Spinal Cord Stimulation in Chronic Pain: Mode of Action.

PubMed

Vallejo, Ricardo; Bradley, Kerry; Kapural, Leonardo

2017-07-15

Literature review. A review of the literature that presents a perspective on mechanisms of actions behind spinal cord stimulation (SCS) therapy for chronic pain. SCS is an effective therapeutic alternative for the treatment of intractable chronic pain. Its application has been mostly based on the gate control theory of pain. Computational models have been fundamental on the understanding of clinical observations and the design of therapies that provide optimal neuromodulation. Research has provided insight into the involvement of specific neurotransmitters that support segmental and supraspinal mechanisms of action. A literature review was performed with emphasis on mechanisms of action for SCS including the effects of electrical fields on spinal cord structures based on computational models and preclinical and clinical explorations. This review provides background on the development of SCS, which has been driven around a paresthesia-based paradigm as a result of the gate control theory. A review of computational models emphasizes their importance on our current understanding of the mechanism of action and clinical optimization of therapy. Electrophysiology and molecular biology have provided a closer, yet narrow, view of the effect of SCS on neurotransmitters and their receptors, which have led to the formulation of segmental and supraspinal mechanisms. Literature supporting the involvement of glial cells in chronic pain and their characteristic response to electrical fields should motivate further investigation of mechanisms involving neuroglia. Finally, a review of recent results paresthesia-free strategies should encourage research on mechanisms of action. The mechanisms of SCS have been extensively studied and several consistent phenomena have emerged. The activation of A-beta fibers to induce paresthesia also involve neurotransmitter release via segmental and supraspinal pathways. Despite advancements, much remains to be understood, particularly as new stimulation strategies are developed. N /A.

Mirror neurons and their clinical relevance.

PubMed

Rizzolatti, Giacomo; Fabbri-Destro, Maddalena; Cattaneo, Luigi

2009-01-01

One of the most exciting events in neurosciences over the past few years has been the discovery of a mechanism that unifies action perception and action execution. The essence of this 'mirror' mechanism is as follows: whenever individuals observe an action being done by someone else, a set of neurons that code for that action is activated in the observers' motor system. Since the observers are aware of the outcome of their motor acts, they also understand what the other individual is doing without the need for intermediate cognitive mediation. In this Review, after discussing the most pertinent data concerning the mirror mechanism, we examine the clinical relevance of this mechanism. We first discuss the relationship between mirror mechanism impairment and some core symptoms of autism. We then outline the theoretical principles of neurorehabilitation strategies based on the mirror mechanism. We conclude by examining the relationship between the mirror mechanism and some features of the environmental dependency syndromes.

Therapeutic Hypothermia: Critical Review of the Molecular Mechanisms of Action

PubMed Central

González-Ibarra, Fernando Pavel; Varon, Joseph; López-Meza, Elmer G.

2010-01-01

Therapeutic hypothermia (TH) is nowadays one of the most important methods of neuroprotection. The events that occur after an episode of ischemia are multiple and hypothermia can affect the various steps of this cascade. The mechanisms of action of TH are varied and the possible explanation for the benefits of this therapy is probably the multiple mechanisms of action blocking the cascade of ischemia on many levels. TH can affect many metabolic pathways, reactions of inflammation, apoptosis processes, and promote neuronal integrity. To know the mechanisms of action of TH will allow a better understanding about the indications for this therapy and the possibility of searching for other therapies when used in conjunction with hypothermia will provide a therapeutic synergistic effect. PMID:21331282

Captured by motion: dance, action understanding, and social cognition.

PubMed

Sevdalis, Vassilis; Keller, Peter E

2011-11-01

In this review article, we summarize the main findings from empirical studies that used dance-related forms of rhythmical full body movement as a research tool for investigating action understanding and social cognition. This work has proven to be informative about behavioral and brain mechanisms that mediate links between perceptual and motor processes invoked during the observation and execution of spatially-temporally coordinated action and interpersonal interaction. The review focuses specifically on processes related to (a) motor experience and expertise, (b) learning and memory, (c) action, intention, and emotion understanding, and (d) audio-visual synchrony and timing. Consideration is given to the relationship between research on dance and more general embodied cognition accounts of action understanding and social cognition. Finally, open questions and issues concerning experimental design are discussed with a view to stimulating future research on social-cognitive aspects of dance. Copyright © 2011 Elsevier Inc. All rights reserved.

The mirror mechanism in the parietal lobe.

PubMed

Rizzolatti, Giacomo; Rozzi, Stefano

2018-01-01

The mirror mechanism is a basic mechanism that transforms sensory representations of others' actions into motor representations of the same actions in the brain of the observer. The mirror mechanism plays an important role in understanding actions of others. In the present chapter we discuss first the basic organization of the posterior parietal lobe in the monkey, stressing that it is best characterized as a motor scaffold, on the top of which sensory information is organized. We then describe the location of the mirror mechanism in the posterior parietal cortex of the monkey, and its functional role in areas PFG, and anterior, ventral, and lateral intraparietal areas. We will then present evidence that a similar functional organization is present in humans. We will conclude by discussing the role of the mirror mechanism in the recognition of action performed with tools. Copyright © 2018 Elsevier B.V. All rights reserved.

What do we (not) know about how paracetamol (acetaminophen) works?

PubMed

Toussaint, K; Yang, X C; Zielinski, M A; Reigle, K L; Sacavage, S D; Nagar, S; Raffa, R B

2010-12-01

Although paracetamol (acetaminophen), N-(4-Hydroxyphenyl)acetamide, is one of the world's most widely used analgesics, the mechanism by which it produces its analgesic effect is largely unknown. This lack is relevant because: (i) optimal pain treatment matches the analgesic mechanism to the (patho)physiology of the pain and (ii) modern drug discovery relies on an appropriate screening assay. To review the clinical profile and preclinical studies of paracetamol as means of gaining insight into its mechanism of analgesic action. A literature search was conducted of clinical and preclinical literature and the information obtained was organized and reviewed from the perspective of its contribution to an understanding of the mechanism of analgesic action of paracetamol. Paracetamol's broad spectrum of analgesic and other pharmacological actions is presented, along with its multiple postulated mechanism(s) of action. No one mechanism has been definitively shown to account for its analgesic activity. Further research is needed to uncover the mechanism of analgesic action of paracetamol. The lack of this knowledge affects optimal clinical use and impedes drug discovery efforts. © 2010 The Authors. JCPT © 2010 Blackwell Publishing Ltd.

New concepts in antimalarial use and mode of action in dermatology.

PubMed

Kalia, Sunil; Dutz, Jan P

2007-01-01

Although chloroquine, hydroxychloroquine and quinacrine were originally developed for the treatment of malaria, these medications have been used to treat skin disease for over 50 years. Recent clinical data have confirmed the usefulness of these medications for the treatment of lupus erythematosus. Current research has further enhanced our understanding of the pharmacologic mechanisms of action of these drugs involving inhibition of endosomal toll-like receptor (TLR) signaling limiting B cell and dendritic cell activation. With this understanding, the use of these medications in dermatology is broadening. This article highlights the different antimalarials used within dermatology through their pharmacologic properties and mechanism of action, as well as indicating their clinical uses. In addition, contraindications, adverse effects, and possible drug interactions of antimalarials are reviewed.

Predictive gaze during observation of irrational actions in adults with autism spectrum conditions.

PubMed

Marsh, L E; Pearson, A; Ropar, D; Hamilton, A F de C

2015-01-01

Understanding irrational actions may require the observer to make mental state inferences about why an action was performed. Individuals with autism spectrum conditions (ASC) have well documented difficulties with mentalizing; however, the degree to which rationality understanding is impaired in autism is not yet clear. The present study uses eye-tracking to measure online understanding of action rationality in individuals with ASC. Twenty adults with ASC and 20 typically developing controls, matched for age and IQ watched movies of rational and irrational actions while their eye movements were recorded. Measures of looking time, scan path and saccade latency were calculated. Results from looking time and scan path analyses demonstrate that participants with ASC have reduced visual attention to salient action features such as the action goal and the hand performing the action, regardless of action rationality. However, when participants with ASC do attend to these features, they are able to make anticipatory goal saccades as quickly as typically developing controls. Taken together these results indicate that individuals with autism have reduced attention to observed actions, but when attention is maintained, goal prediction is typical. We conclude that the basic mechanisms of action understanding are intact in individuals with ASC although there may be impairment in the top-down, social modulation of eye movements.

Producing and understanding prosocial actions in early childhood.

PubMed

Paulus, Markus; Moore, Chris

2012-01-01

Early prosocial development has become a topic of great interest in recent years as experimental studies have provided evidence that instances of prosocial action can already be found in the second year of life. In this contribution, we review the recent literature on young children's production of prosocial actions, in particular helping, sharing, and comforting, and their understanding of others' prosocial behavior. We summarize the novel insights gained by recent studies and point to directions for future studies. Overall, we suggest that while the field consists of considerable knowledge about the developmental timeline of prosocial behavior, more research is needed to examine and better understand underlying social-cognitive mechanisms.

The mirror neuron system: grasping others' actions from birth?

PubMed

Lepage, Jean-François; Théoret, Hugo

2007-09-01

In the adult human brain, the presence of a system matching the observation and the execution of actions is well established. This mechanism is thought to rely primarily on the contribution of so-called 'mirror neurons', cells that are active when a specific gesture is executed as well as when it is seen or heard. Despite the wealth of evidence detailing the existence of a mirror neuron system (MNS) in the adult brain, little is known about its normal development. Yet, a better understanding of the MNS in infants would be of considerable theoretical and clinical interest, as dysfunctions within the MNS have been demonstrated in neurodevelopmental disorders such as autism spectrum disorder. Arguments in favor of an innate, or very early, mechanism underlying action understanding mainly come from studies of neonatal imitation, the existence of which has been questioned by some. Here, we review evidence suggesting the presence of an MNS in the human child, as well as work that suggests, although indirectly, the existence of a mechanism matching the perception and the execution of actions in the human newborn.

Exploring perceptual processing of ASL and human actions: Effects of inversion and repetition priming

PubMed Central

Corina, David P.; Grosvald, Michael

2011-01-01

In this paper, we compare responses of deaf signers and hearing non-signers engaged in a categorization task of signs and non-linguistic human actions. We examine the time it takes to make such categorizations under conditions of 180-degree stimulus inversion and as a function of repetition priming, in an effort to understand whether the processing of sign language forms draws upon special processing mechanisms or makes use of mechanisms used in recognition of non-linguistic human actions. Our data show that deaf signers were much faster in the categorization of both linguistic and non-linguistic actions, and relative to hearing non-signers, show evidence that they were more sensitive to the configural properties of signs. Our study suggests that sign expertise may lead to modifications of a general-purpose human action recognition system rather than evoking a qualitatively different mode of processing, and supports the contention that signed languages make use of perceptual systems through which humans understand or parse human actions and gestures more generally. PMID:22153323

Understanding the role of mirror neurons in action understanding will require more than a domain-general account.

PubMed

Martin, Alia; Santos, Laurie R

2014-04-01

Cook et al. propose that mirror neurons emerge developmentally through a domain-general associative mechanism. We argue that experience-sensitivity does not rule out an adaptive or genetic argument for mirror neuron function, and that current evidence suggests that mirror neurons are more specialized than the authors' account would predict. We propose that future work integrate behavioral and neurophysiological techniques used with primates to examine the proposed functions of mirror neurons in action understanding.

Habit in Personality and Social Psychology.

PubMed

Wood, Wendy

2017-11-01

Habits are largely absent from modern social and personality psychology. This is due to outdated perspectives that placed habits in conflict with goals. In modern theorizing, habits are represented in memory as implicit context-response associations, and they guide responding in conjunction with goals. Habits thus have important implications for our field. Emerging research shows that habits are an important mechanism by which people self-regulate and achieve long-term goals. Also, habits change through specific interventions, such as changes in context cues. I speculate that understanding of habits also holds promise for reducing intergroup discrimination and for understanding lay theories of the causes for action. In short, by recognizing habit, the field gains understanding of a central mechanism by which actions persist in daily life.

Action simulation: time course and representational mechanisms

PubMed Central

Springer, Anne; Parkinson, Jim; Prinz, Wolfgang

2013-01-01

The notion of action simulation refers to the ability to re-enact foreign actions (i.e., actions observed in other individuals). Simulating others' actions implies a mirroring of their activities, based on one's own sensorimotor competencies. Here, we discuss theoretical and experimental approaches to action simulation and the study of its representational underpinnings. One focus of our discussion is on the timing of internal simulation and its relation to the timing of external action, and a paradigm that requires participants to predict the future course of actions that are temporarily occluded from view. We address transitions between perceptual mechanisms (referring to action representation before and after occlusion) and simulation mechanisms (referring to action representation during occlusion). Findings suggest that action simulation runs in real-time; acting on newly created action representations rather than relying on continuous visual extrapolations. A further focus of our discussion pertains to the functional characteristics of the mechanisms involved in predicting other people's actions. We propose that two processes are engaged, dynamic updating and static matching, which may draw on both semantic and motor information. In a concluding section, we discuss these findings in the context of broader theoretical issues related to action and event representation, arguing that a detailed functional analysis of action simulation in cognitive, neural, and computational terms may help to further advance our understanding of action cognition and motor control. PMID:23847563

Translating Knowledge into Action: Supporting Adaptation in Australia's Coastal Zone through Information Provision and Decision Support

NASA Astrophysics Data System (ADS)

Palutikof, J. P.; Rissik, D.; Tonmoy, F. N.; Boulter, S.

2015-12-01

Adaptation to risks from climate change and sea-level rise is particularly important in Australia, where 70% of the population live in major coastal cities and 85% within 50km of the coast. Adaptation activity focuses at local government level and, in the absence of strong leadership from central government, the extent to which local councils have taken action to adapt is highly variable across the nation. Also, although a number of councils have proceeded as far as identifying their exposure to risk and considering adaptation options, this fails to translate into action. A principal reason for this is concern over the response from coastal residents to actions which may affect property values, and fear of litigation. A project is underway to support councils to understand their risks, evaluate adaptation options and proceed to action. This support will consist of a three-pronged framework: provision of information, a tool to support decision-making, and a community forum. Delivery involves research to understand the barriers to adaptation and how these may be overcome, optimal methods for delivery of information, and the information needs of organizations, action-takers and communities. The presentation will focus on the results of consultation undertaken to understand users' information needs around content and delivery, and how understanding of these needs has translated into design of the framework. A strongly preference was expressed to learn from peers, and a challenge for the framework is to understand how to inject adaptation knowledge which is up-to-date and accurate into peer-to-peer conversations. The community forum is one mechanism to achieve this. The basic structure and delivery mechanisms of the framework are shown in the attached.

A Functional Model of the Digital Extensor Mechanism: Demonstrating Biomechanics with Hair Bands

ERIC Educational Resources Information Center

Cloud, Beth A.; Youdas, James W.; Hellyer, Nathan J.; Krause, David A.

2010-01-01

The action of muscles about joints can be explained through analysis of their spatial relationship. A functional model of these relationships can be valuable in learning and understanding the muscular action about a joint. A model can be particularly helpful when examining complex actions across multiple joints such as in the digital extensor…

Action Mechanisms for Social Cognition: Behavioral and Neural Correlates of Developing Theory of Mind

ERIC Educational Resources Information Center

Bowman, Lindsay C.; Thorpe, Samuel G.; Cannon, Erin N.; Fox, Nathan A.

2017-01-01

Many psychological theories posit foundational links between two fundamental constructs: (1) our ability to produce, perceive, and represent action; and (2) our ability to understand the meaning and motivation behind the action (i.e. Theory of Mind; ToM). This position is contentious, however, and long-standing competing theories of…

The Potential of Leptin for Treating Diabetes and Its Mechanism of Action

PubMed Central

Coppari, Roberto; Bjørbæk, Christian

2014-01-01

Following the discovery of leptin in 1994, major research efforts have brought us much closer to a fuller understanding of the cellular and molecular mechanisms underlying the biological effects of the hormone. Interestingly, leptin exerts potent anti-diabetic actions that are independent of its effects on body weight and food intake. In particular, leptin can correct diabetes in animal models of either diabetes mellitus type 1 (T1DM) or type 2 (T2DM). In addition, long-term leptin-replacement therapy is well tolerated and dramatically improves glycemic control, insulin sensitivity, and plasma triglycerides in patients with severe insulin resistance due to lipodystrophy. Together, these results have spurred enthusiasm for the use of leptin therapy to treat humans suffering from diabetes mellitus. Here, we review current understandings of these glucoregulatory functions of leptin, with particular emphasis on its central mechanisms of action, lessons from clinical studies and discuss possible therapeutic applications of leptin in the treatment of T1DM and T2DM. PMID:22935803

The role and mechanism of action of menthol in topical analgesic products.

PubMed

Pergolizzi, J V; Taylor, R; LeQuang, J-A; Raffa, R B

2018-06-01

Menthol has been used as a non-opioid pain reliever since ancient times. A modern understanding of its molecular mechanism of action could form the basis for generating targets for discovery of novel non-opioid analgesic drugs. The PubMed database was queried using search words related to menthol, pain and analgesia. The results were limited to relevant preclinical studies and clinical trials and reviews published in English during the past 5 years, which yielded 31 reports. The bibliographies of these articles were sources of additional supporting articles. Menthol is a selective activator of transient receptor potential melastatin-8 (TRPM8) channels and is also a vasoactive compound. As a topical agent, it acts as a counter-irritant by imparting a cooling effect and by initially stimulating nociceptors and then desensitizing them. Topically applied menthol may also activate central analgesic pathways. At high concentrations, menthol may generate cold allodynia. Recent elucidation of TRPM8 channels has provided a molecular basis for understanding the molecular action of menthol and its ability to produce both a cooling sensation and reduction in pain associated with a wide variety of pain(ful) conditions. The more modern mechanistic understanding of menthol and its pharmacologic mechanism of action may lead to an expanded role for this substance in the search for replacements for opioid analgesics, particularly those that can be applied topically. © 2018 John Wiley & Sons Ltd.

Neural associative memories for the integration of language, vision and action in an autonomous agent.

PubMed

Markert, H; Kaufmann, U; Kara Kayikci, Z; Palm, G

2009-03-01

Language understanding is a long-standing problem in computer science. However, the human brain is capable of processing complex languages with seemingly no difficulties. This paper shows a model for language understanding using biologically plausible neural networks composed of associative memories. The model is able to deal with ambiguities on the single word and grammatical level. The language system is embedded into a robot in order to demonstrate the correct semantical understanding of the input sentences by letting the robot perform corresponding actions. For that purpose, a simple neural action planning system has been combined with neural networks for visual object recognition and visual attention control mechanisms.

Toxicity of 13 different antibiotics towards freshwater green algae Pseudokirchneriella subcapitata and their modes of action.

PubMed

Fu, Ling; Huang, Tao; Wang, Shuo; Wang, Xiaohong; Su, Limin; Li, Chao; Zhao, Yuanhui

2017-02-01

Although modes of action (MOAs) play a key role in the understanding of the toxic mechanism of chemicals, the MOAs have not been investigated for antibiotics to green algae. This paper is to discriminate excess toxicity from baseline level and investigate the MOAs of 13 different antibiotics to algae by using the determined toxicity values. Comparison of the toxicities shows that the inhibitors of protein synthesis to bacteria, such as azithromycin, doxycycline, florfenicol and oxytetracycline, exhibit significantly toxic effects to algae. On the other hand, the cell wall synthesis inhibitors, such as cefotaxime and amoxicillin, show relatively low toxic effects to the algae. The concentrations determined by HPLC indicate that quinocetone and amoxicillin can be easily photodegraded or hydrolyzed during the toxic tests. The toxic effects of quinocetone and amoxicillin to the algae are attributed to not only their parent compounds, but also their metabolites. Investigation on the mode of action shows that, except rifampicin, all the tested antibiotics exhibit excess toxicity to Pseudokirchneriella subcapitata (P. subcapitata). These antibiotics can be identified as reactive modes of action to the algae. They act as electrophilic mechanism of action to P. subcapitata. These results are valuable for the understanding of the toxic mechanism to algae. Copyright © 2016 Elsevier Ltd. All rights reserved.

Understanding the Electrical Behavior of the Action Potential in Terms of Elementary Electrical Sources

ERIC Educational Resources Information Center

Rodriguez-Falces, Javier

2015-01-01

A concept of major importance in human electrophysiology studies is the process by which activation of an excitable cell results in a rapid rise and fall of the electrical membrane potential, the so-called action potential. Hodgkin and Huxley proposed a model to explain the ionic mechanisms underlying the formation of action potentials. However,…

Thyroid Hormone Availability and Action during Brain Development in Rodents.

PubMed

Bárez-López, Soledad; Guadaño-Ferraz, Ana

2017-01-01

Thyroid hormones (THs) play an essential role in the development of all vertebrates; in particular adequate TH content is crucial for proper neurodevelopment. TH availability and action in the brain are precisely regulated by several mechanisms, including the secretion of THs by the thyroid gland, the transport of THs to the brain and neural cells, THs activation and inactivation by the metabolic enzymes deiodinases and, in the fetus, transplacental passage of maternal THs. Although these mechanisms have been extensively studied in rats, in the last decade, models of genetically modified mice have been more frequently used to understand the role of the main proteins involved in TH signaling in health and disease. Despite this, there is little knowledge about the mechanisms underlying THs availability in the mouse brain. This mini-review article gathers information from findings in rats, and the latest findings in mice regarding the ontogeny of TH action and the sources of THs to the brain, with special focus on neurodevelopmental stages. Unraveling TH economy and action in the mouse brain may help to better understand the physiology and pathophysiology of TH signaling in brain and may contribute to addressing the neurological alterations due to hypo and hyperthyroidism and TH resistance syndromes.

From Theory-Inspired to Theory-Based Interventions: A Protocol for Developing and Testing a Methodology for Linking Behaviour Change Techniques to Theoretical Mechanisms of Action.

PubMed

Michie, Susan; Carey, Rachel N; Johnston, Marie; Rothman, Alexander J; de Bruin, Marijn; Kelly, Michael P; Connell, Lauren E

2018-05-18

Understanding links between behaviour change techniques (BCTs) and mechanisms of action (the processes through which they affect behaviour) helps inform the systematic development of behaviour change interventions. This research aims to develop and test a methodology for linking BCTs to their mechanisms of action. Study 1 (published explicit links): Hypothesised links between 93 BCTs (from the 93-item BCT taxonomy, BCTTv1) and mechanisms of action will be identified from published interventions and their frequency, explicitness and precision documented. Study 2 (expert-agreed explicit links): Behaviour change experts will identify links between 61 BCTs and 26 mechanisms of action in a formal consensus study. Study 3 (integrated matrix of explicit links): Agreement between studies 1 and 2 will be evaluated and a new group of experts will discuss discrepancies. An integrated matrix of BCT-mechanism of action links, annotated to indicate strength of evidence, will be generated. Study 4 (published implicit links): To determine whether groups of co-occurring BCTs can be linked to theories, we will identify groups of BCTs that are used together from the study 1 literature. A consensus exercise will be used to rate strength of links between groups of BCT and theories. A formal methodology for linking BCTs to their hypothesised mechanisms of action can contribute to the development and evaluation of behaviour change interventions. This research is a step towards developing a behaviour change 'ontology', specifying relations between BCTs, mechanisms of action, modes of delivery, populations, settings and types of behaviour.

The buzz on caffeine in invertebrates: effects on behavior and molecular mechanisms

PubMed Central

Mustard, Julie A.

2014-01-01

A number of recent studies from as diverse fields as plant-pollinator interactions, analyses of caffeine as an environmental pollutant, and the ability of caffeine to provide protection against neurodegenerative diseases have generated interest in understanding the actions of caffeine in invertebrates. This review summarizes what is currently known about the effects of caffeine on behavior and its molecular mechanisms in invertebrates. Caffeine appears to have similar effects on locomotion and sleep in both invertebrates and mammals. Furthermore, as in mammals, caffeine appears to have complex effects on learning and memory. However, the underlying mechanisms for these effects may differ between invertebrates and vertebrates. While caffeine’s ability to cause release of intracellular calcium stores via ryanodine receptors and its actions as a phosphodiesterase inhibitor have been clearly established in invertebrates, its ability to interact with invertebrate adenosine receptors remains an important open question. Initial studies in insects and mollusks suggest an interaction between caffeine and the dopamine signaling pathway; more work needs to be done to understand the mechanisms by which caffeine influences signaling via biogenic amines. As of yet, little is known about whether other actions of caffeine in vertebrates, such as its effects on GABAA and glycine receptors, are conserved. Furthermore, the pharmacokinetics of caffeine remains to be elucidated. Overall behavioral responses to caffeine appear to be conserved amongst organisms; however, we are just beginning to understand the mechanisms underlying its effects across animal phyla. PMID:24162934

The buzz on caffeine in invertebrates: effects on behavior and molecular mechanisms.

PubMed

Mustard, Julie A

2014-04-01

A number of recent studies from as diverse fields as plant-pollinator interactions, analyses of caffeine as an environmental pollutant, and the ability of caffeine to provide protection against neurodegenerative diseases have generated interest in understanding the actions of caffeine in invertebrates. This review summarizes what is currently known about the effects of caffeine on behavior and its molecular mechanisms in invertebrates. Caffeine appears to have similar effects on locomotion and sleep in both invertebrates and mammals. Furthermore, as in mammals, caffeine appears to have complex effects on learning and memory. However, the underlying mechanisms for these effects may differ between invertebrates and vertebrates. While caffeine's ability to cause release of intracellular calcium stores via ryanodine receptors and its actions as a phosphodiesterase inhibitor have been clearly established in invertebrates, its ability to interact with invertebrate adenosine receptors remains an important open question. Initial studies in insects and mollusks suggest an interaction between caffeine and the dopamine signaling pathway; more work needs to be done to understand the mechanisms by which caffeine influences signaling via biogenic amines. As of yet, little is known about whether other actions of caffeine in vertebrates, such as its effects on GABAA and glycine receptors, are conserved. Furthermore, the pharmacokinetics of caffeine remains to be elucidated. Overall behavioral responses to caffeine appear to be conserved amongst organisms; however, we are just beginning to understand the mechanisms underlying its effects across animal phyla.

Utilizing toxicogenomic data to understand chemical mechanism of action in risk assessment

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

Wilson, Vickie S., E-mail: wilson.vickie@epa.gov; Keshava, Nagalakshmi; Hester, Susan

2013-09-15

The predominant role of toxicogenomic data in risk assessment, thus far, has been one of augmentation of more traditional in vitro and in vivo toxicology data. This article focuses on the current available examples of instances where toxicogenomic data has been evaluated in human health risk assessment (e.g., acetochlor and arsenicals) which have been limited to the application of toxicogenomic data to inform mechanism of action. This article reviews the regulatory policy backdrop and highlights important efforts to ultimately achieve regulatory acceptance. A number of research efforts on specific chemicals that were designed for risk assessment purposes have employed mechanismmore » or mode of action hypothesis testing and generating strategies. The strides made by large scale efforts to utilize toxicogenomic data in screening, testing, and risk assessment are also discussed. These efforts include both the refinement of methodologies for performing toxicogenomics studies and analysis of the resultant data sets. The current issues limiting the application of toxicogenomics to define mode or mechanism of action in risk assessment are discussed together with interrelated research needs. In summary, as chemical risk assessment moves away from a single mechanism of action approach toward a toxicity pathway-based paradigm, we envision that toxicogenomic data from multiple technologies (e.g., proteomics, metabolomics, transcriptomics, supportive RT-PCR studies) can be used in conjunction with one another to understand the complexities of multiple, and possibly interacting, pathways affected by chemicals which will impact human health risk assessment.« less

Colchicine--Update on mechanisms of action and therapeutic uses.

PubMed

Leung, Ying Ying; Yao Hui, Laura Li; Kraus, Virginia B

2015-12-01

To review the literature and provide an update on the mechanisms of action and therapeutic uses of oral colchicine in arthritis and inflammatory conditions. We performed PubMed database searches through June 2014 for relevant studies in the English literature published since the last update of colchicine in 2008. Searches encompassed colchicine mechanisms of action and clinical applications in medical conditions. A total of 381 articles were reviewed. The primary mechanism of action of colchicine is tubulin disruption. This leads to subsequent down regulation of multiple inflammatory pathways and modulation of innate immunity. Newly described mechanisms include various inhibitory effects on macrophages including the inhibition of the NACHT-LRRPYD-containing protein 3 (NALP3) inflammasome, inhibition of pore formation activated by purinergic receptors P2X7 and P2X2, and stimulation of dendritic cell maturation and antigen presentation. Colchicine also has anti-fibrotic activities and various effects on endothelial function. The therapeutic use of colchicine has extended beyond gouty arthritis and familial Mediterranean fever, to osteoarthritis, pericarditis, and atherosclerosis. Further understanding of the mechanisms of action underlying the therapeutic efficacy of colchicine will lead to its potential use in a variety of conditions. Copyright © 2015 Elsevier Inc. All rights reserved.

Neuroanatomical substrates of action perception and understanding: an anatomic likelihood estimation meta-analysis of lesion-symptom mapping studies in brain injured patients

PubMed Central

Urgesi, Cosimo; Candidi, Matteo; Avenanti, Alessio

2014-01-01

Several neurophysiologic and neuroimaging studies suggested that motor and perceptual systems are tightly linked along a continuum rather than providing segregated mechanisms supporting different functions. Using correlational approaches, these studies demonstrated that action observation activates not only visual but also motor brain regions. On the other hand, brain stimulation and brain lesion evidence allows tackling the critical question of whether our action representations are necessary to perceive and understand others’ actions. In particular, recent neuropsychological studies have shown that patients with temporal, parietal, and frontal lesions exhibit a number of possible deficits in the visual perception and the understanding of others’ actions. The specific anatomical substrates of such neuropsychological deficits however, are still a matter of debate. Here we review the existing literature on this issue and perform an anatomic likelihood estimation meta-analysis of studies using lesion-symptom mapping methods on the causal relation between brain lesions and non-linguistic action perception and understanding deficits. The meta-analysis encompassed data from 361 patients tested in 11 studies and identified regions in the inferior frontal cortex, the inferior parietal cortex and the middle/superior temporal cortex, whose damage is consistently associated with poor performance in action perception and understanding tasks across studies. Interestingly, these areas correspond to the three nodes of the action observation network that are strongly activated in response to visual action perception in neuroimaging research and that have been targeted in previous brain stimulation studies. Thus, brain lesion mapping research provides converging causal evidence that premotor, parietal and temporal regions play a crucial role in action recognition and understanding. PMID:24910603

Revealing chemical processes and kinetics of drug action within single living cells via plasmonic Raman probes.

PubMed

Li, Shan-Shan; Guan, Qi-Yuan; Meng, Gang; Chang, Xiao-Feng; Wei, Ji-Wu; Wang, Peng; Kang, Bin; Xu, Jing-Juan; Chen, Hong-Yuan

2017-05-23

Better understanding the drug action within cells may extend our knowledge on drug action mechanisms and promote new drugs discovery. Herein, we studied the processes of drug induced chemical changes on proteins and nucleic acids in human breast adenocarcinoma (MCF-7) cells via time-resolved plasmonic-enhanced Raman spectroscopy (PERS) in combination with principal component analysis (PCA). Using three popular chemotherapy drugs (fluorouracil, cisplatin and camptothecin) as models, chemical changes during drug action process were clearly discriminated. Reaction kinetics related to protein denaturation, conformational modification, DNA damage and their associated biomolecular events were calculated. Through rate constants and reaction delay times, the different action modes of these drugs could be distinguished. These results may provide vital insights into understanding the chemical reactions associated with drug-cell interactions.

Understanding and Self-Organization.

PubMed

Newton, Natika W

2017-01-01

How do we manage to understand a completely novel state of affairs, such as the sudden effects of an unexpected earthquake, or the arrival of a total stranger instead of the sister we were waiting for? In each case, for a moment we might be stunned, but we are able quite quickly to fit these events into our overall framework for understanding the world. However, terrified and despairing we feel, we know what earthquakes are and this event fits that schema; in the case of the stranger we know that this kind of thing happens, and that we must ask the stranger "Who are you, and where is my sister?" This paper asks about the mechanisms by which we rapidly achieve an understanding of our world, both the unexpected changes we may experience, and the ongoing comfortable familiarity we normally have with our surroundings. We attempt a solution by means of examining fundamental questions: What is it to understand something?What sorts of things do we try to understand?Is there a conscious EXPERIENCE of understanding?Does understanding involve conscious mental images?What is self-organization? I will argue that these questions revolve around the need of a living organism to take action, and that understanding anything involves knowing how we might act relative to that thing in our environment. The experience of understanding is a feeling that the action affordances of a situation are clear and available. Action (as opposed to reaction) includes imagery, particularly motor imagery, which can be used in the guidance of action. Understanding requires a conscious process involving motor imagery of action affordances, and action can be understood only in self-organizational terms. I explain how self-organization can ground the kinds of action affordance experience needed for conscious understanding. The paper concludes that our day-to-day understanding of our environment is the result of a self-organizing process.

Synthesis, Properties, and Mechanism of Action of New Generation of Polycyclic Glycopeptide Antibiotics.

PubMed

Olsufyeva, Eugenia N; Tevyashova, Anna N

2017-01-01

The increased resistance of glycopeptide based antibiotics has become a serious problem for the chemotherapy of infections triggered by resistant Gram-positive bacteria. This has motivated the urgent sincere efforts to develop potent glycopeptide-based antibiotics in both academy and industry research laboratories. Understanding of the mechanism of action of natural and modified glycopeptides is considered as the basis for the rational design of compounds with valuable properties to achieve the fundamental results. Several hydrophobic glycopeptide analogues active against resistant strains were developed during the last two decades. Three drugs, namely, oritavancin, telavancin and dalbavancin were approved by FDA in 2013-2014. It was found that hydrophobic derivatives act through different mechanisms without binding with the modified target of resistant bacteria. Types: Different types of chemical modifications led to several glycopeptide analogues active against Gram-negative bacteria as advocated by in vitro studies or demonstrating potent antiviral activity in the cell models. A new class of glycopeptide antibiotics with potent activity against sensitive and resistant bacterial strains has been recently reported with the aim to overcome the resistance, however, there are a lot of obscure problems in the complete understanding of their mechanisms of actions. In this review, we summarized the achievements of synthetic methods devoted to the construction of new polycyclic glycopeptide antibiotics and described the studies related to their mechanism of actions. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Antihypertensive drugs.

PubMed

Laurent, Stéphane

2017-10-01

Successful treatment of hypertension is possible with limited side effects given the availability of multiple antihypertensive drug classes. This review describes the various pharmacological classes of antihypertensive drugs, under two major aspects: their mechanisms of action and side effects. The mechanism of action is analysed through a pharmacological approach, i.e. the molecular receptor targets, the various sites along the arterial system, and the extra-arterial sites of action, in order to better understand in which type of hypertension a given pharmacological class of antihypertensive drug is most indicated. In addition, side effects are described and explained through their pharmacological mechanisms, in order to better understand their mechanism of occurrence and in which patients drugs are contra-indicated. This review does not address the effectiveness of monotherapies in large randomized clinical trials and combination therapies, since these are the matters of other articles of the present issue. Five major pharmacological classes of antihypertensive drugs are detailed here: beta-blockers, diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, and calcium channel blockers. Four additional pharmacological classes are described in a shorter manner: renin inhibitors, alpha-adrenergic receptor blockers, centrally acting agents, and direct acting vasodilators. Copyright © 2017. Published by Elsevier Ltd.

d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology.

