(2+) channel signaling and suppression of action potential-evoked Ca(2+) fluorescent transients mediated by 'big conductance' Ca(2+)-activated K(+) channels (BKCa). In the live animal, we showed that the peripherally acting MOR agonist HS-731 produced analgesia and that BKCa channels were the major effectors of the peripheral MOR signaling. We have identified two key molecular transducers of MOR activation that mediate significant inhibition of nociceptive signaling in primary afferent terminals. Understanding the mechanisms of peripheral MOR signaling may promote the development of pathway selective μ-opioid drugs that offer improved therapeutic profiles for achieving potent analgesia while avoiding serious adverse central side effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

Relevance of quantum mechanics on some aspects of ion channel function

PubMed Central

Roy, Sisir

2010-01-01

Mathematical modeling of ionic diffusion along K ion channels indicates that such diffusion is oscillatory, at the weak non-Markovian limit. This finding leads us to derive a Schrödinger–Langevin equation for this kind of system within the framework of stochastic quantization. The Planck’s constant is shown to be relevant to the Lagrangian action at the level of a single ion channel. This sheds new light on the issue of applicability of quantum formalism to ion channel dynamics and to the physical constraints of the selectivity filter. PMID:19520314

Elucidating Duramycin’s Bacterial Selectivity and Mode of Action on the Bacterial Cell Envelope

DOE PAGES

Hasim, Sahar; Allison, David P.; Mendez, Berlin; ...

2018-02-14

The use of naturally occurring antimicrobial peptides provides a promising route to selectively target pathogenic agents and to shape microbiome structure. Lantibiotics, such as duramycin, are one class of bacterially produced peptidic natural products that can selectively inhibit the growth of other bacteria. However, despite longstanding characterization efforts, the microbial selectivity and mode of action of duramycin are still obscure. We describe here a suite of biological, chemical, and physical characterizations that shed new light on the selective and mechanistic aspects of duramycin activity. Bacterial screening assays have been performed using duramycin and Populus-derived bacterial isolates to determine species selectivity.more » Lipidomic profiles of selected resistant and sensitive strains show that the sensitivity of Gram-positive bacteria depends on the presence of phosphatidylethanolamine (PE) in the cell membrane. Further the surface and interface morphology were studied by high resolution atomic force microscopy and showed a progression of cellular changes in the cell envelope after treatment with duramycin for the susceptible bacterial strains. Together, these molecular and cellular level analyses provide insight into duramycin’s mode of action and a better understanding of its selectivity.« less

Elucidating Duramycin’s Bacterial Selectivity and Mode of Action on the Bacterial Cell Envelope

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hasim, Sahar; Allison, David P.; Mendez, Berlin

The use of naturally occurring antimicrobial peptides provides a promising route to selectively target pathogenic agents and to shape microbiome structure. Lantibiotics, such as duramycin, are one class of bacterially produced peptidic natural products that can selectively inhibit the growth of other bacteria. However, despite longstanding characterization efforts, the microbial selectivity and mode of action of duramycin are still obscure. We describe here a suite of biological, chemical, and physical characterizations that shed new light on the selective and mechanistic aspects of duramycin activity. Bacterial screening assays have been performed using duramycin and Populus-derived bacterial isolates to determine species selectivity.more » Lipidomic profiles of selected resistant and sensitive strains show that the sensitivity of Gram-positive bacteria depends on the presence of phosphatidylethanolamine (PE) in the cell membrane. Further the surface and interface morphology were studied by high resolution atomic force microscopy and showed a progression of cellular changes in the cell envelope after treatment with duramycin for the susceptible bacterial strains. Together, these molecular and cellular level analyses provide insight into duramycin’s mode of action and a better understanding of its selectivity.« less

Strategic Map for Achieving Enceladus Ocean Exploration in Our Time

NASA Astrophysics Data System (ADS)

Sherwood, B.

2015-12-01

At AGU 2014, the author presented a decomposition and sequencing of science questions and technical capabilities that define viable programmatic pathways to enable sample return and advanced in situ exploration of the Enceladan ocean, consistent with NASA mission-opportunity constraints. Elaborated and refined in 2015 via JpGU, AbSciCon, IAC, and COSPAR Water, this plan is now specific: discrete and integrated analyses and coordination actions that, if acted on by the community over the next 45 months, could result in Enceladus ocean exploration appearing in the next Planetary Decadal Survey's mission priorities, issued in 2021. At AGU 2015, a product-based, outcome-measurable, stepwise milestone plan is presented to catalyze the next level of community discussion. Topics covered by the action plan include: hypothesis-driven science questions; mission cost as a function of mission capability; mission selectability as a function of programmatic constraints and evaluation process; exploration technologies as a function of funding and schedule; international consensus on forward and backward planetary protection requirements and solutions for exploring worlds with astrobiologically significant liquid water; and strategic balance among major NASA planetary science initiatives. Key Decadal-runup milestones are analyzed with respect to stakeholders, success criteria, and - critically - calendar and precedence. These results then inform a multi-year action plan to generate, vet, and socialize throughout the community a set of technically and fiscally viable mission concepts, respectively enabled by an achievable technology development roadmap also detailed in the presentation. This can begin to align advocate actions toward a broad community goal of exploring the Enceladan ocean. Without such coordination, which must reach fruition by Sep 2019, the probability that the next Decadal could explicitly prioritize mission objectives for Enceladus ocean exploration - as one of the top Flagship or as New Frontiers priorities - will be low. Missing the 2023-2032 Decadal window would in turn force such missions beyond the career horizon even of today's graduate students.

Selecting the correct solution to a physics problem when given several possibilities

NASA Astrophysics Data System (ADS)

Richards, Evan Thomas

Despite decades of research on what learning actions are associated with effective learners (Palincsar and Brown, 1984; Atkinson, et al., 2000), the literature has not fully addressed how to cue those actions (particularly within the realm of physics). Recent reforms that integrate incorrect solutions suggest a possible avenue to reach those actions. However, there is only a limited understanding as to what actions are invoked with such reforms (Grosse and Renkl, 2007). This paper reports on a study that tasked participants with selecting the correct solution to a physics problem when given three possible solutions, where only one of the solutions was correct and the other two solutions contained errors. Think aloud protocol data (Ericsson and Simon, 1993) was analyzed per a framework adapted from Palincsar and Brown (1984). Cued actions were indeed connected to those identified in the worked example literature. Particularly satisfying is the presence of internal consistency checks (i.e., are the solutions self-consistent?), which is a behavior predicted by the Palincsar and Brown (1984) framework, but not explored in the worked example realm. Participant discussions were also found to be associated with those physics-related solution features that were varied across solutions (such as fundamental principle selection or system and surroundings selections).

Environmental Asthma Reduction Potential Estimates for Selected Mitigation Actions in Finland Using a Life Table Approach

PubMed Central

Rumrich, Isabell Katharina; Hänninen, Otto

2015-01-01

Aims: To quantify the reduction potential of asthma in Finland achievable by adjusting exposures to selected environmental factors. Methods: A life table model for the Finnish population for 1986–2040 was developed and Years Lived with Disability caused by asthma and attributable to the following selected exposures were estimated: tobacco smoke (smoking and second hand tobacco smoke), ambient fine particles, indoor dampness and mould, and pets. Results: At baseline (2011) about 25% of the total asthma burden was attributable to the selected exposures. Banning tobacco was the most efficient mitigation action, leading to 6% reduction of the asthma burden. A 50% reduction in exposure to dampness and mould as well as a doubling in exposure to pets lead each to a 2% reduction. Ban of urban small scale wood combustion, chosen as a mitigation action to reduce exposure to fine particles, leads to a reduction of less than 1% of the total asthma burden. Combination of the most efficient mitigation actions reduces the total asthma burden by 10%. A more feasible combination of mitigation actions leads to 6% reduction of the asthma burden. Conclusions: The adjustment of environmental exposures can reduce the asthma burden in Finland by up to 10%. PMID:26067987

Place Learning Overrides Innate Behaviors in "Drosophila"

ERIC Educational Resources Information Center

Baggett, Vincent; Mishra, Aditi; Kehrer, Abigail L.; Robinson, Abbey O.; Shaw, Paul; Zars, Troy

2018-01-01

Animals in a natural environment confront many sensory cues. Some of these cues bias behavioral decisions independent of experience, and action selection can reveal a stimulus-response (S-R) connection. However, in a changing environment it would be a benefit for an animal to update behavioral action selection based on experience, and learning…

Action video games and improved attentional control: Disentangling selection- and response-based processes.

PubMed

Chisholm, Joseph D; Kingstone, Alan

2015-10-01

Research has demonstrated that experience with action video games is associated with improvements in a host of cognitive tasks. Evidence from paradigms that assess aspects of attention has suggested that action video game players (AVGPs) possess greater control over the allocation of attentional resources than do non-video-game players (NVGPs). Using a compound search task that teased apart selection- and response-based processes (Duncan, 1985), we required participants to perform an oculomotor capture task in which they made saccades to a uniquely colored target (selection-based process) and then produced a manual directional response based on information within the target (response-based process). We replicated the finding that AVGPs are less susceptible to attentional distraction and, critically, revealed that AVGPs outperform NVGPs on both selection-based and response-based processes. These results not only are consistent with the improved-attentional-control account of AVGP benefits, but they suggest that the benefit of action video game playing extends across the full breadth of attention-mediated stimulus-response processes that impact human performance.

Working memory delay period activity marks a domain-unspecific attention mechanism.

PubMed

Katus, Tobias; Müller, Matthias M

2016-03-01

Working memory (WM) recruits neural circuits that also perform perception- and action-related functions. Among the functions that are shared between the domains of WM and perception is selective attention, which supports the maintenance of task-relevant information during the retention delay of WM tasks. The tactile contralateral delay activity (tCDA) component of the event-related potential (ERP) marks the attention-based rehearsal of tactile information in somatosensory brain regions. We tested whether the tCDA reflects the competition for shared attention resources between a WM task and a perceptual task under dual-task conditions. The two tasks were always performed on opposite hands. In different blocks, the WM task had higher or lower priority than the perceptual task. The tCDA's polarity consistently reflected the hand where the currently prioritized task was performed. This suggests that the process indexed by the tCDA is not specific to the domain of WM, but mediated by a domain-unspecific attention mechanism. The analysis of transient ERP components evoked by stimuli in the two tasks further supports the interpretation that the tCDA marks a goal-directed bias in the allocation of selective attention. Larger spatially selective modulations were obtained for stimulus material related to the high-, as compared to low-priority, task. While our results generally indicate functional overlap between the domains of WM and perception, we also found evidence suggesting that selection in internal (mnemonic) and external (perceptual) stimulus representations involves processes that are not active during shifts of preparatory attention. Copyright © 2016 Elsevier Inc. All rights reserved.

RIM-BPs Mediate Tight Coupling of Action Potentials to Ca(2+)-Triggered Neurotransmitter Release.

PubMed

Acuna, Claudio; Liu, Xinran; Gonzalez, Aneysis; Südhof, Thomas C

2015-09-23

Ultrafast neurotransmitter release requires tight colocalization of voltage-gated Ca(2+) channels with primed, release-ready synaptic vesicles at the presynaptic active zone. RIM-binding proteins (RIM-BPs) are multidomain active zone proteins that bind to RIMs and to Ca(2+) channels. In Drosophila, deletion of RIM-BPs dramatically reduces neurotransmitter release, but little is known about RIM-BP function in mammalian synapses. Here, we generated double conditional knockout mice for RIM-BP1 and RIM-BP2, and analyzed RIM-BP-deficient synapses in cultured hippocampal neurons and the calyx of Held. Surprisingly, we find that in murine synapses, RIM-BPs are not essential for neurotransmitter release as such, but are selectively required for high-fidelity coupling of action potential-induced Ca(2+) influx to Ca(2+)-stimulated synaptic vesicle exocytosis. Deletion of RIM-BPs decelerated action-potential-triggered neurotransmitter release and rendered it unreliable, thereby impairing the fidelity of synaptic transmission. Thus, RIM-BPs ensure optimal organization of the machinery for fast release in mammalian synapses without being a central component of the machinery itself. Copyright © 2015 Elsevier Inc. All rights reserved.

Maximum saliency bias in binocular fusion

NASA Astrophysics Data System (ADS)

Lu, Yuhao; Stafford, Tom; Fox, Charles

2016-07-01

Subjective experience at any instant consists of a single ("unitary"), coherent interpretation of sense data rather than a "Bayesian blur" of alternatives. However, computation of Bayes-optimal actions has no role for unitary perception, instead being required to integrate over every possible action-percept pair to maximise expected utility. So what is the role of unitary coherent percepts, and how are they computed? Recent work provided objective evidence for non-Bayes-optimal, unitary coherent, perception and action in humans; and further suggested that the percept selected is not the maximum a posteriori percept but is instead affected by utility. The present study uses a binocular fusion task first to reproduce the same effect in a new domain, and second, to test multiple hypotheses about exactly how utility may affect the percept. After accounting for high experimental noise, it finds that both Bayes optimality (maximise expected utility) and the previously proposed maximum-utility hypothesis are outperformed in fitting the data by a modified maximum-salience hypothesis, using unsigned utility magnitudes in place of signed utilities in the bias function.

PROBING HUMAN AND MONKEY ANTERIOR CINGULATE CORTEX IN VARIABLE ENVIRONMENTS

PubMed Central

Walton, Mark E.; Mars, Rogier B.

2008-01-01

Previous research has identified the anterior cingulate cortex (ACC) as an important node in the neural network underlying decision making in primates. Decision making can, however, be studied under large variety of circumstances, ranging from the standard well-controlled lab situation to more natural, stochastic settings during which multiple agents interact. Here, we illustrate how these different varieties of decision making studied can influence theories of ACC function in monkeys. Converging evidence from unit recordings and lesions studies now suggest that the ACC is important for interpreting outcome information according to the current task context to guide future action selection. We then apply this framework to the study of human ACC function and discuss its potential implications. PMID:18189014

Powered Upper Limb Orthosis Actuation System Based on Pneumatic Artificial Muscles

NASA Astrophysics Data System (ADS)

Chakarov, Dimitar; Veneva, Ivanka; Tsveov, Mihail; Venev, Pavel

2018-03-01

The actuation system of a powered upper limb orthosis is studied in the work. To create natural safety in the mutual "man-robot" interaction, an actuation system based on pneumatic artificial muscles (PAM) is selected. Experimentally obtained force/contraction diagrams for bundles, consisting of different number of muscles are shown in the paper. The pooling force and the stiffness of the pneumatic actuators is assessed as a function of the number of muscles in the bundle and the supply pressure. Joint motion and torque is achieved by antagonistic actions through pulleys, driven by bundles of pneumatic muscles. Joint stiffness and joint torques are determined on condition of a power balance, as a function of the joint position, pressure, number of muscles and muscles

Probabilistic measures of climate change vulnerability, adaptation action benefits, and related uncertainty from maximum temperature metric selection.