PubMed

De Gregorio, Danilo; Comai, Stefano; Posa, Luca; Gobbi, Gabriella

2016-11-23

d-Lysergic Acid Diethylamide (LSD) is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles' reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD's mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT 2A receptor as a partial agonist and 5-HT 1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D₂, Trace Amine Associate receptor 1 (TAAR₁) and 5-HT 2A . More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD's effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA) mechanism or acting on TAAR₁ receptors.

d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology

PubMed Central

De Gregorio, Danilo; Comai, Stefano; Posa, Luca; Gobbi, Gabriella

2016-01-01

d-Lysergic Acid Diethylamide (LSD) is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles’ reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD’s mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT2A receptor as a partial agonist and 5-HT1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D2, Trace Amine Associate receptor 1 (TAAR1) and 5-HT2A. More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD’s effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA) mechanism or acting on TAAR1 receptors. PMID:27886063

Selenium and Anticarcinogenesis: Underlying Mechanisms

USDA-ARS?s Scientific Manuscript database

The manuscript discusses recent research related to anticarcinogenic mechanisms of selenium (Se) action in light of the underlying chemical/biochemical functions of the selenium species likely to be executors of those effects. Recent studies in a variety of model systems have increased understanding...

Motor cognition and its role in the phylogeny and ontogeny of action understanding.

PubMed

Gallese, Vittorio; Rochat, Magali; Cossu, Giuseppe; Sinigaglia, Corrado

2009-01-01

Social life rests in large part on the capacity to understand the intentions behind the behavior of others. What are the origins of this capacity? How is one to construe its development in ontogenesis? By assuming that action understanding can be explained only in terms of the ability to read the minds of others--that is, to represent mental states--the traditional view claims that a sharp discontinuity occurs in both phylogeny and ontogeny. Over the last few years this view has been challenged by a number of ethological and psychological studies, as well as by several neurophysiological findings. In particular, the functional properties of the mirror neuron system and its direct matching mechanism indicate that action understanding may be primarily based on the motor cognition that underpins one's own capacity to act. This article aims to elaborate and motivate the pivotal role of such motor cognition, providing a biologically plausible and theoretically unitary account for the phylogeny and ontogeny of action understanding and also its impairment, as in the case of autistic spectrum disorder.

Androgenic signaling systems and their role in behavioral evolution.

PubMed

Fuxjager, Matthew J; Schuppe, Eric R

2018-06-05

Sex steroids mediate the organization and activation of masculine reproductive phenotypes in diverse vertebrate taxa. However, the effects of sex steroid action in this context vary tremendously, in that steroid action influences reproductive physiology and behavior in markedly different ways (even among closely related species). This leads to the idea that the mechanisms underlying sex steroid action similarly differ across vertebrates in a manner that supports diversification of important sexual traits. Here, we highlight the Evolutionary Potential Hypothesis as a framework for understanding how androgen-dependent reproductive behavior evolves. This idea posits that the cellular mechanisms underlying androgenic action can independently evolve within a given target tissue to adjust the hormone's functional effects. The result is a seemingly endless number of permutations in androgenic signaling pathways that can be mapped onto the incredible diversity of reproductive phenotypes. One reason this hypothesis is important is because it shifts current thinking about the evolution of steroid-dependent traits away from an emphasis on circulating steroid levels and toward a focus on molecular mechanisms of hormone action. To this end, we also provide new empirical data suggesting that certain cellular modulators of androgen action-namely, the co-factors that dynamically adjust transcritpional effects of steroid action either up or down-are also substrates on which evolution can act. We then close the review with a detailed look at a case study in the golden-collared manakin (Manacus vitellinus). Work in this tropical bird shows how androgenic signaling systems are modified in specific parts of the skeletal muscle system to enhance motor performance necessary to produce acrobatic courtship displays. Altogether, this paper seeks to develop a platform to better understand how steroid action influences the evolution of complex animal behavior. Copyright © 2018 Elsevier Ltd. All rights reserved.

Development of a high-content screening assay panel to accelerate mechanism of action studies for oncology research.

PubMed

Towne, Danli L; Nicholl, Emily E; Comess, Kenneth M; Galasinski, Scott C; Hajduk, Philip J; Abraham, Vivek C

2012-09-01

Efficient elucidation of the biological mechanism of action of novel compounds remains a major bottleneck in the drug discovery process. To address this need in the area of oncology, we report the development of a multiparametric high-content screening assay panel at the level of single cells to dramatically accelerate understanding the mechanism of action of cell growth-inhibiting compounds on a large scale. Our approach is based on measuring 10 established end points associated with mitochondrial apoptosis, cell cycle disruption, DNA damage, and cellular morphological changes in the same experiment, across three multiparametric assays. The data from all of the measurements taken together are expected to help increase our current understanding of target protein functions, constrain the list of possible targets for compounds identified using phenotypic screens, and identify off-target effects. We have also developed novel data visualization and phenotypic classification approaches for detailed interpretation of individual compound effects and navigation of large collections of multiparametric cellular responses. We expect this general approach to be valuable for drug discovery across multiple therapeutic areas.

Do physico-chemical properties of silver nanoparticles decide their interaction with biological media and bactericidal action? A review.

PubMed

Pareek, Vikram; Gupta, Rinki; Panwar, Jitendra

2018-09-01

The unprecedented increase in antibiotic resistance in this era has resuscitated the attention of scientific community to exploit silver and its various species as antimicrobial agents. Plenty of studies have been done to measure the antimicrobial potential of silver species (cationic silver, metallic Ag 0 or silver nanoparticles, silver oxide particulates etc.) and indicated that membrane damage, oxidative stress, protein dysfunction and DNA damage to be the possible cause of injury to the microbial cell. However, the precise molecular mechanism of their mode of action has remained unclear, which makes an obstacle towards the generation of potential antibacterial agent against various pathogenic and multidrug resistant (MDR) bacteria. In order to endeavor this issue, one should first have the complete understanding about the resistance mechanisms present in bacteria that can be a therapeutic target for the silver-based drug formulations. Apart from this, in-depth understanding of the interactions of various silver species (with the biological media) is a probable deciding factor for the synthesis of silver-based drug formulations because the particular form and physico-chemical properties of silver can ultimately decide their antimicrobial action. In context to above mentioned serious concerns, the present article aims to discuss the mechanisms behind the confrontation of bacteria against various drugs and the effect of physico-chemical properties of silver species on their bactericidal action as well as critically evaluates the available reports on bacterial transcriptomic and proteomic profiles upon the exposure of various silver species. Further, this review state the mechanism of action that needs to be followed for the complete understanding of toxic potential of silver nanoparticles, which will open a possibility to synthesize new silver nanoparticle based antimicrobial systems with desired properties to ensure their safe use, exposure over extended period and fate in human body and environment. Copyright © 2018 Elsevier B.V. All rights reserved.

Language comprehension warps the mirror neuron system.

PubMed

Zarr, Noah; Ferguson, Ryan; Glenberg, Arthur M

2013-01-01

Is the mirror neuron system (MNS) used in language understanding? According to embodied accounts of language comprehension, understanding sentences describing actions makes use of neural mechanisms of action control, including the MNS. Consequently, repeatedly comprehending sentences describing similar actions should induce adaptation of the MNS thereby warping its use in other cognitive processes such as action recognition and prediction. To test this prediction, participants read blocks of multiple sentences where each sentence in the block described transfer of objects in a direction away or toward the reader. Following each block, adaptation was measured by having participants predict the end-point of videotaped actions. The adapting sentences disrupted prediction of actions in the same direction, but (a) only for videos of biological motion, and (b) only when the effector implied by the language (e.g., the hand) matched the videos. These findings are signatures of the MNS.

Language comprehension warps the mirror neuron system

PubMed Central

Zarr, Noah; Ferguson, Ryan; Glenberg, Arthur M.

2013-01-01

Is the mirror neuron system (MNS) used in language understanding? According to embodied accounts of language comprehension, understanding sentences describing actions makes use of neural mechanisms of action control, including the MNS. Consequently, repeatedly comprehending sentences describing similar actions should induce adaptation of the MNS thereby warping its use in other cognitive processes such as action recognition and prediction. To test this prediction, participants read blocks of multiple sentences where each sentence in the block described transfer of objects in a direction away or toward the reader. Following each block, adaptation was measured by having participants predict the end-point of videotaped actions. The adapting sentences disrupted prediction of actions in the same direction, but (a) only for videos of biological motion, and (b) only when the effector implied by the language (e.g., the hand) matched the videos. These findings are signatures of the MNS. PMID:24381553

Lather-Interior Systems Mechanic: Apprenticeship Course Outline. Apprenticeship and Industry Training. 1709

ERIC Educational Resources Information Center

Alberta Advanced Education and Technology, 2009

2009-01-01

The graduate of the Lather-Interior Systems Mechanic apprenticeship program is a certified journeyperson who will be able to: (1) know the characteristics and understand the actions and interactions of Lathing and Interior Systems Mechanic materials; (2) interpret plans and specifications and layout and develop projects accordingly; (3) calculate…

Visual adaptation dominates bimodal visual-motor action adaptation

PubMed Central

de la Rosa, Stephan; Ferstl, Ylva; Bülthoff, Heinrich H.

2016-01-01

A long standing debate revolves around the question whether visual action recognition primarily relies on visual or motor action information. Previous studies mainly examined the contribution of either visual or motor information to action recognition. Yet, the interaction of visual and motor action information is particularly important for understanding action recognition in social interactions, where humans often observe and execute actions at the same time. Here, we behaviourally examined the interaction of visual and motor action recognition processes when participants simultaneously observe and execute actions. We took advantage of behavioural action adaptation effects to investigate behavioural correlates of neural action recognition mechanisms. In line with previous results, we find that prolonged visual exposure (visual adaptation) and prolonged execution of the same action with closed eyes (non-visual motor adaptation) influence action recognition. However, when participants simultaneously adapted visually and motorically – akin to simultaneous execution and observation of actions in social interactions - adaptation effects were only modulated by visual but not motor adaptation. Action recognition, therefore, relies primarily on vision-based action recognition mechanisms in situations that require simultaneous action observation and execution, such as social interactions. The results suggest caution when associating social behaviour in social interactions with motor based information. PMID:27029781

Role for dopamine in the behavioral functions of the prefrontal corticostriatal system: implications for mental disorders and psychotropic drug action.

PubMed

Jentsch, J D; Roth, R H; Taylor, J R

2000-01-01

We have discussed the role of dopamine in modulating the interactions between cortical and striatal regions that are involved in behavioral regulation. The evidence reviewed seems to suggest that dopamine acts, overall, to promote stimulus-induced responding for conditioned or reward-related stimuli by integrative actions at multiple forebrain sites. It is thus not surprising that dopaminergic dysfunction has been implicated in a number of neuropsychiatric disorders that involve abnormal cognitive and affective function. Future studies aimed at pinpointing the precise anatomical sites of action and molecular mechanisms involved in dopaminergic transmission within the corticolimbic circuit are critical for trying to disentangle the cellular mechanisms by which dopamine exerts its actions. Moreover, the afferent control of dopamine neurons from brainstem and forebrain sites need to be fully explored in order to begin to understand what mechanisms are involved in regulating the dopaminergic response to stimuli with incentive value. Finally, the post-synaptic consequences of prolonged and supranormal dopaminergic activation need to be investigated in order to understand what persistent neuroadaptations result from chronic activation of this neuromodulatory system (e.g. in drug addiction). Answers to these sorts of questions will undoubtedly provide important insights into the nature of dopaminergic function in the animal and human brain.

Thyroid Hormone Availability and Action during Brain Development in Rodents

PubMed Central

Bárez-López, Soledad; Guadaño-Ferraz, Ana

2017-01-01

Thyroid hormones (THs) play an essential role in the development of all vertebrates; in particular adequate TH content is crucial for proper neurodevelopment. TH availability and action in the brain are precisely regulated by several mechanisms, including the secretion of THs by the thyroid gland, the transport of THs to the brain and neural cells, THs activation and inactivation by the metabolic enzymes deiodinases and, in the fetus, transplacental passage of maternal THs. Although these mechanisms have been extensively studied in rats, in the last decade, models of genetically modified mice have been more frequently used to understand the role of the main proteins involved in TH signaling in health and disease. Despite this, there is little knowledge about the mechanisms underlying THs availability in the mouse brain. This mini-review article gathers information from findings in rats, and the latest findings in mice regarding the ontogeny of TH action and the sources of THs to the brain, with special focus on neurodevelopmental stages. Unraveling TH economy and action in the mouse brain may help to better understand the physiology and pathophysiology of TH signaling in brain and may contribute to addressing the neurological alterations due to hypo and hyperthyroidism and TH resistance syndromes. PMID:28855863

On the Behavioral Side of Procrastination: Exploring Behavioral Delay in Real-Life Settings

PubMed Central

Svartdal, Frode; Granmo, Sjur; Færevaag, Fredrik S.

2018-01-01

This paper examines how procrastinators behave differently from non-procrastinators in implementing intended behavior. By focusing on time-related attributes of behavior, we demonstrate in five studies (aggregated N = 965) that onset delay seems to be a preferred option for procrastinators in common daily situations. Thus, when an action possibility is available for intended behavior, procrastinators tend to delay behavior onset, both in actual behavior and in onset preferences, often instigating chains of events with negative consequences. We discuss possible mechanisms responsible for such delays and explore how such mechanisms generate and sustain dilatory behavior. We conclude that a better understanding of why behavioral delays occur in early phases of action implementation is of importance in understanding and preventing procrastination. PMID:29867696

On the Behavioral Side of Procrastination: Exploring Behavioral Delay in Real-Life Settings.

PubMed

Svartdal, Frode; Granmo, Sjur; Færevaag, Fredrik S

2018-01-01

This paper examines how procrastinators behave differently from non-procrastinators in implementing intended behavior. By focusing on time-related attributes of behavior, we demonstrate in five studies (aggregated N = 965) that onset delay seems to be a preferred option for procrastinators in common daily situations. Thus, when an action possibility is available for intended behavior, procrastinators tend to delay behavior onset, both in actual behavior and in onset preferences, often instigating chains of events with negative consequences. We discuss possible mechanisms responsible for such delays and explore how such mechanisms generate and sustain dilatory behavior. We conclude that a better understanding of why behavioral delays occur in early phases of action implementation is of importance in understanding and preventing procrastination.

Cognitive underpinnings of social interaction.

PubMed

Hamilton, Antonia F de C

2015-01-01

Human social interaction is part of what defines us. Here I present an overview of recent studies of imitation, a subdomain of social interaction that can be dissected and examined in a scientific fashion. I use these studies to test two core claims: (a) that there is more than one copying mechanism in the human brain and (b) that mimicry (a form of copying) is particularly relevant for understanding social behaviour. Evidence in favour of the first claim comes from neuroimaging studies that show distinct brain systems for understanding action kinematics, action goals, and irrational actions. Further studies of participants with autism show abnormal copying of irrational actions. Evidence in favour of the second claim comes from behavioural studies of the social cues that prime mimicry and from neuroimaging studies of the pathways involved in this priming. These studies suggest that medial prefrontal cortex has a core role in controlling mimicry responses and support the STORM (social top-down response modulation) model. Future work should determine what organizing principles govern the control of social responses and how these critical mechanisms for interpersonal connection differ in autism.

Massage therapy: understanding the mechanisms of action on blood pressure. A scoping review.

PubMed

Nelson, Nicole L

2015-10-01

Massage therapy (MT) has shown potential in reducing blood pressure (BP); however, the psychophysiological pathways and structures involved in this outcome are unclear. The aims of this scoping review were twofold. (1) To summarize the current knowledge of the mechanisms of action of MT on BP. (2) To highlight the research gaps and challenges that researchers must overcome to further elucidate how MT attenuates BP. A scoping review was conducted to examine the evidence regarding the mechanisms of action of MT on BP. This review included the thematic analysis of 27 publications that considered the influence of MT on BP. Based on this analysis, six potential BP mediating pathways were identified Current theories suggest that MT exerts sympatholytic effects through physiologic and psychological mechanisms, improves hypothalamus-pituitary-adrenocortical axis function, and increases in blood flow, which, in turn, may improve endothelial function. Future study is needed, using more scientifically rigorous methodology, to fully elucidate the mechanism of action of MT. Copyright © 2015 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

Use of Primary Human Cell Systems for Creating Predictive Toxicology Profiles

EPA Science Inventory

Use of cellular regulatory networks to detect and distinguish effects of compounds with a broad range of on- and off-target mechanisms and biological processes provides an opportunity to understand toxicity mechanisms of action. Here we use the Biologically Multiplexed Activity P...

Observation and imitation of actions performed by humans, androids, and robots: an EMG study

PubMed Central

Hofree, Galit; Urgen, Burcu A.; Winkielman, Piotr; Saygin, Ayse P.

2015-01-01

Understanding others’ actions is essential for functioning in the physical and social world. In the past two decades research has shown that action perception involves the motor system, supporting theories that we understand others’ behavior via embodied motor simulation. Recently, empirical approach to action perception has been facilitated by using well-controlled artificial stimuli, such as robots. One broad question this approach can address is what aspects of similarity between the observer and the observed agent facilitate motor simulation. Since humans have evolved among other humans and animals, using artificial stimuli such as robots allows us to probe whether our social perceptual systems are specifically tuned to process other biological entities. In this study, we used humanoid robots with different degrees of human-likeness in appearance and motion along with electromyography (EMG) to measure muscle activity in participants’ arms while they either observed or imitated videos of three agents produce actions with their right arm. The agents were a Human (biological appearance and motion), a Robot (mechanical appearance and motion), and an Android (biological appearance and mechanical motion). Right arm muscle activity increased when participants imitated all agents. Increased muscle activation was found also in the stationary arm both during imitation and observation. Furthermore, muscle activity was sensitive to motion dynamics: activity was significantly stronger for imitation of the human than both mechanical agents. There was also a relationship between the dynamics of the muscle activity and motion dynamics in stimuli. Overall our data indicate that motor simulation is not limited to observation and imitation of agents with a biological appearance, but is also found for robots. However we also found sensitivity to human motion in the EMG responses. Combining data from multiple methods allows us to obtain a more complete picture of action understanding and the underlying neural computations. PMID:26150782

Structural pierce into molecular mechanism underlying Clostridium perfringens Epsilon toxin function.

PubMed

Khalili, Saeed; Jahangiri, Abolfazl; Hashemi, Zahra Sadat; Khalesi, Bahman; Mard-Soltani, Maysam; Amani, Jafar

2017-03-01

Epsilon toxin of the Clostridium perfringens garnered a lot of attention due to its potential for toxicity in humans, extreme potency for cytotoxicity in mice and lack of any approved therapeutics prescribed for human. However, the intricacies of the Epsilon toxin action mechanism are yet to be understood. In this regard, various in silico tools have been exploited to model and refine the 3D structure of the toxin and its two receptors. The receptor proteins were embedded into designed lipid membranes within an aqueous and ionized environment. Thereafter, the modeled structures subjected to series of consecutive molecular dynamics runs to achieve the most natural like coordination for each model. Ultimately, protein-protein interaction analyses were performed to understand the probable action mechanism. The obtained results successfully confirmed the accuracy of employed methods to achieve high quality models for the toxin and its receptors within their lipid bilayers. Molecular dynamics analyses lead the structures to a more native like coordination. Moreover, the results of previous empirical studies were confirmed, while new insights for action mechanisms including the detailed roles of Hepatitis A virus cellular receptor 1 (HAVCR1) and Myelin and lymphocyte protein (MAL) proteins were achieved. In light of previous and our observations, we suggested novel models which elucidated the existing interplay between potential players of Epsilon toxin action mechanism with detailed structural evidences. These models would pave the way to have more robust understanding of the Epsilon toxin biology, more precise vaccine construction and more successful drug (inhibitor) design. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neural mechanisms and models underlying joint action.

PubMed

Chersi, Fabian

2011-06-01

Humans, in particular, and to a lesser extent also other species of animals, possess the impressive capability of smoothly coordinating their actions with those of others. The great amount of work done in recent years in neuroscience has provided new insights into the processes involved in joint action, intention understanding, and task sharing. In particular, the discovery of mirror neurons, which fire both when animals execute actions and when they observe the same actions done by other individuals, has shed light on the intimate relationship between perception and action elucidating the direct contribution of motor knowledge to action understanding. Up to date, however, a detailed description of the neural processes involved in these phenomena is still mostly lacking. Building upon data from single neuron recordings in monkeys observing the actions of a demonstrator and then executing the same or a complementary action, this paper describes the functioning of a biologically constraint neural network model of the motor and mirror systems during joint action. In this model, motor sequences are encoded as independent neuronal chains that represent concatenations of elementary motor acts leading to a specific goal. Action execution and recognition are achieved through the propagation of activity within specific chains. Due to the dual property of mirror neurons, the same architecture is capable of smoothly integrating and switching between observed and self-generated action sequences, thus allowing to evaluate multiple hypotheses simultaneously, understand actions done by others, and to respond in an appropriate way.

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.

Action of microbial transglutaminase (MTGase) in the modification of food proteins: a review.

PubMed

Gaspar, Ana Luisa Camolezi; de Góes-Favoni, Silvana Pedroso

2015-03-15

Microbial transglutaminase (MTGase) is an enzyme of the class of transferases widely known to modify protein functional properties in food systems. The main mechanisms of action involved are polymerisations, which result in changes in the molecule's hydrophobicity. Among the functional properties, MTGase affects solubility and hence gelation, emulsification, foaming, viscosity and water-holding capacity, which all depend on protein solubility. Although the enzyme's benefits for protein functionality in a variety of food systems are widely reported in the literature, few studies have focussed on its mechanisms. The purpose of this review is therefore to investigate the mechanisms of action of MTGase and consider its influence on the functional properties with different protein substrates. Understanding these mechanisms is the first step in the development and application, in food production, of new and better functional properties with improved and/or innovative characteristics that can satisfy consumer expectations. Copyright © 2014 Elsevier Ltd. All rights reserved.

Unexpected Events Induce Motor Slowing via a Brain Mechanism for Action-Stopping with Global Suppressive Effects

PubMed Central

Aron, Adam R.

2013-01-01

When an unexpected event occurs in everyday life (e.g., a car honking), one experiences a slowing down of ongoing action (e.g., of walking into the street). Motor slowing following unexpected events is a ubiquitous phenomenon, both in laboratory experiments as well as such everyday situations, yet the underlying mechanism is unknown. We hypothesized that unexpected events recruit the same inhibition network in the brain as does complete cancellation of an action (i.e., action-stopping). Using electroencephalography and independent component analysis in humans, we show that a brain signature of successful outright action-stopping also exhibits activity following unexpected events, and more so in blocks with greater motor slowing. Further, using transcranial magnetic stimulation to measure corticospinal excitability, we show that an unexpected event has a global motor suppressive effect, just like outright action-stopping. Thus, unexpected events recruit a common mechanism with outright action-stopping, moreover with global suppressive effects. These findings imply that we can now leverage the considerable extant knowledge of the neural architecture and functional properties of the stopping system to better understand the processing of unexpected events, including perhaps how they induce distraction via global suppression. PMID:24259571

Understanding disease mechanisms with models of signaling pathway activities.

PubMed

Sebastian-Leon, Patricia; Vidal, Enrique; Minguez, Pablo; Conesa, Ana; Tarazona, Sonia; Amadoz, Alicia; Armero, Carmen; Salavert, Francisco; Vidal-Puig, Antonio; Montaner, David; Dopazo, Joaquín

2014-10-25

Understanding the aspects of the cell functionality that account for disease or drug action mechanisms is one of the main challenges in the analysis of genomic data and is on the basis of the future implementation of precision medicine. Here we propose a simple probabilistic model in which signaling pathways are separated into elementary sub-pathways or signal transmission circuits (which ultimately trigger cell functions) and then transforms gene expression measurements into probabilities of activation of such signal transmission circuits. Using this model, differential activation of such circuits between biological conditions can be estimated. Thus, circuit activation statuses can be interpreted as biomarkers that discriminate among the compared conditions. This type of mechanism-based biomarkers accounts for cell functional activities and can easily be associated to disease or drug action mechanisms. The accuracy of the proposed model is demonstrated with simulations and real datasets. The proposed model provides detailed information that enables the interpretation disease mechanisms as a consequence of the complex combinations of altered gene expression values. Moreover, it offers a framework for suggesting possible ways of therapeutic intervention in a pathologically perturbed system.

Essential Tremor: What We Can Learn from Current Pharmacotherapy.

PubMed

Ondo, William

2016-01-01

The pathophysiology of essential tremor, especially at the cellular level, is poorly understood. Although no drug has been specifically designed to treat essential tremor, several medications improve tremor, and others worsen it. Studying the mechanism of actions of these medications can help our understanding of tremor pathophysiology and contribute to future rational drug design. We reviewed literature, concentrating on mechanisms of action, of various medications that mitigate tremor. Many medications have multiple mechanisms of actions, making simple correlations difficult. Medications that increase the duration of opening of gamma-aminobutyric acid (GABA)-A receptors are most consistently associated with tremor improvement. Interestingly, drugs that increase GABA availability have not been associated with improved tremor. Other mechanisms possibly associated with tremor improvement include antagonism of alpha-2 delta subunits associated with calcium channels, inhibition of carbonic anhydrase, and inhibition of the synaptic vesicle protein 2A. Drugs that block voltage-gaited sodium channels do not affect tremor. The ideal beta-adrenergic blocker requires B2 affinity (non-cardiac selective), has no sympathomimetic properties, does not require membrane stabilization properties, and may benefit from good central nervous system penetration. To date, serendipitous observations have provided most of our understanding of tremor cellular physiology. Based on similarities to currently effective drugs or rational approximations and inferences, several currently available agents should be considered for tremor trials.

Determining the effects of ammonia on fathead minnow (Pimephales promelas) reproduction

EPA Science Inventory

Aquatic organisms are exposed to a multitude of contaminants and to fully understand the impact of multiple stressors on fish populations, we should first understand the mechanism of action for each toxicant and how the combined effects manifest at the level of the individual. Am...

Understanding communicative actions: a repetitive TMS study.

PubMed

Stolk, Arjen; Noordzij, Matthijs L; Volman, Inge; Verhagen, Lennart; Overeem, Sebastiaan; van Elswijk, Gijs; Bloem, Bas; Hagoort, Peter; Toni, Ivan

2014-02-01

Despite the ambiguity inherent in human communication, people are remarkably efficient in establishing mutual understanding. Studying how people communicate in novel settings provides a window into the mechanisms supporting the human competence to rapidly generate and understand novel shared symbols, a fundamental property of human communication. Previous work indicates that the right posterior superior temporal sulcus (pSTS) is involved when people understand the intended meaning of novel communicative actions. Here, we set out to test whether normal functioning of this cerebral structure is required for understanding novel communicative actions using inhibitory low-frequency repetitive transcranial magnetic stimulation (rTMS). A factorial experimental design contrasted two tightly matched stimulation sites (right pSTS vs left MT+, i.e., a contiguous homotopic task-relevant region) and tasks (a communicative task vs a visual tracking task that used the same sequences of stimuli). Overall task performance was not affected by rTMS, whereas changes in task performance over time were disrupted according to TMS site and task combinations. Namely, rTMS over pSTS led to a diminished ability to improve action understanding on the basis of recent communicative history, while rTMS over MT+ perturbed improvement in visual tracking over trials. These findings qualify the contributions of the right pSTS to human communicative abilities, showing that this region might be necessary for incorporating previous knowledge, accumulated during interactions with a communicative partner, to constrain the inferential process that leads to action understanding. Copyright © 2013 Elsevier Ltd. All rights reserved.

Mirror neurons and motor intentionality.

PubMed

Rizzolatti, Giacomo; Sinigaglia, Corrado

2007-01-01

Our social life rests to a large extent on our ability to understand the intentions of others. What are the bases of this ability? A very influential view is that we understand the intentions of others because we are able to represent them as having mental states. Without this meta-representational (mind-reading) ability their behavior would be meaningless to us. Over the past few years this view has been challenged by neurophysiological findings and, in particular, by the discovery of mirror neurons. The functional properties of these neurons indicate that intentional understanding is based primarily on a mechanism that directly matches the sensory representation of the observed actions with one's own motor representation of those same actions. These findings reveal how deeply motor and intentional components of action are intertwined, suggesting that both can be fully comprehended only starting from a motor approach to intentionality.

Is Reorganization of the Army Under the Unit-of-Action and the Unit-of-Employment Concept Consistent with the Army’s Identity?

DTIC Science & Technology

2004-06-01

thesis is a critical assessment of those organizational changes . The thesis question asks: Is reorganization of the Army under the unit of action/unit...driving these changes are not well understood. It is a far more daunting task to understand the forces that are driving these organizational changes ...than it is to understand the mechanics of those changes . In a sense, every leader in the Army is a technician; officers in particular are called

Towards an understanding of the adjuvant action of aluminium

PubMed Central

Marrack, Philippa; McKee, Amy S.; Munks, Michael W.

2011-01-01

The efficacy of vaccines depends on the presence of an adjuvant in conjunction with the antigen. Of these adjuvants, the ones that contain aluminium, which were first discovered empirically in 1926, are currently the most widely used. However, a detailed understanding of their mechanism of action has only started to be revealed. In this Timeline article, we briefly describe the initial discovery of aluminium adjuvants and discuss historically important advances. We also summarize recent progress in the field and discuss their implications and the remaining questions on how these adjuvants work. PMID:19247370

Learning Switching Control: A Tank Level-Control Exercise

ERIC Educational Resources Information Center

Pasamontes, M.; Alvarez, J. D.; Guzman, J. L.; Berenguel, M.

2012-01-01

A key topic in multicontroller strategies is the mechanism for switching between controllers, depending on the current operating point. The objective of the switching mechanism is to keep the control action coherent. To help students understand the switching strategy involved in multicontroller schema and the relationship between the system…

Understanding the mechanism of action of triazine-phosphonate derivatives as flame retardants for cotton fabrics

USDA-ARS?s Scientific Manuscript database

Countless hours of research and studies on triazine, phosphonate and their combination have provided insightful information into their flame retardant properties on polymeric systems. However, only limited number of studies shed light on the mechanism of flame retardant cotton fabrics. The purpose...

Proton Pumps: Mechanism of Action and Applications

NASA Technical Reports Server (NTRS)

Lanyi, Janos K.; Pohorille, Andrew; DeVincenzi, Donald L. (Technical Monitor)

2001-01-01

Recent progress in understanding molecular structures and mechanisms of action of proton pumps has paved the way to their novel applications in biotechnology. Proton pumps, in particular bacteriorhodopsin and ATP synthases, are capable of continuous, renewable conversion of light to chemical, mechanical or electrical energy, which can be used in macro- or nano-scale devices. The capability of protein systems incorporated into liposomes to generate ATP, which can be further used to drive chemical reactions, and to act as molecular motors has been already demonstrated. Other possible applications of such biochemical devices include targeted drug delivery and biocatalytic re actors. All these devices might prove superior to their inorganic alternatives.

Mechanisms governing the health and performance benefits of exercise

PubMed Central

Bishop-Bailey, D

2013-01-01

Humans are considered among the greatest if not the greatest endurance land animals. Over the last 50 years, as the population has become more sedentary, rates of cardiovascular disease and its associated risk factors such as obesity, type 2 diabetes and hypertension have all increased. Aerobic fitness is considered protective for all-cause mortality, cardiovascular disease, a variety of cancers, joint disease and depression. Here, I will review the emerging mechanisms that underlie the response to exercise, focusing on the major target organ the skeletal muscle system. Understanding the mechanisms of action of exercise will allow us to develop new therapies that mimic the protective actions of exercise. PMID:24033098

Membrane estrogen receptors - is it an alternative way of estrogen action?

PubMed

Soltysik, K; Czekaj, P

2013-04-01

The functions of estrogens are relatively well known, however the molecular mechanism of their action is not clear. The classical pathway of estrogen action is dependent on ERα and ERβ which act as transcription factors. The effects of this pathway occur within hours or days. In addition, so-called, non-classical mechanism of steroid action dependent on membrane estrogen receptors (mER) was described. In this mechanism the effects of estrogen action are observed in a much shorter time. Here we review the structure and cellular localization of mER, molecular basis of non-classical mER action, physiological role of mER as well as implications of mER action for cancer biology. Finally, some concerns about the new estrogen receptor - GPER and candidates for estrogen receptors - ER-X and ERx, are briefly discussed. It seems that mER is a complex containing signal proteins (signalosome), as IGF receptor, EGF receptor, Ras protein, adaptor protein Shc, non-receptor kinase c-Src and PI-3K, what rationalizes production of second messengers. Some features of membrane receptors are almost identical if compared to nuclear receptors. Probably, membrane and nuclear estrogen receptors are not separate units, but rather the components of a complex mechanism in which they both cooperate with each other. We conclude that the image of the estrogen receptor as a simple transcription factor is a far-reaching simplification. A better understanding of the mechanisms of estrogen action will help us to design more effective drugs affecting signal pathways depending on both membrane and nuclear receptors.

Towards a common framework of grounded action cognition: Relating motor control, perception and cognition.

PubMed

Gentsch, Antje; Weber, Arne; Synofzik, Matthis; Vosgerau, Gottfried; Schütz-Bosbach, Simone

2016-01-01

The relation between motor control and action cognition - including action-related thoughts and action-related perception - has been subject to controversial discussions in the last three decades. During these decades, cognitive neuroscience has been increasingly confronted with a huge variety of different accounts trying to understand and explain the relation between these systems, their interdependencies and the mediating mechanisms by establishing notions such as "internal models", "simulation" or "shared representation". These accounts, however, include a large array of partly overlapping, partly contradictory theories using similar terms for different mechanisms and different terms for similar mechanisms. In the absence of a systematic work-up and comparison, this array of accounts and theories leads to confusion in the field, duplication of experimental work, and unconnected parallelism of theory formation within and between different disciplines. Here we provide a systematic comparison of current models and prospective theories that deal with the relation between cognition, perception and motor control mechanisms. In a second step, we propose "grounded action cognition" as a comprehensive metatheoretical framework which defines different hypothetical possibilities of the relations between these domains, offers systematic insights into current models and theories and last but not least may help to increase comparability of empirical research in the domain of action and action cognition. Copyright © 2015 Elsevier B.V. All rights reserved.

Understanding Mechanism of Photocatalytic Microbial Decontamination of Environmental Wastewater

PubMed Central

Regmi, Chhabilal; Joshi, Bhupendra; Ray, Schindra K.; Gyawali, Gobinda; Pandey, Ramesh P.

2018-01-01

Several photocatalytic nanoparticles are synthesized and studied for potential application for the degradation of organic and biological wastes. Although these materials degrade organic compounds by advance oxidation process, the exact mechanisms of microbial decontamination remains partially known. Understanding the real mechanisms of these materials for microbial cell death and growth inhibition helps to fabricate more efficient semiconductor photocatalyst for large-scale decontamination of environmental wastewater or industries and hospitals/biomedical labs generating highly pathogenic bacteria and toxic molecules containing liquid waste by designing a reactor. Recent studies on microbial decontamination by photocatalytic nanoparticles and their possible mechanisms of action is highlighted with examples in this mini review. PMID:29541632

Effect of an educational game on university students' learning about action potentials.

PubMed

Luchi, Kelly Cristina Gaviao; Montrezor, Luís Henrique; Marcondes, Fernanda K

2017-06-01

The aim of this study was to evaluate the effect of an educational game that is used for teaching the mechanisms of the action potentials in cell membranes. The game was composed of pieces representing the intracellular and extracellular environments, ions, ion channels, and the Na + -K + -ATPase pump. During the game activity, the students arranged the pieces to demonstrate how the ions move through the membrane in a resting state and during an action potential, linking the ion movement with a graph of the action potential. To test the effect of the game activity on student understanding, first-year dental students were given the game to play at different times in a series of classes teaching resting membrane potential and action potentials. In all experiments, students who played the game performed better in assessments. According to 98% of the students, the game supported the learning process. The data confirm the students' perception, indicating that the educational game improved their understanding about action potentials. Copyright © 2017 the American Physiological Society.