PubMed

DeWeber, Jefferson T; Wagner, Tyler

2018-06-01

Predictions of the projected changes in species distributions and potential adaptation action benefits can help guide conservation actions. There is substantial uncertainty in projecting species distributions into an unknown future, however, which can undermine confidence in predictions or misdirect conservation actions if not properly considered. Recent studies have shown that the selection of alternative climate metrics describing very different climatic aspects (e.g., mean air temperature vs. mean precipitation) can be a substantial source of projection uncertainty. It is unclear, however, how much projection uncertainty might stem from selecting among highly correlated, ecologically similar climate metrics (e.g., maximum temperature in July, maximum 30-day temperature) describing the same climatic aspect (e.g., maximum temperatures) known to limit a species' distribution. It is also unclear how projection uncertainty might propagate into predictions of the potential benefits of adaptation actions that might lessen climate change effects. We provide probabilistic measures of climate change vulnerability, adaptation action benefits, and related uncertainty stemming from the selection of four maximum temperature metrics for brook trout (Salvelinus fontinalis), a cold-water salmonid of conservation concern in the eastern United States. Projected losses in suitable stream length varied by as much as 20% among alternative maximum temperature metrics for mid-century climate projections, which was similar to variation among three climate models. Similarly, the regional average predicted increase in brook trout occurrence probability under an adaptation action scenario of full riparian forest restoration varied by as much as .2 among metrics. Our use of Bayesian inference provides probabilistic measures of vulnerability and adaptation action benefits for individual stream reaches that properly address statistical uncertainty and can help guide conservation actions. Our study demonstrates that even relatively small differences in the definitions of climate metrics can result in very different projections and reveal high uncertainty in predicted climate change effects. © 2018 John Wiley & Sons Ltd.

Probabilistic measures of climate change vulnerability, adaptation action benefits, and related uncertainty from maximum temperature metric selection

USGS Publications Warehouse

DeWeber, Jefferson T.; Wagner, Tyler

2018-01-01

Predictions of the projected changes in species distributions and potential adaptation action benefits can help guide conservation actions. There is substantial uncertainty in projecting species distributions into an unknown future, however, which can undermine confidence in predictions or misdirect conservation actions if not properly considered. Recent studies have shown that the selection of alternative climate metrics describing very different climatic aspects (e.g., mean air temperature vs. mean precipitation) can be a substantial source of projection uncertainty. It is unclear, however, how much projection uncertainty might stem from selecting among highly correlated, ecologically similar climate metrics (e.g., maximum temperature in July, maximum 30‐day temperature) describing the same climatic aspect (e.g., maximum temperatures) known to limit a species’ distribution. It is also unclear how projection uncertainty might propagate into predictions of the potential benefits of adaptation actions that might lessen climate change effects. We provide probabilistic measures of climate change vulnerability, adaptation action benefits, and related uncertainty stemming from the selection of four maximum temperature metrics for brook trout (Salvelinus fontinalis), a cold‐water salmonid of conservation concern in the eastern United States. Projected losses in suitable stream length varied by as much as 20% among alternative maximum temperature metrics for mid‐century climate projections, which was similar to variation among three climate models. Similarly, the regional average predicted increase in brook trout occurrence probability under an adaptation action scenario of full riparian forest restoration varied by as much as .2 among metrics. Our use of Bayesian inference provides probabilistic measures of vulnerability and adaptation action benefits for individual stream reaches that properly address statistical uncertainty and can help guide conservation actions. Our study demonstrates that even relatively small differences in the definitions of climate metrics can result in very different projections and reveal high uncertainty in predicted climate change effects.

Motor Decisions Are Not Black and White: Selecting Actions in the “Gray Zone”

PubMed Central

Comalli, D. M.; Persand, D.; Adolph, K. E.

2017-01-01

In many situations, multiple actions are possible to achieve a goal. How do people select a particular action among equally possible alternatives? In six experiments, we determined whether action selection is consistent and biased toward one decision by observing participants’ decisions to go over or under a horizontal bar set at varying heights. We assessed the height at which participants transitioned from going over to under the bar within a “gray zone”—the range of bar heights at which going over and under were both possible. In Experiment 1, participants’ transition points were consistently located near the upper boundary of the gray zone, indicating a bias to go over rather than under the bar. Moreover, transitional behaviors were clustered tightly into a small region, indicating that decisions were highly consistent. Subsequent experiments examined potential influences on action selection. In Experiment 2, participants wore ankle weights to increase the cost of going over the bar. In Experiment 3, they were tested on a padded surface that made crawling under the bar more comfortable. In Experiment 4, we introduced a secondary task that required participants to crawl immediately after navigating the bar. None of these manipulations altered participants’ decisions relative to Experiment 1. In Experiment 5, participants started in a crawling position, which led to significantly lower transition points. In Experiment 6, we tested 5- to 6-year-old children as in Experiment 1 to determine the effects of social pressure on action selection. Children displayed lower transition points, larger transition regions, and reduced ability to go over the bar compared to adults. Across experiments, results indicate that adults have a strong and robust bias for upright locomotion. PMID:28293691

Lentiviral Vectors and Protocols for Creation of Stable hESC Lines for Fluorescent Tracking and Drug Resistance Selection of Cardiomyocytes

PubMed Central

Kita-Matsuo, Hiroko; Barcova, Maria; Prigozhina, Natalie; Salomonis, Nathan; Wei, Karen; Jacot, Jeffrey G.; Nelson, Brandon; Spiering, Sean; Haverslag, René; Kim, Changsung; Talantova, Maria; Bajpai, Ruchi; Calzolari, Diego; Terskikh, Alexey; McCulloch, Andrew D.; Price, Jeffrey H.; Conklin, Bruce R.; Chen, H. S. Vincent; Mercola, Mark

2009-01-01

Background Developmental, physiological and tissue engineering studies critical to the development of successful myocardial regeneration therapies require new ways to effectively visualize and isolate large numbers of fluorescently labeled, functional cardiomyocytes. Methodology/Principal Findings Here we describe methods for the clonal expansion of engineered hESCs and make available a suite of lentiviral vectors for that combine Blasticidin, Neomycin and Puromycin resistance based drug selection of pure populations of stem cells and cardiomyocytes with ubiquitous or lineage-specific promoters that direct expression of fluorescent proteins to visualize and track cardiomyocytes and their progenitors. The phospho-glycerate kinase (PGK) promoter was used to ubiquitously direct expression of histone-2B fused eGFP and mCherry proteins to the nucleus to monitor DNA content and enable tracking of cell migration and lineage. Vectors with T/Brachyury and α-myosin heavy chain (αMHC) promoters targeted fluorescent or drug-resistance proteins to early mesoderm and cardiomyocytes. The drug selection protocol yielded 96% pure cardiomyocytes that could be cultured for over 4 months. Puromycin-selected cardiomyocytes exhibited a gene expression profile similar to that of adult human cardiomyocytes and generated force and action potentials consistent with normal fetal cardiomyocytes, documenting these parameters in hESC-derived cardiomyocytes and validating that the selected cells retained normal differentiation and function. Conclusion/Significance The protocols, vectors and gene expression data comprise tools to enhance cardiomyocyte production for large-scale applications. PMID:19352491

Improved selectivity from a wavelength addressable device for wireless stimulation of neural tissue

PubMed Central

Seymour, Elif Ç.; Freedman, David S.; Gökkavas, Mutlu; Özbay, Ekmel; Sahin, Mesut; Ünlü, M. Selim

2014-01-01

Electrical neural stimulation with micro electrodes is a promising technique for restoring lost functions in the central nervous system as a result of injury or disease. One of the problems related to current neural stimulators is the tissue response due to the connecting wires and the presence of a rigid electrode inside soft neural tissue. We have developed a novel, optically activated, microscale photovoltaic neurostimulator based on a custom layered compound semiconductor heterostructure that is both wireless and has a comparatively small volume (<0.01 mm3). Optical activation provides a wireless means of energy transfer to the neurostimulator, eliminating wires and the associated complications. This neurostimulator was shown to evoke action potentials and a functional motor response in the rat spinal cord. In this work, we extend our design to include wavelength selectivity and thus allowing independent activation of devices. As a proof of concept, we fabricated two different microscale devices with different spectral responsivities in the near-infrared region. We assessed the improved addressability of individual devices via wavelength selectivity as compared to spatial selectivity alone through on-bench optical measurements of the devices in combination with an in vivo light intensity profile in the rat cortex obtained in a previous study. We show that wavelength selectivity improves the individual addressability of the floating stimulators, thus increasing the number of devices that can be implanted in close proximity to each other. PMID:24600390

Interim Action Proposed Plan for the Chemicals, Metals, and Pesticides (CMP) Pits Operable Unit

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bradley, J.

2002-06-18

The purpose of this Interim Action Proposed Plan (IAPP) is to describe the preferred interim remedial action for addressing the Chemicals, Metals, and Pesticides (CMP) Pits Operable Unit and to provide an opportunity for public input into the remedial action selection process.

Imitation of Intentional and Accidental Actions by Children with Autism

ERIC Educational Resources Information Center

D'Entremont, Barbara; Yazbek, Aimee

2007-01-01

To determine whether children with autism (CWA) would selectively imitate intentional, as opposed to accidental actions, an experimenter demonstrated either an "intentional" and an "accidental" action or two "intentional" actions on the same toy [Carpenter, Akhtar, & Tomasello ("1998a") "Infant Behavior and Development, 21," 315-330]. CWA tended…

45 CFR 1225.10 - Corrective action.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 45 Public Welfare 4 2011-10-01 2011-10-01 false Corrective action. 1225.10 Section 1225.10 Public... Corrective action. When it has been determined by Final Agency Decision that the aggrieved party has been subjected to illegal discrimination, the following corrective actions may be taken: (a) Selection as a...

45 CFR 1225.10 - Corrective action.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 4 2010-10-01 2010-10-01 false Corrective action. 1225.10 Section 1225.10 Public... Corrective action. When it has been determined by Final Agency Decision that the aggrieved party has been subjected to illegal discrimination, the following corrective actions may be taken: (a) Selection as a...

Evidence of directional and stabilizing selection in contemporary humans.

PubMed

Sanjak, Jaleal S; Sidorenko, Julia; Robinson, Matthew R; Thornton, Kevin R; Visscher, Peter M

2018-01-02

Modern molecular genetic datasets, primarily collected to study the biology of human health and disease, can be used to directly measure the action of natural selection and reveal important features of contemporary human evolution. Here we leverage the UK Biobank data to test for the presence of linear and nonlinear natural selection in a contemporary population of the United Kingdom. We obtain phenotypic and genetic evidence consistent with the action of linear/directional selection. Phenotypic evidence suggests that stabilizing selection, which acts to reduce variance in the population without necessarily modifying the population mean, is widespread and relatively weak in comparison with estimates from other species.

The Role of Extracellular Adenosine Generation in the Development of Autoimmune Diseases

PubMed Central

Rizzo, R.; Malavasi, F.

2018-01-01

Adenosine (ADO) is an immunosuppressive molecule, which suppresses the immune responses by interacting with specific receptors expressed by immune effector cells. ADO is produced from ATP through the enzymatic activities of CD39 and CD73. Alternatively, ADO can be generated starting from NAD+, which is metabolized by the concerted action of CD38, CD203a/PC-1, and CD73. The role of ADO in immunity has been characterized in the last years in physiology and in pathological settings. This review examines a panel of reports focused on the functions of ADO in the context of human autoimmune/inflammatory diseases and the selected animal models. The final aim is to consider the role of adenosinergic ectoenzymes and ADO receptors as novel therapeutic targets for selected diseases. PMID:29769837

Numerical algebraic geometry for model selection and its application to the life sciences

PubMed Central

Gross, Elizabeth; Davis, Brent; Ho, Kenneth L.; Bates, Daniel J.

2016-01-01

Researchers working with mathematical models are often confronted by the related problems of parameter estimation, model validation and model selection. These are all optimization problems, well known to be challenging due to nonlinearity, non-convexity and multiple local optima. Furthermore, the challenges are compounded when only partial data are available. Here, we consider polynomial models (e.g. mass-action chemical reaction networks at steady state) and describe a framework for their analysis based on optimization using numerical algebraic geometry. Specifically, we use probability-one polynomial homotopy continuation methods to compute all critical points of the objective function, then filter to recover the global optima. Our approach exploits the geometrical structures relating models and data, and we demonstrate its utility on examples from cell signalling, synthetic biology and epidemiology. PMID:27733697

Selective androgen receptor modulators in preclinical and clinical development

PubMed Central

Narayanan, Ramesh; Mohler, Michael L.; Bohl, Casey E.; Miller, Duane D.; Dalton, James T.

2008-01-01

Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and hypogonadism. This review summarizes the current standing of research and development of SARMs, crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic indications for this emerging class of drugs. PMID:19079612

The Ontario Food and Nutrition Strategy: identifying indicators of food access and food literacy for early monitoring of the food environment.

PubMed

Boucher, Beatrice A; Manafò, Elizabeth; Boddy, Meaghan R; Roblin, Lynn; Truscott, Rebecca

2017-09-01

To address challenges Canadians face within their food environments, a comprehensive, multistakeholder, intergovernmental approach to policy development is essential. Food environment indicators are needed to assess population status and change. The Ontario Food and Nutrition Strategy (OFNS) integrates the food, agriculture and nutrition sectors, and aims to improve the health of Ontarians through actions that promote healthy food systems and environments. This report describes the process of identifying indicators for 11 OFNS action areas in two strategic directions (SDs): Healthy Food Access, and Food Literacy and Skills. The OFNS Indicators Advisory Group used a five-step process to select indicators: (1) potential indicators from national and provincial data sources were identified; (2) indicators were organized by SD, action area and data type; (3) selection criteria were identified, pilot tested and finalized; (4) final criteria were applied to refine the indicator list; and (5) indicators were prioritized after reapplication of selection criteria. Sixty-nine potential indicators were initially identified; however, many were individual-level rather than system-level measures. After final application of the selection criteria, one individual-level indicator and six system-level indicators were prioritized in five action areas; for six of the action areas, no indicators were available. Data limitations suggest that available data may not measure important aspects of the food environment, highlighting the need for action and resources to improve system-level indicators and support monitoring of the food environment and health in Ontario and across Canada.

Agent Reward Shaping for Alleviating Traffic Congestion

NASA Technical Reports Server (NTRS)

Tumer, Kagan; Agogino, Adrian

2006-01-01

Traffic congestion problems provide a unique environment to study how multi-agent systems promote desired system level behavior. What is particularly interesting in this class of problems is that no individual action is intrinsically "bad" for the system but that combinations of actions among agents lead to undesirable outcomes, As a consequence, agents need to learn how to coordinate their actions with those of other agents, rather than learn a particular set of "good" actions. This problem is ubiquitous in various traffic problems, including selecting departure times for commuters, routes for airlines, and paths for data routers. In this paper we present a multi-agent approach to two traffic problems, where far each driver, an agent selects the most suitable action using reinforcement learning. The agent rewards are based on concepts from collectives and aim to provide the agents with rewards that are both easy to learn and that if learned, lead to good system level behavior. In the first problem, we study how agents learn the best departure times of drivers in a daily commuting environment and how following those departure times alleviates congestion. In the second problem, we study how agents learn to select desirable routes to improve traffic flow and minimize delays for. all drivers.. In both sets of experiments,. agents using collective-based rewards produced near optimal performance (93-96% of optimal) whereas agents using system rewards (63-68%) barely outperformed random action selection (62-64%) and agents using local rewards (48-72%) performed worse than random in some instances.