Semantic processing of actions at 9months is linked to language proficiency at 9 and 18months.

PubMed

Kaduk, Katharina; Bakker, Marta; Juvrud, Joshua; Gredebäck, Gustaf; Westermann, Gert; Lunn, Judith; Reid, Vincent M

2016-11-01

The current study uses event-related potential methodologies to investigate how social-cognitive processes in preverbal infants relate to language performance. We assessed 9-month-olds' understanding of the semantic structure of actions via an N400 event-related potential (ERP) response to action sequences that contained expected and unexpected outcomes. At 9 and 18months of age, infants' language abilities were measured using the Swedish Early Communicative Development Inventory (SECDI). Here we show that 9-month-olds' understanding of the semantic structure of actions, evidenced in an N400 ERP response to action sequences with unexpected outcomes, is related to language comprehension scores at 9months and is related to language production scores at 18months of age. Infants who showed a selective N400 response to unexpected action outcomes are those who are classed as above mean in their language proficiency. The results provide evidence that language performance is related to the ability to detect and interpret human actions at 9months of age. This study suggests that some basic cognitive mechanisms are involved in the processing of sequential events that are shared between two conceptually different cognitive domains and that pre-linguistic social understanding skills and language proficiency are linked to one another. Copyright © 2016. Published by Elsevier Inc.

Action mechanisms for social cognition: behavioral and neural correlates of developing Theory of Mind

PubMed Central

Bowman, Lindsay C.; Thorpe, Samuel G.; Cannon, Erin N.; Fox, Nathan A.

2016-01-01

Many psychological theories posit foundational links between two fundamental constructs: (1) our ability to produce, perceive, and represent action; and (2) our ability to understand the meaning and motivation behind the action (i.e. Theory of Mind; ToM). This position is contentious, however, and long-standing competing theories of social-cognitive development debate roles for basic action-processing in ToM. Developmental research is key to investigating these hypotheses, but whether individual differences in neural and behavioral measures of motor action relate to social-cognitive development is unknown. We examined 3- to 5-year-old children’s (N = 26) EEG mu-desynchronization during production of object-directed action, and explored associations between mu-desynchronization and children’s behavioral motor skills, behavioral action-representation abilities, and behavioral ToM. For children with high (but not low) mu-desynchronization, motor skill related to action-representation abilities, and action-representation mediated relations between motor skill and ToM. Results demonstrate novel foundational links between action-processing and ToM, suggesting that basic motor action may be a key mechanism for social-cognitive development, thus shedding light on the origins and emergence of higher social cognition. PMID:27573916

Mechanisms of action of ligands of potential-dependent sodium channels.

PubMed

Tikhonov, D B

2008-06-01

Potential-dependent sodium channels play a leading role in generating action potentials in excitable cells. Sodium channels are the site of action of a variety of modulator ligands. Despite numerous studies, the mechanisms of action of many modulators remain incompletely understood. The main reason that many important questions cannot be resolved is that there is a lack of precise data on the structures of the channels themselves. Structurally, potential-dependent sodium channels are members of the P-loop channel superfamily, which also include potassium and calcium channels and glutamate receptor channels. Crystallization of a series of potassium channels showed that it was possible to analyze the structures of different members of the superfamily using the "homologous modeling" method. The present study addresses model investigations of the actions of ligands of sodium channels, including tetrodotoxin and batrachotoxin, as well as local anesthetics. Comparison of experimental data on sodium channel ligands with x-ray analysis data allowed us to reach a new level of understanding of the mechanisms of channel modulation and to propose a series of experimentally verifiable hypotheses.

Motor resonance facilitates movement execution: an ERP and kinematic study

PubMed Central

Ménoret, Mathilde; Curie, Aurore; des Portes, Vincent; Nazir, Tatjana A.; Paulignan, Yves

2013-01-01

Action observation, simulation and execution share neural mechanisms that allow for a common motor representation. It is known that when these overlapping mechanisms are simultaneously activated by action observation and execution, motor performance is influenced by observation and vice versa. To understand the neural dynamics underlying this influence and to measure how variations in brain activity impact the precise kinematics of motor behavior, we coupled kinematics and electrophysiological recordings of participants while they performed and observed congruent or non-congruent actions or during action execution alone. We found that movement velocities and the trajectory deviations of the executed actions increased during the observation of congruent actions compared to the observation of non-congruent actions or action execution alone. This facilitation was also discernible in the motor-related potentials of the participants; the motor-related potentials were transiently more negative in the congruent condition around the onset of the executed movement, which occurred 300 ms after the onset of the observed movement. This facilitation seemed to depend not only on spatial congruency but also on the optimal temporal relationship of the observation and execution events. PMID:24133437

Students' Understanding of Loops and Nested Loops in Computer Programming: An APOS Theory Perspective

ERIC Educational Resources Information Center

Cetin, Ibrahim

2015-01-01

The purpose of this study is to explore students' understanding of loops and nested loops concepts. Sixty-three mechanical engineering students attending an introductory programming course participated in the study. APOS (Action, Process, Object, Schema) is a constructivist theory developed originally for mathematics education. This study is the…

[Mechanisms of action of voltage-gated sodium channel ligands].

PubMed

Tikhonov, D B

2007-05-01

The voltage-gated sodium channels play a key role in the generation of action potential in excitable cells. Sodium channels are targeted by a number of modulating ligands. Despite numerous studies, the mechanisms of action of many ligands are still unknown. The main cause of the problem is the absence of the channel structure. Sodium channels belong to the superfamily of P-loop channels that also the data abowt includes potassium and calcium channels and the channels of ionotropic glutamate receptors. Crystallization of several potassium channels has opened a possibility to analyze the structure of other members of the superfamily using the homology modeling approach. The present study summarizes the results of several recent modelling studies of such sodium channel ligands as tetrodotoxin, batrachotoxin and local anesthetics. Comparison of available experimental data with X-ray structures of potassium channels has provided a new level of understanding of the mechanisms of action of sodium channel ligands and has allowed proposing several testable hypotheses.

Studies on Pongamia pinnata (L.) Pierre leaves: understanding the mechanism(s) of action in infectious diarrhea*

PubMed Central

Brijesh, S.; Daswani, P.G.; Tetali, P.; Rojatkar, S.R.; Antia, N.H.; Birdi, T.J.

2006-01-01

While data are available on the effect of medicinal plants on intestinal motility and their antibacterial action, there is a paucity of information on their mode of action on various aspects of diarrheal pathogenicity, namely colonization to intestinal epithelial cells and production/action of enterotoxins. Crude decoction of dried leaves of Pongamia pinnata was evaluated for its antimicrobial (antibacterial, antigiardial and antirotaviral) effect; and its effect on production and action of enterotoxins (cholera toxin, CT; Escherichia coli labile toxin, LT; and E. coli stable toxin, ST); and adherence of enteropathogenic E. coli and invasion of enteroinvasive E. coli and Shigella flexneri to epithelial cells. The decoction had no antibacterial, antigiardial and antirotaviral activity, but reduced production of CT and bacterial invasion to epithelial cells. The observed results indicated that the crude decoction of P. pinnata has selective antidiarrheal action with efficacy against cholera and enteroinvasive bacterial strains causing bloody diarrheal episodes. PMID:16845722

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

Relating spatial perspective taking to the perception of other's affordances: providing a foundation for predicting the future behavior of others

PubMed Central

Creem-Regehr, Sarah H.; Gagnon, Kyle T.; Geuss, Michael N.; Stefanucci, Jeanine K.

2013-01-01

Understanding what another agent can see relates functionally to the understanding of what they can do. We propose that spatial perspective taking and perceiving other's affordances, while two separate spatial processes, together share the common social function of predicting the behavior of others. Perceiving the action capabilities of others allows for a common understanding of how agents may act together. The ability to take another's perspective focuses an understanding of action goals so that more precise understanding of intentions may result. This review presents an analysis of these complementary abilities, both in terms of the frames of reference and the proposed sensorimotor mechanisms involved. Together, we argue for the importance of reconsidering the role of basic spatial processes to explain more complex behaviors. PMID:24068992

A Claw is Like My Hand: Comparison Supports Goal Analysis in Infants

PubMed Central

Gerson, Sarah A.; Woodward, Amanda L.

2012-01-01

Understanding the intentional relations in others' actions is critical to human social life. Origins of this knowledge exist in the first year and are a function of both acting as an intentional agent and observing movement cues in actions. We explore a new mechanism we believe plays an important role in infants' understanding of new actions: comparison. We examine how the opportunity to compare a familiar action with a novel, tool use action helps 7- and 10-month-old infants extract and imitate the goal of a tool use action. Infants given the chance to compare their own reach for a toy with an experimenter's reach using a claw later imitated the goal of an experimenter's tool use action. Infants who engaged with the claw, were familiarized with the claw's causal properties, or learned the associations between claw and toys (but did not align their reaches with the claw's) did not imitate. Further, active participation in the familiar action to be compared was more beneficial than observing a familiar and novel action aligned for 10-month-olds. Infants' ability to extract the goal-relation of a novel action through comparison with a familiar action could have a broad impact on the development of action knowledge and social learning more generally. PMID:22099543

Essential Tremor: What We Can Learn from Current Pharmacotherapy

PubMed Central

Ondo, William

2016-01-01

Background The pathophysiology of essential tremor, especially at the cellular level, is poorly understood. Although no drug has been specifically designed to treat essential tremor, several medications improve tremor, and others worsen it. Studying the mechanism of actions of these medications can help our understanding of tremor pathophysiology and contribute to future rational drug design. Methods We reviewed literature, concentrating on mechanisms of action, of various medications that mitigate tremor. Results Many medications have multiple mechanisms of actions, making simple correlations difficult. Medications that increase the duration of opening of gamma-aminobutyric acid (GABA)-A receptors are most consistently associated with tremor improvement. Interestingly, drugs that increase GABA availability have not been associated with improved tremor. Other mechanisms possibly associated with tremor improvement include antagonism of alpha-2 delta subunits associated with calcium channels, inhibition of carbonic anhydrase, and inhibition of the synaptic vesicle protein 2A. Drugs that block voltage-gaited sodium channels do not affect tremor. The ideal beta-adrenergic blocker requires B2 affinity (non-cardiac selective), has no sympathomimetic properties, does not require membrane stabilization properties, and may benefit from good central nervous system penetration. Discussion To date, serendipitous observations have provided most of our understanding of tremor cellular physiology. Based on similarities to currently effective drugs or rational approximations and inferences, several currently available agents should be considered for tremor trials. PMID:26989572

Mechanisms governing the health and performance benefits of exercise.

PubMed

Bishop-Bailey, D

2013-11-01

Humans are considered among the greatest if not the greatest endurance land animals. Over the last 50 years, as the population has become more sedentary, rates of cardiovascular disease and its associated risk factors such as obesity, type 2 diabetes and hypertension have all increased. Aerobic fitness is considered protective for all-cause mortality, cardiovascular disease, a variety of cancers, joint disease and depression. Here, I will review the emerging mechanisms that underlie the response to exercise, focusing on the major target organ the skeletal muscle system. Understanding the mechanisms of action of exercise will allow us to develop new therapies that mimic the protective actions of exercise. © 2013 The British Pharmacological Society.

Predictive Mechanisms Are Not Involved the Same Way during Human-Human vs. Human-Machine Interactions: A Review

PubMed Central

Sahaï, Aïsha; Pacherie, Elisabeth; Grynszpan, Ouriel; Berberian, Bruno

2017-01-01

Nowadays, interactions with others do not only involve human peers but also automated systems. Many studies suggest that the motor predictive systems that are engaged during action execution are also involved during joint actions with peers and during other human generated action observation. Indeed, the comparator model hypothesis suggests that the comparison between a predicted state and an estimated real state enables motor control, and by a similar functioning, understanding and anticipating observed actions. Such a mechanism allows making predictions about an ongoing action, and is essential to action regulation, especially during joint actions with peers. Interestingly, the same comparison process has been shown to be involved in the construction of an individual's sense of agency, both for self-generated and observed other human generated actions. However, the implication of such predictive mechanisms during interactions with machines is not consensual, probably due to the high heterogeneousness of the automata used in the experimentations, from very simplistic devices to full humanoid robots. The discrepancies that are observed during human/machine interactions could arise from the absence of action/observation matching abilities when interacting with traditional low-level automata. Consistently, the difficulties to build a joint agency with this kind of machines could stem from the same problem. In this context, we aim to review the studies investigating predictive mechanisms during social interactions with humans and with automated artificial systems. We will start by presenting human data that show the involvement of predictions in action control and in the sense of agency during social interactions. Thereafter, we will confront this literature with data from the robotic field. Finally, we will address the upcoming issues in the field of robotics related to automated systems aimed at acting as collaborative agents. PMID:29081744

HIV-1 RT Inhibitors with a Novel Mechanism of Action: NNRTIs that Compete with the Nucleotide Substrate

PubMed Central

Maga, Giovanni; Radi, Marco; Gerard, Marie-Aline; Botta, Maurizio; Ennifar, Eric

2010-01-01

HIV-1 reverse transcriptase (RT) inhibitors currently used in antiretroviral therapy can be divided into two classes: (i) nucleoside analog RT inhibitors (NRTIs), which compete with natural nucleoside substrates and act as terminators of proviral DNA synthesis, and (ii) non-nucleoside RT inhibitors (NNRTIs), which bind to a hydrophobic pocket close to the RT active site. In spite of the efficiency of NRTIs and NNRTIs, the rapid emergence of multidrug-resistant mutations requires the development of new RT inhibitors with an alternative mechanism of action. Recently, several studies reported the discovery of novel non-nucleoside inhibitors with a distinct mechanism of action. Unlike classical NNRTIs, they compete with the nucleotide substrate, thus forming a new class of RT inhibitors: nucleotide-competing RT inhibitors (NcRTIs). In this review, we discuss current progress in the understanding of the peculiar behavior of these compounds. PMID:21994659

Social interaction enhances motor resonance for observed human actions.

PubMed

Hogeveen, Jeremy; Obhi, Sukhvinder S

2012-04-25

Understanding the neural basis of social behavior has become an important goal for cognitive neuroscience and a key aim is to link neural processes observed in the laboratory to more naturalistic social behaviors in real-world contexts. Although it is accepted that mirror mechanisms contribute to the occurrence of motor resonance (MR) and are common to action execution, observation, and imitation, questions remain about mirror (and MR) involvement in real social behavior and in processing nonhuman actions. To determine whether social interaction primes the MR system, groups of participants engaged or did not engage in a social interaction before observing human or robotic actions. During observation, MR was assessed via motor-evoked potentials elicited with transcranial magnetic stimulation. Compared with participants who did not engage in a prior social interaction, participants who engaged in the social interaction showed a significant increase in MR for human actions. In contrast, social interaction did not increase MR for robot actions. Thus, naturalistic social interaction and laboratory action observation tasks appear to involve common MR mechanisms, and recent experience tunes the system to particular agent types.

Mechanism of action of glucocorticoids in nasal polyposis.

PubMed

Fernandes, Atílio Maximino; Valera, Fabiana Cardoso Pereira; Anselmo-Lima, Wilma T

2008-01-01

Glucocorticoids (GC) are the drugs of choice for the clinical treatment of nasal polyposis, according to the medical literature. Its mechanism of action in the regression of clinical symptoms and polyps, however, is not fully understood. The topical and/or systemic use of glucocorticoids lead to variable expression of cytokines, chemokines and lymphokines, as well as changes in cells. It is known that GC suppresses the expression of pro-inflammatory cytokines, chemokines and adhesion molecules such as ICAM-1 and E-selectin; GC also stimulate the transcription of anti-inflammatory cytokines such as TGF-b. GC suppress pro-fibrotic cytokines related to polyp growth, such as IL-11, the basic fibroblast growth factor (b-FGF), and the vascular endotelial growth factor (VEGF). The action of GC depends fundamentally on their interaction with receptors (GR); certain subjects have a degree of resistance to its effect, which appears to be related with the presence of a b isoform of GR. GC also act variably on the genes involved in immunoglobulin production, presentation, and antigen processing. We present a review of the literature on the mechanisms of GC action in nasal polyosis. Understanding the mechanism of action of GC in nasal polyposis will aid in the development of new, more efficient, drugs.

Gesture as Representational Action: A paper about function

PubMed Central

Novack, Miriam A.; Goldin-Meadow, Susan

2016-01-01

A great deal of attention has recently been paid to gesture and its effects on thinking and learning. It is well established that the hand movements that accompany speech are an integral part of communication, ubiquitous across cultures, and a unique feature of human behavior. In an attempt to understand this intriguing phenomenon, researchers have focused on pinpointing the mechanisms that underlie gesture production. One proposal—that gesture arises from simulated action (see Hostetter & Alibali, 2008)—has opened up discussions about action, gesture, and the relation between the two. However, there is another side to understanding a phenomenon, and that is to understand its function. A phenomenon’s function is its purpose rather than its precipitating cause—the why rather than the how. This paper sets forth a theoretical framework for exploring why gesture serves the functions that it does, and reviews where the current literature fits, and fails to fit, this proposal. Our framework proposes that whether or not gesture is simulated action in terms of its mechanism—it is clearly not reducible to action in terms of its function. Most notably, because gestures are abstracted representations and are not actions tied to particular events and objects, they can play a powerful role in thinking and learning beyond the particular, specifically, in supporting generalization and transfer of knowledge. PMID:27604493

Molecular action of sulphonylureas on KATP channels: a real partnership between drugs and nucleotides.

PubMed

de Wet, Heidi; Proks, Peter

2015-10-01

Sulphonylureas stimulate insulin secretion from pancreatic β-cells primarily by closing ATP-sensitive K(+) channels in the β-cell plasma membrane. The mechanism of channel inhibition by these drugs is unusually complex. As direct inhibitors of channel activity, sulphonylureas act only as partial antagonists at therapeutic concentrations. However, they also exert an additional indirect inhibitory effect via modulation of nucleotide-dependent channel gating. In this review, we summarize current knowledge and recent advances in our understanding of the molecular mechanism of action of these drugs. © 2015 Authors; published by Portland Press Limited.

Genus Caulophyllum: An Overview of Chemistry and Bioactivity

PubMed Central

Xia, Yong-Gang; Li, Guo-Yu; Liang, Jun; Yang, Bing-You; Lü, Shao-Wa; Kuang, Hai-Xue

2014-01-01

Recently, some promising advances have been achieved in understanding the chemistry, pharmacology, and action mechanisms of constituents from genus Caulophyllum. Despite this, there is to date no systematic review of those of genus Caulophyllum. This review covers naturally occurring alkaloids and saponins and those resulting from synthetic novel taspine derivatives. The paper further discussed several aspects of this genus, including pharmacological properties, mechanisms of action, pharmacokinetics, and cell membrane chromatography for activity screening. The aim of this paper is to provide a point of reference for pharmaceutical researchers to develop new drugs from constituents of Caulophyllum plants. PMID:24876877

Genus caulophyllum: an overview of chemistry and bioactivity.

PubMed

Xia, Yong-Gang; Li, Guo-Yu; Liang, Jun; Yang, Bing-You; Lü, Shao-Wa; Kuang, Hai-Xue

2014-01-01

Recently, some promising advances have been achieved in understanding the chemistry, pharmacology, and action mechanisms of constituents from genus Caulophyllum. Despite this, there is to date no systematic review of those of genus Caulophyllum. This review covers naturally occurring alkaloids and saponins and those resulting from synthetic novel taspine derivatives. The paper further discussed several aspects of this genus, including pharmacological properties, mechanisms of action, pharmacokinetics, and cell membrane chromatography for activity screening. The aim of this paper is to provide a point of reference for pharmaceutical researchers to develop new drugs from constituents of Caulophyllum plants.

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.

Homeopathic drug discovery: theory update and methodological aspect.

PubMed

Khuda-Bukhsh, Anisur Rahman; Pathak, Surajit

2008-08-01

Homeopathy treats patient on the basis of totality of symptoms and is based on the principle of 'like cures like'. It uses ultra-low doses of highly diluted natural substances as remedies that originate from plants, minerals or animals. The objectives of this review are to discuss concepts, controversies and research related to understanding homeopathy in the light of modern science. Attempts have been made to focus on current views of homeopathy and to delineate its most plausible mechanism(s) of action. Although some areas of concern remain, research carried out so far both in vitro and in vivo validates the effects of highly diluted homeopathic medicines in a wide variety of organisms. The precise mechanism(s) and pathway(s) of action of highly diluted homeopathic drugs are still unknown.

Plant management in natural areas: balancing chemical, mechanical, and cultural control methods

Treesearch

Steven Manning; James Miller

2011-01-01

After determining the best course of action for control of an invasive plant population, it is important to understand the variety of methods available to the integrated pest management professional. A variety of methods are now widely used in managing invasive plants in natural areas, including chemical, mechanical, and cultural control methods. Once the preferred...

Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism

USDA-ARS?s Scientific Manuscript database

Probiotics are health-promoting bacteria which may protect the intestines from injury and inflammatory diseases but our understanding of the mechanisms for probiotic action are limited. In this study, we hypothesized that a protein, known as p40, which is derived from the probiotic bacteria, Lactoba...

Current Understanding of the Hypothalamic Ghrelin Pathways Inducing Appetite and Adiposity.

PubMed

Al Massadi, Omar; López, Miguel; Tschöp, Matthias; Diéguez, Carlos; Nogueiras, Ruben

2017-03-01

Ghrelin is a multifaceted regulator of metabolism. Ghrelin regulates energy balance in the short term via induction of appetite and in the long term via increased body weight and adiposity. Recently, several central pathways modulating the metabolic actions of ghrelin were unmasked, and it was shown to act through different hypothalamic nuclei to induce feeding. Ghrelin also modulates glucose homeostasis, but the central mechanisms responsible for this action have not been studied in detail. Although ghrelin also acts through extrahypothalamic areas to promote feeding, this review specifically dissects hypothalamic control of ghrelin's orexigenic and adipogenic actions and presents current understanding of the intracellular ghrelin orexigenic pathways, including their dependence on other relevant systems implicated in energy balance. Copyright © 2016 Elsevier Ltd. All rights reserved.

Update on the mechanism of action of antiepileptic drugs.

PubMed

Meldrum, B S

1996-01-01

Novel antiepileptic drugs (AEDs) are thought to act on voltage-sensitive ion channels, on inhibitory neurotransmission or on excitatory neurotransmission. Two successful examples of rational AED design that potentiate GABA-mediated inhibition are vigabatrin (VGB) by irreversible inhibition of GABA-transaminase, and tiagabine (TGB) by blocking GABA uptake. Lamotrigine (LTG) prolongs inactivation of voltage-dependent sodium channels. The anticonvulsant action of remacemide (RCM) is probably largely due to blockade of NMDA receptors and prolonged inactivation of sodium channels induced by its desglycinated metabolite. Felbamate (FBM) apparently blocks NMDA receptors, potentiates GABA-mediated responses, blocks L-type calcium channels, and possibly also prolongs sodium channel inactivation. Similarly, topiramate (TPM) has multiple probable sites of action, including sodium channels, GABA receptors, and glutamate (AMPA) receptors. Gabapentin (GBP) apparently has a completely novel type of action, probably involving potentiation of GABA-mediated inhibition and possibly also inactivation of sodium channels. The therapeutic advantages of the novel AEDs are as yet only partially explained by our present understanding of their mechanisms of action.

Modeling the Development of Goal-Specificity in Mirror Neurons.

PubMed

Thill, Serge; Svensson, Henrik; Ziemke, Tom

2011-12-01

Neurophysiological studies have shown that parietal mirror neurons encode not only actions but also the goal of these actions. Although some mirror neurons will fire whenever a certain action is perceived (goal-independently), most will only fire if the motion is perceived as part of an action with a specific goal. This result is important for the action-understanding hypothesis as it provides a potential neurological basis for such a cognitive ability. It is also relevant for the design of artificial cognitive systems, in particular robotic systems that rely on computational models of the mirror system in their interaction with other agents. Yet, to date, no computational model has explicitly addressed the mechanisms that give rise to both goal-specific and goal-independent parietal mirror neurons. In the present paper, we present a computational model based on a self-organizing map, which receives artificial inputs representing information about both the observed or executed actions and the context in which they were executed. We show that the map develops a biologically plausible organization in which goal-specific mirror neurons emerge. We further show that the fundamental cause for both the appearance and the number of goal-specific neurons can be found in geometric relationships between the different inputs to the map. The results are important to the action-understanding hypothesis as they provide a mechanism for the emergence of goal-specific parietal mirror neurons and lead to a number of predictions: (1) Learning of new goals may mostly reassign existing goal-specific neurons rather than recruit new ones; (2) input differences between executed and observed actions can explain observed corresponding differences in the number of goal-specific neurons; and (3) the percentage of goal-specific neurons may differ between motion primitives.

Ebselen, a promising antioxidant drug: mechanisms of action and targets of biological pathways.

PubMed

Azad, Gajendra Kumar; Tomar, Raghuvir S

2014-08-01

Ebselen, an organoselenium compound, mimics glutathione peroxidase activity. It is a multifunctional compound, which catalyzes several essential reactions for the protection of cellular components from oxidative and free radical damage. Based on a number of in vitro and in vivo studies, various mechanisms are proposed to understand the biomedical actions of ebselen in health and diseases. It modulates metallo-proteins, enzymatic cofactors, gene expression, epigenetics, antioxidant defenses and immune systems. Owing to these properties, ebselen is currently under clinical trials for the prevention and treatment of various disorders such as cardiovascular diseases, arthritis, stroke, atherosclerosis, and cancer. A few ebselen-based pharmaceutical agents are under extensive investigation. As ebselen has been shown to have significant cellular toxicity, appropriate studies are needed to redesign the ebselen-based therapy for clinical trials. This review summarizes current understanding of the biochemical and molecular properties, and pharmacological applications of ebselen and future directions in this area of research.

Antifungal agents commonly used in the superficial and mucosal candidiasis treatment: mode of action and resistance development

PubMed Central

Bondaryk, Małgorzata; Kurzątkowski, Wiesław

2013-01-01

Recent progress in medical sciences and therapy resulted in an increased number of immunocompromised individuals. Candida albicans is the leading opportunistic fungal pathogen causing infections in humans, ranging from superficial mucosal lesions to disseminated or bloodstream candidiasis. Superficial candidiasis not always presents a risk to the life of the infected host, however it significantly lowers the quality of life. Superficial Candida infections are difficult to treat and their frequency of occurrence is currently rising. To implement successful treatment doctors should be up to date with better understanding of C. albicans resistance mechanisms. Despite high frequency of Candida infections there is a limited number of antimycotics available for therapy. This review focuses on current understanding of the mode of action and resistance mechanisms to conventional and emerging antifungal agents for treatment of superficial and mucosal candidiasis. PMID:24353489

A Systems Biology Approach to Understanding the Mechanisms of Action of an Alternative Anticancer Compound in Comparison to Cisplatin

PubMed Central

Wright, Elise P.; Padula, Matthew P.; Higgins, Vincent J.; Aldrich-Wright, Janice R.; Coorssen, Jens R.

2014-01-01

Many clinically available anticancer compounds are designed to target DNA. This commonality of action often yields overlapping cellular response mechanisms and can thus detract from drug efficacy. New compounds are required to overcome resistance mechanisms that effectively neutralise compounds like cisplatin and those with similar chemical structures. Studies have shown that 56MESS is a novel compound which, unlike cisplatin, does not covalently bind to DNA, but is more toxic to many cell lines and active against cisplatin-resistant cells. Furthermore, a transcriptional study of 56MESS in yeast has implicated iron and copper metabolism as well as the general yeast stress response following challenge with 56MESS. Beyond this, the cytotoxicity of 56MESS remains largely uncharacterised. Here, yeast was used as a model system to facilitate a systems-level comparison between 56MESS and cisplatin. Preliminary experiments indicated that higher concentrations than seen in similar studies be used. Although a DNA interaction with 56MESS had been theorized, this work indicated that an effect on protein synthesis/ degradation was also implicated in the mechanism(s) of action of this novel anticancer compound. In contrast to cisplatin, the different mechanisms of action that are indicated for 56MESS suggest that this compound could overcome cisplatin resistance either as a stand-alone treatment or a synergistic component of therapeutics. PMID:28250393

Sensemaking: Conceptual Changes, Cognitive Mechanisms, and Structural Representations. a Qualitative User Study

ERIC Educational Resources Information Center

Zhang, Pengyi

2010-01-01

The purpose of this thesis is to improve our understanding of sensemaking process as a basis for building better systems to assist sensemaking. Sensemaking is the task of creating an understanding of a problem or task so that further actions may be taken in an informed manner. Sensemaking is a pre-requisite for many other tasks such as decision…

Determining the effects of a mixture of an endocrine disrupting compound, 17a-ethinylestradiol, and ammonia on fathead minnow (Pimephales promelas) reproduction

EPA Science Inventory

Aquatic organisms are exposed to a multitude of contaminants and to fully understand the impact of multiple stressors on fish populations, we must first understand the mechanism of action for each toxicant and how the combined effects manifest at the level of the individual. 17α-...

NMDA receptor as a newly identified member of the metabotropic glutamate receptor family: clinical implications for neurodegenerative diseases.

PubMed

Chung, ChiHye

2013-08-01

Recent reports have proposed a novel function for the N-methyl-D-aspartate (NMDA) receptor (NMDAR), a well-known excitatory, ionotropic receptor. A series of observations employing pharmacological techniques has proposed that upon ligand binding, this ionotropic receptor can actually function via signaling cascades independent of traditional ionotropic action. Moreover, the "metabotropic" action of NMDARs is suggested to mediate a form of synaptic plasticity, namely long-term synaptic depression (LTD), which shares cellular mechanisms with the synaptic deficits observed in Alzheimer's disease. Given that a growing body of clinical and preclinical evidence strongly recommends NMDAR antagonists for their therapeutic potentials and advantages in a variety of diseases, further investigation into their molecular and cellular mechanisms is required to better understand the "metabotropic" action of NMDARs.

The simulating social mind: the role of the mirror neuron system and simulation in the social and communicative deficits of autism spectrum disorders.

PubMed

Oberman, Lindsay M; Ramachandran, Vilayanur S

2007-03-01

The mechanism by which humans perceive others differs greatly from how humans perceive inanimate objects. Unlike inanimate objects, humans have the distinct property of being "like me" in the eyes of the observer. This allows us to use the same systems that process knowledge about self-performed actions, self-conceived thoughts, and self-experienced emotions to understand actions, thoughts, and emotions in others. The authors propose that internal simulation mechanisms, such as the mirror neuron system, are necessary for normal development of recognition, imitation, theory of mind, empathy, and language. Additionally, the authors suggest that dysfunctional simulation mechanisms may underlie the social and communicative deficits seen in individuals with autism spectrum disorders.

Understanding Cytokine and Growth Factor Receptor Activation Mechanisms

PubMed Central

Atanasova, Mariya; Whitty, Adrian

2012-01-01

Our understanding of the detailed mechanism of action of cytokine and growth factor receptors – and particularly our quantitative understanding of the link between structure, mechanism and function – lags significantly behind our knowledge of comparable functional protein classes such as enzymes, G protein-coupled receptors, and ion channels. In particular, it remains controversial whether such receptors are activated by a mechanism of ligand-induced oligomerization, versus a mechanism in which the ligand binds to a pre-associated receptor dimer or oligomer that becomes activated through subsequent conformational rearrangement. A major limitation to progress has been the relative paucity of methods for performing quantitative mechanistic experiments on unmodified receptors expressed at endogenous levels on live cells. In this article we review the current state of knowledge on the activation mechanisms of cytokine and growth factor receptors, critically evaluate the evidence for and against the different proposed mechanisms, and highlight other key questions that remain unanswered. New approaches and techniques have led to rapid recent progress in this area, and the field is poised for major advances in the coming years, which promises to revolutionize our understanding of this large and biologically and medically important class of receptors. PMID:23046381

Behavioral Nutraceuticals and Diets.

PubMed

Orlando, Jillian M

2018-05-01

Behavioral problems of companion animals are becoming more widely recognized. As a result, there are a growing number of behavioral nutraceuticals and diets on the market. These products may be useful for the treatment of mild conditions, for clients who are hesitant to give their pet a psychopharmacologic agent, or sometimes in conjunction with psychopharmacologic agents. Veterinarians should critically review the research associated with nutraceuticals and diets, and have an understanding of the functional ingredients and their mechanisms of action before prescribing treatment. This article provides an overview of nutraceuticals, their mechanisms of action, and relevant research regarding their use. Copyright © 2018 Elsevier Inc. All rights reserved.

Towards understanding the mechanisms and the kinetics of nanoparticle penetration through protective gloves

NASA Astrophysics Data System (ADS)

Vinches, L.; Peyrot, C.; Lemarchand, L.; Boutrigue, N.; Zemzem, M.; Wilkinson, K. J.; Hallé, S.; Tufenkji, N.

2015-05-01

Parallel to the increased use of engineered nanoparticles (ENP) in the formulation of commercial products or in medicine, numerous health & safety agencies have recommended the application of the precautionary principle to handle ENP; namely, the recommendation to use protective gloves against chemicals. However, recent studies reveal the penetration of titanium dioxide nanoparticles through nitrile rubber protective gloves in conditions simulating occupational use. This project is designed to understand the links between the penetration of gold nanoparticles (nAu) through nitrile rubber protective gloves and the mechanical and physical behaviour of the elastomer material subjected to conditions simulating occupational use (i.e., mechanical deformations (MD) and sweat). Preliminary analyses show that nAu suspensions penetrate selected glove materials after exposure to prolonged (3 hours) dynamic deformations. Significant morphological changes are observed on the outer surface of the glove sample; namely, the number and the surface of the micropores on the surface increase. Moreover, nitrile rubber protective gloves are also shown to be sensitive to the action of nAu suspension and to the action of the saline solution used to simulate sweat (swelling).

Insights into Parkinson's disease from computational models of the basal ganglia.

PubMed

Humphries, Mark D; Obeso, Jose Angel; Dreyer, Jakob Kisbye

2018-04-17

Movement disorders arise from the complex interplay of multiple changes to neural circuits. Successful treatments for these disorders could interact with these complex changes in myriad ways, and as a consequence their mechanisms of action and their amelioration of symptoms are incompletely understood. Using Parkinson's disease as a case study, we review here how computational models are a crucial tool for taming this complexity, across causative mechanisms, consequent neural dynamics and treatments. For mechanisms, we review models that capture the effects of losing dopamine on basal ganglia function; for dynamics, we discuss models that have transformed our understanding of how beta-band (15-30 Hz) oscillations arise in the parkinsonian basal ganglia. For treatments, we touch on the breadth of computational modelling work trying to understand the therapeutic actions of deep brain stimulation. Collectively, models from across all levels of description are providing a compelling account of the causes, symptoms and treatments for Parkinson's disease. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

PubMed Central

Bruchas, Michael R.; Calo', Girolamo; Cox, Brian M.; Zaveri, Nurulain T.

2016-01-01

The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor. PMID:26956246

Survival Evasion Resistance Escape (SERE) Operations

DTIC Science & Technology

2017-03-27

result of fear and anger, for example, tend to increase alertness and provide extra energy to either run away or fight. These and other mechanisms can...People have been known to complete a fight with a fractured hand, to run on a fractured or sprained ankle, to land an aircraft despite severely burned...IP cannot run away from fear and must take action to control it. Appropriate actions include: • Understanding fear. • Admitting that it exists

Ultimate explanations and suboptimal choice.

PubMed

Vasconcelos, Marco; Machado, Armando; Pandeirada, Josefa N S

2018-07-01

Researchers have unraveled multiple cases in which behavior deviates from rationality principles. We propose that such deviations are valuable tools to understand the adaptive significance of the underpinning mechanisms. To illustrate, we discuss in detail an experimental protocol in which animals systematically incur substantial foraging losses by preferring a lean but informative option over a rich but non-informative one. To understand how adaptive mechanisms may fail to maximize food intake, we review a model inspired by optimal foraging principles that reconciles sub-optimal choice with the view that current behavioral mechanisms were pruned by the optimizing action of natural selection. To move beyond retrospective speculation, we then review critical tests of the model, regarding both its assumptions and its (sometimes counterintuitive) predictions, all of which have been upheld. The overall contention is that (a) known mechanisms can be used to develop better ultimate accounts and that (b) to understand why mechanisms that generate suboptimal behavior evolved, we need to consider their adaptive value in the animal's characteristic ecology. Copyright © 2018 Elsevier B.V. All rights reserved.

Smart food policies for obesity prevention.

PubMed

Hawkes, Corinna; Smith, Trenton G; Jewell, Jo; Wardle, Jane; Hammond, Ross A; Friel, Sharon; Thow, Anne Marie; Kain, Juliana

2015-06-13

Prevention of obesity requires policies that work. In this Series paper, we propose a new way to understand how food policies could be made to work more effectively for obesity prevention. Our approach draws on evidence from a range of disciplines (psychology, economics, and public health nutrition) to develop a theory of change to understand how food policies work. We focus on one of the key determinants of obesity: diet. The evidence we review suggests that the interaction between human food preferences and the environment in which those preferences are learned, expressed, and reassessed has a central role. We identify four mechanisms through which food policies can affect diet: providing an enabling environment for learning of healthy preferences, overcoming barriers to the expression of healthy preferences, encouraging people to reassess existing unhealthy preferences at the point-of-purchase, and stimulating a food-systems response. We explore how actions in three specific policy areas (school settings, economic instruments, and nutrition labelling) work through these mechanisms, and draw implications for more effective policy design. We find that effective food-policy actions are those that lead to positive changes to food, social, and information environments and the systems that underpin them. Effective food-policy actions are tailored to the preference, behavioural, socioeconomic, and demographic characteristics of the people they seek to support, are designed to work through the mechanisms through which they have greatest effect, and are implemented as part of a combination of mutually reinforcing actions. Moving forward, priorities should include comprehensive policy actions that create an enabling environment for infants and children to learn healthy food preferences and targeted actions that enable disadvantaged populations to overcome barriers to meeting healthy preferences. Policy assessments should be carefully designed on the basis of a theory of change, using indicators of progress along the various pathways towards the long-term goal of reducing obesity rates. Copyright © 2015 Elsevier Ltd. All rights reserved.

Lenalidomide in the treatment of chronic lymphocytic leukemia.

PubMed

Gentile, Massimo; Recchia, Anna Grazia; Vigna, Ernesto; Mazzone, Carla; Lucia, Eugenio; Gigliotti, Vincenzo; Bossio, Sabrina; Madeo, Antonio; Morabito, Lucio; Servillo, Pasquale; Franzese, Stefania; Caruso, Nadia; De Stefano, Laura; Bisconte, Maria Grazia; Gentile, Carlo; Morabito, Fortunato

2011-02-01

insights into the role of the tumor microenvironment and of immune dysfunction in chronic lymphocytic leukemia (CLL) have opened the way for further augmenting the therapeutic armamentarium for CLL patients. In this respect, lenalidomide represents an exciting drug since it is able to eliminate CLL cells without immunosuppression. mechanism of action and clinical trials of lenalidomide in CLL, and suggestions for its future utilization are reviewed. The most relevant papers and the meeting abstracts published up to July 2010 were used as sources for this review. This review will help readers understand the mechanism of action of lenalidomide and will provide a comprehensive summary regarding efficacy and safety of this drug in CLL patients. lenalidomide shows good activity against CLL. However, the toxicity profile is significant and can result in serious and potentially life-threatening side effects. Definitive data from ongoing trials will aid better definition of its status in CLL therapy. Moreover, clarification of the exact mechanism(s) of action in CLL will allow more precise use of lenalidomide and design of more efficacious combination therapies.

Action understanding as inverse planning.

PubMed

Baker, Chris L; Saxe, Rebecca; Tenenbaum, Joshua B

2009-12-01

Humans are adept at inferring the mental states underlying other agents' actions, such as goals, beliefs, desires, emotions and other thoughts. We propose a computational framework based on Bayesian inverse planning for modeling human action understanding. The framework represents an intuitive theory of intentional agents' behavior based on the principle of rationality: the expectation that agents will plan approximately rationally to achieve their goals, given their beliefs about the world. The mental states that caused an agent's behavior are inferred by inverting this model of rational planning using Bayesian inference, integrating the likelihood of the observed actions with the prior over mental states. This approach formalizes in precise probabilistic terms the essence of previous qualitative approaches to action understanding based on an "intentional stance" [Dennett, D. C. (1987). The intentional stance. Cambridge, MA: MIT Press] or a "teleological stance" [Gergely, G., Nádasdy, Z., Csibra, G., & Biró, S. (1995). Taking the intentional stance at 12 months of age. Cognition, 56, 165-193]. In three psychophysical experiments using animated stimuli of agents moving in simple mazes, we assess how well different inverse planning models based on different goal priors can predict human goal inferences. The results provide quantitative evidence for an approximately rational inference mechanism in human goal inference within our simplified stimulus paradigm, and for the flexible nature of goal representations that human observers can adopt. We discuss the implications of our experimental results for human action understanding in real-world contexts, and suggest how our framework might be extended to capture other kinds of mental state inferences, such as inferences about beliefs, or inferring whether an entity is an intentional agent.

Does Joe influence Fred's action? Not if Fred has autism spectrum disorder.

PubMed

Welsh, Timothy N; Ray, Matthew C; Weeks, Daniel J; Dewey, Deborah; Elliott, Digby

2009-01-12

It has been proposed that the deficits in social interaction seen in autism spectrum disorder (ASD) arise from problems in action perception stemming from a dysfunction of the mirror neuron system (MNS)--a neural network that becomes active during the performance and observation of action. A dysfunction of this system could have a cascading effect leading to deficits in social cognition because poor activation of the MNS during action observation may lead to an incomplete understanding of another person's actions, intentions and, ultimately, mental states. The present study tested the MNS dysfunction explanation by determining if people with ASD demonstrate a between-person inhibition of return (BP-IOR) effect. The BP-IOR effect, longer reaction times to targets presented at the location of another person's previous response relative to an unresponded-to location, has been hypothesized to be the result of the MNS co-representing the observed response and subsequently activating the mechanisms that cause IOR when individuals respond on their own (within-person IOR [WP-IOR]). Consistent with the MNS dysfunction hypothesis, participants with ASD did not demonstrate a BP-IOR effect in a condition in which they only observed the movement of the partner. The participants with ASD did demonstrate a WP-IOR effect suggesting that the mechanisms underlying IOR are intact in ASD. The contrast between the BP- and WP-IOR effects in the participants with ASD provides significant behavioural evidence for MNS dysfunction in ASD and has important implications for understanding this disorder.

Computational studies of protegrin antimicrobial peptides: a review

PubMed Central

Bolintineanu, Dan S.; Kaznessis, Yiannis N.

2010-01-01

Antimicrobial peptides (AMPs) are small, naturally-occurring peptides that exhibit strong antibacterial properties generally believed to be a result of selective bacterial membrane disruption. As a result, there has been significant interest in the development of therapeutic antibiotics based on AMPs; however, the poor understanding of the fundamental mechanism of action of these peptides has largely hampered such efforts. We present a summary of computational and theoretical investigations of protegrin, a particularly potent peptide that is both an excellent model for the mechanism of action of AMPs and a promising therapeutic candidate. Experimental investigations have shed light on many of the key steps in the action of protegrin: protegrin monomers are known to dimerize in various lipid environments; protegrin peptides interact strongly with lipid bilayer membranes, particularly anionic lipids; protegrins have been shown to form pores in lipid bilayers, which results in uncontrolled ion transport and may be a key factor in bacterial death. In this work, we present a comprehensive review of the computational and theoretical studies that have complemented and extended the information obtained from experimental work with protegrins, as well as a brief survey of the experimental biophysical studies that are most pertinent to such computational work. We show that a consistent, mechanistic description of the bactericidal mechanism of action of protegrins is emerging, and briefly outline areas where the current understanding is deficient. We hope that the research reviewed herein offers compelling evidence of the benefits of computational investigations of protegrins and other AMPs, as well as providing a useful guide to future work in this area. PMID:20946928

Convergence and divergence, a concept for explaining drug actions.

PubMed

Watanabe, Takehiko; Kamisaki, Yoshinori; Timmerman, Henk

2004-10-01

For the teaching and/or learning about drug actions and for the discovery and development of new drugs, it is important to understand how drugs act on living bodies. So far, there has been no clear description on the general principle of drug action in pharmacology textbooks. We propose two principles to depict the action mechanism of drugs. The first is that most, if not all, drugs act on proteins at the molecular level, that is, enzymes, receptors, ion channels, and transporters. The second is that a drug may cause divergent or convergent responses, resulting in changes of a physiological or pathological function of the human body. The concept of divergence and convergence can be used to explain the complex individuality of drug actions.

NMDA Receptor as a Newly Identified Member of the Metabotropic Glutamate Receptor Family: Clinical Implications for Neurodegenerative Diseases

PubMed Central

Chung, ChiHye

2013-01-01

Recent reports have proposed a novel function for the N-methyl-d-aspartate (NMDA) receptor (NMDAR), a well-known excitatory, ionotropic receptor. A series of observations employing pharmacological techniques has proposed that upon ligand binding, this ionotropic receptor can actually function via signaling cascades independent of traditional ionotropic action. Moreover, the “metabotropic” action of NMDARs is suggested to mediate a form of synaptic plasticity, namely long-term synaptic depression (LTD), which shares cellular mechanisms with the synaptic deficits observed in Alzheimer’s disease. Given that a growing body of clinical and preclinical evidence strongly recommends NMDAR antagonists for their therapeutic potentials and advantages in a variety of diseases, further investigation into their molecular and cellular mechanisms is required to better understand the “metabotropic” action of NMDARs. PMID:23740429

Grasping actions and social interaction: neural bases and anatomical circuitry in the monkey

PubMed Central

Rozzi, Stefano; Coudé, Gino

2015-01-01

The study of the neural mechanisms underlying grasping actions showed that cognitive functions are deeply embedded in motor organization. In the first part of this review, we describe the anatomical structure of the motor cortex in the monkey and the cortical and sub-cortical connections of the different motor areas. In the second part, we review the neurophysiological literature showing that motor neurons are not only involved in movement execution, but also in the transformation of object physical features into motor programs appropriate to grasp them (through visuo-motor transformations). We also discuss evidence indicating that motor neurons can encode the goal of motor acts and the intention behind action execution. Then, we describe one of the mechanisms—the mirror mechanism—considered to be at the basis of action understanding and intention reading, and describe the anatomo-functional pathways through which information about the social context can reach the areas containing mirror neurons. Finally, we briefly show that a clear similarity exists between monkey and human in the organization of the motor and mirror systems. Based on monkey and human literature, we conclude that the mirror mechanism relies on a more extended network than previously thought, and possibly subserves basic social functions. We propose that this mechanism is also involved in preparing appropriate complementary response to observed actions, allowing two individuals to become attuned and cooperate in joint actions. PMID:26236258

Antidromic propagation of action potentials in branched axons: implications for the mechanisms of action of deep brain stimulation.

PubMed

Grill, Warren M; Cantrell, Meredith B; Robertson, Matthew S

2008-02-01

Electrical stimulation of the central nervous system creates both orthodromically propagating action potentials, by stimulation of local cells and passing axons, and antidromically propagating action potentials, by stimulation of presynaptic axons and terminals. Our aim was to understand how antidromic action potentials navigate through complex arborizations, such as those of thalamic and basal ganglia afferents-sites of electrical activation during deep brain stimulation. We developed computational models to study the propagation of antidromic action potentials past the bifurcation in branched axons. In both unmyelinated and myelinated branched axons, when the diameters of each axon branch remained under a specific threshold (set by the antidromic geometric ratio), antidromic propagation occurred robustly; action potentials traveled both antidromically into the primary segment as well as "re-orthodromically" into the terminal secondary segment. Propagation occurred across a broad range of stimulation frequencies, axon segment geometries, and concentrations of extracellular potassium, but was strongly dependent on the geometry of the node of Ranvier at the axonal bifurcation. Thus, antidromic activation of axon terminals can, through axon collaterals, lead to widespread activation or inhibition of targets remote from the site of stimulation. These effects should be included when interpreting the results of functional imaging or evoked potential studies on the mechanisms of action of DBS.

Understanding the process of fascial unwinding.

PubMed

Minasny, Budiman

2009-09-23

Fascial or myofascial unwinding is a process in which a client undergoes a spontaneous reaction in response to the therapist's touch. It can be induced by using specific techniques that encourage a client's body to move into areas of ease. Unwinding is a popular technique in massage therapy, but its mechanism is not well understood. In the absence of a scientific explanation or hypothesis of the mechanism of action, it can be interpreted as "mystical." This paper proposes a model that builds on the neurobiologic, ideomotor action, and consciousness theories to explain the process and mechanism of fascial unwinding. HYPOTHETICAL MODEL: During fascial unwinding, the therapist stimulates mechanoreceptors in the fascia by applying gentle touch and stretching. Touch and stretching induce relaxation and activate the parasympathetic nervous system. They also activate the central nervous system, which is involved in the modulation of muscle tone as well as movement. As a result, the central nervous system is aroused and thereby responds by encouraging muscles to find an easier, or more relaxed, position and by introducing the ideomotor action. Although the ideomotor action is generated via normal voluntary motor control systems, it is altered and experienced as an involuntary response. Fascial unwinding occurs when a physically induced suggestion by a therapist prompts ideomotor action that the client experiences as involuntary. This action is guided by the central nervous system, which produces continuous action until a state of ease is reached. Consequently, fascial unwinding can be thought of as a neurobiologic process employing the self-regulation dynamic system theory.

The Use of Nonsteroidal Anti-Inflammatory Drugs in Sports.

ERIC Educational Resources Information Center

Calabrese, Leonard H.; Rooney, Theodore W.

1986-01-01

Recent advances in the understanding of the mechanism of action and clinical pharmacology of the new nonsteroidal anti-inflammatory drugs (NSAIDs) can help practitioners decide which to use and how to administer them. Indications for and effects of NSAIDs are described. (MT)

The role of mirroring and mentalizing networks in mediating action intentions in autism.

PubMed

Libero, Lauren E; Maximo, Jose O; Deshpande, Hrishikesh D; Klinger, Laura G; Klinger, Mark R; Kana, Rajesh K

2014-01-01

The ability to interpret agents' intent from their actions is a vital skill in successful social interaction. However, individuals with autism spectrum disorders (ASD) have been found to have difficulty in attributing intentions to others. The present study investigated the neural mechanisms of inferring intentions from actions in individuals with ASD. Functional magnetic resonance imaging (fMRI) data were acquired from 21 high-functioning young adults with ASD and 22 typically developing (TD) control participants, while making judgments about the means (how an action is performed) and intention (why an action is performed) of a model's actions. Across both groups of participants, the middle and superior temporal cortex, extending to temporoparietal junction, and posterior cingulate cortex, responded significantly to inferring the intent of an action, while inferior parietal lobule and occipital cortices were active for judgments about the means of an action. Participants with ASD had significantly reduced activation in calcarine sulcus and significantly increased activation in left inferior frontal gyrus, compared to TD peers, while attending to the intentions of actions. Also, ASD participants had weaker functional connectivity between frontal and posterior temporal regions while processing intentions. These results suggest that processing actions and intentions may not be mutually exclusive, with reliance on mirroring and mentalizing mechanisms mediating action understanding. Overall, inferring information about others' actions involves activation of the mirror neuron system and theory-of-mind regions, and this activation (and the synchrony between activated brain regions) appears altered in young adults with ASD.

Low-level laser therapy for fat layer reduction: a comprehensive review.

PubMed

Avci, Pinar; Nyame, Theodore T; Gupta, Gaurav K; Sadasivam, Magesh; Hamblin, Michael R

2013-08-01

Low-level laser (light) therapy (LLLT) is a noninvasive, nonthermal approach to disorders requiring reduction of pain and inflammation and stimulation of healing and tissue regeneration. Within the last decade, LLLT started being investigated as an adjuvant to liposuction, for noninvasive body contouring, reduction of cellulite, and improvement of blood lipid profile. LLLT may also aid autologous fat transfer procedures by enhancing the viability of adipocytes. However the underlying mechanism of actions for such effects still seems to be unclear. It is important, therefore, to understand the potential efficacy and proposed mechanism of actions of this new procedure for fat reduction. A review of the literature associated with applications of LLLT related to fat layer reduction was performed to evaluate the findings from pre-clinical and clinical studies with respect to the mechanism of action, efficacy, and safety. The studies as of today suggest that LLLT has a potential to be used in fat and cellulite reduction as well as in improvement of blood lipid profile without any significant side effects. One of the main proposed mechanism of actions is based upon production of transient pores in adipocytes, allowing lipids to leak out. Another is through activation of the complement cascade which could cause induction of adipocyte apoptosis and subsequent release of lipids. Although the present studies have demonstrated safety and efficacy of LLLT in fat layer reduction, studies demonstrating the efficacy of LLLT as a stand-alone procedure are still inadequate. Moreover, further studies are necessary to identify the mechanism of action. Copyright © 2013 Wiley Periodicals, Inc.

Low-Level Laser Therapy for Fat Layer Reduction: A Comprehensive Review

PubMed Central

Avci, Pinar; Nyame, Theodore T.; Gupta, Gaurav K.; Sadasivam, Magesh; Hamblin, Michael R.

2013-01-01

Background and Objective Low-level laser (light) therapy (LLLT) is a noninvasive, nonthermal approach to disorders requiring reduction of pain and inflammation and stimulation of healing and tissue regeneration. Within the last decade, LLLT started being investigated as an adjuvant to liposuction, for noninvasive body contouring, reduction of cellulite, and improvement of blood lipid profile. LLLT may also aid autologous fat transfer procedures by enhancing the viability of adipocytes. However the underlying mechanism of actions for such effects still seems to be unclear. It is important, therefore, to understand the potential efficacy and proposed mechanism of actions of this new procedure for fat reduction. Materials and Methods A review of the literature associated with applications of LLLT related to fat layer reduction was performed to evaluate the findings from pre-clinical and clinical studies with respect to the mechanism of action, efficacy, and safety. Results The studies as of today suggest that LLLT has a potential to be used in fat and cellulite reduction as well as in improvement of blood lipid profile without any significant side effects. One of the main proposed mechanism of actions is based upon production of transient pores in adipocytes, allowing lipids to leak out. Another is through activation of the complement cascade which could cause induction of adipocyte apoptosis and subsequent release of lipids. Conclusion Although the present studies have demonstrated safety and efficacy of LLLT in fat layer reduction, studies demonstrating the efficacy of LLLT as a stand-alone procedure are still inadequate. Moreover, further studies are necessary to identify the mechanism of action. PMID:23749426

Neural hijacking: action of high-frequency electrical stimulation on cortical circuits.

PubMed

Cheney, P D; Griffin, D M; Van Acker, G M

2013-10-01

Electrical stimulation of the brain was one of the first experimental methods applied to understanding brain organization and function and it continues as a highly useful method both in research and clinical applications. Intracortical microstimulation (ICMS) involves applying electrical stimuli through a microelectrode suitable for recording the action potentials of single neurons. ICMS can be categorized into single-pulse stimulation; high-frequency, short-duration stimulation; and high-frequency, long-duration stimulation. For clinical and experimental reasons, considerable interest focuses on the mechanism of neural activation by electrical stimuli. In this article, we discuss recent results suggesting that action potentials evoked in cortical neurons by high-frequency electrical stimulation do not sum with the natural, behaviorally related background activity; rather, high-frequency stimulation eliminates and replaces natural activity. We refer to this as neural hijacking. We propose that a major component of the mechanism underlying neural hijacking is excitation of axons by ICMS and elimination of natural spikes by antidromic collision with stimulus-driven spikes evoked at high frequency. Evidence also supports neural hijacking as an important mechanism underlying the action of deep brain stimulation in the subthalamic nucleus and its therapeutic effect in treating Parkinson's disease.

CCR scientists gain new understanding of cellular mechanisms during infection | Center for Cancer Research

Cancer.gov

A new study published August 10, 2017, in Molecular Cell reveals how changes in the architecture of the nucleus can enable B lymphocytes to spring to action during an immune system attack and help fight infection. The discovery could lead scientists to a better understanding of how some tumor cells, especially blood cancer cells, make similar transitions from a dormant to an

Human health effects of air pollution.

PubMed Central

Folinsbee, L J

1993-01-01

Over the past three or four decades, there have been important advances in the understanding of the actions, exposure-response characteristics, and mechanisms of action of many common air pollutants. A multidisciplinary approach using epidemiology, animal toxicology, and controlled human exposure studies has contributed to the database. This review will emphasize studies of humans but will also draw on findings from the other disciplines. Air pollutants have been shown to cause responses ranging from reversible changes in respiratory symptoms and lung function, changes in airway reactivity and inflammation, structural remodeling of pulmonary airways, and impairment of pulmonary host defenses, to increased respiratory morbidity and mortality. Quantitative and qualitative understanding of the effects of a small group of air pollutants has advanced considerably, but the understanding is by no means complete, and the breadth of effects of all air pollutants is only partially understood. PMID:8354181

Analysis of Growth and Molecular Responses to Ethylene in Etiolated Rice Seedlings.

PubMed

Ma, Biao; Zhang, Jin-Song

2017-01-01

Ethylene plays a key role in various submergence responses of rice plants, but the mechanism of ethylene action remains largely unclear in rice. Regarding the differences between rice and Arabidopsis in ethylene-regulated processes, rice plants may possess divergent mechanisms in ethylene signaling in addition to the conserved aspects. Forward genetic analysis is essential to fully understand the ethylene signaling mechanism in rice. Here, we describe a method for screening ethylene-response mutants and evaluating ethylene responsiveness in etiolated rice seedlings.

Eighth International Chorea-Acanthocytosis Symposium: Summary of Workshop Discussion and Action Points.

PubMed

Pappas, Samuel S; Bonifacino, Juan; Danek, Adrian; Dauer, William T; De, Mithu; De Franceschi, Lucia; DiPaolo, Gilbert; Fuller, Robert; Haucke, Volker; Hermann, Andreas; Kornmann, Benoit; Landwehrmeyer, Bernhard; Levin, Johannes; Neiman, Aaron M; Rudnicki, Dobrila D; Sibon, Ody; Velayos-Baeza, Antonio; Vonk, Jan J; Walker, Ruth H; Weisman, Lois S; Albin, Roger L

2017-01-01

Chorea-Acanthocytosis (ChAc) is a rare hereditary neurological disorder characterized by abnormal movements, red blood cell pathology, and progressive neurodegeneration. Little is understood of the pathogenesis of ChAc and related disorders (collectively Neuroacanthocytosis). The Eighth International Chorea-Acanthocytosis Symposium was held in May 2016 in Ann Arbor, MI, USA, and focused on molecular mechanisms driving ChAc pathophysiology. Accompanying the meeting, members of the neuroacanthocytosis research community and other invited scientists met in a workshop to discuss the current understanding and next steps needed to better understand ChAc pathogenesis. These discussions identified several broad and critical needs for advancing ChAc research and patient care, and led to the definition of 18 specific action points related to functional and molecular studies, animal models, and clinical research. These action points, described below, represent tractable research goals to pursue for the next several years.

Colour Vision: Understanding #TheDress.

PubMed

Brainard, David H; Hurlbert, Anya C

2015-06-29

A widely-viewed image of a dress elicits striking individual variation in colour perception. Experiments with multiple variants of the image suggest that the individual differences may arise through the action of visual mechanisms that normally stabilise object colour. Copyright © 2015 Elsevier Ltd. All rights reserved.

Exploring biomedical applications of cotton

USDA-ARS?s Scientific Manuscript database

The use of cotton as a biomaterial for design of improved wound dressings, and other non-implantable medical textiles will be considered. The research and development of cotton-based wound dressings, which possess a mechanism-based mode of action, has entered a new level of understanding in recent ...

Central and Peripheral Mechanisms of Antipsychotic Medication-Induced Metabolic Dysregulation

DTIC Science & Technology

2017-10-01

hepatic insulin action; we have found that our diet induced obese , glucose and insulin intolerant animals survive the surgery well, and have stable...significantly contribute to our fundamental understanding of obesity and lead to novel treatments. Since APD-induced metabolic disturbances also

TOXICOPROTEOMICS AND ITS APPLICATION TO HUMAN HEALTH RISK ASSESSMENT

EPA Science Inventory

Humans are exposed to a variety of environmental toxicants, and this together with a large number of interacting factors can contribute to an individual's risk for health. To understand the toxic mechanisms and/or modes of action for human health risk assessment, molecular charac...

The mirror mechanism and mu rhythm in social development.

PubMed

Vanderwert, Ross E; Fox, Nathan A; Ferrari, Pier F

2013-04-12

Since the discovery of mirror neurons (MNs) in the monkey there has been a renewed interest in motor theories of cognitive and social development in humans by providing a potential neural mechanism underlying an action observation/execution matching system. It has been proposed that this system plays a fundamental role in the development of complex social and cognitive behaviors such as imitation and action recognition. In this review we discuss what is known about MNs from the work using single-cell recordings in the adult monkey, the evidence for the putative MN system in humans, and the extent to which research using electroencephalography (EEG) methods has contributed to our understanding of the development of these motor systems and their role in the social behaviors postulated by the MN hypothesis. We conclude with directions for future research that will improve our understanding of the putative human MN system and the functional role of MNs in social development. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Proteomics in Traditional Chinese Medicine with an Emphasis on Alzheimer's Disease

PubMed Central

Sulistio, Yanuar Alan

2015-01-01

In recent years, there has been an increasing worldwide interest in traditional Chinese medicine (TCM). This increasing demand for TCM needs to be accompanied by a deeper understanding of the mechanisms of action of TCM-based therapy. However, TCM is often described as a concept of Chinese philosophy, which is incomprehensible for Western medical society, thereby creating a gap between TCM and Western medicine (WM). In order to meet this challenge, TCM research has applied proteomics technologies for exploring the mechanisms of action of TCM treatment. Proteomics enables TCM researchers to oversee various pathways that are affected by treatment, as well as the dynamics of their interactions with one another. This review discusses the utility of comparative proteomics to better understand how TCM treatment may be used as a complementary therapy for Alzheimer's disease (AD). Additionally, we review the data from comparative AD-related TCM proteomics studies and establish the relevance of the data with available AD hypotheses, most notably regarding the ubiquitin proteasome system (UPS). PMID:26557146

Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis.

PubMed

Varela, Luis; Horvath, Tamas L

2012-12-01

With the steady rise in the prevalence of obesity and its associated diseases, research aimed at understanding the mechanisms that regulate and control whole body energy homeostasis has gained new interest. Leptin and insulin, two anorectic hormones, have key roles in the regulation of body weight and energy homeostasis, as highlighted by the fact that several obese patients develop resistance to these hormones. Within the brain, the hypothalamic proopiomelanocortin and agouti-related protein neurons have been identified as major targets of leptin and insulin action. Many studies have attempted to discern the individual contributions of various components of the principal pathways that mediate the central effects of leptin and insulin. The aim of this review is to discuss the latest findings that might shed light on, and lead to a better understanding of, energy balance and glucose homeostasis. In addition, recently discovered targets and mechanisms that mediate hormonal action in the brain are highlighted.

Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis

PubMed Central

Varela, Luis; Horvath, Tamas L

2012-01-01

With the steady rise in the prevalence of obesity and its associated diseases, research aimed at understanding the mechanisms that regulate and control whole body energy homeostasis has gained new interest. Leptin and insulin, two anorectic hormones, have key roles in the regulation of body weight and energy homeostasis, as highlighted by the fact that several obese patients develop resistance to these hormones. Within the brain, the hypothalamic proopiomelanocortin and agouti-related protein neurons have been identified as major targets of leptin and insulin action. Many studies have attempted to discern the individual contributions of various components of the principal pathways that mediate the central effects of leptin and insulin. The aim of this review is to discuss the latest findings that might shed light on, and lead to a better understanding of, energy balance and glucose homeostasis. In addition, recently discovered targets and mechanisms that mediate hormonal action in the brain are highlighted. PMID:23146889

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.

Understanding lunar magnetic field through magnetization and dynamo mechanism

NASA Astrophysics Data System (ADS)

Singh, K. H.; Kuang, W.

2016-12-01

It has been known that the Moon does not have an active global magnetic field. But past missions to the Moon (e.g. Apollo missions, Lunar Prospector) have detected magnetic anomalies in many areas on the lunar surface. They carry rich information about geophysical processes on and within the Moon, thus central for understanding the structure and dynamics in the interior, e.g. the core and the suggested magma ocean. One unsettling problem for understanding the lunar magnetic anomaly is its origin. There have been several mechanisms suggested in the past, either on the anomalies in specific regions, or only at the conceptual stage. The latter include the paleo dynamo. The lunar dynamo mechanism is conceptually very simple: lunar crustal magnetization was acquired in an internal magnetic field that was generated and maintained by dynamo action in the lunar core. Could this simple mechanism suffice to explain most of the observed lunar magnetic anomalies? We present our theoretical calculations of possible paleo-lunar magnetic field strengths based on paleomagnetic measurements of Apollo samples.

Intravenous immunoglobulins – understanding properties and mechanisms

PubMed Central

Durandy, A; Kaveri, S V; Kuijpers, T W; Basta, M; Miescher, S; Ravetch, J V; Rieben, R

2009-01-01

High-dose intravenous immunoglobulin (IVIg) preparations are used currently for the treatment of autoimmune or inflammatory diseases. Despite numerous studies demonstrating efficacy, the precise mode of action of IVIg remains unclear. Paradoxically, IgG can exert both pro- and anti-inflammatory activities, depending on its concentration. The proinflammatory activity of low-dose IVIg requires complement activation or binding of the Fc fragment of IgG to IgG-specific receptors (FcγR) on innate immune effector cells. In contrast, when administered in high concentrations, IVIg has anti-inflammatory properties. How this anti-inflammatory effect is mediated has not yet been elucidated fully, and several mutually non-exclusive mechanisms have been proposed. This paper represents the proceedings of a session entitled ‘IVIg – Understanding properties and mechanisms’ at the 6th International Immunoglobulin Symposium that was held in Interlaken on 26–28 March 2009. The presentations addressed how IgG may affect the cellular compartment, evidence for IVIg-mediated scavenging of complement fragments, the role of the dimeric fraction of IVIg, the anti-inflammatory properties of the minor fraction of sialylated IgG molecules, and the genetic organization and variation in FcγRs. These findings demonstrate the considerable progress that has been made in understanding the mechanisms of action of IVIgs, and may influence future perspectives in the field of Ig therapy. PMID:19883419

Estradiol's interesting life at the cell's plasma membrane.

PubMed

Caldwell, J D; Gebhart, V M; Jirikowski, G F

2016-07-01

Clearly, we have presented here evidence of a very complex set of mechanisms and proteins involved with various and intricate actions of steroids at the plasma membrane. Steroids do MUCH more at the plasma membrane than simply passing passively through it. They may sit in the membrane; they are bound by numerous proteins in the membrane, including ERs, SHBG, steroid-binding globulin receptors, and perhaps elements of cellular architecture such as tubulin. It also seems likely that the membrane itself responds graphically to the presence of steroids by actually changing its shape as well, perhaps, as accumulating steroids. Clara Szego suggested in the 1980s that actions of E2 at one level would act synergistically with its actions at another level (e.g. membrane actions would complement nuclear actions). Given the sheer number of proteins involved in steroid actions, just at the membrane level, it seems unlikely that every action of a steroid on every potential protein effector will act to the same end. It seems more likely that these multiple effects and sites of effect of steroids contribute to the confusion that exists as to what actions steroids always have. For example, there is confusion with regard to synthetic agents (SERMs etc.) that have different and often opposite actions depending on which organ they act upon. A better understanding of the basic actions of steroids should aid in understanding the variability of their clinical effects. Copyright © 2016 Elsevier Inc. All rights reserved.

Potential Molecular Mechanisms on the Role of the Sigma-1 Receptor in the Action of Cocaine and Methamphetamine

PubMed Central

Yasui, Yuko; Su, Tsung-Ping

2016-01-01

The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum membrane protein that involves a wide range of physiological functions. The Sig-1R has been shown to bind psychostimulants including cocaine and methamphetamine (METH) and thus has been implicated in the actions of those psychostimulants. For example, it has been demonstrated that the Sig-1R antagonists mitigate certain behavioral and cellular effects of psychostimulants including hyperactivity and neurotoxicity. Thus, the Sig-1R has become a potential therapeutic target of medication development against drug abuse that differs from traditional monoamine-related strategies. In this review, we will focus on the molecular mechanisms of the Sig-1R and discuss in such a manner with a hope to further understand or unveil unexplored relations between the Sig-1R and the actions of cocaine and METH, particularly in the context of cellular biological relevance. PMID:27088037

Imitation, empathy, and mirror neurons.

PubMed

Iacoboni, Marco

2009-01-01

There is a convergence between cognitive models of imitation, constructs derived from social psychology studies on mimicry and empathy, and recent empirical findings from the neurosciences. The ideomotor framework of human actions assumes a common representational format for action and perception that facilitates imitation. Furthermore, the associative sequence learning model of imitation proposes that experience-based Hebbian learning forms links between sensory processing of the actions of others and motor plans. Social psychology studies have demonstrated that imitation and mimicry are pervasive, automatic, and facilitate empathy. Neuroscience investigations have demonstrated physiological mechanisms of mirroring at single-cell and neural-system levels that support the cognitive and social psychology constructs. Why were these neural mechanisms selected, and what is their adaptive advantage? Neural mirroring solves the "problem of other minds" (how we can access and understand the minds of others) and makes intersubjectivity possible, thus facilitating social behavior.

A Brief Review of the Pharmacology of Amitriptyline and Clinical Outcomes in Treating Fibromyalgia

PubMed Central

Lawson, Kim

2017-01-01

Fibromyalgia is a complex chronic condition characterized by pain, physical fatigue, sleep disorder and cognitive impairment. Evidence-based guidelines recommend antidepressants as treatments of fibromyalgia where tricyclics are often considered to have the greatest efficacy, with amitriptyline often being a first-line treatment. Amitriptyline evokes a preferential reduction in pain and fatigue of fibromyalgia, and in the Fibromyalgia Impact Questionnaire (FIQ) score, which is a quality of life assessment. The multimodal profile of the mechanisms of action of amitriptyline include monoamine reuptake inhibition, receptor modulation and ion channel modulation. Several of the actions of amitriptyline on multiple nociceptive and sensory processes at central and peripheral locations have the potential to act cumulatively to suppress the characteristic symptoms of fibromyalgia. Greater understanding of the role of these mechanisms of action of amitriptyline could provide further clues to the pathophysiology of fibromyalgia and to a preferable pharmacological profile for future drug development. PMID:28536367

Gambling and the Reasoned Action Model: Predicting Past Behavior, Intentions, and Future Behavior.