Neural Correlates of Intentional Communication

PubMed Central

Noordzij, Matthijs L.; Newman-Norlund, Sarah E.; de Ruiter, Jan Peter; Hagoort, Peter; Levinson, Stephen C.; Toni, Ivan

2010-01-01

We know a great deal about the neurophysiological mechanisms supporting instrumental actions, i.e., actions designed to alter the physical state of the environment. In contrast, little is known about our ability to select communicative actions, i.e., actions directly designed to modify the mental state of another agent. We have recently provided novel empirical evidence for a mechanism in which a communicator selects his actions on the basis of a prediction of the communicative intentions that an addressee is most likely to attribute to those actions. The main novelty of those findings was that this prediction of intention recognition is cerebrally implemented within the intention recognition system of the communicator, is modulated by the ambiguity in meaning of the communicative acts, and not by their sensorimotor complexity. The characteristics of this predictive mechanism support the notion that human communicative abilities are distinct from both sensorimotor and linguistic processes. PMID:21151781

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

PubMed Central

Millar, Robert P.; Pawson, Adam J.; Morgan, Kevin; Rissman, Emilie F.; Lu, Zhi-Liang

2009-01-01

Geoffrey Wingfield Harris’ demonstration of hypothalamic hormones regulating pituitary function led to their structural identification and therapeutic utilization in a wide spectrum of diseases. Amongst these, Gonadotropin Releasing Hormone (GnRH) and its analogs are widely employed in modulating gonadotropin and sex steroid secretion to treat infertility, precocious puberty and many hormone-dependent diseases including endometriosis, uterine fibroids and prostatic cancer. While these effects are all mediated via modulation of the pituitary gonadotrope GnRH receptor and the Gq signaling pathway, it has become increasingly apparent that GnRH regulates many extrapituitary cells in the nervous system and periphery. This review focuses on two such examples, namely GnRH analog effects on reproductive behaviors and GnRH analog effects on the inhibition of cancer cell growth. For both effects the relative activities of a range of GnRH analogs is distinctly different from their effects on the pituitary gonadotrope and different signaling pathways are utilized. As there is only a single functional GnRH receptor type in man we have proposed that the GnRH receptor can assume different conformations which have different selectivity for GnRH analogs and intracellular signaling proteins complexes. This ligand-induced selective-signaling recruits certain pathways while by-passing others and has implications in developing more selective GnRH analogs for highly specific therapeutic intervention. PMID:17976709

Mechanisms and Evidence of Genital Coevolution: The Roles of Natural Selection, Mate Choice, and Sexual Conflict.

PubMed

Brennan, Patricia L R; Prum, Richard O

2015-07-01

Genital coevolution between the sexes is expected to be common because of the direct interaction between male and female genitalia during copulation. Here we review the diverse mechanisms of genital coevolution that include natural selection, female mate choice, male-male competition, and how their interactions generate sexual conflict that can lead to sexually antagonistic coevolution. Natural selection on genital morphology will result in size coevolution to allow for copulation to be mechanically possible, even as other features of genitalia may reflect the action of other mechanisms of selection. Genital coevolution is explicitly predicted by at least three mechanisms of genital evolution: lock and key to prevent hybridization, female choice, and sexual conflict. Although some good examples exist in support of each of these mechanisms, more data on quantitative female genital variation and studies of functional morphology during copulation are needed to understand more general patterns. A combination of different approaches is required to continue to advance our understanding of genital coevolution. Knowledge of the ecology and behavior of the studied species combined with functional morphology, quantitative morphological tools, experimental manipulation, and experimental evolution have been provided in the best-studied species, all of which are invertebrates. Therefore, attention to vertebrates in any of these areas is badly needed. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

Violent media exposure, aggression and CU traits in adolescence: Testing the selection and socialization hypotheses.

PubMed

Rydell, Ann-Margret

2016-10-01

We investigated the role of exposure to violent action for later aggression and for later callous-unemotional traits in a sample of Swedish adolescents (N = 77-85), testing the selection and socialization hypotheses. Adolescents reported on violent delinquency and on callous-unemotional (CU) traits at age 15, on their media habits at age 16 and on reactive and proactive aggression and CU traits at age 18. The socialization hypothesis was supported with regard to aggression, that is, violent delinquency did not affect consumption of violent action, but controlling for violent delinquency, consumption of violent action added to proactive aggression and, marginally, to reactive aggression. The selection hypothesis was supported with regard to CU traits, that is, high levels of CU traits predicted frequent consumption of violent action, but consumption of violent action did not affect later levels of CU traits. Frequent violent media use was associated with later aggression. The associations between CU traits and violent media need further study. Copyright © 2016 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

Basolateral amygdala rapid glutamate release encodes an outcome-specific representation vital for reward-predictive cues to selectively invigorate reward-seeking actions

PubMed Central

Malvaez, Melissa; Greenfield, Venuz Y.; Wang, Alice S.; Yorita, Allison M.; Feng, Lili; Linker, Kay E.; Monbouquette, Harold G.; Wassum, Kate M.

2015-01-01

Environmental stimuli have the ability to generate specific representations of the rewards they predict and in so doing alter the selection and performance of reward-seeking actions. The basolateral amygdala participates in this process, but precisely how is unknown. To rectify this, we monitored, in near-real time, basolateral amygdala glutamate concentration changes during a test of the ability of reward-predictive cues to influence reward-seeking actions (Pavlovian-instrumental transfer). Glutamate concentration was found to be transiently elevated around instrumental reward seeking. During the Pavlovian-instrumental transfer test these glutamate transients were time-locked to and correlated with only those actions invigorated by outcome-specific motivational information provided by the reward-predictive stimulus (i.e., actions earning the same specific outcome as predicted by the presented CS). In addition, basolateral amygdala AMPA, but not NMDA glutamate receptor inactivation abolished the selective excitatory influence of reward-predictive cues over reward seeking. These data the hypothesis that transient glutamate release in the BLA can encode the outcome-specific motivational information provided by reward-predictive stimuli. PMID:26212790

Rise and fall of the two visual systems theory.

PubMed

Rossetti, Yves; Pisella, Laure; McIntosh, Robert D

2017-06-01

Among the many dissociations describing the visual system, the dual theory of two visual systems, respectively dedicated to perception and action, has yielded a lot of support. There are psychophysical, anatomical and neuropsychological arguments in favor of this theory. Several behavioral studies that used sensory and motor psychophysical parameters observed differences between perceptive and motor responses. The anatomical network of the visual system in the non-human primate was very readily organized according to two major pathways, dorsal and ventral. Neuropsychological studies, exploring optic ataxia and visual agnosia as characteristic deficits of these two pathways, led to the proposal of a functional double dissociation between visuomotor and visual perceptual functions. After a major wave of popularity that promoted great advances, particularly in knowledge of visuomotor functions, the guiding theory is now being reconsidered. Firstly, the idea of a double dissociation between optic ataxia and visual form agnosia, as cleanly separating visuomotor from visual perceptual functions, is no longer tenable; optic ataxia does not support a dissociation between perception and action and might be more accurately viewed as a negative image of action blindsight. Secondly, dissociations between perceptive and motor responses highlighted in the framework of this theory concern a very elementary level of action, even automatically guided action routines. Thirdly, the very rich interconnected network of the visual brain yields few arguments in favor of a strict perception/action dissociation. Overall, the dissociation between motor function and perceptive function explored by these behavioral and neuropsychological studies can help define an automatic level of action organization deficient in optic ataxia and preserved in action blindsight, and underlines the renewed need to consider the perception-action circle as a functional ensemble. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Impact of action primes on implicit processing of thematic and functional similarity relations: evidence from eye-tracking.

PubMed

Pluciennicka, Ewa; Wamain, Yannick; Coello, Yann; Kalénine, Solène

2016-07-01

The aim of this study was to specify the role of action representations in thematic and functional similarity relations between manipulable artifact objects. Recent behavioral and neurophysiological evidence indicates that while they are all relevant for manipulable artifact concepts, semantic relations based on thematic (e.g., saw-wood), specific function similarity (e.g., saw-axe), and general function similarity (e.g., saw-knife) are differently processed, and may relate to different levels of action representation. Point-light displays of object-related actions previously encoded at the gesture level (e.g., "sawing") or at the higher level of action representation (e.g., "cutting") were used as primes before participants identified target objects (e.g., saw) among semantically related and unrelated distractors (e.g., wood, feather, piano). Analysis of eye movements on the different objects during target identification informed about the amplitude and the timing of implicit activation of the different semantic relations. Results showed that action prime encoding impacted the processing of thematic relations, but not that of functional similarity relations. Semantic competition with thematic distractors was greater and earlier following action primes encoded at the gesture level compared to action primes encoded at higher level. As a whole, these findings highlight the direct influence of action representations on thematic relation processing, and suggest that thematic relations involve gesture-level representations rather than intention-level representations.

Molecular evolution of the betagamma lens crystallin superfamily: evidence for a retained ancestral function in gamma N crystallins?

PubMed

Weadick, Cameron J; Chang, Belinda S W

2009-05-01

Within the vertebrate eye, betagamma crystallins are extremely stable lens proteins that are uniquely adapted to increase refractory power while maintaining transparency. Unlike alpha crystallins, which are well-characterized, multifunctional proteins that have important functions both in and out of the lens, betagamma lens crystallins are a diverse group of proteins with no clear ancestral or contemporary nonlens role. We carried out phylogenetic and molecular evolutionary analyses of the betagamma-crystallin superfamily in order to study the evolutionary history of the gamma N crystallins, a recently discovered, biochemically atypical family suggested to possess a divergent or ancestral function. By including nonlens, betagamma-motif-containing sequences in our analysis as outgroups, we confirmed the phylogenetic position of the gamma N family as sister to other gamma crystallins. Using maximum likelihood codon models to estimate lineage-specific nonsynonymous-to-synonymous rate ratios revealed strong positive selection in all of the early lineages within the betagamma family, with the striking exception of the lineage leading to the gamma N crystallins which was characterized by strong purifying selection. Branch-site analysis, used to identify candidate sites involved in functional divergence between gamma N crystallins and its sister clade containing all other gamma crystallins, identified several positively selected changes at sites of known functional importance in the betagamma crystallin protein structure. Further analyses of a fish-specific gamma N crystallin gene duplication revealed a more recent episode of positive selection in only one of the two descendant lineages (gamma N2). Finally, from the guppy, Poecilia reticulata, we isolated complete gamma N1 and gamma N2 coding sequence data from cDNA and partial coding sequence data from genomic DNA in order to confirm the presence of a novel gamma N2 intron, discovered through data mining of two pufferfish genomes. We conclude that the function of the gamma N family likely resembles the ancestral vertebrate betagamma crystallin more than other betagamma families. Furthermore, owing to the presence of an additional intron in some fish gamma N2 crystallins, and the inferred action of positive selection following the fish-specific gamma N duplication, we suggest that further study of fish gamma N crystallins will be critical in further elucidating possible ancestral functions of gamma N crystallins and any nonstructural role they may have.

Update on Aire and thymic negative selection.

PubMed

Passos, Geraldo A; Speck-Hernandez, Cesar A; Assis, Amanda F; Mendes-da-Cruz, Daniella A

2018-01-01

Twenty years ago, the autoimmune regulator (Aire) gene was associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, and was cloned and sequenced. Its importance goes beyond its abstract link with human autoimmune disease. Aire identification opened new perspectives to better understand the molecular basis of central tolerance and self-non-self distinction, the main properties of the immune system. Since 1997, a growing number of immunologists and molecular geneticists have made important discoveries about the function of Aire, which is essentially a pleiotropic gene. Aire is one of the functional markers in medullary thymic epithelial cells (mTECs), controlling their differentiation and expression of peripheral tissue antigens (PTAs), mTEC-thymocyte adhesion and the expression of microRNAs, among other functions. With Aire, the immunological tolerance became even more apparent from the molecular genetics point of view. Currently, mTECs represent the most unusual cells because they express almost the entire functional genome but still maintain their identity. Due to the enormous diversity of PTAs, this uncommon gene expression pattern was termed promiscuous gene expression, the interpretation of which is essentially immunological - i.e. it is related to self-representation in the thymus. Therefore, this knowledge is strongly linked to the negative selection of autoreactive thymocytes. In this update, we focus on the most relevant results of Aire as a transcriptional and post-transcriptional controller of PTAs in mTECs, its mechanism of action, and its influence on the negative selection of autoreactive thymocytes as the bases of the induction of central tolerance and prevention of autoimmune diseases. © 2017 John Wiley & Sons Ltd.

Optogenetic stimulation in a computational model of the basal ganglia biases action selection and reward prediction error.

PubMed

Berthet, Pierre; Lansner, Anders

2014-01-01

Optogenetic stimulation of specific types of medium spiny neurons (MSNs) in the striatum has been shown to bias the selection of mice in a two choices task. This shift is dependent on the localisation and on the intensity of the stimulation but also on the recent reward history. We have implemented a way to simulate this increased activity produced by the optical flash in our computational model of the basal ganglia (BG). This abstract model features the direct and indirect pathways commonly described in biology, and a reward prediction pathway (RP). The framework is similar to Actor-Critic methods and to the ventral/dorsal distinction in the striatum. We thus investigated the impact on the selection caused by an added stimulation in each of the three pathways. We were able to reproduce in our model the bias in action selection observed in mice. Our results also showed that biasing the reward prediction is sufficient to create a modification in the action selection. However, we had to increase the percentage of trials with stimulation relative to that in experiments in order to impact the selection. We found that increasing only the reward prediction had a different effect if the stimulation in RP was action dependent (only for a specific action) or not. We further looked at the evolution of the change in the weights depending on the stage of learning within a block. A bias in RP impacts the plasticity differently depending on that stage but also on the outcome. It remains to experimentally test how the dopaminergic neurons are affected by specific stimulations of neurons in the striatum and to relate data to predictions of our model.

Misdirection of Regenerating Axons and Functional Recovery Following Sciatic Nerve Injury in Rats

PubMed Central

Hamilton, Shirley K.; Hinkle, Marcus L.; Nicolini, Jennifer; Rambo, Lindsay N.; Rexwinkle, April M.; Rose, Sam J.; Sabatier, Manning J.; Backus, Deborah; English, Arthur W.