PubMed

Dahl, Ethan; Tagler, Michael J; Hohman, Zachary P

2018-03-01

Gambling is a serious concern for society because it is highly addictive and is associated with a myriad of negative outcomes. The current study applied the Reasoned Action Model (RAM) to understand and predict gambling intentions and behavior. Although prior studies have taken a reasoned action approach to understand gambling, no prior study has fully applied the RAM or used the RAM to predict future gambling. Across two studies the RAM was used to predict intentions to gamble, past gambling behavior, and future gambling behavior. In study 1 the model significantly predicted intentions and past behavior in both a college student and Amazon Mechanical Turk sample. In study 2 the model predicted future gambling behavior, measured 2 weeks after initial measurement of the RAM constructs. This study stands as the first to show the utility of the RAM in predicting future gambling behavior. Across both studies, attitudes and perceived normative pressure were the strongest predictors of intentions to gamble. These findings provide increased understanding of gambling and inform the development of gambling interventions based on the RAM.

Uncovering the mechanism(s) of deep brain stimulation

NASA Astrophysics Data System (ADS)

Gang, Li; Chao, Yu; Ling, Lin; C-Y Lu, Stephen

2005-01-01

Deep brain stimulators, often called `pacemakers for the brain', are implantable devices which continuously deliver impulse stimulation to specific targeted nuclei of deep brain structure, namely deep brain stimulation (DBS). To date, deep brain stimulation (DBS) is the most effective clinical technique for the treatment of several medically refractory movement disorders (e.g., Parkinson's disease, essential tremor, and dystonia). In addition, new clinical applications of DBS for other neurologic and psychiatric disorders (e.g., epilepsy and obsessive-compulsive disorder) have been put forward. Although DBS has been effective in the treatment of movement disorders and is rapidly being explored for the treatment of other neurologic disorders, the scientific understanding of its mechanisms of action remains unclear and continues to be debated in the scientific community. Optimization of DBS technology for present and future therapeutic applications will depend on identification of the therapeutic mechanism(s) of action. The goal of this review is to address our present knowledge of the effects of high-frequency stimulation within the central nervous system and comment on the functional implications of this knowledge for uncovering the mechanism(s) of DBS.

Unpacking 'Artemisinin Resistance'.

PubMed

Wang, Jigang; Xu, Chengchao; Lun, Zhao-Rong; Meshnick, Steven R

2017-06-01

Artemisinin and its derivatives, in combination with partner drugs, are currently the most effective treatments for malaria parasite infection. Even though artemisinin has been widely used for decades, its mechanism of action had remained controversial until recently. Artemisinin combination therapies (ACTs) have recently been found to be losing efficacy in Southeast Asia. This 'artemisinin resistance', defined by a delayed parasite clearance time, has been associated with several genetic mutations. As with any other drug resistance phenotype, resistance can best be understood based on its mechanism of action. Recently, it was demonstrated that artemisinin attacks multiple parasitic targets, suggesting that mutations in drug targets are unlikely to cause high-level artemisinin resistance. These findings will help us to better understand the mechanisms of artemisinin resistance and suggest protocol modifications that may improve the efficacy of ACTs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Facilitating Understanding of Movements in Dynamic Visualizations: An Embodied Perspective

ERIC Educational Resources Information Center

de Koning, Bjorn B.; Tabbers, Huib K.

2011-01-01

Learners studying mechanical or technical processes via dynamic visualizations often fail to build an accurate mental representation of the system's movements. Based on embodied theories of cognition assuming that action, perception, and cognition are closely intertwined, this paper proposes that the learning effectiveness of dynamic…

Utilizing Toxicogenomic Data to Understand Chemical Mechanism of Action in Risk Assessment

EPA Science Inventory

A recent National Academy of Sciences report pointed to the strong potential for genomic technologies to contribute to the risk assessment process. The report, however, also acknowledged that neither has the full impact of genomic technology been realized nor has it been broadly ...

Systematic Evaluation of Dissolved Lead Sorption Losses to Particulate Syringe Filter Materials

EPA Science Inventory

Distinguishing between soluble and particulate lead in drinking water is useful in understanding the mechanism of lead release and identifying remedial action. Typically, particulate lead is defined as the amount of lead removed by a 0.45 µm filter. Unfortunately, there is little...

Exploring biomedical ppplications of cotton

USDA-ARS?s Scientific Manuscript database

The use of cotton as a biomaterial for design of improved wound dressings, and other non-implantable medical textiles will be considered. The research and development of cotton-based wound dressings, which possess a mechanism-based mode of action, has entered a new level of understanding in recent y...

Glucocorticoids: exemplars of multi-tasking

PubMed Central

Buckingham, Julia C

2006-01-01

Well over 80 years ago Philip Smith described the beneficial clinical effects of adrenocortical extracts in animal models of adrenal insufficiency. In the ensuing years, scientists across the globe have sought to understand the mechanisms by which adrenal hormones and their synthetic analogues produce their complex and varied actions. Particular attention has focused on the glucocorticoids, partly because they have a vital place in the treatment of inflammatory and autoimmune disorders but also because dysregulation of the secretion and/or activity of endogenous glucocorticoids is increasingly implicated in a number of common disorders that pose a growing clinical burden, such as obesity, type II diabetes, the metabolic syndrome, hypertension and depression. This review considers some of the key advances that have been made in our understanding of the physiology, pathology and pharmacology of the glucocorticoids. Emphasis is placed on the molecular mechanisms of glucocorticoid signalling and the complex mechanisms that regulate the access of steroids in the systemic circulation to their receptors in their various target cells and tissues. In addition, consideration is given to the irreversible ‘organisational' actions of glucocorticoids in perinatal life and to the potential role of the steroids in the aetiology of disease. PMID:16402112

Botanical modulation of menopausal symptoms: Mechanisms of action?

PubMed Central

Hajirahimkhan, Atieh; Dietz, Birgit M.; Bolton, Judy L.

2013-01-01

Menopausal women suffer from a variety of symptoms, including hot flashes and night sweats which can affect quality of life. Although hormone therapy (HT) has been the treatment of choice for relieving these symptoms, HT has been associated with increased breast cancer risk leading many women to search for natural, efficacious, and safe alternatives such as botanical supplements. Data from clinical trials suggesting that botanicals have efficacy for menopausal symptom relief, have been controversial and several mechanisms of action have been proposed including estrogenic, progestogenic, and serotonergic pathways. Plant extracts with potential estrogenic activities include soy, red clover, kudzu, hops, licorice, rhubarb, yam, and chasteberry. Botanicals with reported progestogenic activities are red clover, hops, yam, and chasteberry. Serotonergic mechanisms have also been proposed since women taking antidepressants often report reduction in hot flashes and night sweats. Black cohosh, kudzu, kava, licorice, and dong quai all either have reported 5-HT7 ligands or inhibit serotonin re-uptake, therefore have potential serotonergic activities. Understanding the mechanisms of action of these natural remedies used for women’s health, could lead to more efficacious formulations and to the isolation of active components which have the potential of becoming effective medications in the future. PMID:23408273

On the Control of Social Approach-Avoidance Behavior: Neural and Endocrine Mechanisms.

PubMed

Kaldewaij, Reinoud; Koch, Saskia B J; Volman, Inge; Toni, Ivan; Roelofs, Karin

The ability to control our automatic action tendencies is crucial for adequate social interactions. Emotional events trigger automatic approach and avoidance tendencies. Although these actions may be generally adaptive, the capacity to override these emotional reactions may be key to flexible behavior during social interaction. The present chapter provides a review of the neuroendocrine mechanisms underlying this ability and their relation to social psychopathologies. Aberrant social behavior, such as observed in social anxiety or psychopathy, is marked by abnormalities in approach-avoidance tendencies and the ability to control them. Key neural regions involved in the regulation of approach-avoidance behavior are the amygdala, widely implicated in automatic emotional processing, and the anterior prefrontal cortex, which exerts control over the amygdala. Hormones, especially testosterone and cortisol, have been shown to affect approach-avoidance behavior and the associated neural mechanisms. The present chapter also discusses ways to directly influence social approach and avoidance behavior and will end with a research agenda to further advance this important research field. Control over approach-avoidance tendencies may serve as an exemplar of emotional action regulation and might have a great value in understanding the underlying mechanisms of the development of affective disorders.

CCR scientists gain new understanding of cellular mechanisms during infection | Center for Cancer Research

Cancer.gov

A new study published August 10, 2017, in Molecular Cell reveals how changes in the architecture of the nucleus can enable B lymphocytes to spring to action during an immune system attack and help fight infection. The discovery could lead scientists to a better understanding of how some tumor cells, especially blood cancer cells, make similar transitions from a dormant to an active state. Read more. . .

You can't always get what you want: infants understand failed goal-directed actions.

PubMed

Brandone, Amanda C; Wellman, Henry M

2009-01-01

At what age do infants understand that goals exist independently of the actions that result from them? Exploring infants' understanding of failed intentional actions-when the goal of the action is unfulfilled and thus not apparent in the actor's movements-is a critical step in answering this question. Using a visual habituation paradigm, we assessed when infants understand that a failed intentional action is goal directed and whether an understanding of successful intentional actions (actions that do overtly attain their goals) precedes an understanding of failed intentional actions. Results demonstrated that 10- and 12-month-olds recognized the goal directedness of both successful and failed reaching actions. Eight-month-olds also recognized the goal directedness of successful actions, but not of unsuccessful attempts. Thus, by the end of the 1st year of life, infants possess an impressive understanding of intentional action, and an understanding of failed intentional actions follows an earlier understanding of successful ones.

Mirror neuron system: basic findings and clinical applications.

PubMed

Iacoboni, Marco; Mazziotta, John C

2007-09-01

In primates, ventral premotor and rostral inferior parietal neurons fire during the execution of hand and mouth actions. Some cells (called mirror neurons) also fire when hand and mouth actions are just observed. Mirror neurons provide a simple neural mechanism for understanding the actions of others. In humans, posterior inferior frontal and rostral inferior parietal areas have mirror properties. These human areas are relevant to imitative learning and social behavior. Indeed, the socially isolating condition of autism is associated with a deficit in mirror neuron areas. Strategies inspired by mirror neuron research recently have been used in the treatment of autism and in motor rehabilitation after stroke.

The Sturm und Drang of anabolic steroid use: angst, anxiety, and aggression

PubMed Central

Oberlander, Joseph G.; Henderson, Leslie P.

2014-01-01

Anabolic androgenic steroids (AAS) are illicitly administered to enhance athletic performance and body image. Although conferring positive actions on performance, steroid abuse is associated with changes in anxiety and aggression. AAS users are often keenly invested in understanding the biological actions of these drugs. Thus, mechanistic information on AAS actions is important not only for the biomedical community, but also for steroid users. Here we review findings from animal studies on the impact of AAS exposure on neural systems that are crucial for the production of anxiety and aggression, and compare the effects of the different classes of AAS and their potential signaling mechanisms, as well as context-, age- and sex-dependent aspects of their actions. PMID:22516619

Molecular mechanisms of immunosuppression.

PubMed

Baumann, G; Zenke, G; Wenger, R; Hiestand, P; Quesniaux, V; Andersen, E; Schreier, M H

1992-04-01

The immunosuppressive drug cyclosporin A (CsA, Sandimmun, SIM) is currently being evaluated in a variety of autoimmune disorders with some remarkable successes. Despite the wide empiric application of CsA, the precise mechanism of action of this drug remains elusive. To identify the molecular mode of action of CsA in the process of T cell activation, we have compared the biological profile of cyclophilin-binding cyclosporin analogues (CBCA), which lack immunosuppressive properties, with CsA. We have found that CsA binding to its intracellular receptor (cyclophilin) is required but not sufficient for immunosuppression. Moreover, inhibition of the peptidyl-prolyl cis-trans isomerase activity of cyclophilin does not seem to be relevant for the inhibitory effects of CsA. In analogy to the immunosuppressants FK506 and rapamycin, a specific structure at the 'effector' domain of the CsA molecule different from the immunophilin 'binding' domain determines the biological activity. Overall, a significant understanding of the structure-activity relationship of CsA has emerged. This will have a major impact on the identification of the precise mechanism of action of CsA and its side effects in the process of immunosuppression.

The mechanism of action of Russian propolis ethanol extracts against two antibiotic-resistant biofilm-forming bacteria.

PubMed

Bryan, J; Redden, P; Traba, C

2016-02-01

The interaction between antibiotic-resistant Staphylococcus aureus and antibiotic-sensitive Escherichia coli biofilm-forming bacteria and Russian propolis ethanol extracts was evaluated. In this study, bacterial cell death occurred when the cell membranes of bacteria interacted specifically with the antibacterial compounds found in propolis. In order to understand the Russian propolis ethanol extract mechanism of action, microscopy and bacterial lysis studies were conducted. Results uncovered from these experiments imply that the mechanism of action of Russian propolis ethanol extracts is structural rather than functional. The results obtained throughout this study demonstrate cell membrane damage, resulting in cell lysis and eventually bacterial death. Most strains of bacteria and subsequently biofilms, have evolved and have altered their chemical composition in an attempt to protect themselves from antibiotics. The resistant nature of bacteria stems from the chemical rather than the physical means of inactivation of antibiotics. The results uncovered in this work demonstrate the potential application of Russian propolis ethanol extracts as a very efficient and effective method for bacterial and biofilm inactivation. © 2015 The Society for Applied Microbiology.

Does levonorgestrel emergency contraceptive have a post-fertilization effect? A review of its mechanism of action

PubMed Central

Peck, Rebecca; Rella, Walter; Tudela, Julio; Aznar, Justo; Mozzanega, Bruno

2016-01-01

Background Recent studies have identified that levonorgestrel administered orally in emergency contraception (LNG-EC) is only efficacious when taken before ovulation. However, the drug does not consistently prevent follicular rupture or impair sperm function. Objective The present systematic review is performed to analyze and more precisely define the extent to which pre-fertilization mechanisms of action may explain the drug's efficacy in pregnancy avoidance. We also examine the available evidence to determine if pre-ovulatory drug administration may be associated with post-fertilization effects. Conclusion The mechanism of action of LNG-EC is reviewed. The drug has no ability to alter sperm function at doses used in vivo and has limited ability to suppress ovulation. Our analysis estimates that the drug's ovulatory inhibition potential could prevent less than 15 percent of potential conceptions, thus making a pre-fertilization mechanism of action significantly less likely than previously thought. Luteal effects (such as decreased progesterone, altered glycodelin levels, and shortened luteal phase) present in the literature may suggest a pre-ovulatory induced post-fertilization drug effect. Lay Summary Plan B is the most widely used emergency contraceptive available. It is important for patients and physicians to clearly understand the drug’s mechanism of action (MOA). The drug was originally thought to work by preventing fertilization. Recent research has cast doubt on this. Our review of the research suggests that it could act in a pre-fertilization capacity, and we estimate that it could prevent ovulation in only 15 percent or less of cases. The drug has no ability to alter sperm function and limited ability to suppress ovulation. Further, data suggest that when administered pre-ovulation, it may have a post-fertilization MOA. PMID:27833181

Does levonorgestrel emergency contraceptive have a post-fertilization effect? A review of its mechanism of action.

PubMed

Peck, Rebecca; Rella, Walter; Tudela, Julio; Aznar, Justo; Mozzanega, Bruno

2016-02-01

Recent studies have identified that levonorgestrel administered orally in emergency contraception (LNG-EC) is only efficacious when taken before ovulation. However, the drug does not consistently prevent follicular rupture or impair sperm function. The present systematic review is performed to analyze and more precisely define the extent to which pre-fertilization mechanisms of action may explain the drug's efficacy in pregnancy avoidance. We also examine the available evidence to determine if pre-ovulatory drug administration may be associated with post-fertilization effects. The mechanism of action of LNG-EC is reviewed. The drug has no ability to alter sperm function at doses used in vivo and has limited ability to suppress ovulation. Our analysis estimates that the drug's ovulatory inhibition potential could prevent less than 15 percent of potential conceptions, thus making a pre-fertilization mechanism of action significantly less likely than previously thought. Luteal effects (such as decreased progesterone, altered glycodelin levels, and shortened luteal phase) present in the literature may suggest a pre-ovulatory induced post-fertilization drug effect. Plan B is the most widely used emergency contraceptive available. It is important for patients and physicians to clearly understand the drug's mechanism of action (MOA). The drug was originally thought to work by preventing fertilization. Recent research has cast doubt on this. Our review of the research suggests that it could act in a pre-fertilization capacity, and we estimate that it could prevent ovulation in only 15 percent or less of cases. The drug has no ability to alter sperm function and limited ability to suppress ovulation. Further, data suggest that when administered pre-ovulation, it may have a post-fertilization MOA.

The vascular endothelium in diabetes--a therapeutic target?

PubMed

Mather, Kieren J

2013-03-01

Insulin resistance affects the vascular endothelium, and contributes to systemic insulin resistance by directly impairing the actions of insulin to redistribute blood flow as part of its normal actions driving muscle glucose uptake. Impaired vascular function is a component of the insulin resistance syndrome, and is a feature of type 2 diabetes. On this basis, the vascular endothelium has emerged as a therapeutic target where the intent is to improve systemic metabolic state by improving vascular function. We review the available literature presenting studies in humans, evaluating the effects of metabolically targeted and vascular targeted therapies on insulin action and systemic metabolism. Therapies that improve systemic insulin resistance exert strong concurrent effects to improve vascular function and vascular insulin action. RAS-acting agents and statins have widely recognized beneficial effects on vascular function but have not uniformly produced the hoped-for metabolic benefits. These observations support the notion that systemic metabolic benefits can arise from therapies targeted at the endothelium, but improving vascular insulin action does not result from all treatments that improve endothelium-dependent vasodilation. A better understanding of the mechanisms of insulin's actions in the vascular wall will advance our understanding of the specificity of these responses, and allow us to better target the vasculature for metabolic benefits.

Sleep Deprivation Promotes Habitual Control over Goal-Directed Control: Behavioral and Neuroimaging Evidence.

PubMed

Chen, Jie; Liang, Jie; Lin, Xiao; Zhang, Yang; Zhang, Yan; Lu, Lin; Shi, Jie

2017-12-06

Sleep is one of the most fundamental processes of life, playing an important role in the regulation of brain function. The long-term lack of sleep can cause memory impairments, declines in learning ability, and executive dysfunction. In the present study, we evaluated the effects of sleep deprivation on instrumental learning behavior, particularly goal-directed and habitual actions in humans, and investigated the underlying neural mechanisms. Healthy college students of either gender were enrolled and randomly divided into sleep deprivation group and sleep control group. fMRI data were collected. We found that one night of sleep deprivation led to greater responsiveness to stimuli that were associated with devalued outcomes in the slips-of-action test, indicating a deficit in the formation of goal-directed control and an overreliance on habits. Furthermore, sleep deprivation had no effect on the expression of acquired goal-directed action. The level of goal-directed action after sleep deprivation was positively correlated with baseline working memory capacity. The neuroimaging data indicated that goal-directed learning mainly recruited the ventromedial PFC (vmPFC), the activation of which was less pronounced during goal-directed learning after sleep deprivation. Activation of the vmPFC during goal-directed learning during training was positively correlated with the level of goal-directed action performance. The present study suggests that people rely predominantly on habits at the expense of goal-directed control after sleep deprivation, and this process involves the vmPFC. These results contribute to a better understanding of the effects of sleep loss on decision-making. SIGNIFICANCE STATEMENT Understanding the cognitive consequences of sleep deprivation has become extremely important over the past half century, given the continued decline in sleep duration in industrialized societies. Our results provide novel evidence that goal-directed action may be particularly vulnerable to sleep loss, and the brain mechanism underlying this effect was explored. Elucidation of the effects of sleep deprivation on decision-making will deepen our understanding of the function of sleep, emphasizing the role of sleep in cognitive impairments and mental health. Copyright © 2017 the authors 0270-6474/17/3711979-14$15.00/0.

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

THE APPLICATION OF COMPUTATIONAL MOLECULAR METHODS TO UNDERSTAND THE HEALTH EFFECTS OF ENVIRONMENTAL CHEMICALS-POLYCYCLIC AROMATIC HYDROCARBONS

EPA Science Inventory

In evaluating the risk posed by chemicals introduced into the environment, information
about their molecular mechanism of action provides a basis for extrapolating from the
laboratory to the environment. Polycyclic aromatic hydrocarbons (PAH) are a large class
of...

Neuroscience and morality.

PubMed

Allison, T

2001-10-01

Humans are social animals who use specialized brain mechanisms to assess the actions of others. This system for social cognition can be studied by imaging techniques, and its damage can lead to inappropriate social and moral behavior. Neuroscience can thus enrich our understanding of behaviors traditionally thought to be outside the province of science.

Ballistocardiography in the Physics Classroom

ERIC Educational Resources Information Center

Paul, Prabasaj; Symes, Laurel B.

2008-01-01

Ballistocardiograms (BCGs) are graphical representations of the recoil from the pumping action of the heart. Introductory mechanics and a basic knowledge of the circulatory system are sufficient to understand the key features of a BCG. BCGs with adequate detail for instructional purposes may be produced easily and rapidly using hardware (a force…

Children's Use of Categories and Mental States to Predict Social Behavior

ERIC Educational Resources Information Center

Chalik, Lisa; Rivera, Cyrielle; Rhodes, Marjorie

2014-01-01

Integrating generic information about categories with knowledge of specific individuals is a critical component of successful inductive inferences. The present study tested whether children's approach to this task systematically shifts as they develop causal understandings of the mechanisms that shape individual action. In the current study, 3-and…

BDNF mRNA abundance regulated by antidromic action potentials and AP-LTD in hippocampus.

PubMed

Bukalo, Olena; Lee, Philip R; Fields, R Douglas

2016-12-02

Action-potential-induced LTD (AP-LTD) is a form of synaptic plasticity that reduces synaptic strength in CA1 hippocampal neurons firing antidromically during sharp-wave ripples. This firing occurs during slow-wave sleep and quiet moments of wakefulness, which are periods of offline replay of neural sequences learned during encoding sensory information. Here we report that rapid and persistent down-regulation of different mRNA transcripts of the BDNF gene accompanies AP-LTD, and that AP-LTD is abolished in mice with the BDNF gene knocked out in CA1 hippocampal neurons. These findings increase understanding of the mechanism of AP-LTD and the cellular mechanisms of memory consolidation. Published by Elsevier Ireland Ltd.

Bioanalytical qualification of clinical biomarker assays in plasma using a novel multi-analyte Simple Plex™ platform.

PubMed

Gupta, Vinita; Davancaze, Teresa; Good, Jeremy; Kalia, Navdeep; Anderson, Michael; Wallin, Jeffrey J; Brady, Ann; Song, An; Xu, Wenfeng

2016-12-01

Immune-checkpoint inhibitors are presumed to break down the tolerogenic state of immune cells by activating T-lymphocytes that release cytokines and enhance effector cell function for elimination of tumors. Measurement of cytokines is being pursued for better understanding of the mechanism of action of immune-checkpoint inhibitors, as well as to identify potential predictive biomarkers. In this study, we show bioanalytical qualification of cytokine assays in plasma on a novel multi-analyte immunoassay platform, Simple Plex ™ . The qualified assays exhibited excellent sensitivity as evidenced by measurement of all samples within the quantifiable range. The accuracy and precision were 80-120% and 10%, respectively. The qualified assays will be useful in assessing mechanism of action cancer immunotherapies.

Targeted therapies: a nursing perspective.

PubMed

Kay, Polly

2006-02-01

To review the development of targeted therapies and the biology of relevant therapeutic targets. To analyze the relevance of targeted agents as part of current clinical practice. Research articles. Several targeted agents are now available for clinical use. Their mechanisms of action are more specific against tumor cells than traditional cytotoxics. Monotherapy regimens based on targeted agents tend to be better tolerated than chemotherapy, and most combination regimens with targeted agents have proven feasible. Their availability has greatly expanded cancer treatment options, especially for chemorefractory patients. Nurses involved in the care of patients with cancer can benefit from an increased understanding of targeted therapies, including their mechanisms of action, their efficacy profile, as well as prophylaxis and management of adverse events and administration procedures.

Dynamin: possible mechanism of "Pinchase" action.

PubMed

Kozlov, M M

1999-07-01

Dynamin is a GTPase playing an essential role in ubiquitous intra cellular processes involving separation of vesicles from plasma membranes and membranes of cellular compartments. Recent experimental progress (. Cell. 93:1021-1029;. Cell. 94:131-141) has made it possible to attempt to understand the action of dynamin in physical terms. Dynamin molecules are shown to bind to a lipid membrane, to self-assemble into a helicoidal structure constricting the membrane into a tubule, and, as a result of GTP hydrolysis, to mediate fission of this tubule (). In a similar way, dynamin is supposed to mediate fission of a neck connecting an endocytic bud and the plasma membrane, i.e., to complete endocytosis. We suggest a mechanism of this "pinchase" action of dynamin. We propose that, as a result of GTP hydrolysis, dynamin undergoes a conformational change manifested in growth of the pitch of the dynamin helix. We show that this gives rise to a dramatic change of shape of the tubular membrane constricted inside the helix, resulting in a local tightening of the tubule, which is supposed to promote its fission. We treat this model in terms of competing elasticities of the dynamin helix and the tubular membrane and discuss the predictions of the model in relation to the previous views on the mechanism of dynamin action.

What is an affordance? 40 years later.

PubMed

Osiurak, François; Rossetti, Yves; Badets, Arnaud

2017-06-01

About 40 years ago, James J. Gibson coined the term "affordance" to describe the action possibilities offered to an animal by the environment with reference to the animal's action capabilities. Since then, this notion has acquired a multitude of meanings, generating confusion in the literature. Here, we offer a clear operationalization of the concept of affordances and related concepts in the field of tool use. Our operationalization is organized around the distinction between the physical (what is objectively observable) and neurocognitive (what is subjectively experienced) levels. This leads us to propose that motor control (dorso-dorsal system), mechanical knowledge (ventro-dorsal system) and function knowledge (ventral system) could be neurocognitive systems respectively involved in the perception of affordances, the understanding of mechanical actions and the storage of contextual relationships (three action-system model; 3AS). We end by turning to two key issues that can be addressed within 3AS. These issues concern the link between affordances and tool incorporation, and the constraints posed by affordances for tool use. Copyright © 2017 Elsevier Ltd. All rights reserved.

Traditional Chinese medicine and Western psychopharmacology: building bridges.

PubMed

Shorter, Edward; Segesser, Kathryn

2013-12-01

This paper demonstrates that in the treatment of psychiatric disorders, there are striking similarities between the mechanisms of psychoactive agents used in Traditional Chinese Medicine (TCM) and those of western psychopharmacology. While western researchers search for new treatments and novel mechanisms of action, investigators in Asia are analyzing traditional remedies in order to understand the mechanisms responsible for their effectiveness. A review of contemporary pharmacologic studies of agents used in TCM for psychiatric indications reveals that virtually all of the active principles of drug action established in 20th century psychopharmacology were encountered empirically in Chinese herbal medicine over the past 2000 years. Building bridges between these two traditions may thus be of benefit to both cultures. In addition to providing western patients with a wider selection of treatment options, the effort may help Asian clinicians and researchers avoid some of the errors that have troubled their western counterparts. Copyright © 2013 John Wiley & Sons, Ltd.

Electronic audit and feedback intervention with action implementation toolbox to improve pain management in intensive care: protocol for a laboratory experiment and cluster randomised trial.

PubMed

Gude, Wouter T; Roos-Blom, Marie-José; van der Veer, Sabine N; de Jonge, Evert; Peek, Niels; Dongelmans, Dave A; de Keizer, Nicolette F

2017-05-25

Audit and feedback is often used as a strategy to improve quality of care, however, its effects are variable and often marginal. In order to learn how to design and deliver effective feedback, we need to understand their mechanisms of action. This theory-informed study will investigate how electronic audit and feedback affects improvement intentions (i.e. information-intention gap), and whether an action implementation toolbox with suggested actions and materials helps translating those intentions into action (i.e. intention-behaviour gap). The study will be executed in Dutch intensive care units (ICUs) and will be focused on pain management. We will conduct a laboratory experiment with individual ICU professionals to assess the impact of feedback on their intentions to improve practice. Next, we will conduct a cluster randomised controlled trial with ICUs allocated to feedback without or feedback with action implementation toolbox group. Participants will not be told explicitly what aspect of the intervention is randomised; they will only be aware that there are two variations of providing feedback. ICUs are eligible for participation if they submit indicator data to the Dutch National Intensive Care Evaluation (NICE) quality registry and agree to allocate a quality improvement team that spends 4 h per month on the intervention. All participating ICUs will receive access to an online quality dashboard that provides two functionalities: gaining insight into clinical performance on pain management indicators and developing action plans. ICUs with access to the toolbox can develop their action plans guided by a list of potential barriers in the care process, associated suggested actions, and supporting materials to facilitate implementation of the actions. The primary outcome measure for the laboratory experiment is the proportion of improvement intentions set by participants that are consistent with recommendations based on peer comparisons; for the randomised trial it is the proportion of patient shifts during which pain has been adequately managed. We will also conduct a process evaluation to understand how the intervention is implemented and used in clinical practice, and how implementation and use affect the intervention's impact. The results of this study will inform care providers and managers in ICU and other clinical settings how to use indicator-based performance feedback in conjunction with an action implementation toolbox to improve quality of care. Within the ICU context, this study will produce concrete and directly applicable knowledge with respect to what is or is not effective for improving pain management, and under which circumstances. The results will further guide future research that aims to understand the mechanisms behind audit and feedback and contribute to identifying the active ingredients of successful interventions. ClinicalTrials.gov NCT02922101 . Registered 26 September 2016.

The Comparative Toxicogenomics Database (CTD): A Resource for Comparative Toxicological Studies

PubMed Central

CJ, Mattingly; MC, Rosenstein; GT, Colby; JN, Forrest; JL, Boyer

2006-01-01

The etiology of most chronic diseases involves interactions between environmental factors and genes that modulate important biological processes (Olden and Wilson, 2000). We are developing the publicly available Comparative Toxicogenomics Database (CTD) to promote understanding about the effects of environmental chemicals on human health. CTD identifies interactions between chemicals and genes and facilitates cross-species comparative studies of these genes. The use of diverse animal models and cross-species comparative sequence studies has been critical for understanding basic physiological mechanisms and gene and protein functions. Similarly, these approaches will be valuable for exploring the molecular mechanisms of action of environmental chemicals and the genetic basis of differential susceptibility. PMID:16902965

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.

[An integrative model of the psychological benefits of gardening in older adults].

PubMed

Tournier, Isabelle; Postal, Virginie

2014-12-01

This review of the literature tackles the question of the psychological benefits linked to gardening in older adults. First, the current data on these benefits are reviewed, and the findings reveal that gardening is linked to feelings of accomplishment, well-being and peace, a decrease of depressive symptoms, a protective effect on cognitive functions as well as to the development of social links for community living older adults. In institutionalized older adults, gardening promotes internal locus of control and well-being, and is related to a decrease of sadness and anxiety. Second, several explanatory theories are discussed. All of them postulate an action on the cognitive and/or emotional spheres, which were included into a integrated model that must be tested in future research. In conclusion, gardening appears to be a beneficial activity for promoting older adults' functioning but the current knowledge still has to be extended to understand the specific mechanisms of action. This deeper understanding is necessary in order to improve the future actions depending on this activity.

Perception and understanding of intentions and actions: does gender matter?

PubMed

Pavlova, Marina

2009-01-09

Perception of intentions and dispositions of others through body motion, body language, gestures and actions is of immense importance for a variety of daily-life situations and adaptive social behavior. This ability is of particular value because of the potential discrepancy between verbal and non-verbal communication levels. Recent data shows that some aspects of visual social perception are gender dependent. The present study asks whether and, if so, how the ability for perception and understanding of others' intentions and actions depends on perceivers' gender. With this purpose in mind, a visual event arrangement (EA) task was administered to female and male participants of two groups, adolescents aged 13-16 years and young adults. The main outcome of the study shows no difference in performance on the EA task between female and male participants in both groups. The findings are discussed in terms of gender-related differences in behavioral components and brain mechanisms engaged in visual social perception.

EFFECTS OF ARSENITE IN TELOMERE AND TELOMERASE IN RELATION TO CELL PROLIFERATION AND APOPTOSIS IN HUMAN KERATINOCYTES AND LEUKEMIA CELLS IN VITRO

EPA Science Inventory

Telomeres are critical in maintaining chromosome and genomic stability. Arsenic, a human carcinogen as well as an anticancer agent, is known for its clastogenicity. To better understand molecular mechanisms of arsenic actions, we investigated arsenite effects on telomere and telo...

Aroclor-1254, a developmental neurotoxicant, alters energy metabolism-and intracellular signaling-associated protein networks in rat cerebellum and hippocampus

EPA Science Inventory

The vast literature on the mode of action of polychlorinated biphenyls (PCBs) indicates that PCBs are a unique model for understanding the mechanisms of toxicity of environmental mixtures of persistent chemicals. PCBs have been shown to adversely affect psychomotor function and l...

Chemical control methods and tools

Treesearch

Steven Manning; James Miller

2011-01-01

After determining the best course of action for control of an invasive plant population, it is important to understand the variety of methods available to the integrated pest management professional. A variety of methods are now widely used in managing invasive plants in natural areas, including chemical, mechanical, and cultural control methods. Once the preferred...

Coming of Age in America. VERCAP: A Guide for High School Students.

ERIC Educational Resources Information Center

Bever, James A.

Guidelines are provided for implementing the modular Voter Education, Registration, Community Action Program (VERCAP) in high schools. VERCAP was developed in 1976 by the National Association of Secondary School Principals. The purposes of VERCAP are to help students become informed, active citizens who can understand the mechanics of registering…

QUANTITATIVE TOXICOPROTEOMIC ANALYSIS OF CARCINOGEN-TREATED ANIMAL TISSUES AND HUMAN CELLS FOR HUMAN HEALTH RISK ASSESSMENT

EPA Science Inventory

Humans are exposed to a variety of environmental toxicants, and this together with a large number of interacting factors can contribute to an individual's risk for health. To understand the toxic mechanisms and/or modes of action for human health risk assessment, molecular charac...

Molecular targets of antihypertensive peptides: understanding the mechanisms of action based on the pathophysiology of hypertension.

PubMed

Majumder, Kaustav; Wu, Jianping

2014-12-24

There is growing interest in using functional foods or nutraceuticals for the prevention and treatment of hypertension or high blood pressure. Although numerous preventive and therapeutic pharmacological interventions are available on the market, unfortunately, many patients still suffer from poorly controlled hypertension. Furthermore, most pharmacological drugs, such as inhibitors of angiotensin-I converting enzyme (ACE), are often associated with significant adverse effects. Many bioactive food compounds have been characterized over the past decades that may contribute to the management of hypertension; for example, bioactive peptides derived from various food proteins with antihypertensive properties have gained a great deal of attention. Some of these peptides have exhibited potent in vivo antihypertensive activity in both animal models and human clinical trials. This review provides an overview about the complex pathophysiology of hypertension and demonstrates the potential roles of food derived bioactive peptides as viable interventions targeting specific pathways involved in this disease process. This review offers a comprehensive guide for understanding and utilizing the molecular mechanisms of antihypertensive actions of food protein derived peptides.

Antigen-Specific Therapeutic Approaches in Type 1 Diabetes

PubMed Central

Clemente-Casares, Xavier; Tsai, Sue; Huang, Carol; Santamaria, Pere

2012-01-01

Development of strategies capable of specifically curbing pathogenic autoimmune responses in a disease- and organ-specific manner without impairing foreign or tumor antigen-specific immune responses represents a long sought-after goal in autoimmune disease research. Unfortunately, our current understanding of the intricate details of the different autoimmune diseases that affect mankind, including type 1 diabetes, is rudimentary. As a result, progress in the development of the so-called “antigen-specific” therapies for autoimmunity has been slow and fraught with limitations that interfere with bench-to-bedside translation. Absent or incomplete understanding of mechanisms of action and lack of adequate immunological biomarkers, for example, preclude the rational design of effective drug development programs. Here, we provide an overview of antigen-specific approaches that have been tested in preclinical models of T1D and, in some cases, human subjects. The evidence suggests that effective translation of these approaches through clinical trials and into patients will continue to meet with failure unless detailed mechanisms of action at the level of the organism are defined. PMID:22355799

Molecular Targets of Antihypertensive Peptides: Understanding the Mechanisms of Action Based on the Pathophysiology of Hypertension

PubMed Central

Majumder, Kaustav; Wu, Jianping

2014-01-01

There is growing interest in using functional foods or nutraceuticals for the prevention and treatment of hypertension or high blood pressure. Although numerous preventive and therapeutic pharmacological interventions are available on the market, unfortunately, many patients still suffer from poorly controlled hypertension. Furthermore, most pharmacological drugs, such as inhibitors of angiotensin-I converting enzyme (ACE), are often associated with significant adverse effects. Many bioactive food compounds have been characterized over the past decades that may contribute to the management of hypertension; for example, bioactive peptides derived from various food proteins with antihypertensive properties have gained a great deal of attention. Some of these peptides have exhibited potent in vivo antihypertensive activity in both animal models and human clinical trials. This review provides an overview about the complex pathophysiology of hypertension and demonstrates the potential roles of food derived bioactive peptides as viable interventions targeting specific pathways involved in this disease process. This review offers a comprehensive guide for understanding and utilizing the molecular mechanisms of antihypertensive actions of food protein derived peptides. PMID:25547491

The relationship between action anticipation and emotion recognition in athletes of open skill sports.

PubMed

Shih, Yu-Ling; Lin, Chia-Yen

2016-08-01

Action anticipation plays an important role in the successful performance of open skill sports, such as ball and combat sports. Evidence has shown that elite athletes of open sports excel in action anticipation. Most studies have targeted ball sports and agreed that information on body mechanics is one of the key determinants for successful action anticipation in open sports. However, less is known about combat sports, and whether facial emotions have an influence on athletes' action anticipation skill. It has been suggested that the understanding of intention in combat sports relies heavily on emotional context. Based on this suggestion, the present study compared the action anticipation performances of taekwondo athletes, weightlifting athletes, and non-athletes and then correlated these with their performances of emotion recognition. This study primarily found that accurate action anticipation does not necessarily rely on the dynamic information of movement, and that action anticipation performance is correlated with that of emotion recognition in taekwondo athletes, but not in weightlifting athletes. Our results suggest that the recognition of facial emotions plays a role in the action prediction in such combat sports as taekwondo.

State estimation bias induced by optimization under uncertainty and error cost asymmetry is likely reflected in perception.

PubMed

Shimansky, Y P

2011-05-01

It is well known from numerous studies that perception can be significantly affected by intended action in many everyday situations, indicating that perception and related decision-making is not a simple, one-way sequence, but a complex iterative cognitive process. However, the underlying functional mechanisms are yet unclear. Based on an optimality approach, a quantitative computational model of one such mechanism has been developed in this study. It is assumed in the model that significant uncertainty about task-related parameters of the environment results in parameter estimation errors and an optimal control system should minimize the cost of such errors in terms of the optimality criterion. It is demonstrated that, if the cost of a parameter estimation error is significantly asymmetrical with respect to error direction, the tendency to minimize error cost creates a systematic deviation of the optimal parameter estimate from its maximum likelihood value. Consequently, optimization of parameter estimate and optimization of control action cannot be performed separately from each other under parameter uncertainty combined with asymmetry of estimation error cost, thus making the certainty equivalence principle non-applicable under those conditions. A hypothesis that not only the action, but also perception itself is biased by the above deviation of parameter estimate is supported by ample experimental evidence. The results provide important insights into the cognitive mechanisms of interaction between sensory perception and planning an action under realistic conditions. Implications for understanding related functional mechanisms of optimal control in the CNS are discussed.

Learning immunology from the yellow fever vaccine: innate immunity to systems vaccinology.

PubMed

Pulendran, Bali

2009-10-01

Despite their great success, we understand little about how effective vaccines stimulate protective immune responses. Two recent developments promise to yield such understanding: the appreciation of the crucial role of the innate immune system in sensing microorganisms and tuning immune responses, and advances in systems biology. Here I review how these developments are yielding insights into the mechanism of action of the yellow fever vaccine, one of the most successful vaccines ever developed, and the broader implications for vaccinology.

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

Cournia, Zoe; Allen, Toby W.; Andricioaei, Ioan

It is fundamental for the flourishing biological cells that membrane proteins mediate the process. Membrane-embedded transporters move ions and larger solutes across membranes; receptors mediate communication between the cell and its environment and membrane-embedded enzymes catalyze chemical reactions. Understanding these mechanisms of action requires knowledge of how the proteins couple to their fluid, hydrated lipid membrane environment. Here, we present here current studies in computational and experimental membrane protein biophysics, and show how they address outstanding challenges in understanding the complex environmental effects on the structure, function, and dynamics of membrane proteins.

Overlearned responses hinder S-R binding.

PubMed

Moeller, Birte; Frings, Christian

2017-01-01

Two mechanisms that are important for human action control are the integration of individual action plans (see Hommel, Müsseler, Aschersleben, & Prinz, 2001) and the automatization of overlearned actions to familiar stimuli (see Logan, 1988). In the present study, we analyzed the influence of automatization on action plan integration. Integration with pronunciation responses were compared for response incompatible word and nonword stimuli. Stimulus-response binding effects were observed for nonwords. In contrast, words that automatically triggered an overlearned pronunciation response were not integrated with pronunciation of a different word. That is, automatized response retrieval hindered binding effects regarding the retrieving stimulus and a new response. The results are a first indication of the way that binding and learning processes interact, and might also be a first step to understanding the more complex interdependency of the processes responsible for stimulus-response binding in action control and stimulus-response associations in learning research. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Exploring the mechanism of βamyloid toxicity attenuation by multivalent sialic acid polymers through the use of mathematical models

PubMed Central

Cowan, Christopher B.; Patel, Dhara A.; Good, Theresa A.

2009-01-01

β-Amyloid peptide (Aβ), the primary protein component in senile plaques associated with Alzheimer’s disease (AD), has been implicated in neurotoxicity associated with AD. Previous studies have shown that the Aβ-neuronal membrane interaction plays a role in the mechanism of Aβ toxicity. More specifically, it is thought that Aβ interacts with ganglioside rich and sialic acid rich regions of cell surfaces. In light of such evidence, we have used a number of different sialic acid compounds of different valency or number of sialic acid moieties per molecule to attenuate Aβ toxicity in a cell culture model. In this work, we proposed various mathematical models of Aβ interaction with both the cell membrane and with the multivalent sialic acid compounds, designed to act as membrane mimics. These models allow us to explore the mechanism of action of this class of sialic acid membrane mimics in attenuating the toxicity of Aβ. The mathematical models, when compared with experimental data, facilitate the discrimination between different modes of action of these materials. Understanding the mechanism of action of Aβ toxicity inhibitors should provide insight into the design of the next generation of molecules that could be used to prevent Aβ toxicity associated with Alzheimer’s disease. PMID:19217912

Studies on tribology

PubMed Central

Hori, Yukio; Kato, Koji

2008-01-01

In high speed rotating machines such as turbines and generators, vibrations of a rotating shaft often hinder the smooth operation of the machine or even cause failure. Oil whip is one of such vibrations due to oil film action of journal bearing. Its mechanism and preventive method is explained and proposed in this paper. Further theoretical and experimental analyses are made for considering heat generation and temperature rise in hydrodynamic lubrication. The usefulness of the lubrication theory based on the k–ε model is also shown for bearings with high eccentricity ratios. In the latter half of this paper, water lubrication, nitrogen gas lubrication and tribo-coated indium lubrication are shown as new promising methods, and their mechanisms are discussed and the importance of tribo-layer is explained. Some mechanisms of wear are introduced for better understanding of tribo-layer. In the last part of this paper, the mechanisms of generating static friction are shown for the cases of plastic contact and elastic contact, which is the base for understanding the mechanism of initiation of macroscopic sliding. PMID:18941304

Studies on tribology.

PubMed

Hori, Yukio; Kato, Koji

2008-01-01

In high speed rotating machines such as turbines and generators, vibrations of a rotating shaft often hinder the smooth operation of the machine or even cause failure. Oil whip is one of such vibrations due to oil film action of journal bearing. Its mechanism and preventive method is explained and proposed in this paper. Further theoretical and experimental analyses are made for considering heat generation and temperature rise in hydrodynamic lubrication. The usefulness of the lubrication theory based on the k-epsilon model is also shown for bearings with high eccentricity ratios. In the latter half of this paper, water lubrication, nitrogen gas lubrication and tribo-coated indium lubrication are shown as new promising methods, and their mechanisms are discussed and the importance of tribo-layer is explained. Some mechanisms of wear are introduced for better understanding of tribo-layer. In the last part of this paper, the mechanisms of generating static friction are shown for the cases of plastic contact and elastic contact, which is the base for understanding the mechanism of initiation of macroscopic sliding.

Glyphosate resistance: state of knowledge

PubMed Central

Sammons, Robert Douglas; Gaines, Todd A

2014-01-01

Studies of mechanisms of resistance to glyphosate have increased current understanding of herbicide resistance mechanisms. Thus far, single-codon non-synonymous mutations of EPSPS (5-enolypyruvylshikimate-3-phosphate synthase) have been rare and, relative to other herbicide mode of action target-site mutations, unconventionally weak in magnitude for resistance to glyphosate. However, it is possible that weeds will emerge with non-synonymous mutations of two codons of EPSPS to produce an enzyme endowing greater resistance to glyphosate. Today, target-gene duplication is a common glyphosate resistance mechanism and could become a fundamental process for developing any resistance trait. Based on competition and substrate selectivity studies in several species, rapid vacuole sequestration of glyphosate occurs via a transporter mechanism. Conversely, as the chloroplast requires transporters for uptake of important metabolites, transporters associated with the two plastid membranes may separately, or together, successfully block glyphosate delivery. A model based on finite glyphosate dose and limiting time required for chloroplast loading sets the stage for understanding how uniquely different mechanisms can contribute to overall glyphosate resistance. PMID:25180399

Study of Profile Changes during Mechanical Polishing using Relocation Profilometry

NASA Astrophysics Data System (ADS)

Kumaran, S. Chidambara; Shunmugam, M. S.

2017-10-01

Mechanical polishing is a finishing process practiced conventionally to enhance quality of surface. Surface finish is improved by mechanical cutting action of abrasive particles on work surface. Polishing is complex in nature and research efforts have been focused on understanding the polishing mechanism. Study of changes in profile is a useful method of understanding behavior of the polishing process. Such a study requires tracing same profile at regular process intervals, which is a tedious job. An innovative relocation technique is followed in the present work to study profile changes during mechanical polishing of austenitic stainless steel specimen. Using special locating fixture, micro-indentation mark and cross-correlation technique, the same profile is traced at certain process intervals. Comparison of different parameters of profiles shows the manner in which metal removal takes place in the polishing process. Mass removal during process estimated by the same relocation technique is checked with that obtained using weight measurement. The proposed approach can be extended to other micro/nano finishing processes and favorable process conditions can be identified.

Mechanical basis of bone strength: influence of bone material, bone structure and muscle action.

PubMed

Hart, N H; Nimphius, S; Rantalainen, T; Ireland, A; Siafarikas, A; Newton, R U

2017-09-01

This review summarises current understanding of how bone is sculpted through adaptive processes, designed to meet the mechanical challenges it faces in everyday life and athletic pursuits, serving as an update for clinicians, researchers and physical therapists. Bone's ability to resist fracture under the large muscle and locomotory forces it experiences during movement and in falls or collisions is dependent on its established mechanical properties, determined by bone's complex and multidimensional material and structural organisation. At all levels, bone is highly adaptive to habitual loading, regulating its structure according to components of its loading regime and mechanical environment, inclusive of strain magnitude, rate, frequency, distribution and deformation mode. Indeed, the greatest forces habitually applied to bone arise from muscular contractions, and the past two decades have seen substantial advances in our understanding of how these forces shape bone throughout life. Herein, we also highlight the limitations of in vivo methods to assess and understand bone collagen, and bone mineral at the material or tissue level. The inability to easily measure or closely regulate applied strain in humans is identified, limiting the translation of animal studies to human populations, and our exploration of how components of mechanical loading regimes influence mechanoadaptation.

Solving the Antibiotic Crisis.

PubMed

Wright, Gerard D

2015-02-13

Antibiotics are essential for both treating and preventing infectious diseases. Paradoxically, despite their importance as pillars of modern medicine, we are in danger of losing antibiotics because of the evolution and dissemination of resistance mechanisms throughout all pathogenic microbes. This fact, coupled with an inability to bring new drugs to market at a pace that matches resistance, has resulted in a crisis of global proportion. Solving this crisis requires the actions of many stakeholders, but chemists, chemical biologists, and microbiologists must drive the scientific innovation that is required to maintain our antibiotic arsenal. This innovation requires (1) a deep understanding of the evolution and reservoirs of resistance; (2) full knowledge of the molecular mechanisms of antibiotic action and resistance; (3) the discovery of chemical and genetic probes of antibiotic action and resistance; (4) the integration of systems biology into antibiotic discovery; and (5) the discovery of new antimicrobial chemical matter. Addressing these pressing scientific gaps will ensure that we can meet the antibiotic crisis with creativity and purpose.

Novel actions of IGFBP-3 on intracellular signaling pathways of insulin-secreting cells

PubMed Central

Chen, Xiaoyan; Ferry, Robert J.

2011-01-01

Understanding mechanisms underlying apoptotic destruction of insulin-secreting cells is critical to validate therapeutic targets for type 1 diabetes mellitus. We recently reported insulin-like growth factor binding protein-3 (IGFBP-3) as a novel mediator of apoptosis in insulin-secreting cells. In light of emerging IGF-independent roles for IGFBP-3, we investigated the mechanisms underlying actions of the novel, recombinant human mutant G56G80G81-IGFBP-3, which lacks intrinsic IGF binding affinity. Using the rat insulinoma RINm5F cell line, we report the first studies in insulin-secreting cells that IGFBP-3 selectively suppresses multiple, key intracellular phosphorelays. By immunoblot, we demonstrate that G56G80G81-IGFBP-3 suppresses phosphorylation of c-raf-MEK-ERK pathway and p38 kinase in time-dependent and dose-dependent manners. SAPK/JNK signaling was unaffected. These data delineate several novel intracellular sites of action for IGFBP-3 in insulin-secreting cells. PMID:16275148

Non-Genomic Effects of Xenoestrogen Mixtures

PubMed Central

Viñas, René; Jeng, Yow-Jiun; Watson, Cheryl S.

2012-01-01

Xenoestrogens (XEs) are chemicals derived from a variety of natural and anthropogenic sources that can interfere with endogenous estrogens by either mimicking or blocking their responses via non-genomic and/or genomic signaling mechanisms. Disruption of estrogens’ actions through the less-studied non-genomic pathway can alter such functional end points as cell proliferation, peptide hormone release, catecholamine transport, and apoptosis, among others. Studies of potentially adverse effects due to mixtures and to low doses of endocrine-disrupting chemicals have recently become more feasible, though few so far have included actions via the non-genomic pathway. Physiologic estrogens and XEs evoke non-monotonic dose responses, with different compounds having different patterns of actions dependent on concentration and time, making mixture assessments all the more challenging. In order to understand the spectrum of toxicities and their mechanisms, future work should focus on carefully studying individual and mixture components across a range of concentrations and cellular pathways in a variety of tissue types. PMID:23066391

Agomelatine: mechanism of action and pharmacological profile in relation to antidepressant properties

PubMed Central

Guardiola-Lemaitre, B; De Bodinat, C; Delagrange, P; Millan, M J; Munoz, C; Mocaër, E

2014-01-01

Agomelatine behaves both as a potent agonist at melatonin MT1 and MT2 receptors and as a neutral antagonist at 5-HT2C receptors. Accumulating evidence in a broad range of experimental procedures supports the notion that the psychotropic effects of agomelatine are due to the synergy between its melatonergic and 5-hydroxytryptaminergic effects. The recent demonstration of the existence of heteromeric complexes of MT1 and MT2 with 5-HT2C receptors at the cellular level may explain how these two properties of agomelatine translate into a synergistic action that, for example, leads to increases in hippocampal proliferation, maturation and survival through modulation of multiple cellular pathways (increase in trophic factors, synaptic remodelling, glutamate signalling) and key targets (early genes, kinases). The present review focuses on the pharmacological properties of this novel antidepressant. Its mechanism of action, strikingly different from that of conventional classes of antidepressants, opens perspectives towards a better understanding of the physiopathological bases underlying depression. PMID:24724693

Mechanisms of Action of Isothiocyanates in Cancer Chemoprevention: An Update

PubMed Central

Navarro, Sandi L.; Li, Fei; Lampe, Johanna W.

2011-01-01

Isothiocyanates, derived from glucosinolates, are thought to be responsible for the chemoprotective actions conferred by higher cruciferous vegetable intake. Evidence suggests that isothiocyanates exert their effects through a variety of distinct but interconnected signaling pathways important for inhibiting carcinogenesis, including those involved in detoxification, inflammation, apoptosis, and cell cycle and epigenetic regulation, among others. This article provides an update on the latest research on isothiocyanates and these mechanisms, and points out remaining gaps in our understanding of these events. Given the variety of ITC produced from glucosinolates, and the diverse pathways on which these compounds act, a systems biology approach, in vivo, may help to better characterize their integrated role in cancer prevention. In addition, the effects of dose, duration of exposure, and specificity of different ITC should be considered. PMID:21935537

Autonomy in chimpanzees.

PubMed

Beauchamp, Tom L; Wobber, Victoria

2014-04-01

Literature on the mental capacities and cognitive mechanisms of the great apes has been silent about whether they can act autonomously. This paper provides a philosophical theory of autonomy supported by psychological studies of the cognitive mechanisms that underlie chimpanzee behavior to argue that chimpanzees can act autonomously even though their psychological mechanisms differ from those of humans. Chimpanzees satisfy the two basic conditions of autonomy: (1) liberty (the absence of controlling influences) and (2) agency (self-initiated intentional action), each of which is specified here in terms of conditions of understanding, intention, and self-control. In this account, chimpanzees make knowledge-based choices reflecting a richly information-based and socially sophisticated understanding of the world. Finally, two major theories of autonomy (Kantian theory and two-level theory) are rejected as too narrow to adequately address these issues, necessitating the modifications made in the present approach.

Steroids and osteoporosis: the quest for mechanisms

PubMed Central

Manolagas, Stavros C.

2013-01-01

Advances made during the last 35 years have improved our understanding of the mechanisms of steroid hormone action on bone and how physiologic, pathologic, or iatrogenic changes in hormone levels can lead to increased fracture risk. Estrogens, androgens, and glucocorticoids alter the cellular composition of bone by regulating the supply and lifespan of osteoclasts and osteoblasts. Additionally, they influence the survival of osteocytes, long-lived cells that are entombed within the mineralized matrix and mediate the homeostatic adaptation of bone to mechanical forces. Altered redox balance is a proximal underlying mechanism of some of these effects, and sex steroid deficiency or glucocorticoid excess contributes to the aging of the skeleton. PMID:23635790

Trial-and-error copying of demonstrated actions reveals how fledglings learn to ‘imitate’ their mothers

PubMed Central

Lotem, Arnon

2017-01-01

Understanding how humans and other animals learn to perform an act from seeing it done has been a major challenge in the study of social learning. To determine whether this ability is based on ‘true imitation’, many studies have applied the two-action experimental paradigm, examining whether subjects learn to perform the specific action demonstrated to them. Here, we show that the insights gained from animals' success in two-action experiments may be limited, and that a better understanding is achieved by monitoring subjects' entire behavioural repertoire. Hand-reared house sparrows that followed a model of a mother demonstrator were successful in learning to find seeds hidden under a leaf, using the action demonstrated by the mother (either pushing the leaf or pecking it). However, they also produced behaviours that had not been demonstrated but were nevertheless related to the demonstrated act. This finding suggests that while the learners were clearly influenced by the demonstrator, they did not accurately imitate her. Rather, they used their own behavioural repertoire, gradually fitting it to the demonstrated task solution through trial and error. This process is consistent with recent views on how animals learn to imitate, and may contribute to a unified process-level analysis of social learning mechanisms. PMID:28228516

On the quest for the elusive mechanism of action of daptomycin: Binding, fusion, and oligomerization.

PubMed

Zhang, Jin; Scott, Walter R P; Gabel, Frank; Wu, Miao; Desmond, Ruqaiba; Bae, JungHwan; Zaccai, Giuseppe; Algar, W Russ; Straus, Suzana K

2017-11-01

Daptomycin, sold under the trade name CUBICIN, is the first lipopeptide antibiotic to be approved for use against Gram-positive organisms, including a number of highly resistant species. Over the last few decades, a number of studies have tried to pinpoint the mechanism of action of daptomycin. These proposed modes of action often have points in common (e.g. the requirement for Ca 2+ and lipid membranes containing a high proportion of phosphatidylglycerol (PG) headgroups), but also points of divergence (e.g. oligomerization in solution and in membranes, membrane perturbation vs. inhibition of cell envelope synthesis). In this study, we investigate how concentration effects may have an impact on the interpretation of the biophysical data used to support a given mechanism of action. Results obtained from small angle neutron scattering (SANS) experiments and molecular dynamics (MD) simulations show that daptomycin oligomerizes at high concentrations (both with and without Ca 2+ ) in solution, but that this oligomer readily falls apart. Photon correlation spectroscopy (PCS) experiments demonstrate that daptomycin causes fusion more readily in DMPC/PG membranes than in POPC/PG, suggesting that the latter may be a better model system. Finally, fluorescence and Förster resonance energy transfer (FRET) experiments reveal that daptomycin binds strongly to the lipid membrane and that oligomerization occurs in a concentration-dependent manner. The combined experiments provide an improved framework for more general and rigorous biophysical studies toward understanding the elusive mechanism of action of daptomycin. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. Copyright © 2017 Elsevier B.V. All rights reserved.

Covert rapid action-memory simulation (CRAMS): a hypothesis of hippocampal-prefrontal interactions for adaptive behavior.

PubMed

Wang, Jane X; Cohen, Neal J; Voss, Joel L

2015-01-01

Effective choices generally require memory, yet little is known regarding the cognitive or neural mechanisms that allow memory to influence choices. We outline a new framework proposing that covert memory processing of hippocampus interacts with action-generation processing of prefrontal cortex in order to arrive at optimal, memory-guided choices. Covert, rapid action-memory simulation (CRAMS) is proposed here as a framework for understanding cognitive and/or behavioral choices, whereby prefrontal-hippocampal interactions quickly provide multiple simulations of potential outcomes used to evaluate the set of possible choices. We hypothesize that this CRAMS process is automatic, obligatory, and covert, meaning that many cycles of action-memory simulation occur in response to choice conflict without an individual's necessary intention and generally without awareness of the simulations, leading to adaptive behavior with little perceived effort. CRAMS is thus distinct from influential proposals that adaptive memory-based behavior in humans requires consciously experienced memory-based construction of possible future scenarios and deliberate decisions among possible future constructions. CRAMS provides an account of why hippocampus has been shown to make critical contributions to the short-term control of behavior, and it motivates several new experimental approaches and hypotheses that could be used to better understand the ubiquitous role of prefrontal-hippocampal interactions in situations that require adaptively using memory to guide choices. Importantly, this framework provides a perspective that allows for testing decision-making mechanisms in a manner that translates well across human and nonhuman animal model systems. Copyright © 2014 Elsevier Inc. All rights reserved.

Membrane Active Antimicrobial Peptides: Translating Mechanistic Insights to Design

PubMed Central

Li, Jianguo; Koh, Jun-Jie; Liu, Shouping; Lakshminarayanan, Rajamani; Verma, Chandra S.; Beuerman, Roger W.

2017-01-01

Antimicrobial peptides (AMPs) are promising next generation antibiotics that hold great potential for combating bacterial resistance. AMPs can be both bacteriostatic and bactericidal, induce rapid killing and display a lower propensity to develop resistance than do conventional antibiotics. Despite significant progress in the past 30 years, no peptide antibiotic has reached the clinic yet. Poor understanding of the action mechanisms and lack of rational design principles have been the two major obstacles that have slowed progress. Technological developments are now enabling multidisciplinary approaches including molecular dynamics simulations combined with biophysics and microbiology toward providing valuable insights into the interactions of AMPs with membranes at atomic level. This has led to increasingly robust models of the mechanisms of action of AMPs and has begun to contribute meaningfully toward the discovery of new AMPs. This review discusses the detailed action mechanisms that have been put forward, with detailed atomistic insights into how the AMPs interact with bacterial membranes. The review further discusses how this knowledge is exploited toward developing design principles for novel AMPs. Finally, the current status, associated challenges, and future directions for the development of AMP therapeutics are discussed. PMID:28261050

Artemisinin-based antimalarial research: application of biotechnology to the production of artemisinin, its mode of action, and the mechanism of resistance of Plasmodium parasites.

PubMed

Muangphrom, Paskorn; Seki, Hikaru; Fukushima, Ery Odette; Muranaka, Toshiya

2016-07-01

Malaria is a worldwide disease caused by Plasmodium parasites. A sesquiterpene endoperoxide artemisinin isolated from Artemisia annua was discovered and has been accepted for its use in artemisinin-based combinatorial therapies, as the most effective current antimalarial treatment. However, the quantity of this compound produced from the A. annua plant is very low, and the availability of artemisinin is insufficient to treat all infected patients. In addition, the emergence of artemisinin-resistant Plasmodium has been reported recently. Several techniques have been applied to enhance artemisinin availability, and studies related to its mode of action and the mechanism of resistance of malaria-causing parasites are ongoing. In this review, we summarize the application of modern technologies to improve the production of artemisinin, including our ongoing research on artemisinin biosynthetic genes in other Artemisia species. The current understanding of the mode of action of artemisinin as well as the mechanism of resistance against this compound in Plasmodium parasites is also presented. Finally, the current situation of malaria infection and the future direction of antimalarial drug development are discussed.

Deciphering the Mechanism of Action of Wrightia tinctoria for Psoriasis Based on Systems Pharmacology Approach.

PubMed

Sundarrajan, Sudharsana; Lulu, Sajitha; Arumugam, Mohanapriya

2017-11-01

Psoriasis is a chronic immune-mediated disorder of the skin. The disease manifests itself with red or silvery scaly plaques distributing over the lower back, scalp, and extensor aspects of limbs. Several medications are available for the treatment of psoriasis; however, high rates of remission and side-effects still persist as a major concern. Siddha, one of the traditional systems of Indian medicine offers cure to many dermatological conditions, including psoriasis. The oil prepared from the leaves of Wrightia tinctoria is prescribed by many healers for the treatment of psoriasis. This work aims to decipher the mechanism of action of the W. tinctoria in curing psoriasis and its associated comorbidities. The work integrates various pharmacology approaches such as drug-likeness evaluation, oral bioavailability predictions, and network pharmacology approaches to understand the roles of various bioactive components of the herb. This work identified 67 compounds of W. tinctoria interacting with 238 protein targets. The compounds were found to act through synergistic mechanism in reviving the disrupted process in the diseased state. The results of this work not only shed light on the pharmacological action of the herb but also validate the usage of safe herbal drugs.

Performance of tablet disintegrants: impact of storage conditions and relative tablet density.

PubMed

Quodbach, Julian; Kleinebudde, Peter

2015-01-01

Tablet disintegration can be influenced by several parameters, such as storage conditions, type and amount of disintegrant, and relative tablet density. Even though these parameters have been mentioned in the literature, the understanding of the disintegration process is limited. In this study, water uptake and force development of disintegrating tablets are analyzed, as they reveal underlying processes and interactions. Measurements were performed on dibasic calcium phosphate tablets containing seven different disintegrants stored at different relative humidities (5-97%), and on tablets containing disintegrants with different mechanisms of action (swelling and shape recovery), compressed to different relative densities. Disintegration times of tablets containing sodium starch glycolate are affected most by storage conditions, which is displayed in decreased water uptake and force development kinetics. Disintegration times of tablets with a swelling disintegrant are only marginally affected by relative tablet density, whereas the shape recovery disintegrant requires high relative densities for quick disintegration. The influence of relative tablet density on the kinetics of water uptake and force development greatly depends on the mechanism of action. Acquired data allows a detailed analysis of the influence of storage conditions and mechanisms of action on disintegration behavior.

Immunotherapeutics in Pediatric Autoimmune Central Nervous System Disease: Agents and Mechanisms.

PubMed

Nosadini, Margherita; Sartori, Stefano; Sharma, Suvasini; Dale, Russell C

2017-08-01

Beyond the major advances produced by careful clinical-radiological phenotyping and biomarker development in autoimmune central nervous system disorders, a comprehensive knowledge of the range of available immune therapies and a deeper understanding of their action should benefit therapeutic decision-making. This review discusses the agents used in neuroimmunology and their mechanisms of action. First-line treatments typically include corticosteroids, intravenous immunoglobulin, and plasmapheresis, while for severe disease second-line "induction" agents such as rituximab or cyclophosphamide are used. Steroid-sparing agents such as mycophenolate, azathioprine, or methotrexate are often used in potentially relapsing or corticosteroid-dependent diseases. Lessons from adult neuroimmunology and rheumatology could be translated into pediatric autoimmune central nervous system disease in the future, including the potential utility of monoclonal antibodies targeting lymphocytes, adhesion molecules for lymphocytic migration, cytokines or their receptors, or complement. Finally, many agents used in other fields have multiple mechanisms of action, including immunomodulation, with potential usefulness in neuroimmunology, such as antibiotics, psychotropic drugs, probiotics, gut health, and ketogenic diet. All currently accepted and future potential agents have adverse effects, which can be severe; therefore, a "risk-versus-benefit" determination should guide therapeutic decision-making. Copyright © 2017 Elsevier Inc. All rights reserved.

From language comprehension to action understanding and back again.

PubMed

Tremblay, Pascale; Small, Steven L

2011-05-01

A controversial question in cognitive neuroscience is whether comprehension of words and sentences engages brain mechanisms specific for decoding linguistic meaning or whether language comprehension occurs through more domain-general sensorimotor processes. Accumulating behavioral and neuroimaging evidence suggests a role for cortical motor and premotor areas in passive action-related language tasks, regions that are known to be involved in action execution and observation. To examine the involvement of these brain regions in language and nonlanguage tasks, we used functional magnetic resonance imaging (fMRI) on a group of 21 healthy adults. During the fMRI session, all participants 1) watched short object-related action movies, 2) looked at pictures of man-made objects, and 3) listened to and produced short sentences describing object-related actions and man-made objects. Our results are among the first to reveal, in the human brain, a functional specialization within the ventral premotor cortex (PMv) for observing actions and for observing objects, and a different organization for processing sentences describing actions and objects. These findings argue against the strongest version of the simulation theory for the processing of action-related language.

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.

Risk communication of terrorist acts, natural disasters, and criminal violence: comparing the processes of understanding and responding.

PubMed

Heilbrun, Kirk; Wolbransky, Melinda; Shah, Sanjay; Kelly, Rebecca

2010-01-01

Risk communication is an important vehicle for the scientific understanding of the perception of and response to various kinds of threats. The present study provides apparently the first empirical attempt to compare perceptions, decision-making, and anticipated action in response to threats of three kinds: natural disaster, violent crime, and terrorism. A total of 258 college undergraduates were surveyed using a vignette-based, 2 × 2 × 3 between-subjects design that systematically manipulated threat imminence (high vs. low), risk level (high vs. low), and nature of the threat (natural disaster vs. crime vs. terrorism). There were substantial differences in participants' perceptions and reported actions in response to natural disaster, relative to the other domains of risk, under conditions of high risk. The risk of natural disaster was more likely to lead participants to report that they would change their daily activities and to relocate. It was also more likely than terrorism to lead to action securing the home. It appears that the mechanisms for perception, decision-making, and action in response to threats cannot be generalized in a straightforward way across these domains of threat. Copyright © 2010 John Wiley & Sons, Ltd.

N400 ERPs for actions: building meaning in context

PubMed Central

Amoruso, Lucía; Gelormini, Carlos; Aboitiz, Francisco; Alvarez González, Miguel; Manes, Facundo; Cardona, Juan F.; Ibanez, Agustín

2013-01-01

Converging neuroscientific evidence suggests the existence of close links between language and sensorimotor cognition. Accordingly, during the comprehension of meaningful actions, our brain would recruit semantic-related operations similar to those associated with the processing of language information. Consistent with this view, electrophysiological findings show that the N400 component, traditionally linked to the semantic processing of linguistic material, can also be elicited by action-related material. This review outlines recent data from N400 studies that examine the understanding of action events. We focus on three specific domains, including everyday action comprehension, co-speech gesture integration, and the semantics involved in motor planning and execution. Based on the reviewed findings, we suggest that both negativities (the N400 and the action-N400) reflect a common neurocognitive mechanism involved in the construction of meaning through the expectancies created by previous experiences and current contextual information. To shed light on how this process is instantiated in the brain, a testable contextual fronto-temporo-parietal model is proposed. PMID:23459873

[Molecular mechanisms of action of gold in treatment of rheumatoid arthritis--an update].

PubMed

Burmester, G R

2001-06-01

Gold was first used 90 years ago by Robert Koch for the treatment of tuberculosis based on the assumption that rheumatoid arthritis was caused by microbacteria. It soon became clear that this would not explain the action of gold in rheumatoid arthritis, and since then scientists have been struggling to elucidate the mechanisms of gold's action in the treatment of rheumatic diseases. In nearly every area of immunology inhibiting actions of gold could be documented; however, it is still unclear if there is a common denominator or if there are parallel modes of actions which are independent of each other. In any case, also based on recent studies the reactivity of gold compounds with thiol groups appears to the predominant factor. Analyzing the actions of gold in the different phases of an immune reaction suggested that gold plays an important role already in the initiation, namely the uptake and presentation of foreign antigens. Thus, gold is taken up by the macrophages and stored in the lysosomes which are called aureosomes where gold inhibits antigen processing. Especially peptide antigens, which contain sulfur such as cysteine and methionine, are important. Moreover, it could be shown that gold suppresses NF-kappa B binding activity as well as the activation of the I-kappa B-kinase. This mechanism results in a subsequently reduced production of pro-inflammatory cytokines, most notably TNF-alpha, interleukin-1 and interleukin-6. On the subsequent T-cell level, gold has been shown to induce an upregulation of IL-4 mRNA, resulting in a shift of the T-cell population to the Th2 phenotype. Moreover, the activation of T-cells is inhibited. On the effector level, gold inhibits proteolytic enzymes and can result in the destruction of synovial fibroblasts. In conclusion, gold remains one of the most fascinating antirheumatic drugs with multiple modes of actions. The future analysis of molecular mechanisms, especially with regard to signal transduction, will lead to new fundamental knowledge of gold action, possible allowing a further understanding of the pathogenesis of rheumatoid arthritis.

A potential nitrergic mechanism of action for indomethacin, but not of other COX inhibitors: relevance to indomethacin-sensitive headaches.