2013-01-01

Poor functional recovery found after peripheral nerve injury has been attributed to the misdirection of regenerating axons to reinnervate functionally inappropriate muscles. We applied brief electrical stimulation (ES) to the common fibular (CF) but not the tibial (Tib) nerve just prior to transection and repair of the entire rat sciatic nerve, to attempt to influence the misdirection of its regenerating axons. The specificity with which regenerating axons reinnervated appropriate targets was evaluated physiologically using compound muscle action potentials (M responses) evoked from stimulation of the two nerve branches above the injury site. Functional recovery was assayed using the timing of electromyography (EMG) activity recorded from the tibialis anterior (TA) and soleus (Sol) muscles during treadmill locomotion and kinematic analysis of hindlimb locomotor movements. Selective ES of the CF nerve resulted in restored M-responses at earlier times than in unstimulated controls in both TA and Sol muscles. Stimulated CF axons reinnervated inappropriate targets to a greater extent than unstimulated Tib axons. During locomotion, functional antagonist muscles, TA and Sol, were coactivated both in stimulated rats and in unstimulated but injured rats. Hindlimb kinematics in stimulated rats were comparable to untreated rats, but significantly different from intact controls. Selective ES promotes enhanced axon regeneration but does so with decreased fidelity of muscle reinnervation. Functional recovery is neither improved nor degraded, suggesting that compensatory changes in the outputs of the spinal circuits driving locomotion may occur irrespective of the extent of misdirection of regenerating axons in the periphery. PMID:21120925

Sv-map between type I and heterotic sigma models

NASA Astrophysics Data System (ADS)

Fan, Wei; Fotopoulos, A.; Stieberger, S.; Taylor, T. R.

2018-05-01

The scattering amplitudes of gauge bosons in heterotic and open superstring theories are related by the single-valued projection which yields heterotic amplitudes by selecting a subset of multiple zeta value coefficients in the α‧ (string tension parameter) expansion of open string amplitudes. In the present work, we argue that this relation holds also at the level of low-energy expansions (or individual Feynman diagrams) of the respective effective actions, by investigating the beta functions of two-dimensional sigma models describing world-sheets of open and heterotic strings. We analyze the sigma model Feynman diagrams generating identical effective action terms in both theories and show that the heterotic coefficients are given by the single-valued projection of the open ones. The single-valued projection appears as a result of summing over all radial orderings of heterotic vertices on the complex plane representing string world-sheet.

Studies on the Mechanism of Action of Dinitramine

PubMed Central

Travis, Robert L.; Woods, William G.

1977-01-01

The effect of dinitramine, a selective herbicide, on the plasma membrane of the soybean (Glycine max L.) root was studied. Used as marker systems to observe the herbicide effect were two plasma-membrane-specific enzymes, pH 6.5 ATPase and glucan synthetase. The activity of pH 6.5 ATPase decreased significantly in membrane vesicles prepared from roots harvested 15 minutes after treatment with dinitramine. Maximum inhibition occurred in roots harvested 2 hours after treatment. Glucan synthetase activity decreased similarly within 2 hours of treatment. Membrane permeability to 86Rb was rapidly increased by dinitramine. The activity of pH 6.5 ATPase returned to the control level within 8 hours of treatment with dinitramine. These results show dinitramine's initial site of action to be the plasma membrane, producing an over-all reduction in membrane function through inactivation of membrane-associated proteins. PMID:16660043

Role of the superior colliculus in choosing mixed-strategy saccades.

PubMed

Thevarajah, Dhushan; Mikulić, Areh; Dorris, Michael C

2009-02-18

Game theory outlines optimal response strategies during mixed-strategy competitions. The neural processes involved in choosing individual strategic actions, however, remain poorly understood. Here, we tested whether the superior colliculus (SC), a brain region critical for generating sensory-guided saccades, is also involved in choosing saccades under strategic conditions. Monkeys were free to choose either of two saccade targets as they competed against a computer opponent during the mixed-strategy game "matching pennies." The accuracy with which presaccadic SC activity predicted upcoming choice gradually increased in the time leading up to the saccade. Probing the SC with suprathreshold stimulation demonstrated that these evolving signals were functionally involved in preparing strategic saccades. Finally, subthreshold stimulation of the SC increased the likelihood that contralateral saccades were selected. Together, our results suggest that motor regions of the brain play an active role in choosing strategic actions rather than passively executing those prespecified by upstream executive regions.

Evolutionary genomics and HIV restriction factors.

PubMed

Pyndiah, Nitisha; Telenti, Amalio; Rausell, Antonio

2015-03-01

To provide updated insights into innate antiviral immunity and highlight prototypical evolutionary features of well characterized HIV restriction factors. Recently, a new HIV restriction factor, Myxovirus resistance 2, has been discovered and the region/residue responsible for its activity identified using an evolutionary approach. Furthermore, IFI16, an innate immunity protein known to sense several viruses, has been shown to contribute to the defense to HIV-1 by causing cell death upon sensing HIV-1 DNA. Restriction factors against HIV show characteristic signatures of positive selection. Different patterns of accelerated sequence evolution can distinguish antiviral strategies--offense or defence--as well as the level of specificity of the antiviral properties. Sequence analysis of primate orthologs of restriction factors serves to localize functional domains and sites responsible for antiviral action. We use recent discoveries to illustrate how evolutionary genomic analyses help identify new antiviral genes and their mechanisms of action.

The anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamine.

PubMed

Chidley, Christopher; Trauger, Sunia A; Birsoy, Kıvanç; O'Shea, Erin K

2016-07-12

Phenotypic screens allow the identification of small molecules with promising anticancer activity, but the difficulty in characterizing the mechanism of action of these compounds in human cells often undermines their value as drug leads. Here, we used a loss-of-function genetic screen in human haploid KBM7 cells to discover the mechanism of action of the anticancer natural product ophiobolin A (OPA). We found that genetic inactivation of de novo synthesis of phosphatidylethanolamine (PE) mitigates OPA cytotoxicity by reducing cellular PE levels. OPA reacts with the ethanolamine head group of PE in human cells to form pyrrole-containing covalent cytotoxic adducts and these adducts lead to lipid bilayer destabilization. Our characterization of this unusual cytotoxicity mechanism, made possible by unbiased genetic screening in human cells, suggests that the selective antitumor activity displayed by OPA may be due to altered membrane PE levels in cancer cells.

Cerebellar and prefrontal cortex contributions to adaptation, strategies, and reinforcement learning.

PubMed

Taylor, Jordan A; Ivry, Richard B

2014-01-01

Traditionally, motor learning has been studied as an implicit learning process, one in which movement errors are used to improve performance in a continuous, gradual manner. The cerebellum figures prominently in this literature given well-established ideas about the role of this system in error-based learning and the production of automatized skills. Recent developments have brought into focus the relevance of multiple learning mechanisms for sensorimotor learning. These include processes involving repetition, reinforcement learning, and strategy utilization. We examine these developments, considering their implications for understanding cerebellar function and how this structure interacts with other neural systems to support motor learning. Converging lines of evidence from behavioral, computational, and neuropsychological studies suggest a fundamental distinction between processes that use error information to improve action execution or action selection. While the cerebellum is clearly linked to the former, its role in the latter remains an open question. © 2014 Elsevier B.V. All rights reserved.

Cerebellar and Prefrontal Cortex Contributions to Adaptation, Strategies, and Reinforcement Learning

PubMed Central

Taylor, Jordan A.; Ivry, Richard B.

2014-01-01

Traditionally, motor learning has been studied as an implicit learning process, one in which movement errors are used to improve performance in a continuous, gradual manner. The cerebellum figures prominently in this literature given well-established ideas about the role of this system in error-based learning and the production of automatized skills. Recent developments have brought into focus the relevance of multiple learning mechanisms for sensorimotor learning. These include processes involving repetition, reinforcement learning, and strategy utilization. We examine these developments, considering their implications for understanding cerebellar function and how this structure interacts with other neural systems to support motor learning. Converging lines of evidence from behavioral, computational, and neuropsychological studies suggest a fundamental distinction between processes that use error information to improve action execution or action selection. While the cerebellum is clearly linked to the former, its role in the latter remains an open question. PMID:24916295

Obesity-related hypertension: is there a role for selective leptin resistance?

PubMed

Correia, Marcelo L G; Haynes, William G

2004-06-01

Obesity is a risk factor for cardiovascular diseases, in particular for hypertension. Serum leptin levels and sympathetic nerve activity are both increased in obesity. Leptin has been demonstrated to increase sympathetic nerve activity. Thus, leptin-dependent sympathoactivation might contribute to obesity-related hypertension. However, leptin resistance occurs in obesity. One possibility is that leptin resistance is selective to the metabolic effects of leptin, sparing its sympathoexcitatory actions. In this article, we review experimental evidence supporting the novel concept of selective leptin resistance. We also discuss the sympathetic actions of leptin that are relevant to blood pressure modulation and potential mechanisms of leptin resistance. Disruption of leptin intracellular signaling pathways and resistance of specific leptin-responsive neural networks provide theoretic models of selective leptin resistance. However, most information about leptin-sympathetic actions and leptin-resistance mechanisms derive from in vitro and animal studies. Future research in humans is widely awaited.

Dopamine D2 receptor-mediated G-protein activation in rat striatum: functional autoradiography and influence of unilateral 6-hydroxydopamine lesions of the substantia nigra.

PubMed

Newman-Tancredi, A; Cussac, D; Brocco, M; Rivet, J M; Chaput, C; Touzard, M; Pasteau, V; Millan, M J

2001-11-30

Unilateral 6-hydroxydopamine (6-OHDA) lesions of substantia nigra pars compacta (SNPC) neurons in rats induce behavioural hypersensitivity to dopaminergic agonists. However, the role of specific dopamine receptors is unclear, and potential alterations in their transduction mechanisms remain to be evaluated. The present study addressed these issues employing the dopaminergic agonist, quinelorane, which efficaciously stimulated G-protein activation (as assessed by [35S]GTPgammaS binding) at cloned hD2 (and hD3) receptors. At rat striatal membranes, dopamine stimulated [35S]GTPgammaS binding by 1.9-fold over basal, but its actions were only partially reversed by the selective D2/D3 receptor antagonist, raclopride, indicating the involvement of other receptor subtypes. In contrast, quinelorane-induced stimulation (48% of the effect of dopamine) was abolished by raclopride, and by the D2 receptor antagonist, L741,626. Further, novel antagonists selective for D3 and D4 receptors, S33084 and S18126, respectively, blocked the actions of quinelorane at concentrations corresponding to their affinities for D2 receptors. Quinelorane potently induced contralateral rotation in unilaterally 6-OHDA-lesioned rats, an effect abolished by raclopride and L741,626, but not by D3 and D4 receptor-selective doses of S33084 and S18126, respectively. In functional ([35S]GTPgammaS) autoradiography experiments, quinelorane stimulated G-protein activation in caudate putamen and, to a lesser extent, in nucleus accumbens and cingulate cortex of naive rats. In unilaterally SNPC-lesioned rats, quinelorane-induced G-protein activation in the caudate putamen on the non-lesioned side was similar to that seen in naive animals (approximately 50% stimulation), but significantly greater on the lesioned side (approximately 80%). This increase was both pharmacologically and regionally specific since it was reversed by raclopride, and was not observed in nucleus accumbens or cingulate cortex. In conclusion, the present data indicate that, in rat striatum, the actions of quinelorane are mediated primarily by D2 receptors, and suggest that behavioural hypersensitivity to this agonist, induced by unilateral SNPC lesions, is associated with an increase in D2, but not D3 or D4, receptor-mediated G-protein activation.

First Generation College Students and Selective College Admission: A Quantitative Examination of Class-Based Affirmative Action

ERIC Educational Resources Information Center

McGann, Matthew L.

2017-01-01

Relatively few students from lower socioeconomic backgrounds are enrolled in the most selective American colleges and universities. To improve enrollment, scholars have suggested that college admission offices provide these low SES students an admissions advantage, also known as class-based affirmative action. This study examined to what degree…

A Common Capacity Limitation for Response and Item Selection in Working Memory

ERIC Educational Resources Information Center

Janczyk, Markus

2017-01-01

Successful completion of any cognitive task requires selecting a particular action and the object the action is applied to. Oberauer (2009) suggested a working memory (WM) model comprising a declarative and a procedural part with analogous structures. One important assumption of this model is that both parts work independently of each other, and…

Genomic resources and their influence on the detection of the signal of positive selection in genome scans.

PubMed

Manel, S; Perrier, C; Pratlong, M; Abi-Rached, L; Paganini, J; Pontarotti, P; Aurelle, D

2016-01-01

Genome scans represent powerful approaches to investigate the action of natural selection on the genetic variation of natural populations and to better understand local adaptation. This is very useful, for example, in the field of conservation biology and evolutionary biology. Thanks to Next Generation Sequencing, genomic resources are growing exponentially, improving genome scan analyses in non-model species. Thousands of SNPs called using Reduced Representation Sequencing are increasingly used in genome scans. Besides, genome sequences are also becoming increasingly available, allowing better processing of short-read data, offering physical localization of variants, and improving haplotype reconstruction and data imputation. Ultimately, genome sequences are also becoming the raw material for selection inferences. Here, we discuss how the increasing availability of such genomic resources, notably genome sequences, influences the detection of signals of selection. Mainly, increasing data density and having the information of physical linkage data expand genome scans by (i) improving the overall quality of the data, (ii) helping the reconstruction of demographic history for the population studied to decrease false-positive rates and (iii) improving the statistical power of methods to detect the signal of selection. Of particular importance, the availability of a high-quality reference genome can improve the detection of the signal of selection by (i) allowing matching the potential candidate loci to linked coding regions under selection, (ii) rapidly moving the investigation to the gene and function and (iii) ensuring that the highly variable regions of the genomes that include functional genes are also investigated. For all those reasons, using reference genomes in genome scan analyses is highly recommended. © 2015 John Wiley & Sons Ltd.

Using the theory of reasoned action to predict organizational misbehavior.

PubMed

Vardi, Yoav; Weitz, Ely

2002-12-01

A review of literature on organizational behavior and management on predicting work behavior indicated that most reported studies emphasize positive work outcomes, e.g., attachment, performance, and satisfaction, while job related misbehaviors have received relatively less systematic research attention. Yet, forms of employee misconduct in organizations are pervasive and quite costly for both individuals and organizations. We selected two conceptual frameworks for the present investigation: Vardi and Wiener's model of organizational misbehavior and Fishbein and Ajzen's Theory of Reasoned Action. The latter views individual behavior as intentional, a function of rationally based attitudes toward the behavior, and internalized normative pressures concerning such behavior. The former model posits that different (normative and instrumental) internal forces lead to the intention to engage in job-related misbehavior. In this paper we report a scenario based quasi-experimental study especially designed to test the utility of the Theory of Reasoned Action in predicting employee intentions to engage in self-benefitting (Type S), organization-benefitting (Type O, or damaging (Type D) organizational misbehavior. Results support the Theory of Reasoned Action in predicting negative workplace behaviors. Both attitude and subjective norm are useful in explaining organizational misbehavior. We discuss some theoretical and methodological implications for the study of misbehavior intentions in organizations.

Overlapping and Divergent Actions of Structurally Distinct Histone Deacetylase Inhibitors in Cardiac Fibroblasts

PubMed Central

Schuetze, Katherine B.; Stratton, Matthew S.; Blakeslee, Weston W.; Wempe, Michael F.; Wagner, Florence F.; Holson, Edward B.; Kuo, Yin-Ming; Andrews, Andrew J.; Gilbert, Tonya M.; Hooker, Jacob M.

2017-01-01

Inhibitors of zinc-dependent histone deacetylases (HDACs) profoundly affect cellular function by altering gene expression via changes in nucleosomal histone tail acetylation. Historically, investigators have employed pan-HDAC inhibitors, such as the hydroxamate trichostatin A (TSA), which simultaneously targets members of each of the three zinc-dependent HDAC classes (classes I, II, and IV). More recently, class- and isoform-selective HDAC inhibitors have been developed, providing invaluable chemical biology probes for dissecting the roles of distinct HDACs in the control of various physiologic and pathophysiological processes. For example, the benzamide class I HDAC-selective inhibitor, MGCD0103 [N-(2-aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]methyl] benzamide], was shown to block cardiac fibrosis, a process involving excess extracellular matrix deposition, which often results in heart dysfunction. Here, we compare the mechanisms of action of structurally distinct HDAC inhibitors in isolated primary cardiac fibroblasts, which are the major extracellular matrix–producing cells of the heart. TSA, MGCD0103, and the cyclic peptide class I HDAC inhibitor, apicidin, exhibited a common ability to enhance histone acetylation, and all potently blocked cardiac fibroblast cell cycle progression. In contrast, MGCD0103, but not TSA or apicidin, paradoxically increased expression of a subset of fibrosis-associated genes. Using the cellular thermal shift assay, we provide evidence that the divergent effects of HDAC inhibitors on cardiac fibroblast gene expression relate to differential engagement of HDAC1- and HDAC2-containing complexes. These findings illustrate the importance of employing multiple compounds when pharmacologically assessing HDAC function in a cellular context and during HDAC inhibitor drug development. PMID:28174211

Studies on the kinetics of killing and the proposed mechanism of action of microemulsions against fungi.

PubMed

Al-Adham, Ibrahim S I; Ashour, Hana; Al-Kaissi, Elham; Khalil, Enam; Kierans, Martin; Collier, Phillip J

2013-09-15

Microemulsions are physically stable oil/water clear dispersions, spontaneously formed and thermodynamically stable. They are composed in most cases of water, oil, surfactant and cosurfactant. Microemulsions are stable, self-preserving antimicrobial agents in their own right. The observed levels of antimicrobial activity associated with microemulsions may be due to the direct effect of the microemulsions themselves on the bacterial cytoplasmic membrane. The aim of this work is to study the growth behaviour of different microbes in presence of certain prepared physically stable microemulsion formulae over extended periods of time. An experiment was designed to study the kinetics of killing of a microemulsion preparation (17.3% Tween-80, 8.5% n-pentanol, 5% isopropyl myristate and 69.2% sterile distilled water) against selected test microorganisms (Candida albicans, Aspergillus niger, Schizosaccharomyces pombe and Rhodotorula spp.). Secondly, an experiment was designed to study the effects of the microemulsion preparation on the cytoplasmic membrane structure and function of selected fungal species by observation of 260 nm component leakage. Finally, the effects of the microemulsion on the fungal membrane structure and function using S. pombe were studied using transmission electron microscopy. The results showed that the prepared microemulsions are stable, effective antimicrobial systems with effective killing rates against C. albicans, A. niger, S. pombe and Rhodotorula spp. The results indicate a proposed mechanism of action of significant anti-membrane activity, resulting in the gross disturbance and dysfunction of the cytoplasmic membrane structure which is followed by cell wall modifications, cytoplasmic coagulation, disruption of intracellular metabolism and cell death. Copyright © 2013 Elsevier B.V. All rights reserved.

Chronic Exposure to Anabolic Androgenic Steroids Alters Neuronal Function in the Mammalian Forebrain via Androgen Receptor- and Estrogen Receptor-Mediated Mechanisms

PubMed Central

Penatti, Carlos A A; Porter, Donna M; Henderson, Leslie P

2009-01-01

Anabolic androgenic steroids (AAS) can promote detrimental effects on social behaviors for which γ-aminobutyric acid type A (GABAA) receptor-mediated circuits in the forebrain play a critical role. While all AAS bind to androgen receptors (AR), they may also be aromatized to estrogens and thus potentially impart effects via estrogen receptors (ER). Chronic exposure of wild type male mice to a combination of chemically distinct AAS increased action potential (AP) frequency, selective GABAA receptor subunit mRNAs, and GABAergic synaptic current decay in the medial preoptic area (mPOA). Experiments performed with pharmacological agents and in AR-deficient Tfm mutant mice suggest that the AAS-dependent enhancement of GABAergic transmission in wild type mice is AR-mediated. In AR-deficient mice, the AAS elicited dramatically different effects, decreasing AP frequency, sIPSC amplitude and frequency and the expression of selective GABAA receptor subunit mRNAs. Surprisingly, in the absence of AR signaling, the data indicate that the AAS do not act as ER agonists, but rather suggest a novel in vivo action in which the AAS inhibit aromatase and impair endogenous ER signaling. These results show that the AAS have the capacity to alter neuronal function in the forebrain via multiple steroid signaling mechanisms and suggest that effects of these steroids in the brain will depend not only on the balance of AR- vs. ER-mediated regulation for different target genes, but also on the ability of these drugs to alter steroid metabolism and thus the endogenous steroid milieu. PMID:19812324

34 CFR 426.24 - What selection criteria does the Secretary use for Agriculture Action Centers?

Code of Federal Regulations, 2010 CFR

2010-07-01

... Agriculture Action Centers? 426.24 Section 426.24 Education Regulations of the Offices of the Department of... use for Agriculture Action Centers? The Secretary uses the following criteria to evaluate an application for an Agriculture Action Center: (a) Program factors. (10 points) The Secretary reviews each...

34 CFR 426.24 - What selection criteria does the Secretary use for Agriculture Action Centers?

Code of Federal Regulations, 2012 CFR

2012-07-01

... Agriculture Action Centers? 426.24 Section 426.24 Education Regulations of the Offices of the Department of... use for Agriculture Action Centers? The Secretary uses the following criteria to evaluate an application for an Agriculture Action Center: (a) Program factors. (10 points) The Secretary reviews each...

34 CFR 426.24 - What selection criteria does the Secretary use for Agriculture Action Centers?

Code of Federal Regulations, 2014 CFR

2014-07-01

... Agriculture Action Centers? 426.24 Section 426.24 Education Regulations of the Offices of the Department of... use for Agriculture Action Centers? The Secretary uses the following criteria to evaluate an application for an Agriculture Action Center: (a) Program factors. (10 points) The Secretary reviews each...

34 CFR 426.24 - What selection criteria does the Secretary use for Agriculture Action Centers?

Code of Federal Regulations, 2013 CFR

2013-07-01

... Agriculture Action Centers? 426.24 Section 426.24 Education Regulations of the Offices of the Department of... use for Agriculture Action Centers? The Secretary uses the following criteria to evaluate an application for an Agriculture Action Center: (a) Program factors. (10 points) The Secretary reviews each...

34 CFR 426.24 - What selection criteria does the Secretary use for Agriculture Action Centers?

Code of Federal Regulations, 2011 CFR

2011-07-01

... Agriculture Action Centers? 426.24 Section 426.24 Education Regulations of the Offices of the Department of... use for Agriculture Action Centers? The Secretary uses the following criteria to evaluate an application for an Agriculture Action Center: (a) Program factors. (10 points) The Secretary reviews each...

What motivates participation in violent political action: selective incentives or parochial altruism?

PubMed

Ginges, Jeremy; Atran, Scott

2009-06-01

In standard models of decision making, participation in violent political action is understood as the product of instrumentally rational reasoning. According to this line of thinking, instrumentally rational individuals will participate in violent political action only if there are selective incentives that are limited to participants. We argue in favor of an alternate model of political violence where participants are motivated by moral commitments to collective sacred values. Correlative and experimental empirical evidence in the context of the Israeli-Palestinian conflict strongly supports this alternate view.

Selective Influences of Precision and Power Grips on Speech Categorization.

PubMed

Tiainen, Mikko; Tiippana, Kaisa; Vainio, Martti; Peromaa, Tarja; Komeilipoor, Naeem; Vainio, Lari

2016-01-01

Recent studies have shown that articulatory gestures are systematically associated with specific manual grip actions. Here we show that executing such actions can influence performance on a speech-categorization task. Participants watched and/or listened to speech stimuli while executing either a power or a precision grip. Grip performance influenced the syllable categorization by increasing the proportion of responses of the syllable congruent with the executed grip (power grip-[ke] and precision grip-[te]). Two follow-up experiments indicated that the effect was based on action-induced bias in selecting the syllable.

Prefrontal cortex-projecting glutamatergic thalamic paraventricular nucleus-excited by hypocretin: a feedforward circuit that may enhance cognitive arousal.

PubMed

Huang, Hao; Ghosh, Prabhat; van den Pol, Anthony N

2006-03-01

The paraventricular thalamic nucleus (PVT) receives one of the most dense innervations by hypothalamic hypocretin/orexin (Hcrt) neurons, which play important roles in sleep-wakefulness, attention, and autonomic function. The PVT projects to several loci, including the medial prefrontal cortex (mPFC), a cortical region involved in associative function and attention. To study the effect of Hcrt on excitatory PVT neurons that project to the mPFC, we used a new line of transgenic mice expressing green fluorescent protein (GFP) under the control of the vesicular glutamate-transporter-2 promoter. These neurons were retrogradely labeled with cholera toxin subunit B that had been microinjected into the mPFC. Membrane characteristics and responses to hypocretin-1 and -2 (Hcrt-1 and -2) were studied using whole cell recording (n > 300). PVT neurons showed distinct membrane properties including inward rectification, H-type potassium currents, low threshold spikes, and spike frequency adaptation. Cortically projecting neurons were depolarized and excited by Hcrt-2. Hcrt-2 actions were stronger than those of Hcrt-1, and the action persisted in TTX and in low calcium/high magnesium artificial cerebrospinal fluid, consistent with direct actions mediated by Hcrt receptor-2. Two mechanisms of Hcrt excitation were found: an increase in input resistance caused by closure of potassium channels and activation of nonselective cation channels. The robust excitation evoked by Hcrt-2 on cortically projecting glutamate PVT neurons could generate substantial excitation in multiple layers of the mPFC, adding to the more selective direct excitatory actions of Hcrt in the mPFC and potentially increasing cortical arousal and attention to limbic or visceral states.

Quantum identities for the action

NASA Astrophysics Data System (ADS)

Gozzi, E.

2018-04-01

In this paper we derive various identities involving the action functional which enters the path-integral formulation of quantum mechanics. They provide some kind of generalisations of the Ehrenfest theorem giving correlations between powers of the action and its functional derivatives.

Action-based flood forecasting for triggering humanitarian action

NASA Astrophysics Data System (ADS)

Coughlan de Perez, Erin; van den Hurk, Bart; van Aalst, Maarten K.; Amuron, Irene; Bamanya, Deus; Hauser, Tristan; Jongma, Brenden; Lopez, Ana; Mason, Simon; Mendler de Suarez, Janot; Pappenberger, Florian; Rueth, Alexandra; Stephens, Elisabeth; Suarez, Pablo; Wagemaker, Jurjen; Zsoter, Ervin

2016-09-01

Too often, credible scientific early warning information of increased disaster risk does not result in humanitarian action. With financial resources tilted heavily towards response after a disaster, disaster managers have limited incentive and ability to process complex scientific data, including uncertainties. These incentives are beginning to change, with the advent of several new forecast-based financing systems that provide funding based on a forecast of an extreme event. Given the changing landscape, here we demonstrate a method to select and use appropriate forecasts for specific humanitarian disaster prevention actions, even in a data-scarce location. This action-based forecasting methodology takes into account the parameters of each action, such as action lifetime, when verifying a forecast. Forecasts are linked with action based on an understanding of (1) the magnitude of previous flooding events and (2) the willingness to act "in vain" for specific actions. This is applied in the context of the Uganda Red Cross Society forecast-based financing pilot project, with forecasts from the Global Flood Awareness System (GloFAS). Using this method, we define the "danger level" of flooding, and we select the probabilistic forecast triggers that are appropriate for specific actions. Results from this methodology can be applied globally across hazards and fed into a financing system that ensures that automatic, pre-funded early action will be triggered by forecasts.

β-adrenergic Receptor Blocker ICI 118,551 Selectively Increases Intermediate-Conductance Calcium-Activated Potassium Channel (IKCa )-Mediated Relaxations in Rat Main Mesenteric Artery.

PubMed

Ozkan, Melike Hacer; Uma, Serdar

2018-06-01

Endothelial IK C a and/or SK C a channels play an important role in the control of vascular tone by participating in endothelium-dependent relaxation. Whether β-AR antagonists, mainly used in hypertension, affect endothelial K C a channel function is unknown. In this study, we examined the effect of the β2-AR antagonist and inverse agonist ICI 118,551 on the IK C a /SK C a channel activity by assessing functional relaxation responses to several agonists that stimulate these channels. Mesenteric arterial rings isolated from male Sprague Dawley mounted to organ baths. Acetylcholine elicited IK C a - and SK C a -mediated relaxations that were abolished by TRAM-34 and apamin, respectively. ICI 118,551, which did not dilate the arteries per se, increased the IK C a -mediated relaxations, whereas SK C a -mediated relaxations remained unaltered. Same potentiating effect was also detected on the IK C a -mediated relaxations to carbachol and A23187, but not to NS309. Neither acetylcholine-induced nitric oxide-mediated relaxations nor SNP relaxations changed with ICI 118,551. The PKA inhibitor KT-5720, the selective β2-AR agonist salbutamol, the selective β2-AR antagonist butoxamine, the non-selective β-AR antagonist propranolol, and the inverse agonists carvedilol or nadolol failed to affect the IK C a -mediated relaxations. ICI 118,551-induced increase was not reversed by salbutamol or propranolol as well. Besides, low potassium-induced relaxations in endothelium-removed arteries remained the same in the presence of ICI 118,551. These data demonstrate a previously unrecognized action of ICI 118,551, the ability to potentiate endothelial IK C a channel-mediated vasodilation, through a mechanism independent of β2-AR antagonistic or inverse agonistic action. Instead, the enhancement of acetylcholine relaxation seems likely to occur by a mechanism secondary to endothelial calcium increase. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Novel ion channel targets in atrial fibrillation.