PubMed

Summ, Oliver; Andreou, Anna P; Akerman, Simon; Goadsby, Peter J

2010-12-01

Non-steroidal anti-inflammatory drugs (NSAIDs) that act as cyclo-oxygenase (COX) inhibitors are commonly used in the treatment of a range of headache disorders, although their mechanism of action is unclear. Indomethacin is of particular interest given its very special effect in some primary headaches. Here the in vivo technique of intravital microscopy in rats has been utilised as a model of trigeminovascular nociception to study the potential mechanism of action of indomethacin. Dural vascular changes were produced using electrical (neurogenic) dural vasodilation (NDV), calcitonin gene-related peptide (CGRP) induced dural vasodilation and nitric oxide (NO) induced dural vasodilation using NO donors. In each of these settings the effect of intravenously administered indomethacin (5 mg kg(-1)), naproxen (30 mg kg(-1)) and ibuprofen (30 mg kg(-1)) was tested. All of the tested drugs significantly inhibited NDV (between 30 and 52%). Whilst none of them was able to inhibit CGRP-induced dural vasodilation, only indomethacin reduced NO induced dural vasodilation (35 ± 7%, 10 min post administration). We conclude NSAIDs inhibit release of CGRP after NDV without an effect on CGRP directly. Further we describe a differentiating effect of indomethacin inhibiting nitric oxide induced dural vasodilation that is potentially relevant to understanding its unique action in disorders such as paroxysmal hemicrania and hemicrania continua.

Understanding the electrical behavior of the action potential in terms of elementary electrical sources.

PubMed

Rodriguez-Falces, Javier

2015-03-01

A concept of major importance in human electrophysiology studies is the process by which activation of an excitable cell results in a rapid rise and fall of the electrical membrane potential, the so-called action potential. Hodgkin and Huxley proposed a model to explain the ionic mechanisms underlying the formation of action potentials. However, this model is unsuitably complex for teaching purposes. In addition, the Hodgkin and Huxley approach describes the shape of the action potential only in terms of ionic currents, i.e., it is unable to explain the electrical significance of the action potential or describe the electrical field arising from this source using basic concepts of electromagnetic theory. The goal of the present report was to propose a new model to describe the electrical behaviour of the action potential in terms of elementary electrical sources (in particular, dipoles). The efficacy of this model was tested through a closed-book written exam. The proposed model increased the ability of students to appreciate the distributed character of the action potential and also to recognize that this source spreads out along the fiber as function of space. In addition, the new approach allowed students to realize that the amplitude and sign of the extracellular electrical potential arising from the action potential are determined by the spatial derivative of this intracellular source. The proposed model, which incorporates intuitive graphical representations, has improved students' understanding of the electrical potentials generated by bioelectrical sources and has heightened their interest in bioelectricity. Copyright © 2015 The American Physiological Society.

Subunit Arrangement and Phenylethanolamine Binding in GluN1/GluN2B NMDA Receptors

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

E Karakas; N Simorowski; H Furukawa

2011-12-31

Since it was discovered that the anti-hypertensive agent ifenprodil has neuroprotective activity through its effects on NMDA (N-methyl-D-aspartate) receptors, a determined effort has been made to understand the mechanism of action and to develop improved therapeutic compounds on the basis of this knowledge. Neurotransmission mediated by NMDA receptors.

Pinpointing Needles in Giant Haystacks: Use of Text Mining to Reduce Impractical Screening Workload in Extremely Large Scoping Reviews

ERIC Educational Resources Information Center

Shemilt, Ian; Simon, Antonia; Hollands, Gareth J.; Marteau, Theresa M.; Ogilvie, David; O'Mara-Eves, Alison; Kelly, Michael P.; Thomas, James

2014-01-01

In scoping reviews, boundaries of relevant evidence may be initially fuzzy, with refined conceptual understanding of interventions and their proposed mechanisms of action an intended output of the scoping process rather than its starting point. Electronic searches are therefore sensitive, often retrieving very large record sets that are…

Characteristics of Waves. Physical Science in Action[TM]. Schlessinger Science Library. [Videotape].

ERIC Educational Resources Information Center

2000

Waves are disturbances that transfer energy from place to place. All waves have amplitude, wavelength and frequency regardless of whether they are mechanical waves, electromagnetic waves or waves in the ocean! Students will learn more about the role waves play in everyday life and why understanding them is so important. With fun demonstrations and…

Aerospace Mechanisms and Tribology Technology: Case Studies

NASA Technical Reports Server (NTRS)

Miyoshi, Kazuhisa

1999-01-01

This chapter focuses attention on tribology technology practice related to vacuum tribology and space tribology. Two case studies describe aspects of real problems in sufficient detail for the engineer and the scientist to understand the tribological situations and the failures. The nature of the problems is analyzed and the range of potential solutions is evaluated. Courses of action are recommended.

Molecular insight into the differential anti-androgenic activity of resveratrol and its natural analogs: In Silico approach to understand biological actions

USDA-ARS?s Scientific Manuscript database

The androgen receptor (AR) is a therapeutic target for the treatment of prostate cancer. Androgen receptor reactivation during the androgen-independent stage of prostate cancer is mediated by numerous mechanisms including expression of AR mutants and splice variants that become non-responsive to con...

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.

Mapping Proteome-Wide Interactions of Reactive Chemicals Using Chemoproteomic Platforms

PubMed Central

Counihan, Jessica L.; Ford, Breanna; Nomura, Daniel K.

2015-01-01

A large number of pharmaceuticals, endogenous metabolites, and environmental chemicals act through covalent mechanisms with protein targets. Yet, their specific interactions with the proteome still remain poorly defined for most of these reactive chemicals. Deciphering direct protein targets of reactive small-molecules is critical in understanding their biological action, off-target effects, potential toxicological liabilities, and development of safer and more selective agents. Chemoproteomic technologies have arisen as a powerful strategy that enable the assessment of proteome-wide interactions of these irreversible agents directly in complex biological systems. We review here several chemoproteomic strategies that have facilitated our understanding of specific protein interactions of irreversibly-acting pharmaceuticals, endogenous metabolites, and environmental electrophiles to reveal novel pharmacological, biological, and toxicological mechanisms. PMID:26647369

Emerging role of immunotherapy in urothelial carcinoma-Future directions and novel therapies.

PubMed

Park, Jong Chul; Hahn, Noah M

2016-12-01

Tremendous advances in our understanding of the tumor immunology and molecular biology of urothelial carcinoma (UC) have led to the recent approval of immunotherapy as a novel option for patients with UC with advanced disease. Despite the promising data of novel immune checkpoint inhibitors, only a small subset of patients with UC achieves durable remissions. Because an optimal antitumor response requires coordination of multiple immune, tumor, and microenvironment effector cells, novel approaches targeting distinct mechanisms of action likely in combination are needed. In addition, discovery of reliable immune biomarkers, understanding of mechanisms of resistance, and novel clinical trial designs are warranted for maximum benefit of UC immunotherapy. Copyright © 2016 Elsevier Inc. All rights reserved.

The affordance-matching hypothesis: how objects guide action understanding and prediction

PubMed Central

Bach, Patric; Nicholson, Toby; Hudson, Matthew

2014-01-01

Action understanding lies at the heart of social interaction. Prior research has often conceptualized this capacity in terms of a motoric matching of observed actions to an action in one’s motor repertoire, but has ignored the role of object information. In this manuscript, we set out an alternative conception of intention understanding, which places the role of objects as central to our observation and comprehension of the actions of others. We outline the current understanding of the interconnectedness of action and object knowledge, demonstrating how both rely heavily on the other. We then propose a novel framework, the affordance-matching hypothesis, which incorporates these findings into a simple model of action understanding, in which object knowledge—what an object is for and how it is used—can inform and constrain both action interpretation and prediction. We will review recent empirical evidence that supports such an object-based view of action understanding and we relate the affordance matching hypothesis to recent proposals that have re-conceptualized the role of mirror neurons in action understanding. PMID:24860468

What are you doing? How active and observational experience shape infants' action understanding

PubMed Central

Hunnius, Sabine; Bekkering, Harold

2014-01-01

From early in life, infants watch other people's actions. How do young infants come to make sense of actions they observe? Here, we review empirical findings on the development of action understanding in infancy. Based on this review, we argue that active action experience is crucial for infants' developing action understanding. When infants execute actions, they form associations between motor acts and the sensory consequences of these acts. When infants subsequently observe these actions in others, they can use their motor system to predict the outcome of the ongoing actions. Also, infants come to an understanding of others’ actions through the repeated observation of actions and the effects associated with them. In their daily lives, infants have plenty of opportunities to form associations between observed events and learn about statistical regularities of others’ behaviours. We argue that based on these two forms of experience—active action experience and observational experience—infants gradually develop more complex action understanding capabilities. PMID:24778386

EEG theta and Mu oscillations during perception of human and robot actions

PubMed Central

Urgen, Burcu A.; Plank, Markus; Ishiguro, Hiroshi; Poizner, Howard; Saygin, Ayse P.

2013-01-01

The perception of others’ actions supports important skills such as communication, intention understanding, and empathy. Are mechanisms of action processing in the human brain specifically tuned to process biological agents? Humanoid robots can perform recognizable actions, but can look and move differently from humans, and as such, can be used in experiments to address such questions. Here, we recorded EEG as participants viewed actions performed by three agents. In the Human condition, the agent had biological appearance and motion. The other two conditions featured a state-of-the-art robot in two different appearances: Android, which had biological appearance but mechanical motion, and Robot, which had mechanical appearance and motion. We explored whether sensorimotor mu (8–13 Hz) and frontal theta (4–8 Hz) activity exhibited selectivity for biological entities, in particular for whether the visual appearance and/or the motion of the observed agent was biological. Sensorimotor mu suppression has been linked to the motor simulation aspect of action processing (and the human mirror neuron system, MNS), and frontal theta to semantic and memory-related aspects. For all three agents, action observation induced significant attenuation in the power of mu oscillations, with no difference between agents. Thus, mu suppression, considered an index of MNS activity, does not appear to be selective for biological agents. Observation of the Robot resulted in greater frontal theta activity compared to the Android and the Human, whereas the latter two did not differ from each other. Frontal theta thus appears to be sensitive to visual appearance, suggesting agents that are not sufficiently biological in appearance may result in greater memory processing demands for the observer. Studies combining robotics and neuroscience such as this one can allow us to explore neural basis of action processing on the one hand, and inform the design of social robots on the other. PMID:24348375

EEG theta and Mu oscillations during perception of human and robot actions.

PubMed

Urgen, Burcu A; Plank, Markus; Ishiguro, Hiroshi; Poizner, Howard; Saygin, Ayse P

2013-01-01

The perception of others' actions supports important skills such as communication, intention understanding, and empathy. Are mechanisms of action processing in the human brain specifically tuned to process biological agents? Humanoid robots can perform recognizable actions, but can look and move differently from humans, and as such, can be used in experiments to address such questions. Here, we recorded EEG as participants viewed actions performed by three agents. In the Human condition, the agent had biological appearance and motion. The other two conditions featured a state-of-the-art robot in two different appearances: Android, which had biological appearance but mechanical motion, and Robot, which had mechanical appearance and motion. We explored whether sensorimotor mu (8-13 Hz) and frontal theta (4-8 Hz) activity exhibited selectivity for biological entities, in particular for whether the visual appearance and/or the motion of the observed agent was biological. Sensorimotor mu suppression has been linked to the motor simulation aspect of action processing (and the human mirror neuron system, MNS), and frontal theta to semantic and memory-related aspects. For all three agents, action observation induced significant attenuation in the power of mu oscillations, with no difference between agents. Thus, mu suppression, considered an index of MNS activity, does not appear to be selective for biological agents. Observation of the Robot resulted in greater frontal theta activity compared to the Android and the Human, whereas the latter two did not differ from each other. Frontal theta thus appears to be sensitive to visual appearance, suggesting agents that are not sufficiently biological in appearance may result in greater memory processing demands for the observer. Studies combining robotics and neuroscience such as this one can allow us to explore neural basis of action processing on the one hand, and inform the design of social robots on the other.

Novel aspects of glucocorticoid actions.

PubMed

Uchoa, E T; Aguilera, G; Herman, J P; Fiedler, J L; Deak, T; de Sousa, M B C

2014-09-01

Normal hypothalamic-pituitary-adrenal (HPA) axis activity leading to the rhythmic and episodic release of adrenal glucocorticoids (GCs) is essential for body homeostasis and survival during stress. Acting through specific intracellular receptors in the brain and periphery, GCs regulate behaviour, as well as metabolic, cardiovascular, immune and neuroendocrine activities. By contrast to chronic elevated levels, circadian and acute stress-induced increases in GCs are necessary for hippocampal neuronal survival and memory acquisition and consolidation, as a result of the inhibition of apoptosis, the facilitation of glutamatergic neurotransmission and the formation of excitatory synapses, and the induction of immediate early genes and dendritic spine formation. In addition to metabolic actions leading to increased energy availability, GCs have profound effects on feeding behaviour, mainly via the modulation of orexigenic and anorixegenic neuropeptides. Evidence is also emerging that, in addition to the recognised immune suppressive actions of GCs by counteracting adrenergic pro-inflammatory actions, circadian elevations have priming effects in the immune system, potentiating acute defensive responses. In addition, negative-feedback by GCs involves multiple mechanisms leading to limited HPA axis activation and prevention of the deleterious effects of excessive GC production. Adequate GC secretion to meet body demands is tightly regulated by a complex neural circuitry controlling hypothalamic corticotrophin-releasing hormone (CRH) and vasopressin secretion, which are the main regulators of pituitary adrenocorticotrophic hormone (ACTH). Rapid feedback mechanisms, likely involving nongenomic actions of GCs, mediate the immediate inhibition of hypothalamic CRH and ACTH secretion, whereas intermediate and delayed mechanisms mediated by genomic actions involve the modulation of limbic circuitry and peripheral metabolic messengers. Consistent with their key adaptive roles, HPA axis components are evolutionarily conserved, being present in the earliest vertebrates. An understanding of these basic mechanisms may lead to novel approaches for the development of diagnostic and therapeutic tools for disorders related to stress and alterations of GC secretion. © 2014 British Society for Neuroendocrinology.

Where’s the Action? Understanding What Works and Why in Relationship Education

PubMed Central

Wadsworth, Martha E.; Markman, Howard J.

2012-01-01

The field of Couples Relationship Education has come to a critical junction. We have generally demonstrated that our interventions work (at least in the short-run) but to what extent have we shown that the skills and processes we teach are in fact responsible for the success of the intervention? In this paper we review progress made in understanding mechanisms of change in relationship education, explore limitations of this body of research, explicate the barriers that interfere with progress in understanding mechanisms of change in intervention research, and present recommendations on how to proceed from here. While our goal in this paper is to focus more on issues in the field rather than to present a comprehensive review of the literature, we provide overarching research summaries to illustrate some of our points. We conclude with offering recommendations for the next generation of research in the Couples Relationship Education field. PMID:22304882

'Long-Cell Action' Corrosion: A Basic Mechanism Hidden Behind Components Degradation Issues in Nuclear Power Plants

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

Genn Saji

2006-07-01

In spite of industries' effort over the last 40 years, corrosion-related issues continue to be one of the largest unresolved problems for nuclear power plants worldwide. There are several types of strange corrosion phenomena from the point of view of our current understanding of corrosion science established in other fields. Some of these are IGSCC, PWSCC, AOA, and FAC (Erosion-Corrosion). Through studying and coping with diverse corrosion phenomena, the author believes that they share a common basis with respect to the assumed corrosion mechanism (e.g., 'local cell action' hypothesis). In general, local cell action is rarely severe since it producesmore » a fairly uniform corrosion. The 'long cell action' that transports electrons through structures far beyond the region of local cell corrosion activities has been identified as a basic mechanism in soil corrosion. If this mechanism is assumed in nuclear power plants, the structure becomes anodic in the area where the potential is less positive and cathodic where this potential is more positive. Metallic ions generated at anodic corrosion sites are transported to remote cathodic sites through the circulation of water and deposits as corrosion products. The SCC, FAC (E-C) and PWSCC occur in the anodic sites as the structure itself acts as a short-circuiting conductor between the two sites, the action is similar to a galvanic cell but in a very large scale. This situation is the same as a battery that has been short-circuited at the terminals. No apparent external potential difference exists between the two electrodes, but an electrochemical reaction is still taking place inside the battery cell with a large internal short current. In this example what is important is the potential difference between the local coolant and the surface of the structural material. Long cell action corrosion is likely enhancing the local cell action's anodic corrosion activities, such as SCC, FAC/E-C, and PWSCC. It tends to be more hazardous because of its localized nature compared with the local cell action corrosion. There exist various mechanisms (electrochemical cell configurations) that induce such potential differences, including: ionic concentration, aeration, temperature, flow velocity, radiation and corrosion potentials. In this paper, the author will discuss these potential differences and their relevance to the un-resolved corrosion issues in nuclear power plants. Due to the importance of this potential mechanism the author is calling for further verification experiments as a joint international project. (author)« less

Existence of dark matter with observed properties of cosmic microwave background radiation substantiates three conservation laws of classical physics and all principles of quantum mechanics as creates the value of Planck’s constant

NASA Astrophysics Data System (ADS)

Boriev, I. A.

2018-03-01

Astronomical data indicate a presence of dark matter (DM) in the space, what is necessary for explanation of observed dynamics of the galaxies within Newtonian mechanics. DM, at its very low density (∼10-26kg/m3), constitutes main part of the matter in the Universe, 10 times the mass of all visible cosmic bodies. No doubt, namely properties of DM, which fills space, must determine its physical properties and fundamental physical laws. Taking into account observed properties of cosmic microwave background radiation (CMBR), whose energy is ∼90% of all cosmic radiation, and understanding that this radiation is produced by DM motion, conservation laws of classical physics and principles of quantum mechanics receive their materialistic substantiation. Thus, CMBR high homogeneity and isotropy (∼10-4), and hence the same properties of DM (and space) justify momentum and angular momentum conservation laws, respectively, according to E. Noether's theorems. CMBR has black body spectrum at ∼2.7K with maximum wavelength ∼1.9·10-3m, what allows calculate the value of mechanical action produced by DM thermal motion (∼7·10-34 J·s). This value corresponds well to the Planck’s constant, which is the mechanical action too, what gives materialistic basis for all principles of quantum mechanics. Obtained results directly confirm the reality of DM existence, and show that CMBR is an observed display of DM thermal motion. Understanding that namely from DM occur known creation of electron-positron pairs as contrarily rotating material vortexes (according to their spins) let substantiate positron nature of ball lightning what first explains all its observed specific properties.

Using in vitro models for expression profiling studies on ethanol and drugs of abuse.

PubMed

Thibault, Christelle; Hassan, Sajida; Miles, Michael

2005-03-01

The use of expression profiling with microarrays offers great potential for studying the mechanisms of action of drugs of abuse. Studies with the intact nervous system seem likely to be most relevant to understanding the mechanisms of drug abuse-related behaviours. However, the use of expression profiling with in vitro culture models offers significant advantages for identifying details of cellular signalling actions and toxicity for drugs of abuse. This study discusses general issues of the use of microarrays and cell culture models for studies on drugs of abuse. Specific results from existing studies are also discussed, providing clear examples of relevance for in vitro studies on ethanol, nicotine, opiates, cannabinoids and hallucinogens such as LSD. In addition to providing details on signalling mechanisms relevant to the neurobiology of drugs of abuse, microarray studies on a variety of cell culture systems have also provided important information on mechanisms of cellular/organ toxicity with drugs of abuse. Efforts to integrate genomic studies on drugs of abuse with both in vivo and in vitro models offer the potential for novel mechanistic rigor and physiological relevance.

FUNDAMENTALS OF VITAMIN D HORMONE-REGULATED GENE EXPRESSION

PubMed Central

Pike, J. Wesley; Meyer, Mark B.

2014-01-01

Initial research focused upon several known genetic targets provided early insight into the mechanism of action of the vitamin D hormone (1,25-dihydroxyvitamin D3 (1,25(OH)2D3)). Recently, however, a series of technical advances involving the coupling of chromatin immunoprecipitation (ChIP) to unbiased methodologies that initially involved tiled DNA microarrays (ChIP-chip analysis) and now Next Generation DNA Sequencing techniques (ChIP-Seq analysis) has opened new avenues of research into the mechanisms through which 1,25(OH)2D3 regulates gene expression. In this review, we summarize briefly the results of this early work and then focus on more recent studies in which ChIP-chip and ChIP-seq analyses have been used to explore the mechanisms of 1,25(OH)2D3 action on a genome-wide scale providing specific target genes as examples. The results of this work have advanced our understanding of the mechanisms involved at both genetic and epigenetic levels and have revealed a series of new principles through which the vitamin D hormone functions to control the expression of genes. PMID:24239506

Exploring Wound-Healing Genomic Machinery with a Network-Based Approach

PubMed Central

Vitali, Francesca; Marini, Simone; Balli, Martina; Grosemans, Hanne; Sampaolesi, Maurilio; Lussier, Yves A.; Cusella De Angelis, Maria Gabriella; Bellazzi, Riccardo

2017-01-01

The molecular mechanisms underlying tissue regeneration and wound healing are still poorly understood despite their importance. In this paper we develop a bioinformatics approach, combining biology and network theory to drive experiments for better understanding the genetic underpinnings of wound healing mechanisms and for selecting potential drug targets. We start by selecting literature-relevant genes in murine wound healing, and inferring from them a Protein-Protein Interaction (PPI) network. Then, we analyze the network to rank wound healing-related genes according to their topological properties. Lastly, we perform a procedure for in-silico simulation of a treatment action in a biological pathway. The findings obtained by applying the developed pipeline, including gene expression analysis, confirms how a network-based bioinformatics method is able to prioritize candidate genes for in vitro analysis, thus speeding up the understanding of molecular mechanisms and supporting the discovery of potential drug targets. PMID:28635674

Infections in patients with multiple sclerosis: Implications for disease-modifying therapy.

PubMed

Celius, E G

2017-11-01

Patients with multiple sclerosis have an increased risk of infections compared to the general population. The increased risk has been described for decades and is not alone attributed to the use of disease-modifying drugs, but secondary to the disability. The introduction of more potent immunomodulatory drugs may cause an additional challenge, and depending on the mechanism of action, a treatment-induced increased risk of bacterial, viral, fungal or parasitic infections is observed. The choice of treatment in the individual patient with infections and multiple sclerosis must be guided by the drugs' specific mechanism of action, the drug-specific risk of infection and comorbidities. Increased monitoring and follow-up through treatment registries is warranted to increase our understanding and thereby improve management. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Laboratory research in homeopathy: pro.

PubMed

Khuda-Bukhsh, Anisur R

2006-12-01

Homeopathy is a holistic method of treatment that uses ultralow doses of highly diluted natural substances originating from plants, minerals, or animals and is based on the principle of "like cures like." Despite being occasionally challenged for its scientific validity and mechanism of action, homeopathy continues to enjoy the confidence of millions of patients around the world who opt for this mode of treatment. Contrary to skeptics' views, research on home-opathy using modern tools mostly tends to support its efficacy and advocates new ideas toward understanding its mechanism of action. As part of a Point-Counterpoint feature, this review and its companion piece in this issue by Moffett et al (Integr Cancer Ther. 2006;5:333-342) are composed of a thesis section, a response section in reaction to the companion thesis, and a rebuttal section to address issues raised in the companion response.

Physiology, production and action of progesterone.

PubMed

Taraborrelli, Stefania

2015-11-01

The aim of this article is to review the physiology of progesterone and focus on its physiological actions on tissues such as endometrium, uterus, mammary gland, cardiovascular system, central nervous system and bones. In the last decades, the interest of researchers has focused on the role of progesterone in genomic and non-genomic receptor mechanisms. We searched PubMed up to December 2014 for publications on progesterone/steroidogenesis. A better understanding of the biological genomic and non-genomic receptor mechanisms could enable us in the near future to obtain a more comprehensive knowledge of the safety and efficacy of this agent during hormone replacement therapy (natural progesterone), in vitro fertilization (water-soluble subcutaneous progesterone), in traumatic brain injury, Alzheimer's disease and diabetic neuropathy, even though further clinical studies are needed to prove its usefulness. © 2015 Nordic Federation of Societies of Obstetrics and Gynecology.

Periodic magnetorotational dynamo action as a prototype of nonlinear magnetic-field generation in shear flows.

PubMed

Herault, J; Rincon, F; Cossu, C; Lesur, G; Ogilvie, G I; Longaretti, P-Y

2011-09-01

The nature of dynamo action in shear flows prone to magnetohydrodynamc instabilities is investigated using the magnetorotational dynamo in Keplerian shear flow as a prototype problem. Using direct numerical simulations and Newton's method, we compute an exact time-periodic magnetorotational dynamo solution to three-dimensional dissipative incompressible magnetohydrodynamic equations with rotation and shear. We discuss the physical mechanism behind the cycle and show that it results from a combination of linear and nonlinear interactions between a large-scale axisymmetric toroidal magnetic field and nonaxisymmetric perturbations amplified by the magnetorotational instability. We demonstrate that this large-scale dynamo mechanism is overall intrinsically nonlinear and not reducible to the standard mean-field dynamo formalism. Our results therefore provide clear evidence for a generic nonlinear generation mechanism of time-dependent coherent large-scale magnetic fields in shear flows and call for new theoretical dynamo models. These findings may offer important clues to understanding the transitional and statistical properties of subcritical magnetorotational turbulence.

Review article: gut-directed hypnotherapy in the management of irritable bowel syndrome and inflammatory bowel disease.

PubMed

Peters, S L; Muir, J G; Gibson, P R

2015-06-01

Gut-directed hypnotherapy is being increasingly applied to patients with irritable bowel syndrome (IBS) and to a lesser extent, inflammatory bowel disease (IBD). To review the technique, mechanisms of action and evidence for efficacy, and to identify gaps in the understanding of gut-directed hypnotherapy as a treatment for IBS and IBD. A review of published literature and a systematic review of clinical trials in its application to patients with IBS and IBD were performed. Gut-directed hypnotherapy is a clearly described technique. Its potential mechanisms of action on the brain-gut axis are multiple with evidence spanning psychological effects through to physiological gastrointestinal modifications. Six of seven randomised IBS studies reported a significant reduction (all P < 0.05) in overall gastrointestinal symptoms following treatment usually compared to supportive therapy only. Response rates amongst those who received gut-directed hypnotherapy ranged between 24% and 73%. Efficacy was maintained long-term in four of five studies. A therapeutic effect was also observed in the maintenance of clinical remission in patients with ulcerative colitis. Uncontrolled trials supported the efficacy and durability of gut-directed hypnotherapy in IBS. Gaps in understanding included to whom and when it should be applied, the paucity of adequately trained hypnotherapists, and the difficulties in designing well controlled-trials. Gut-directed hypnotherapy has durable efficacy in patients with IBS and possibly ulcerative colitis. Whether it sits in the therapeutic arsenal as a primary and/or adjunctive therapy cannot be ascertained on the current evidence base. Further research into efficacy, mechanisms of action and predictors of response is required. © 2015 John Wiley & Sons Ltd.

Bacillus thuringiensis insecticidal three-domain Cry toxins: mode of action, insect resistance and consequences for crop protection.

PubMed

Pardo-López, Liliana; Soberón, Mario; Bravo, Alejandra

2013-01-01

Bacillus thuringiensis bacteria are insect pathogens that produce different Cry and Cyt toxins to kill their hosts. Here we review the group of three-domain Cry (3d-Cry) toxins. Expression of these 3d-Cry toxins in transgenic crops has contributed to efficient control of insect pests and a reduction in the use of chemical insecticides. The mode of action of 3d-Cry toxins involves sequential interactions with several insect midgut proteins that facilitate the formation of an oligomeric structure and induce its insertion into the membrane, forming a pore that kills midgut cells. We review recent progress in our understanding of the mechanism of action of these Cry toxins and focus our attention on the different mechanisms of resistance that insects have evolved to counter their action, such as mutations in cadherin, APN and ABC transporter genes. Activity of Cry1AMod toxins, which are able to form toxin oligomers in the absence of receptors, against different resistant populations, including those affected in the ABC transporter and the role of dominant negative mutants as antitoxins, supports the hypothesis that toxin oligomerization is a limiting step in the Cry insecticidal activity. Knowledge of the action of 3d-Cry toxin and the resistance mechanisms to these toxins will set the basis for a rational design of novel toxins to overcome insect resistance, extending the useful lifespan of Cry toxins in insect control programs. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Current perspectives on behavioural and cellular mechanisms of illness anorexia.

PubMed

Asarian, Lori; Langhans, Wolfgang

2005-12-01

Here we review our current understanding of the integration of immune, neural, metabolic and endocrine signals involved in the generation of anorexia during acute infection, with the focus on anorexia elicited by peripheral administration of bacterial lipopolysaccharide (LPS). We chose to limit this review to peripheral LPS-anorexia because the mechanisms underlying this response may also be valid for anorexia during other types of acute or chronic infections, with slight differences in the duration of anorexia, levels of circulating concentrations of pro-inflammatory cytokines and hypermetabolism. Evidence so far indicates that LPS-anorexia is a complex response beneficial to host defence that involves both peripheral and central action of pro-inflammatory cytokines, other immune factors, such as prostanoids, and neurotransmitters, such as serotonin. One interesting characteristic of LPS-anorexia is its sexual differentiation, an aspect mainly mediated by the gonadal hormone estradiol. Understanding the behavioural and molecular mechanisms of LPS-anorexia may even provide useful leads for identifying mechanisms of eating disorders in humans.

Computer simulations of local anesthetic mechanisms: Quantum chemical investigation of procaine

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

Smith, Jeremy C; Bondar, A.N.; Suhai, Sandor

2007-02-01

A description at the atomic level of detail of the interaction between local anesthetics, lipid membranes and membrane proteins, is essential for understanding the mechanism of local anesthesia. The importance of performing computer simulations to decipher the mechanism of local anesthesia is discussed here in the context of the current status of understanding of the local anesthetics action. As a first step towards accurate simulations of the interaction between local anesthetics, proteins, lipid and water molecules, here we use quantum mechanical methods to assess the charge distribution and structural properties of procaine in the presence and in the absence ofmore » water molecules. The calculations indicate that, in the absence of hydrogen-bonding water molecules, protonated procaine strongly prefers a compact structure enabled by intramolecular hydrogen bonding. In the presence of water molecules the torsional energy pro?le of procaine is modified, and hydrogen bonding to water molecules is favored relative to intra-molecular hydrogen bonding.« less

Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases

PubMed Central

Beurel, Eleonore; Grieco, Steven F.; Jope, Richard S.

2014-01-01

Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders. PMID:25435019

Biological indicators in response to radiofrequency/microwave exposure.

PubMed

Marjanović, Ana Marija; Pavičić, Ivan; Trošić, Ivančica

2012-09-01

Over the years, due to rapid technological progress, radiation from man-made sources exceeded that of natural origin. There is a general concern regarding a growing number of appliances that use radiofrequency/ microwave (RF/MW) radiation with particular emphasis on mobile communication systems. Since nonthermal biological effects and mechanisms of RF/MW radiation are still uncertain, laboratory studies on animal models, tissues, cells, and cell free system are of extraordinary importance in bioelectromagnetic research. We believe that such investigations play a supporting role in public risk assessment. Cellular systems with the potential for a clear response to RF/MW exposures should be used in those studies. It is known that organism is a complex electrochemical system where processes of oxidation and reduction regularly occur. One of the plausible mechanisms is connected with generation of reactive oxygen species (ROS). Depending on concentration, ROS can have both beneficial and deleterious effects. Positive effects are connected with cell signalling, defence against infectious agents, and proliferative cell ability. On the other hand, excessive production, which overloads antioxidant defence mechanism, leads to cellular damage with serious potential for disease development. ROS concentration increase within the cell caused by RF/MW radiation seems to be a biologically relevant hypothesis to give clear insight into the RF/MW action at non-thermal level of radiation. In order to better understand the exact mechanism of action and its consequences, further research is needed in the field. We would like to present current knowledge on possible biological mechanisms of RF/MW actions.

In depth analysis of the mechanism of action of metal-dependent sigma factors: characterization of CorE2 from Myxococcus xanthus

PubMed Central

Marcos-Torres, Francisco Javier; Pérez, Juana; Gómez-Santos, Nuria; Moraleda-Muñoz, Aurelio; Muñoz-Dorado, José

2016-01-01

Extracytoplasmic function sigma factors represent the third pillar of signal-transduction mechanisms in bacteria. The variety of stimuli they recognize and mechanisms of action they use have allowed their classification into more than 50 groups. We have characterized CorE2 from Myxococcus xanthus, which belongs to group ECF44 and upregulates the expression of two genes when it is activated by cadmium and zinc. Sigma factors of this group contain a Cys-rich domain (CRD) at the C terminus which is essential for detecting metals. Point mutations at the six Cys residues of the CRD have revealed the contribution of each residue to CorE2 activity. Some of them are essential, while others are either dispensable or their mutations only slightly affect the activity of the protein. However, importantly, mutation of Cys174 completely shifts the specificity of CorE2 from cadmium to copper, indicating that the Cys arrangement of the CRD determines the metal specificity. Moreover, the conserved CxC motif located between the σ2 domain and the σ4.2 region has also been found to be essential for activity. The results presented here contribute to our understanding of the mechanism of action of metal-dependent sigma factors and help to define new common features of the members of this group of regulators. PMID:26951374

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.

Improving organizational capacity to address health literacy in public health: a rapid realist review.

PubMed

Willis, C D; Saul, J E; Bitz, J; Pompu, K; Best, A; Jackson, B

2014-06-01

Despite the growing significance of health literacy to public health, relatively little is known about how organizational capacity may be improved for planning, implementing and sustaining health literacy interventions. This study aimed to connect decision makers in a public health agency with evidence of how organizational capacity may be improved for delivering health literacy services. A rapid realist review of published and grey literature was conducted by a partnership between the Public Health Agency of Canada (PHAC) and the InSource Research Group. Realist review methodology attempts to understand what works for whom under what circumstances, and is characterized by its focus on strategies/interventions, contexts, mechanisms and their relationship to outcome. This review was completed in collaboration with a reference panel (comprised of a broad range of PHAC representatives) and an expert panel. Literature searching was conducted using three databases supplemented with bibliographic hand searches and articles recommended by panels. Data were extracted on key variables related to definitions, strategies/interventions associated with increased organizational capacity, contextual factors associated with success (and failure), mechanisms activated as a result of different strategies and contexts, key outcomes, and evidence cited. Strategies found to be associated with improved organizational capacity for delivering health literacy services may be classified into three domains: (1) government action; (2) organizational/practitioner action; and (3) partnership action. Government action includes developing policies to reinforce social norms; setting standards for education; conducting research; and measuring health literacy levels. Organizational/practitioner action relates to appropriate models of leadership (both high-level government engagement and distributed leadership). Innovative partnership action includes collaborations with media outlets, those producing electronic materials, community organizations and school-based programs. Contextual factors for success include positive leadership models, interorganizational relationships, and a culture committed to experimentation and learning. Potential mechanisms activated by strategies and contextual factors include increased visibility and recognition of health literacy efforts, enthusiasm and momentum for health literacy activities, reduced cognitive dissonance between vision and action, a sense of ownership for health literacy data, and creation of a common language and understanding. Government initiated interventions and policies are powerful strategies by which organizational capacity to improve health literacy may be affected. Using the foundations created by the government policy environment, organizations may improve the impact of health literacy interventions through supported distributed leadership. Copyright © 2014 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

Mechanical basis of bone strength: influence of bone material, bone structure and muscle action

PubMed Central

Hart, N.H.; Nimphius, S.; Rantalainen, T.; Ireland, A.; Siafarikas, A.; Newton, R.U.