PubMed

Hancox, Jules C; James, Andrew F; Marrion, Neil V; Zhang, Henggui; Thomas, Dierk

2016-08-01

Atrial fibrillation (AF) is the most common arrhythmia in humans. It is progressive and the development of electrical and structural remodeling makes early intervention desirable. Existing antiarrhythmic pharmacological approaches are not always effective and can produce unwanted side effects. Additional atrial-selective antiarrhythmic strategies are therefore desirable. Evidence for three novel ion channel atrial-selective therapeutic targets is evaluated: atrial-selective fast sodium channel current (INa) inhibition; small conductance calcium-activated potassium (SK) channels; and two-pore (K2P) potassium channels. Data from animal models support atrial-ventricular differences in INa kinetics and also suggest atrial-ventricular differences in sodium channel β subunit expression. Further work is required to determine whether intrinsic atrial-ventricular differences in human INa exist or whether functional differences occur due to distinct atrial and ventricular action and resting potentials. SK and K2P channels (particularly K2P 3.1) offer potentially attractive atrial-selective targets. Work is needed to identify the underlying basis of SK current that contributes to (patho)physiological atrial repolarization and settings in which SK inhibition is anti- versus pro-arrhythmic. Although K2P3.1 appears to be a promising target with comparatively selective drugs for experimental use, a lack of selective pharmacology hinders evaluation of other K2P channels as potential atrial-selective targets.

Context-specific control and the Stroop negative priming effect.

PubMed

Milliken, Bruce; Thomson, David R; Bleile, Karmen; MacLellan, Ellen; Giammarco, Maria

2012-01-01

The present study highlights the utility of context-specific learning for different probe types in accounting for the commonly observed dependence of negative priming on probe selection. Using a Stroop priming procedure, Experiments 1a and 1b offered a demonstration that Stroop priming effects can differ qualitatively for selection and no-selection probes when probe selection is manipulated between subjects, but not when it is manipulated randomly from trial to trial within subject (see also Moore, 1994). In Experiments 2 and 3, selection and no-selection probes served as two contexts that varied randomly from trial to trial, but for which proportion repeated was manipulated separately. A context-specific proportion repeated effect was observed in Experiment 2, characterized by modest quantitative shifts in the repetition effects as a function of the context-specific proportion repeated manipulation. However, with a longer intertrial interval in Experiment 3, a context-specific proportion repeated manipulation that focused on the no-selection probes changed the repetition effect qualitatively, from negative priming when the proportion repeated was .25 to positive priming when the proportion repeated was .75. The results are discussed with reference to the role of rapid, context-specific learning processes in the integration of prior experiences with current perception and action.

Growth factors in the anterior segment: role in tissue maintenance, wound healing and ocular pathology.

PubMed

Klenkler, Bettina; Sheardown, Heather

2004-11-01

A number of growth factors and their associated receptors, including epidermal growth factor, transforming growth factor-beta, keratinocyte growth factor, hepatocyte growth factor, fibroblast growth factor and platelet-derived growth factor have been detected in the anterior segment of the eye. On binding to cellular receptors, these factors activate signalling cascades, which regulate functions including mitosis, differentiation, motility and apoptosis. Production of growth factors by corneal cells and their presence in the tear fluid and aqueous humour is essential for maintenance and renewal of normal tissue in the anterior eye and the prevention of undesirable immune or angiogenic reactions. Growth factors also play a vital role in corneal wound healing, mediating the proliferation of epithelial and stromal tissue and affecting the remodelling of the extracellular matrix (ECM). These functions depend on a complex interplay between growth factors of different types, the ECM, and regulatory mechanisms of the affected cells. Imbalances may lead to deficient wound healing and various ocular pathologies, including edema, neovascularization and glaucoma. Growth factors may be targeted in therapeutic ophthalmic applications, through exogenous application or selective inhibition, and may be used to elicit specific cellular responses to ophthalmic materials. A thorough understanding of the mechanism and function of growth factors and their actions in the complex environment of the anterior eye is required for these purposes. Growth factors, their function and mechanisms of action as well as the interplay between different growth factors based on recent in vitro and in vivo studies are presented.

Neural processing of intentional biological motion in unaffected siblings of children with autism spectrum disorder: an fMRI study.

PubMed

Ahmed, Alex A; Vander Wyk, Brent C

2013-12-01

Despite often showing behaviorally typical levels of social cognitive ability, unaffected siblings of children with autism spectrum disorder have been found to show similar functional and morphological deficits within brain regions associated with social processing. They have also been reported to show increased activation to biological motion in these same regions, such as the posterior superior temporal sulcus (pSTS), relative to both children with autism and control children. It has been suggested that this increased activation may represent a compensatory reorganization of these regions as a result of the highly heritable genetic influence of autism. However, the response patterns of unaffected siblings in the domain of action perception are unstudied, and the phenomenon of compensatory activation has not yet been replicated. The present study used functional magnetic resonance imaging to determine the neural responses to intentional biological actions in 22 siblings of children with autism and 22 matched controls. The presented actions were either congruent or incongruent with the actor's emotional cue. Prior studies reported that typically developing children and adults, but not children with autism, show increased activation to incongruent actions (relative to congruent), within the pSTS and dorsolateral prefrontal cortex. We report that unaffected siblings did not show a compensatory response, or a preference for incongruent over congruent trials, in any brain region. Moreover, interaction analyses revealed a sub-region of the pSTS in which control children showed an incongruency preference to a significantly greater degree than siblings, which suggests a localized deficit in siblings. A sample of children with autism also did not show differential activation in the pSTS, providing further evidence that it is an area of selective disruption in children with autism and siblings. While reduced activation to both conditions was unique to the autism sample, lack of differentiation to incongruent and congruent intentional actions was common to both children with ASD and unaffected siblings. Copyright © 2013 Elsevier Inc. All rights reserved.

Action video game training reduces the Simon Effect.

PubMed

Hutchinson, Claire V; Barrett, Doug J K; Nitka, Aleksander; Raynes, Kerry

2016-04-01

A number of studies have shown that training on action video games improves various aspects of visual cognition including selective attention and inhibitory control. Here, we demonstrate that action video game play can also reduce the Simon Effect, and, hence, may have the potential to improve response selection during the planning and execution of goal-directed action. Non-game-players were randomly assigned to one of four groups; two trained on a first-person-shooter game (Call of Duty) on either Microsoft Xbox or Nintendo DS, one trained on a visual training game for Nintendo DS, and a control group who received no training. Response times were used to contrast performance before and after training on a behavioral assay designed to manipulate stimulus-response compatibility (the Simon Task). The results revealed significantly faster response times and a reduced cost of stimulus-response incompatibility in the groups trained on the first-person-shooter game. No benefit of training was observed in the control group or the group trained on the visual training game. These findings are consistent with previous evidence that action game play elicits plastic changes in the neural circuits that serve attentional control, and suggest training may facilitate goal-directed action by improving players' ability to resolve conflict during response selection and execution.

Aging and response conflict solution: Behavioural and functional connectivity changes

PubMed Central

Cieslik, Edna C.; Behrwind, Simone D.; Roski, Christian; Caspers, Svenja; Amunts, Katrin; Eickhoff, Simon B.

2014-01-01

Healthy aging has been found associated with less efficient response conflict solution, but the cognitive and neural mechanisms remain elusive. In a two-experiment study, we first examined the behavioural consequences of this putative age-related decline for conflicts induced by spatial stimulus–response incompatibility. We then used resting-state functional magnetic resonance imaging data from a large, independent sample of adults (n = 399; 18–85 years) to investigate age differences in functional connectivity between the nodes of a network previously found associated with incompatibility-induced response conflicts in the very same paradigm. As expected, overcoming interference from conflicting response tendencies took longer in older adults, even after accounting for potential mediator variables (general response speed and accuracy, motor speed, visuomotor coordination ability, and cognitive flexibility). Experiment 2 revealed selective age-related decreases in functional connectivity between bilateral anterior insula, pre-supplementary motor area, and right dorsolateral prefrontal cortex. Importantly, these age effects persisted after controlling for regional gray-matter atrophy assessed by voxel-based morphometry. Meta-analytic functional profiling using the BrainMap database showed these age-sensitive nodes to be more strongly linked to highly abstract cognition, as compared with the remaining network nodes, which in turn were more strongly linked to action-related processing. These findings indicate changes in interregional coupling with age among task-relevant network nodes that are not specifically associated with conflict resolution per se. Rather, our behavioural and neural data jointly suggest that healthy aging is associated with difficulties in properly activating non-dominant but relevant task schemata necessary to exert efficient cognitive control over action. PMID:24718622

Aging and response conflict solution: behavioural and functional connectivity changes.

PubMed

Langner, Robert; Cieslik, Edna C; Behrwind, Simone D; Roski, Christian; Caspers, Svenja; Amunts, Katrin; Eickhoff, Simon B

2015-01-01

Healthy aging has been found associated with less efficient response conflict solution, but the cognitive and neural mechanisms have remained elusive. In a two-experiment study, we first examined the behavioural consequences of this putative age-related decline for conflicts induced by spatial stimulus-response incompatibility. We then used resting-state functional magnetic resonance imaging data from a large, independent sample of adults (n = 399; 18-85 years) to investigate age differences in functional connectivity between the nodes of a network previously found associated with incompatibility-induced response conflicts in the very same paradigm. As expected, overcoming interference from conflicting response tendencies took longer in older adults, even after accounting for potential mediator variables (general response speed and accuracy, motor speed, visuomotor coordination ability, and cognitive flexibility). Experiment 2 revealed selective age-related decreases in functional connectivity between bilateral anterior insula, pre-supplementary motor area, and right dorsolateral prefrontal cortex. Importantly, these age effects persisted after controlling for regional grey-matter atrophy assessed by voxel-based morphometry. Meta-analytic functional profiling using the BrainMap database showed these age-sensitive nodes to be more strongly linked to highly abstract cognition, as compared with the remaining network nodes, which were more strongly linked to action-related processing. These findings indicate changes in interregional coupling with age among task-relevant network nodes that are not specifically associated with conflict resolution per se. Rather, our behavioural and neural data jointly suggest that healthy aging is associated with difficulties in properly activating non-dominant but relevant task schemata necessary to exert efficient cognitive control over action.

Visual recognition and visually guided action after early bilateral lesion of occipital cortex: a behavioral study of a 4.6-year-old girl.

PubMed

Amicuzi, Ileana; Stortini, Massimo; Petrarca, Maurizio; Di Giulio, Paola; Di Rosa, Giuseppe; Fariello, Giuseppe; Longo, Daniela; Cannatà, Vittorio; Genovese, Elisabetta; Castelli, Enrico

2006-10-01

We report the case of a 4.6-year-old girl born pre-term with early bilateral occipital damage. It was revealed that the child had non-severely impaired basic visual abilities and ocular motility, a selective perceptual deficit of figure-ground segregation, impaired visual recognition and abnormal navigating through space. Even if the child's visual functioning was not optimal, this was the expression of adaptive anatomic and functional brain modifications that occurred following the early lesion. Anatomic brain structure was studied with anatomic MRI and Diffusor Tensor Imaging (DTI)-MRI. This behavioral study may provide an important contribution to understanding the impact of an early lesion of the visual system on the development of visual functions and on the immature brain's potential for reorganisation related to when the damage occurred.

Epigenetic mechanisms in memory and synaptic function

PubMed Central

Sultan, Faraz A; Day, Jeremy J

2011-01-01

Although the term ‘epigenetics’ was coined nearly seventy years ago, its critical function in memory processing by the adult CNS has only recently been appreciated. The hypothesis that epigenetic mechanisms regulate memory and behavior was motivated by the need for stable molecular processes that evade turnover of the neuronal proteome. In this article, we discuss evidence that supports a role for neural epigenetic modifications in the formation, consolidation and storage of memory. In addition, we will review the evidence that epigenetic mechanisms regulate synaptic plasticity, a cellular correlate of memory. We will also examine how the concerted action of multiple epigenetic mechanisms with varying spatiotemporal profiles influence selective gene expression in response to behavioral experience. Finally, we will suggest key areas for future research that will help elucidate the complex, vital and still mysterious, role of epigenetic mechanisms in neural function and behavior. PMID:22122279

Cost-benefit decision circuitry: proposed modulatory role for acetylcholine.

PubMed

Fobbs, Wambura C; Mizumori, Sheri J Y

2014-01-01

In order to select which action should be taken, an animal must weigh the costs and benefits of possible outcomes associate with each action. Such decisions, called cost-benefit decisions, likely involve several cognitive processes (including memory) and a vast neural circuitry. Rodent models have allowed research to begin to probe the neural basis of three forms of cost-benefit decision making: effort-, delay-, and risk-based decision making. In this review, we detail the current understanding of the functional circuits that subserve each form of decision making. We highlight the extensive literature by detailing the ability of dopamine to influence decisions by modulating structures within these circuits. Since acetylcholine projects to all of the same important structures, we propose several ways in which the cholinergic system may play a local modulatory role that will allow it to shape these behaviors. A greater understanding of the contribution of the cholinergic system to cost-benefit decisions will permit us to better link the decision and memory processes, and this will help us to better understand and/or treat individuals with deficits in a number of higher cognitive functions including decision making, learning, memory, and language. © 2014 Elsevier Inc. All rights reserved.

Toward molecular mechanism of xenon anesthesia: a link to studies of xenon complexes with small aromatic molecules.

PubMed

Andrijchenko, Natalya N; Ermilov, Alexander Yu; Khriachtchev, Leonid; Räsänen, Markku; Nemukhin, Alexander V

2015-03-19

The present study illustrates the steps toward understanding molecular mechanism of xenon anesthesia by focusing on a link to the structures and spectra of intermolecular complexes of xenon with small aromatic molecules. A primary cause of xenon anesthesia is attributed to inhibition of N-methyl-D-aspartate (NMDA) receptors by an unknown mechanism. Following the results of quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) calculations we report plausible xenon action sites in the ligand binding domain of the NMDA receptor, which are due to interaction of xenon atoms with aromatic amino-acid residues. We rely in these calculations on computational protocols adjusted in combined experimental and theoretical studies of intermolecular complexes of xenon with phenol. Successful reproduction of vibrational shifts in molecular species upon complexation with xenon measured in low-temperature matrices allowed us to select a proper functional form in density functional theory (DFT) approach for use in QM subsystems, as well as to calibrate force field parameters for MD simulations. The results of molecular modeling show that xenon atoms can compete with agonists for a place in the corresponding protein cavity, thus indicating their active role in anesthetic action.

Immunomodulatory effects of fluoxetine: A new potential pharmacological action for a classic antidepressant drug?

PubMed

Di Rosso, María Emilia; Palumbo, María Laura; Genaro, Ana María

2016-07-01

Selective serotonin reuptake inhibitors are frequently used antidepressants. In particular, fluoxetine is usually chosen for the treatment of the symptoms of depression, obsessive-compulsive, panic attack and bulimia nervosa. Antidepressant therapy has been associated with immune dysfunction. However, there is contradictory evidence about the effect of fluoxetine on the immune system. Experimental findings indicate that lymphocytes express the serotonin transporter. Moreover it has been shown that fluoxetine is able to modulate the immune function through a serotonin-dependent pathway and through a novel independent mechanism. In addition, several studies have shown that fluoxetine can alter tumor cell viability. Thus, it was recently demonstrated in vivo that chronic fluoxetine treatment inhibits tumor growth by increasing antitumor T-cell activity. Here we briefly review some of the literature referring to how fluoxetine is able to modify, for better or worse, the functionality of the immune system. These results of our analysis point to the relevance of the novel pharmacological action of this drug as an immunomodulator helping to treat several pathologies in which immune deficiency and/or deregulation is present. Copyright © 2015 Elsevier Ltd. All rights reserved.

Neuroestrogen signaling in the songbird auditory cortex propagates into a sensorimotor network via an `interface' nucleus

PubMed Central

Pawlisch, Benjamin A.; Remage-Healey, Luke

2014-01-01

Neuromodulators rapidly alter activity of neural circuits and can therefore shape higher-order functions, such as sensorimotor integration. Increasing evidence suggests that brain-derived estrogens, such as 17-β-estradiol, can act rapidly to modulate sensory processing. However, less is known about how rapid estrogen signaling can impact downstream circuits. Past studies have demonstrated that estradiol levels increase within the songbird auditory cortex (the caudomedial nidopallium, NCM) during social interactions. Local estradiol signaling enhances the auditory-evoked firing rate of neurons in NCM to a variety of stimuli, while also enhancing the selectivity of auditory-evoked responses of neurons in a downstream sensorimotor brain region, HVC (proper name). Since these two brain regions are not directly connected, we employed dual extracellular recordings in HVC and the upstream nucleus interfacialis of the nidopallium (NIf) during manipulations of estradiol within NCM to better understand the pathway by which estradiol signaling propagates to downstream circuits. NIf has direct input into HVC, passing auditory information into the vocal motor output pathway, and is a possible source of the neural selectivity within HVC. Here, during acute estradiol administration in NCM, NIf neurons showed increases in baseline firing rates and auditory-evoked firing rates to all stimuli. Furthermore, when estradiol synthesis was blocked in NCM, we observed simultaneous decreases in the selectivity of NIf and HVC neurons. These effects were not due to direct estradiol actions because NIf has little to no capability for local estrogen synthesis or estrogen receptors, and these effects were specific to NIf because other neurons immediately surrounding NIf did not show these changes. Our results demonstrate that transsynaptic, rapid fluctuations in neuroestrogens are transmitted into NIf and subsequently HVC, both regions important for sensorimotor integration. Overall, these findings support the hypothesis that acute neurosteroid actions can propagate within and between neural circuits to modulate their functional connectivity. PMID:25453773

The 5HT(1A) receptor ligand, S15535, antagonises G-protein activation: a [35S]GTPgammaS and [3H]S15535 autoradiography study.

PubMed

Newman-Tancredi, A; Rivet, J; Chaput, C; Touzard, M; Verrièle, L; Millan, M J

1999-11-19

4-(Benzodioxan-5-yl)1-(indan-2-yl)piperazine (S15535) is a highly selective ligand at 5-HT(1A) receptors. The present study compared its autoradiographic labelling of rat brain sections with its functional actions, visualised by guanylyl-5'-[gamma-thio]-triphosphate ([35S]GTPgammaS) autoradiography, which affords a measure of G-protein activation. [3H]S15535 binding was highest in hippocampus, frontal cortex, entorhinal cortex, lateral septum, interpeduncular nucleus and dorsal raphe, consistent with specific labelling of 5-HT(1A) receptors. In functional studies, S15535 (10 microM) did not markedly stimulate G-protein activation in any brain region, but abolished the activation induced by the selective 5-HT(1A) agonist, (+)-8-hydroxy-dipropyl-aminotetralin ((+)-8-OH-DPAT, 1 microM), in structures enriched in [3H]S15535 labelling. S15535 did not block 5-HT-stimulated activation in caudate nucleus or substantia nigra, regions where (+)-8-OH-DPAT was ineffective and [3H]S15535 binding was absent. Interestingly, S15535 attenuated (+)-8-OH-DPAT and 5-HT-stimulated G-protein activation in dorsal raphe, a region in which S15535 is known to exhibit agonist properties in vivo [Lejeune, F., Millan, M.J., 1998. Induction of burst firing in ventral tegmental area dopaminergic neurons by activation of serotonin (5-HT)(1A) receptors: WAY100,635-reversible actions of the highly selective ligands, flesinoxan and S15535. Synapse 30, 172-180.]. The present data show that (i) [3H]S15535 labels pre- and post-synaptic populations of 5-HT(1A) sites in rat brain sections, (ii) S15535 exhibits antagonist properties at post-synaptic 5-HT(1A) receptors in corticolimbic regions, and (iii) S15535 also attenuates agonist-stimulated G-protein activation at raphe-localised 5-HT(1A) receptors.

Neuroestrogen signaling in the songbird auditory cortex propagates into a sensorimotor network via an 'interface' nucleus.

PubMed

Pawlisch, B A; Remage-Healey, L

2015-01-22

Neuromodulators rapidly alter activity of neural circuits and can therefore shape higher order functions, such as sensorimotor integration. Increasing evidence suggests that brain-derived estrogens, such as 17-β-estradiol, can act rapidly to modulate sensory processing. However, less is known about how rapid estrogen signaling can impact downstream circuits. Past studies have demonstrated that estradiol levels increase within the songbird auditory cortex (the caudomedial nidopallium, NCM) during social interactions. Local estradiol signaling enhances the auditory-evoked firing rate of neurons in NCM to a variety of stimuli, while also enhancing the selectivity of auditory-evoked responses of neurons in a downstream sensorimotor brain region, HVC (proper name). Since these two brain regions are not directly connected, we employed dual extracellular recordings in HVC and the upstream nucleus interfacialis of the nidopallium (NIf) during manipulations of estradiol within NCM to better understand the pathway by which estradiol signaling propagates to downstream circuits. NIf has direct input into HVC, passing auditory information into the vocal motor output pathway, and is a possible source of the neural selectivity within HVC. Here, during acute estradiol administration in NCM, NIf neurons showed increases in baseline firing rates and auditory-evoked firing rates to all stimuli. Furthermore, when estradiol synthesis was blocked in NCM, we observed simultaneous decreases in the selectivity of NIf and HVC neurons. These effects were not due to direct estradiol actions because NIf has little to no capability for local estrogen synthesis or estrogen receptors, and these effects were specific to NIf because other neurons immediately surrounding NIf did not show these changes. Our results demonstrate that transsynaptic, rapid fluctuations in neuroestrogens are transmitted into NIf and subsequently HVC, both regions important for sensorimotor integration. Overall, these findings support the hypothesis that acute neurosteroid actions can propagate within and between neural circuits to modulate their functional connectivity. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Rethinking 'rational imitation' in 14-month-old infants: a perceptual distraction approach.

PubMed

Beisert, Miriam; Zmyj, Norbert; Liepelt, Roman; Jung, Franziska; Prinz, Wolfgang; Daum, Moritz M

2012-01-01

In their widely noticed study, Gergely, Bekkering, and Király (2002) showed that 14-month-old infants imitated an unusual action only if the model freely chose to perform this action and not if the choice of the action could be ascribed to external constraints. They attributed this kind of selective imitation to the infants' capacity of understanding the principle of rational action. In the current paper, we present evidence that a simpler approach of perceptual distraction may be more appropriate to explain their results. When we manipulated the saliency of context stimuli in the two original conditions, the results were exactly opposite to what rational imitation predicts. Based on these findings, we reject the claim that the notion of rational action plays a key role in selective imitation in 14-month-olds.

Selective regulation of YB-1 mRNA translation by the mTOR signaling pathway is not mediated by 4E-binding protein.

PubMed

Lyabin, D N; Ovchinnikov, L P

2016-03-02

The Y-box binding protein 1 (YB-1) is a key regulator of gene expression at the level of both translation and transcription. The mode of its action on cellular events depends on its subcellular distribution and the amount in the cell. So far, the regulatory mechanisms of YB-1 synthesis have not been adequately studied. Our previous finding was that selective inhibition of YB-1 mRNA translation was caused by suppression of activity of the mTOR signaling pathway. It was suggested that this event may be mediated by phosphorylation of the 4E-binding protein (4E-BP). Here, we report that 4E-BP alone can only slightly inhibit YB-1 synthesis both in the cell and in vitro, although it essentially decreases binding of the 4F-group translation initiation factors to mRNA. With inhibited mTOR kinase, the level of mRNA binding to the eIF4F-group factors was decreased, while that to 4E-BP1 was increased, as was observed for both mTOR kinase-sensitive mRNAs and those showing low sensitivity. This suggests that selective inhibition of translation of YB-1 mRNA, and probably some other mRNAs as well, by mTOR kinase inhibitors is not mediated by the action of the 4E-binding protein upon functions of the 4F-group translation initiation factors.

Assays for the biochemical and ultrastructural measurement of selective and nonselective types of autophagy in the yeast Saccharomyces cerevisiae.

PubMed

Guimaraes, Rodrigo Soares; Delorme-Axford, Elizabeth; Klionsky, Daniel J; Reggiori, Fulvio

2015-03-01

Autophagy is a conserved intracellular catabolic pathway that degrades unnecessary or dysfunctional cellular components. Components destined for degradation are sequestered into double-membrane vesicles called autophagosomes, which subsequently fuse with the vacuole/lysosome delivering their cargo into the interior of this organelle for turnover. Autophagosomes are generated through the concerted action of the autophagy-related (Atg) proteins. The yeast Saccharomyces cerevisiae has been key in the identification of the corresponding genes and their characterization, and it remains one of the leading model systems for the investigation of the molecular mechanism and functions of autophagy. In particular, it is still pivotal for the study of selective types of autophagy. The objective of this review is to present detailed protocols of the methods available to monitor the progression of both nonselective and selective types of autophagy, and to discuss their advantages and disadvantages. The ultimate aim is to provide researchers with the information necessary to select the optimal approach to address their biological question. Copyright © 2014 Elsevier Inc. All rights reserved.

Rhodium metalloinsertor binding generates a lesion with selective cytotoxicity for mismatch repair-deficient cells.

PubMed

Bailis, Julie M; Weidmann, Alyson G; Mariano, Natalie F; Barton, Jacqueline K

2017-07-03

The DNA mismatch repair (MMR) pathway recognizes and repairs errors in base pairing and acts to maintain genome stability. Cancers that have lost MMR function are common and comprise an important clinical subtype that is resistant to many standard of care chemotherapeutics such as cisplatin. We have identified a family of rhodium metalloinsertors that bind DNA mismatches with high specificity and are preferentially cytotoxic to MMR-deficient cells. Here, we characterize the cellular mechanism of action of the most potent and selective complex in this family, [Rh(chrysi)(phen)(PPO)] 2+ (Rh-PPO). We find that Rh-PPO binding induces a lesion that triggers the DNA damage response (DDR). DDR activation results in cell-cycle blockade and inhibition of DNA replication and transcription. Significantly, the lesion induced by Rh-PPO is not repaired in MMR-deficient cells, resulting in selective cytotoxicity. The Rh-PPO mechanism is reminiscent of DNA repair enzymes that displace mismatched bases, and is differentiated from other DNA-targeted chemotherapeutics such as cisplatin by its potency, cellular mechanism, and selectivity for MMR-deficient cells.

Brain training with non-action video games enhances aspects of cognition in older adults: a randomized controlled trial.

PubMed

Ballesteros, Soledad; Prieto, Antonio; Mayas, Julia; Toril, Pilar; Pita, Carmen; Ponce de León, Laura; Reales, José M; Waterworth, John

2014-01-01

Age-related cognitive and brain declines can result in functional deterioration in many cognitive domains, dependency, and dementia. A major goal of aging research is to investigate methods that help to maintain brain health, cognition, independent living and wellbeing in older adults. This randomized controlled study investigated the effects of 20 1-h non-action video game training sessions with games selected from a commercially available package (Lumosity) on a series of age-declined cognitive functions and subjective wellbeing. Two groups of healthy older adults participated in the study, the experimental group who received the training and the control group who attended three meetings with the research team along the study. Groups were similar at baseline on demographics, vocabulary, global cognition, and depression status. All participants were assessed individually before and after the intervention, or a similar period of time, using neuropsychological tests and laboratory tasks to investigate possible transfer effects. The results showed significant improvements in the trained group, and no variation in the control group, in processing speed (choice reaction time), attention (reduction of distraction and increase of alertness), immediate and delayed visual recognition memory, as well as a trend to improve in Affection and Assertivity, two dimensions of the Wellbeing Scale. Visuospatial working memory (WM) and executive control (shifting strategy) did not improve. Overall, the current results support the idea that training healthy older adults with non-action video games will enhance some cognitive abilities but not others.

Brain training with non-action video games enhances aspects of cognition in older adults: a randomized controlled trial

PubMed Central

Ballesteros, Soledad; Prieto, Antonio; Mayas, Julia; Toril, Pilar; Pita, Carmen; Ponce de León, Laura; Reales, José M.; Waterworth, John

2014-01-01

Age-related cognitive and brain declines can result in functional deterioration in many cognitive domains, dependency, and dementia. A major goal of aging research is to investigate methods that help to maintain brain health, cognition, independent living and wellbeing in older adults. This randomized controlled study investigated the effects of 20 1-h non-action video game training sessions with games selected from a commercially available package (Lumosity) on a series of age-declined cognitive functions and subjective wellbeing. Two groups of healthy older adults participated in the study, the experimental group who received the training and the control group who attended three meetings with the research team along the study. Groups were similar at baseline on demographics, vocabulary, global cognition, and depression status. All participants were assessed individually before and after the intervention, or a similar period of time, using neuropsychological tests and laboratory tasks to investigate possible transfer effects. The results showed significant improvements in the trained group, and no variation in the control group, in processing speed (choice reaction time), attention (reduction of distraction and increase of alertness), immediate and delayed visual recognition memory, as well as a trend to improve in Affection and Assertivity, two dimensions of the Wellbeing Scale. Visuospatial working memory (WM) and executive control (shifting strategy) did not improve. Overall, the current results support the idea that training healthy older adults with non-action video games will enhance some cognitive abilities but not others. PMID:25352805

Scopolamine rapidly increases mTORC1 signaling, synaptogenesis, and antidepressant behavioral responses

PubMed Central

Voleti, Bhavya; Navarria, Andrea; Liu, Rong-Jian; Banasr, Mounira; Li, Nanxin; Terwilliger, Rose; Sanacora, Gerard; Eid, Tore; Aghajanian, George; Duman, Ronald S.

2013-01-01

Background Clinical studies report that scopolamine, an acetylcholine muscarinic receptor antagonist, produces rapid antidepressant effects in depressed patients, but the mechanisms underlying the therapeutic response have not been determined. The present study examines the role of the mammalian target of rapamycin complex 1 (mTORC1) and synaptogenesis, which have been implicated in the rapid actions of NMDA receptor antagonists. Methods The influence of scopolamine on mTORC1 signaling was determined by analysis of the phosphorylated and activated forms of mTORC1 signaling proteins in the prefrontal cortex (PFC). The numbers and function of spine synapses were analyzed by whole cell patch clamp recording and 2-photon image analysis of PFC neurons. The actions of scopolamine were examined in the forced swim test in the absence or presence of selective mTORC1 and AMPA receptor inhibitors. Results The results demonstrate that a single, low dose of scopolamine rapidly increases mTORC1 signaling and the number and function of spine synapses in layer V pyramidal neurons in the PFC. Scopolamine administration also produces an antidepressant response in the forced swim test that is blocked by pretreatment with the mTORC1 inhibitor or by a glutamate AMPA receptor antagonist. Conclusions Taken together, the results demonstrate that the antidepressant actions of scopolamine require mTORC1 signaling and are associated with increased glutamate transmission, and synaptogenesis, similar to NMDA receptor antagonists. These findings provide novel targets for safer and more efficacious rapid acting antidepressant agents. PMID:23751205

Concurrent activation of striatal direct and indirect pathways during action initiation.

PubMed

Cui, Guohong; Jun, Sang Beom; Jin, Xin; Pham, Michael D; Vogel, Steven S; Lovinger, David M; Costa, Rui M

2013-02-14

The basal ganglia are subcortical nuclei that control voluntary actions, and they are affected by a number of debilitating neurological disorders. The prevailing model of basal ganglia function proposes that two orthogonal projection circuits originating from distinct populations of spiny projection neurons (SPNs) in the striatum--the so-called direct and indirect pathways--have opposing effects on movement: activity of direct-pathway SPNs is thought to facilitate movement, whereas activity of indirect-pathway SPNs is presumed to inhibit movement. This model has been difficult to test owing to the lack of methods to selectively measure the activity of direct- and indirect-pathway SPNs in freely moving animals. Here we develop a novel in vivo method to specifically measure direct- and indirect-pathway SPN activity, using Cre-dependent viral expression of the genetically encoded calcium indicator (GECI) GCaMP3 in the dorsal striatum of D1-Cre (direct-pathway-specific) and A2A-Cre (indirect-pathway-specific) mice. Using fibre optics and time-correlated single-photon counting (TCSPC) in mice performing an operant task, we observed transient increases in neural activity in both direct- and indirect-pathway SPNs when animals initiated actions, but not when they were inactive. Concurrent activation of SPNs from both pathways in one hemisphere preceded the initiation of contraversive movements and predicted the occurrence of specific movements within 500 ms. These observations challenge the classical view of basal ganglia function and may have implications for understanding the origin of motor symptoms in basal ganglia disorders.

Impaired theory of mind for moral judgment in high-functioning autism.

PubMed

Moran, Joseph M; Young, Liane L; Saxe, Rebecca; Lee, Su Mei; O'Young, Daniel; Mavros, Penelope L; Gabrieli, John D

2011-02-15

High-functioning autism (ASD) is characterized by real-life difficulties in social interaction; however, these individuals often succeed on laboratory tests that require an understanding of another person's beliefs and intentions. This paradox suggests a theory of mind (ToM) deficit in adults with ASD that has yet to be demonstrated in an experimental task eliciting ToM judgments. We tested whether ASD adults would show atypical moral judgments when they need to consider both the intentions (based on ToM) and outcomes of a person's actions. In experiment 1, ASD and neurotypical (NT) participants performed a ToM task designed to test false belief understanding. In experiment 2, the same ASD participants and a new group of NT participants judged the moral permissibility of actions, in a 2 (intention: neutral/negative) × 2 (outcome: neutral/negative) design. Though there was no difference between groups on the false belief task, there was a selective difference in the moral judgment task for judgments of accidental harms, but not neutral acts, attempted harms, or intentional harms. Unlike the NT group, which judged accidental harms less morally wrong than attempted harms, the ASD group did not reliably judge accidental and attempted harms as morally different. In judging accidental harms, ASD participants appeared to show an underreliance on information about a person's innocent intention and, as a direct result, an overreliance on the action's negative outcome. These findings reveal impairments in integrating mental state information (e.g., beliefs, intentions) for moral judgment.

The Effect of Approach/Avoidance Training on Alcohol Consumption Is Mediated by Change in Alcohol Action Tendency

PubMed Central

Sharbanee, Jason M.; Hu, Litje; Stritzke, Werner G. K.; Wiers, Reinout W.; Rinck, Mike; MacLeod, Colin

2014-01-01

Training people to respond to alcohol images by making avoidance joystick movements can affect subsequent alcohol consumption, and has shown initial efficacy as a treatment adjunct. However, the mechanisms that underlie the training’s efficacy are unknown. The present study aimed to determine 1) whether the training’s effect is mediated by a change in action tendency or a change in selective attention, and 2) whether the training’s effect is moderated by individual differences in working memory capacity (WMC). Three groups of social drinkers (total N = 74) completed either approach-alcohol training, avoid-alcohol training or a sham-training on the Approach-Avoidance Task (AAT). Participants’ WMC was assessed prior to training, while their alcohol-related action tendency and selective attention were assessed before and after the training on the recently developed Selective-Attention/Action Tendency Task (SA/ATT), before finally completing an alcohol taste-test. There was no significant main effect of approach/avoidance training on alcohol consumption during the taste-test. However, there was a significant indirect effect of training on alcohol consumption mediated by a change in action tendency, but no indirect effect mediated by a change in selective attention. There was inconsistent evidence of WMC moderating training efficacy, with moderation found only for the effect of approach-alcohol training on the AAT but not on the SA/ATT. Thus approach/avoidance training affects alcohol consumption specifically by changing the underlying action tendency. Multiple training sessions may be required in order to observe more substantive changes in drinking behaviour. PMID:24465750

Selective redox regulation of cytokine receptor signaling by extracellular thioredoxin-1

PubMed Central

Schwertassek, Ulla; Balmer, Yves; Gutscher, Marcus; Weingarten, Lars; Preuss, Marc; Engelhard, Johanna; Winkler, Monique; Dick, Tobias P

2007-01-01

The thiol-disulfide oxidoreductase thioredoxin-1 (Trx1) is known to be secreted by leukocytes and to exhibit cytokine-like properties. Extracellular effects of Trx1 require a functional active site, suggesting a redox-based mechanism of action. However, specific cell surface proteins and pathways coupling extracellular Trx1 redox activity to cellular responses have not been identified so far. Using a mechanism-based kinetic trapping technique to identify disulfide exchange interactions on the intact surface of living lymphocytes, we found that Trx1 catalytically interacts with a single principal target protein. This target protein was identified as the tumor necrosis factor receptor superfamily member 8 (TNFRSF8/CD30). We demonstrate that the redox interaction is highly specific for both Trx1 and CD30 and that the redox state of CD30 determines its ability to engage the cognate ligand and transduce signals. Furthermore, we confirm that Trx1 affects CD30-dependent changes in lymphocyte effector function. Thus, we conclude that receptor–ligand signaling interactions can be selectively regulated by an extracellular redox catalyst. PMID:17557078

The control of voluntary eye movements: new perspectives.

PubMed

Krauzlis, Richard J

2005-04-01

Primates use two types of voluntary eye movements to track objects of interest: pursuit and saccades. Traditionally, these two eye movements have been viewed as distinct systems that are driven automatically by low-level visual inputs. However, two sets of findings argue for a new perspective on the control of voluntary eye movements. First, recent experiments have shown that pursuit and saccades are not controlled by entirely different neural pathways but are controlled by similar networks of cortical and subcortical regions and, in some cases, by the same neurons. Second, pursuit and saccades are not automatic responses to retinal inputs but are regulated by a process of target selection that involves a basic form of decision making. The selection process itself is guided by a variety of complex processes, including attention, perception, memory, and expectation. Together, these findings indicate that pursuit and saccades share a similar functional architecture. These points of similarity may hold the key for understanding how neural circuits negotiate the links between the many higher order functions that can influence behavior and the singular and coordinated motor actions that follow.

Activation and desensitization of ionotropic glutamate receptors by selectively triggering pre-existing motions.

PubMed

Krieger, James; Lee, Ji Young; Greger, Ingo H; Bahar, Ivet

2018-02-23

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are key players in synaptic transmission and plasticity. They are composed of four subunits, each containing four functional domains, the quaternary packing and collective structural dynamics of which are important determinants of their molecular mechanism of function. With the explosion of structural studies on different members of the family, including the structures of activated open channels, the mechanisms of action of these central signaling machines are now being elucidated. We review the current state of computational studies on two major members of the family, AMPA and NMDA receptors, with focus on molecular simulations and elastic network model analyses that have provided insights into the coupled movements of extracellular and transmembrane domains. We describe the newly emerging mechanisms of activation, allosteric signaling and desensitization, as mainly a selective triggering of pre-existing soft motions, as deduced from computational models and analyses that leverage structural data on intact AMPA and NMDA receptors in different states. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Integrating computational and chemical biology tools in the discovery of antiangiogenic small molecule ligands of FGF2 derived from endogenous inhibitors

PubMed Central

Foglieni, Chiara; Pagano, Katiuscia; Lessi, Marco; Bugatti, Antonella; Moroni, Elisabetta; Pinessi, Denise; Resovi, Andrea; Ribatti, Domenico; Bertini, Sabrina; Ragona, Laura; Bellina, Fabio; Rusnati, Marco; Colombo, Giorgio; Taraboletti, Giulia

2016-01-01

The FGFs/FGFRs system is a recognized actionable target for therapeutic approaches aimed at inhibiting tumor growth, angiogenesis, metastasis, and resistance to therapy. We previously identified a non-peptidic compound (SM27) that retains the structural and functional properties of the FGF2-binding sequence of thrombospondin-1 (TSP-1), a major endogenous inhibitor of angiogenesis. Here we identified new small molecule inhibitors of FGF2 based on the initial lead. A similarity-based screening of small molecule libraries, followed by docking calculations and experimental studies, allowed selecting 7 bi-naphthalenic compounds that bound FGF2 inhibiting its binding to both heparan sulfate proteoglycans and FGFR-1. The compounds inhibit FGF2 activity in in vitro and ex vivo models of angiogenesis, with improved potency over SM27. Comparative analysis of the selected hits, complemented by NMR and biochemical analysis of 4 newly synthesized functionalized phenylamino-substituted naphthalenes, allowed identifying the minimal stereochemical requirements to improve the design of naphthalene sulfonates as FGF2 inhibitors. PMID:27000667

The functional organization of preschool-age children's emotion expressions and actions in challenging situations.

PubMed

Dennis, Tracy A; Cole, Pamela M; Wiggins, Crystal N; Cohen, Laura H; Zalewski, Maureen

2009-08-01

Although functional links between emotion and action are implied in emotion regulation research, there is limited evidence that specific adaptive actions for coping with a challenge are more probable when certain negative emotions are expressed. The current study examined this question among 3- and 4-year-olds (N = 113; M age = 47.84 months, SD = 6.19). Emotion expressions and actions were observed during 2 challenging tasks: children waited for a gift while the mother worked, and children worked alone to retrieve a prize from a locked box with the wrong key. Angry and happy expressions, compared with sad expressions, were associated with more actions. These actions varied with the nature of the task, reflecting appreciation of situational appropriateness. In addition, when waiting with the mother, happiness was associated with the broadest range of actions, whereas when working alone on the locked box, anger was associated with the broadest range of actions. Results are discussed in terms of the adaptive function of negative emotions and in terms of functional and dimensional models of emotion. Findings have implications for the development of emotion regulation and social-emotional competence. 2009 APA, all rights reserved.

The Functional Organization of Preschool-Age Children’s Emotion Expressions and Actions in Challenging Situations

PubMed Central

Dennis, Tracy A.; Cole, Pamela M.; Wiggins, Crystal N.; Cohen, Laura H.; Zalewski, Maureen

2010-01-01

Although functional links between emotion and action are implied in emotion regulation research, there is limited evidence that specific adaptive actions for coping with a challenge are more probable when certain negative emotions are expressed. The current study examined this question among 3- and 4-year-olds (N = 113; M age = 47.84 months, SD = 6.19). Emotion expressions and actions were observed during 2 challenging tasks: children waited for a gift while the mother worked, and children worked alone to retrieve a prize from a locked box with the wrong key. Angry and happy expressions, compared with sad expressions, were associated with more actions. These actions varied with the nature of the task, reflecting appreciation of situational appropriateness. In addition, when waiting with the mother, happiness was associated with the broadest range of actions, whereas when working alone on the locked box, anger was associated with the broadest range of actions. Results are discussed in terms of the adaptive function of negative emotions and in terms of functional and dimensional models of emotion. Findings have implications for the development of emotion regulation and social–emotional competence. PMID:19653775

A Biologically Plausible Action Selection System for Cognitive Architectures: Implications of Basal Ganglia Anatomy for Learning and Decision-Making Models

ERIC Educational Resources Information Center

Stocco, Andrea

2018-01-01

Several attempts have been made previously to provide a biological grounding for cognitive architectures by relating their components to the computations of specific brain circuits. Often, the architecture's action selection system is identified with the basal ganglia. However, this identification overlooks one of the most important features of…

A Comprehensive Evaluation of OEO Community Action Programs on Six Selected American Indian Reservations. Report 4 - Final Report.

ERIC Educational Resources Information Center

Smith, James G. E.; And Others

The impact of the Office of Economic Opportunity (OEO) Community Action Programs (CAP) on 6 selected American Indian reservations (Gila River and Papago, Arizona; Santa Clara Pueblo, New Mexico; Pine Ridge, South Dakota; Turtle Mountain, North Dakota, and White Earth Chippewa, Minnesota) are evaluated. After considering the development of Indian…

Temperament and arousal systems: A new synthesis of differential psychology and functional neurochemistry.

PubMed

Trofimova, Irina; Robbins, Trevor W

2016-05-01

This paper critically reviews the unidimensional construct of General Arousal as utilised by models of temperament in differential psychology for example, to underlie 'Extraversion'. Evidence suggests that specialization within monoamine neurotransmitter systems contrasts with the attribution of a "general arousal" of the Ascending Reticular Activating System. Experimental findings show specialized roles of noradrenaline, dopamine, and serotonin systems in hypothetically mediating three complementary forms of arousal that are similar to three functional blocks described in classical models of behaviour within kinesiology, clinical neuropsychology, psychophysiology and temperament research. In spite of functional diversity of monoamine receptors, we suggest that their functionality can be classified using three universal aspects of actions related to expansion, to selection-integration and to maintenance of chosen behavioural alternatives. Monoamine systems also differentially regulate analytic vs. routine aspects of activities at cortical and striatal neural levels. A convergence between main temperament models in terms of traits related to described functional aspects of behavioural arousal also supports the idea of differentiation between these aspects analysed here in a functional perspective. Copyright © 2016 Elsevier Ltd. All rights reserved.