2017-01-01

This review summarises current understanding of how bone is sculpted through adaptive processes, designed to meet the mechanical challenges it faces in everyday life and athletic pursuits, serving as an update for clinicians, researchers and physical therapists. Bone’s ability to resist fracture under the large muscle and locomotory forces it experiences during movement and in falls or collisions is dependent on its established mechanical properties, determined by bone’s complex and multidimensional material and structural organisation. At all levels, bone is highly adaptive to habitual loading, regulating its structure according to components of its loading regime and mechanical environment, inclusive of strain magnitude, rate, frequency, distribution and deformation mode. Indeed, the greatest forces habitually applied to bone arise from muscular contractions, and the past two decades have seen substantial advances in our understanding of how these forces shape bone throughout life. Herein, we also highlight the limitations of in vivo methods to assess and understand bone collagen, and bone mineral at the material or tissue level. The inability to easily measure or closely regulate applied strain in humans is identified, limiting the translation of animal studies to human populations, and our exploration of how components of mechanical loading regimes influence mechanoadaptation. PMID:28860414

Over the Counter Drugs (and Dietary Supplement) Exercise: A Team-based Introduction to Biochemistry for Health Professional Students

ERIC Educational Resources Information Center

Phadtare, Sangita; Abali, Emine; Brodsky, Barbara

2013-01-01

For successful delivery of basic science topics for health-professional students, it is critical to reduce apprehension and illustrate relevance to clinical settings and everyday life. At the beginning of the Biochemistry course for Physician Assistants, a team-based assignment was designed to develop an understanding of the mechanism of action,…

Capsaicin, from Hot to Not; Can New Pain-Relieving Drugs Be Derived from This Substance Known to Cause Pain?

ERIC Educational Resources Information Center

Rusterholz, David B.

2006-01-01

The systematic developments of synthetically modified structures related to capsaicin known to have pungent properties found in chili peppers that could be useful as analgesic drug are described. It is found that identification of the receptor for capsaicin and the mechanism of its action greatly contributed to an understanding of the role…

Biomedical Potential of mTOR Modulation by Nanoparticles.

PubMed

Hulea, Laura; Markovic, Zoran; Topisirovic, Ivan; Simmet, Thomas; Trajkovic, Vladimir

2016-05-01

Modulation of the mammalian target of rapamycin (mTOR), the principal regulator of cellular homeostasis, underlies the biological effects of engineered nanoparticles, including regulation of cell death/survival and metabolic responses. Understanding the mechanisms and biological actions of nanoparticle-mediated mTOR modulation may help in developing safe and efficient nanotherapeutics to fight human disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Immunotherapy in lung cancer.

PubMed Central

Al-Moundhri, M.; O'Brien, M.; Souberbielle, B. E.

1998-01-01

More research and new treatment options are needed in all stages of lung cancer. To this end immunotherapy needs a revival in view of recent improved technologies and greater understanding of the underlying biology. In this review we discuss mechanisms of tumour immunotherapy, non-specific, specific and adoptive, with particular reference to a direct therapeutic action on all subtypes of lung cancer. PMID:9703271

Tool use in left-brain-damaged patients: Difficulties in reasoning but not in estimating the physical properties of objects.

PubMed

Faye, Alexandrine; Jacquin-Courtois, Sophie; Osiurak, François

2018-03-01

The purpose of this study was to deepen our understanding of the cognitive bases of human tool use based on the technical reasoning hypothesis (i.e., the reasoning-based approach). This approach assumes that tool use is supported by the ability to reason about an object's physical properties (e.g., length, weight, strength, etc.) to perform mechanical actions (e.g., lever). In this framework, an important issue is to understand whether left-brain-damaged (LBD) individuals with tool-use deficits are still able to estimate the physical object's properties necessary to use the tool. Eleven LBD patients and 12 control participants performed 3 original experimental tasks: Use-Length (visual evaluation of the length of a stick to bring down a target), Visual-Length (to visually compare objects of different lengths) and Addition-Length (to visually compare added lengths). Participants were also tested on conventional tasks: Familiar Tool Use and Mechanical Problem-Solving (novel tools). LBD patients had more difficulties than controls on both conventional tasks. No significant differences were observed for the 3 experimental tasks. These results extend the reasoning-based approach, stressing that it might not be the representation of length that is impaired in LBD patients, but rather the ability to generate mechanical actions based on physical object properties. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Fractography, NDE, and fracture mechanics applications in failure analysis studies

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

Morin, C.R.; Shipley, R.J.; Wilkinson, J.A.

1994-10-01

While identification of the precise mode of a failure can lead logically to the underlying cause, a thorough failure investigation requires much more than just the identification of a specific metallurgical mechanism, for example, fatigue, creep, stress corrosion cracking, etc. Failures involving fracture provide good illustrations of this concept. An initial step in characterizing fracture surfaces is often the identification of an origin or origins. However, the analysis should not stop there. If the origin is associated with a discontinuity, the manner in which it was formed must also be addressed. The stresses that would have existed at the originmore » must be determined and compared with material properties to determine whether or not a crack should have initiated and propagated during normal operation. Many critical components are inspected throughout their lives by nondestructive methods. When a crack progresses to failure, its nondetection at earlier inspections must also be understood. Careful study of the fracture surface combined with crack growth analysis based on fracture mechanics can provide an estimate of the crack length at the times of previous inspections. An important issue often overlooked in such studies is how processing of parts during manufacture or rework affects the probability of detection of such cracks. The ultimate goal is to understand thoroughly the progression of the failure, to understand the root cause(s), and to design appropriate corrective action(s) to minimize recurrence.« less

Microbiome manipulation with faecal microbiome transplantation as a therapeutic strategy in Clostridium difficile infection

PubMed Central

Marchesi, J.R.; Thursz, M.R.; Williams, H.R.T.

2015-01-01

Faecal microbiome transplantation (FMT) has generated huge recent interest as it presents a potential solution to a significant clinical problem—the increasing incidence of Clostridium difficile infection (CDI). In the short term, however, there remain many practical questions regarding its use, including the optimal selection of donors, material preparation and the mechanics of delivery. In the longer term, enhanced understanding of the mechanisms of action of FMT may potentiate novel therapies, such as targeted manipulation of the microbiome in CDI and beyond. PMID:25193538

Searching for roots of entrainment and joint action in early musical interactions.

PubMed

Phillips-Silver, Jessica; Keller, Peter E

2012-01-01

When people play music and dance together, they engage in forms of musical joint action that are often characterized by a shared sense of rhythmic timing and affective state (i.e., temporal and affective entrainment). In order to understand the origins of musical joint action, we propose a model in which entrainment is linked to dual mechanisms (motor resonance and action simulation), which in turn support musical behavior (imitation and complementary joint action). To illustrate this model, we consider two generic forms of joint musical behavior: chorusing and turn-taking. We explore how these common behaviors can be founded on entrainment capacities established early in human development, specifically during musical interactions between infants and their caregivers. If the roots of entrainment are found in early musical interactions which are practiced from childhood into adulthood, then we propose that the rehearsal of advanced musical ensemble skills can be considered to be a refined, mimetic form of temporal and affective entrainment whose evolution begins in infancy.

Central leptin action on euglycemia restoration in type 1 diabetes: Restraining responses normally induced by fasting?

PubMed

Xu, Yuanzhong; Tong, Qingchun

2017-07-01

Leptin monotherapy is sufficient to restore euglycemia in insulinopenic type 1 diabetes (T1D), yet the underlying mechanism remains poorly understood. Accumulating evidence demonstrates that the brain mediates the leptin action on euglycemia restoration. Here, we first review evidence supporting that symptoms in T1D resemble an uncontrolled response to fasting. Then, we discuss recent research progress on brain neurons and their neurotransmitters that potentially mediate the leptin action. Finally, peripheral effective pathways, which are normally involved in fasting responses and associated with leptin action on euglycemia restoration in T1D, will also be discussed. This summary complements several previous excellent reviews on this topic (Meek and Morton, 2016; Perry et al., 2016; Fujikawa and Coppari, 2015). A deep understanding of neurocircuitry and the peripheral effective pathways that mediate the leptin action on euglycemia restoration will likely lead to novel targets for an insulin-independent therapeutics against T1D. Copyright © 2016 Elsevier Ltd. All rights reserved.

Searching for Roots of Entrainment and Joint Action in Early Musical Interactions

PubMed Central

Phillips-Silver, Jessica; Keller, Peter E.

2012-01-01

When people play music and dance together, they engage in forms of musical joint action that are often characterized by a shared sense of rhythmic timing and affective state (i.e., temporal and affective entrainment). In order to understand the origins of musical joint action, we propose a model in which entrainment is linked to dual mechanisms (motor resonance and action simulation), which in turn support musical behavior (imitation and complementary joint action). To illustrate this model, we consider two generic forms of joint musical behavior: chorusing and turn-taking. We explore how these common behaviors can be founded on entrainment capacities established early in human development, specifically during musical interactions between infants and their caregivers. If the roots of entrainment are found in early musical interactions which are practiced from childhood into adulthood, then we propose that the rehearsal of advanced musical ensemble skills can be considered to be a refined, mimetic form of temporal and affective entrainment whose evolution begins in infancy. PMID:22375113

Mechanisms of the gabapentinoids and α 2 δ-1 calcium channel subunit in neuropathic pain.

PubMed

Patel, Ryan; Dickenson, Anthony H

2016-04-01

The gabapentinoid drugs gabapentin and pregabalin are key front-line therapies for various neuropathies of peripheral and central origin. Originally designed as analogs of GABA, the gabapentinoids bind to the α 2 δ-1 and α 2 δ-2 auxiliary subunits of calcium channels, though only the former has been implicated in the development of neuropathy in animal models. Transgenic approaches also identify α 2 δ-1 as key in mediating the analgesic effects of gabapentinoids, however the precise molecular mechanisms remain unclear. Here we review the current understanding of the pathophysiological role of the α 2 δ-1 subunit, the mechanisms of analgesic action of gabapentinoid drugs and implications for efficacy in the clinic. Despite widespread use, the number needed to treat for gabapentin and pregabalin averages from 3 to 8 across neuropathies. The failure to treat large numbers of patients adequately necessitates a novel approach to treatment selection. Stratifying patients by sensory profiles may imply common underlying mechanisms, and a greater understanding of these mechanisms could lead to more direct targeting of gabapentinoids.

Moving beyond a knowledge deficit perspective to understand climate action by youth

NASA Astrophysics Data System (ADS)

Busch, K. C.

2016-12-01

This presentation reports on an experiment testing two framings of uncertainty on students' intent to take action to mitigate climate change. Additionally, to explore possible mechanisms involved in the choice of taking mitigating action, several factors highlighted within behavior theory literature were measured to create a theoretical model for youth's choice to take mitigating action. The factors explored were: knowledge, certainty, affect, efficacy, and social norms. The experiment was conducted with 453 middle and high school students within the Bay Area. Findings indicated that these students did hold a basic understanding of the causes and effects of climate change. They were worried and felt negatively about the topic. They felt somewhat efficacious about their personal ability to mitigate climate change. The students reported that they associated with people who were more likely to think climate change was real and caused by humans. Students also reported that they often take part in private pro-environmental behaviors such as using less electricity. When asked to respond freely to a question about what think about climate change, participants described the negative effects of human-caused climate change on Earth systems at the global scale and as a current phenomenon. The results of the experiment showed that while the text portraying climate change with high uncertainty did affect student's own certainty and their perception of scientists' certainty, it did not affect behavioral intention. This result can be explained through regression analysis. It was found that efficacy and social norms were direct determinants of pro-environmental behaviors. The cognitive variables - knowledge and certainty - and the psychological variable - affect - were not significant predictors of pro-environmental behavior. The implications for this study are that while students hold basic understanding of the causes and effects of climate change, this understanding lacks personal relevance. Another implication of this study is that if we wish to have action-taking as an outcome of climate change education efforts, then the learning activities should include components to address efficacy and social norms.

Alcohol-Binding Sites in Distinct Brain Proteins: The Quest for Atomic Level Resolution

PubMed Central

Howard, Rebecca J.; Slesinger, Paul A.; Davies, Daryl L.; Das, Joydip; Trudell, James R.; Harris, R. Adron

2011-01-01

Defining the sites of action of ethanol on brain proteins is a major prerequisite to understanding the molecular pharmacology of this drug. The main barrier to reaching an atomic-level understanding of alcohol action is the low potency of alcohols, ethanol in particular, which is a reflection of transient, low-affinity interactions with their targets. These mechanisms are difficult or impossible to study with traditional techniques such as radioligand binding or spectroscopy. However, there has been considerable recent progress in combining X-ray crystallography, structural modeling, and site-directed mutagenesis to define the sites and mechanisms of action of ethanol and related alcohols on key brain proteins. We review such insights for several diverse classes of proteins including inwardly rectifying potassium, transient receptor potential, and neurotransmit-ter-gated ion channels, as well as protein kinase C epsilon. Some common themes are beginning to emerge from these proteins, including hydrogen bonding of the hydroxyl group and van der Waals interactions of the methylene groups of ethanol with specific amino acid residues. The resulting binding energy is proposed to facilitate or stabilize low-energy state transitions in the bound proteins, allowing ethanol to act as a “molecular lubricant” for protein function. We discuss evidence for characteristic, discrete alcohol-binding sites on protein targets, as well as evidence that binding to some proteins is better characterized by an interaction region that can accommodate multiple molecules of ethanol. PMID:21676006

Tetracycline compounds with non-antimicrobial organ protective properties: possible mechanisms of action

PubMed Central

Griffin, Michael O.; Ceballos, Guillermo; Villarreal, Francisco

2010-01-01

Tetracyclines were developed as a result of the screening of soil samples for antibiotics. The firstt of these compounds, chlortetracycline, was introduced in 1947. Tetracyclines were found to be highly effective against various pathogens including rickettsiae, as well as both gram-positive and gram-negative bacteria, thus becoming the first class of broad spectrum antibiotics. Many other interesting properties, unrelated to their antibiotic activity, have been identified for tetracyclines which have led to widely divergent experimental and clinical uses. For example, tetracyclines are also an effective anti-malarial drug. Minocycline, which can readily cross cell membranes, is known to be a potent anti-apoptotic agent. Another tetracycline, doxycycline is known to exert anti-protease activities. Doxycycline can inhibit matrix metalloproteinases which contribute to tissue destruction activities in diseases such as periodontitis. A large body of literature has provided additional evidence for the “beneficial” actions of tetracyclines, including their ability to act as reactive oxygen species scavengers and anti-inflammatory agents. This review provides a summary of tetracycline’s multiple mechanisms of action as a means to understand their beneficial effects. PMID:20951211

Advances in Understanding of Penile Carcinogenesis: The Search for Actionable Targets

PubMed Central

Chaing, Sharon; Azizi, Mounsif; Kidd, Laura C.; Kim, Patricia; Spiess, Philippe E.

2017-01-01

Penile cancer (PeCa) is a rare malignancy with potentially devastating effects. Squamous cell carcinoma is the most common variant with distinct precancerous lesions before development into invasive disease. Involvement of the inguinal lymph nodes is the most important prognostic factor in PeCa, and once disease is present outside the groin, prognosis is poor. Metastatic PeCa is challenging to treat and often requires multidisciplinary approaches in management. Due to its rarity, molecular understanding of the disease continues to be limited with most studies based on small, single center series. Thus far, it appears PeCa has diverse mechanisms of carcinogenesis affecting similar molecular pathways. In this review, we evaluate the current landscape of the molecular carcinogenesis of PeCa and explore ongoing research on potential actionable targets of therapy. The emergence of anti-epidermal growth factor receptor (EGFR) and other immunotherapeutic strategies may improve outcomes for PeCa patients. PMID:28813024

Decoding intention: A neuroergonomic perspective

PubMed Central

Grafton, Scott T.; Tipper, Christine M.

2011-01-01

Decoding the intentions of other people based on non-linguistic cues such as their body movement is a major requirement of many jobs. Whether it is maintaining security at an airport or negotiating with locals in a foreign country, there is a need to augment maximize the effectiveness of training or real-time performance in this decoding process. This review considers the potential utility of neuroergonomic solutions, and in particular, of electroencephalographic (EEG) methods for augmenting action understanding. Focus is given to body movements and hand-object interactions, where there is a rapid growth in relevant science. The interpretation of EEG-based signals is reinforced by a consideration of functional magnetic resonance imaging experiments demonstrating underlying brain mechanisms that support goal oriented action. While no EEG method is currently implemented as a practical application for enhancing the understanding of unspoken intentions, there are a number of promising approaches that merit further development. PMID:21651985

Neural mechanisms of understanding rational actions: middle temporal gyrus activation by contextual violation.

PubMed

Jastorff, Jan; Clavagnier, Simon; Gergely, György; Orban, Guy A

2011-02-01

Performing goal-directed actions toward an object in accordance with contextual constraints, such as the presence or absence of an obstacle, has been widely used as a paradigm for assessing the capacity of infants or nonhuman primates to evaluate the rationality of others' actions. Here, we have used this paradigm in a functional magnetic resonance imaging experiment to visualize the cortical regions involved in the assessment of action rationality while controlling for visual differences in the displays and directly correlating magnetic resonance activity with rationality ratings. Bilateral middle temporal gyrus (MTG) regions, anterior to extrastriate body area and the human middle temporal complex, were involved in the visual evaluation of action rationality. These MTG regions are embedded in the superior temporal sulcus regions processing the kinematics of observed actions. Our results suggest that rationality is assessed initially by purely visual computations, combining the kinematics of the action with the physical constraints of the environmental context. The MTG region seems to be sensitive to the contingent relationship between a goal-directed biological action and its relevant environmental constraints, showing increased activity when the expected pattern of rational goal attainment is violated.

From pulses to pain relief: an update on the mechanisms of rTMS-induced analgesic effects.

PubMed

Moisset, X; de Andrade, D C; Bouhassira, D

2016-05-01

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that allows cortical stimulation. Recent studies have shown that rTMS of the primary motor cortex or dorsolateral prefrontal cortex decreases pain in various pain conditions. The aim of this review was to summarize the main characteristics of rTMS-induced analgesic effects and to analyse the current data on its mechanisms of action. Medline, PubMed and Web of Science were searched for studies on the analgesic effects and mechanisms of rTMS-induced analgesic effects. Studies on epidural motor cortex stimulation (EMCS) were also included when required, as several mechanisms of action are probably shared between both techniques. Stimulation site and stimulation parameters have a major impact on rTMS-related analgesic effects. Local cortical stimulation is able to elicit changes in the functioning of distant brain areas. These modifications outlast the duration of the rTMS session and probably involve LTP-like mechanisms via its influence on glutamatergic networks. Analgesic effects seem to be correlated to restoration of normal cortical excitability in chronic pain patients and depend on pain modulatory systems, in particular endogenous opioids. Dopamine, serotonin, norepinephrine and GABAergic circuitry may also be involved in its effects, as well as rostrocaudal projections. rTMS activates brain areas distant from the stimulation site. LTP-like mechanisms, dependence on endogenous opioids and increase in concentration of neurotransmitters (monoamines, GABA) have all been implicated in its analgesic effects, although more studies are needed to fill in the still existing gaps in the understanding of its mechanisms of action. © 2015 European Pain Federation - EFIC®

Zero-gravity movement studies

NASA Technical Reports Server (NTRS)

Badler, N. I.; Fishwick, P.; Taft, N.; Agrawala, M.

1985-01-01

The use of computer graphics to simulate the movement of articulated animals and mechanisms has a number of uses ranging over many fields. Human motion simulation systems can be useful in education, medicine, anatomy, physiology, and dance. In biomechanics, computer displays help to understand and analyze performance. Simulations can be used to help understand the effect of external or internal forces. Similarly, zero-gravity simulation systems should provide a means of designing and exploring the capabilities of hypothetical zero-gravity situations before actually carrying out such actions. The advantage of using a simulation of the motion is that one can experiment with variations of a maneuver before attempting to teach it to an individual. The zero-gravity motion simulation problem can be divided into two broad areas: human movement and behavior in zero-gravity, and simulation of articulated mechanisms.

Botulinum toxin: A review of the mode of action in migraine.

PubMed

Do, T P; Hvedstrup, J; Schytz, H W

2018-05-01

Botulinum toxin serotype A (BoNT/A) was originally used in neurology for the treatment of dystonia and blepharospasms, but is now clinically used worldwide for the treatment of chronic migraine. Still, the possible mode of action of BoNT/A in migraine is not fully known. However, the mode of action of BoNT/A has been investigated in experimental pain as well as migraine models, which may elucidate the underlying mechanisms in migraine. The aim of this study was to review studies on the possible mode of action of BoNT/A in relation to chronic migraine treatment. Observations suggest that the mode of action of BoNT/A may not be limited to the injection site, but also includes anatomically connected sites due to axonal transport. The mechanisms behind the effect of BoNT/A in chronic migraine may also include modulation of neurotransmitter release, changes in surface expression of receptors and cytokines as well as enhancement of opioidergic transmission. Clinical and experimental studies with botulinum toxin in the last decade have advanced our understanding of headache and other pain states. More research into botulinum toxin as treatment for headache is warranted as it can be an attractive alternative for patients who do not respond positively to other drugs. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mechanism of antibacterial action of the alcoholic extracts of Hemidesmus indicus (L.) R. Br. ex Schult, Leucas aspera (Wild.), Plumbago zeylanica L., and Tridax procumbens (L.) R. Br. ex Schult

PubMed Central

Saritha, Kongari; Rajesh, Angireddy; Manjulatha, Khanapur; Setty, Oruganti H.; Yenugu, Suresh

2015-01-01

Herbal products derived from Hemidesmus indicus (L.) R. Br. ex Schult, Leucas aspera (Wild.), Plumbago zeylanica L., and Tridax procumbens (L.) R. Br. ex Schult. are widely used in traditional medicine. Though the extracts of these plants were found to be antimicrobial in nature and have the potential to be used in clinics, the mechanism of action of is not reported. The ethanolic extracts of Hemidesmus indicus (L.) R. Br. ex Schult, Hemidesmus indicus ethanolic extract (HIEE), Leucas aspera (Wild.), Leucas aspera ethanolic extract (LAEE), Plumbago zeylanica L., Plumbago zeylanica ethanolic extract (PZEE), and Tridax procumbens (L.) R. Br. ex Schult, Tridax procumbens ethanolic extract (TPEE) were tested for their antibacterial activity against E. coli. Antibacterial activity was analyzed by CFU assay and the effect on the bacterial membrane by fluorescence activated cell sorting and scanning electron microscopy. LAEE, PZEE, and HIEE displayed potent bacterial killing activity in a time and concentration dependent manner. TPEE did not display appreciable antibacterial activity. The antibacterial action involved disruption of membrane potential, inner membrane permeabilization, blebbing and leakage of cellular contents. Our results contribute to the understanding of the antibacterial mechanism of alcoholic extracts of the medicinal plants used in this study. PMID:26106379

Mechanism of antibacterial action of the alcoholic extracts of Hemidesmus indicus (L.) R. Br. ex Schult, Leucas aspera (Wild.), Plumbago zeylanica L., and Tridax procumbens (L.) R. Br. ex Schult.

PubMed

Saritha, Kongari; Rajesh, Angireddy; Manjulatha, Khanapur; Setty, Oruganti H; Yenugu, Suresh

2015-01-01

Herbal products derived from Hemidesmus indicus (L.) R. Br. ex Schult, Leucas aspera (Wild.), Plumbago zeylanica L., and Tridax procumbens (L.) R. Br. ex Schult. are widely used in traditional medicine. Though the extracts of these plants were found to be antimicrobial in nature and have the potential to be used in clinics, the mechanism of action of is not reported. The ethanolic extracts of Hemidesmus indicus (L.) R. Br. ex Schult, Hemidesmus indicus ethanolic extract (HIEE), Leucas aspera (Wild.), Leucas aspera ethanolic extract (LAEE), Plumbago zeylanica L., Plumbago zeylanica ethanolic extract (PZEE), and Tridax procumbens (L.) R. Br. ex Schult, Tridax procumbens ethanolic extract (TPEE) were tested for their antibacterial activity against E. coli. Antibacterial activity was analyzed by CFU assay and the effect on the bacterial membrane by fluorescence activated cell sorting and scanning electron microscopy. LAEE, PZEE, and HIEE displayed potent bacterial killing activity in a time and concentration dependent manner. TPEE did not display appreciable antibacterial activity. The antibacterial action involved disruption of membrane potential, inner membrane permeabilization, blebbing and leakage of cellular contents. Our results contribute to the understanding of the antibacterial mechanism of alcoholic extracts of the medicinal plants used in this study.

Harnessing Big Data for Systems Pharmacology

PubMed Central

Xie, Lei; Draizen, Eli J.; Bourne, Philip E.

2017-01-01

Systems pharmacology aims to holistically understand mechanisms of drug actions to support drug discovery and clinical practice. Systems pharmacology modeling (SPM) is data driven. It integrates an exponentially growing amount of data at multiple scales (genetic, molecular, cellular, organismal, and environmental). The goal of SPM is to develop mechanistic or predictive multiscale models that are interpretable and actionable. The current explosions in genomics and other omics data, as well as the tremendous advances in big data technologies, have already enabled biologists to generate novel hypotheses and gain new knowledge through computational models of genome-wide, heterogeneous, and dynamic data sets. More work is needed to interpret and predict a drug response phenotype, which is dependent on many known and unknown factors. To gain a comprehensive understanding of drug actions, SPM requires close collaborations between domain experts from diverse fields and integration of heterogeneous models from biophysics, mathematics, statistics, machine learning, and semantic webs. This creates challenges in model management, model integration, model translation, and knowledge integration. In this review, we discuss several emergent issues in SPM and potential solutions using big data technology and analytics. The concurrent development of high-throughput techniques, cloud computing, data science, and the semantic web will likely allow SPM to be findable, accessible, interoperable, reusable, reliable, interpretable, and actionable. PMID:27814027

Harnessing Big Data for Systems Pharmacology.

PubMed

Xie, Lei; Draizen, Eli J; Bourne, Philip E

2017-01-06

Systems pharmacology aims to holistically understand mechanisms of drug actions to support drug discovery and clinical practice. Systems pharmacology modeling (SPM) is data driven. It integrates an exponentially growing amount of data at multiple scales (genetic, molecular, cellular, organismal, and environmental). The goal of SPM is to develop mechanistic or predictive multiscale models that are interpretable and actionable. The current explosions in genomics and other omics data, as well as the tremendous advances in big data technologies, have already enabled biologists to generate novel hypotheses and gain new knowledge through computational models of genome-wide, heterogeneous, and dynamic data sets. More work is needed to interpret and predict a drug response phenotype, which is dependent on many known and unknown factors. To gain a comprehensive understanding of drug actions, SPM requires close collaborations between domain experts from diverse fields and integration of heterogeneous models from biophysics, mathematics, statistics, machine learning, and semantic webs. This creates challenges in model management, model integration, model translation, and knowledge integration. In this review, we discuss several emergent issues in SPM and potential solutions using big data technology and analytics. The concurrent development of high-throughput techniques, cloud computing, data science, and the semantic web will likely allow SPM to be findable, accessible, interoperable, reusable, reliable, interpretable, and actionable.

Ideology as instrument.

PubMed

Glassman, Michael; Karno, Donna

2007-12-01

Comments on the article by J. T. Jost, which argued that the end-of-ideology claims that emerged in the aftermath of World War II were both incorrect and detrimental to the field of political psychology. M. Glassman and D. Karno make three critical points. First, Jost objectified ideology as a grand strategy implemented at the individual level, rather than as an instrument used for a specific purpose in activity. In doing so, he set ideology up as an "object" that guides human behavior rather than as a rational part of human experience. Second, they take issue with the idea that, because somebody acts in a manner that can be categorized as ideological, there actually is such a thing as ideology separate from that event and/or political experience and that psychologists ought to understand the meaning of ideology in order to understand future human activities as outside observers. Third, Jost seems to see this objective ideology as a unidirectional, causal mechanism for activity, a mechanism that assumes individuals act according to ideology, which eclipses the possibility that immediate ideological positions are the residue of purposeful activity. Glassman and Karno suggest that it may be better to take a pluralistic view of ideology in human action. Where ideology does exist, it is as a purposeful instrument--part of a logically based action to meet some ends-in-view--a mixture of immediate goals tied to secondary belief systems (which have been integrated to serve the material purposes of the purveyors of these ideologies). So if we are to understand ideology, we can only understand it through its use in human activity. (Copyright) 2007 APA.

Unravelling the Mystery of Capsaicin: A Tool to Understand and Treat Pain

PubMed Central

Brock, Christina; Olesen, Anne Estrup; Andresen, Trine; Nilsson, Matias; Dickenson, Anthony H.

2012-01-01

A large number of pharmacological studies have used capsaicin as a tool to activate many physiological systems, with an emphasis on pain research but also including functions such as the cardiovascular system, the respiratory system, and the urinary tract. Understanding the actions of capsaicin led to the discovery its receptor, transient receptor potential (TRP) vanilloid subfamily member 1 (TRPV1), part of the superfamily of TRP receptors, sensing external events. This receptor is found on key fine sensory afferents, and so the use of capsaicin to selectively activate pain afferents has been exploited in animal studies, human psychophysics, and imaging studies. Its effects depend on the dose and route of administration and may include sensitization, desensitization, withdrawal of afferent nerve terminals, or even overt death of afferent fibers. The ability of capsaicin to generate central hypersensitivity has been valuable in understanding the consequences and mechanisms behind enhanced central processing of pain. In addition, capsaicin has been used as a therapeutic agent when applied topically, and antagonists of the TRPV1 receptor have been developed. Overall, the numerous uses for capsaicin are clear; hence, the rationale of this review is to bring together and discuss the different types of studies that exploit these actions to shed light upon capsaicin working both as a tool to understand pain but also as a treatment for chronic pain. This review will discuss the various actions of capsaicin and how it lends itself to these different purposes. PMID:23023032

Adjuvants: Classification, Modus Operandi, and Licensing.

PubMed

Apostólico, Juliana de Souza; Lunardelli, Victória Alves Santos; Coirada, Fernanda Caroline; Boscardin, Silvia Beatriz; Rosa, Daniela Santoro

2016-01-01

Vaccination is one of the most efficient strategies for the prevention of infectious diseases. Although safer, subunit vaccines are poorly immunogenic and for this reason the use of adjuvants is strongly recommended. Since their discovery in the beginning of the 20th century, adjuvants have been used to improve immune responses that ultimately lead to protection against disease. The choice of the adjuvant is of utmost importance as it can stimulate protective immunity. Their mechanisms of action have now been revealed. Our increasing understanding of the immune system, and of correlates of protection, is helping in the development of new vaccine formulations for global infections. Nevertheless, few adjuvants are licensed for human vaccines and several formulations are now being evaluated in clinical trials. In this review, we briefly describe the most well known adjuvants used in experimental and clinical settings based on their main mechanisms of action and also highlight the requirements for licensing new vaccine formulations.

Intentional attunement: a neurophysiological perspective on social cognition and its disruption in autism.

PubMed

Gallese, Vittorio

2006-03-24

A direct form of experiential understanding of others, "intentional attunement", is achieved by modeling their behavior as intentional experiences on the basis of the activation of shared neural systems underpinning what the others do an feel and what we do and feel. This modeling mechanism is embodied simulation. In parallel with the detached sensory description of the observed social stimuli, internal representations of the body states associated with actions, emotions, and sensations are evoked in the observer, as if he/she would be doing a similar action or experiencing a similar emotion or sensation. Mirror neuron systems are likely the neural correlate of this mechanism. By means of a shared neural state realized in two different bodies, the "objectual other" becomes "another self". A defective intentional attunement caused by a lack of embodies simulation might cause some of the social impairments of autistic individuals.

EVIDENCE FOR BASE EXCISION REPAIR PROCESSING OF DNA INTERSTRAND CROSSLINKS

PubMed Central

Kothandapani, Anbarasi; Patrick, Steve M

2013-01-01

Many bifunctional alkylating agents and anticancer drugs exert their cytotoxicity by producing cross links between the two complementary strands of DNA, termed interstrand crosslinks (ICLs). This blocks the strand separating processes during DNA replication and transcription, which can lead to cell cycle arrest and apoptosis. Cells use multiple DNA repair systems to eliminate the ICLs. Concerted action of repair proteins involved in Nucleotide Excision Repair and Homologous Recombination pathways are suggested to play a key role in the ICL repair. However, recent studies indicate a possible role for Base Excision Repair (BER) in mediating the cytotoxicity of ICL inducing agents in mammalian cells. Elucidating the mechanism of BER mediated modulation of ICL repair would help in understanding the recognition and removal of ICLs and aid in the development of potential therapeutic agents. In this review, the influence of BER proteins on ICL DNA repair and the possible mechanisms of action are discussed. PMID:23219605

Effect of Calea serrata Less. n-hexane extract on acetylcholinesterase of larvae ticks and brain Wistar rats.

PubMed

Ribeiro, Vera Lucia Sardá; Vanzella, Cláudia; Moysés, Felipe dos Santos; Santos, Jaqueline Campiol Dos; Martins, João Ricardo Souza; von Poser, Gilsane Lino; Siqueira, Ionara Rodrigues

2012-10-26

Acetylcholinesterase (AChE), an enzyme that hydrolyses acetylcholine (ACh) at cholinergic synapses, is a target for pesticides and its inhibition by organophosphates leads to paralysis and death of arthropods. It has been demonstrated that the n-hexane extract of Calea serrata had acaricidal activity against larvae of Rhipicephalus (Boophilus) microplus and Rhipicephalus sanguineus. The aim of the present study was to understand the mechanism of the acaricidal action of C. serrata n-hexane extract are specifically to investigate the in vitro anticholinesterase activity on larvae of R. microplus and in brain structures of male Wistar rats. The n-hexane extract significantly inhibited in vitro acetylcholinesterase activity in R. microplus larvae and rat brain structures. The results confirm that inhibition of acetylcholinesterase is a possible mechanism of action of hexane extract at C. serrata. Copyright © 2012 Elsevier B.V. All rights reserved.

Network-based Approaches in Pharmacology.

PubMed

Boezio, Baptiste; Audouze, Karine; Ducrot, Pierre; Taboureau, Olivier

2017-10-01

In drug discovery, network-based approaches are expected to spotlight our understanding of drug action across multiple layers of information. On one hand, network pharmacology considers the drug response in the context of a cellular or phenotypic network. On the other hand, a chemical-based network is a promising alternative for characterizing the chemical space. Both can provide complementary support for the development of rational drug design and better knowledge of the mechanisms underlying the multiple actions of drugs. Recent progress in both concepts is discussed here. In addition, a network-based approach using drug-target-therapy data is introduced as an example. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Understanding modern-day vaccines: what you need to know.

PubMed

Vetter, Volker; Denizer, Gülhan; Friedland, Leonard R; Krishnan, Jyothsna; Shapiro, Marla

2018-03-01

Vaccines are considered to be one of the greatest public health achievements of the last century. Depending on the biology of the infection, the disease to be prevented, and the targeted population, a vaccine may require the induction of different adaptive immune mechanisms to be effective. Understanding the basic concepts of different vaccines is therefore crucial to understand their mode of action, benefits, risks, and their potential real-life impact on protection. This review aims to provide healthcare professionals with background information about the main vaccine designs and concepts of protection in a simplified way to improve their knowledge and understanding, and increase their confidence in the science of vaccination ( Supplementary Material ). KEY MESSAGE Different vaccine designs, each with different advantages and limitations, can be applied for protection against a particular disease. Vaccines may contain live-attenuated pathogens, inactivated pathogens, or only parts of pathogens and may also contain adjuvants to stimulate the immune responses. This review explains the mode of action, benefits, risks and real-life impact of vaccines by highlighting key vaccine concepts. An improved knowledge and understanding of the main vaccine designs and concepts of protection will help support the appropriate use and expectations of vaccines, increase confidence in the science of vaccination, and help reduce vaccine hesitancy.

How do secretory products cross the plant cell wall to be released? A new hypothesis involving cyclic mechanical actions of the protoplast

PubMed Central

Paiva, Elder Antônio Sousa

2016-01-01

Background In plants, the products of secretory activity leave the protoplast and cross the plasma membrane by means of transporters, fusion with membranous vesicles or, less commonly, as result of disintegration of the cell. These mechanisms do not address an intriguing question: How do secretory products cross the cell wall? Furthermore, how do these substances reach the external surface of the plant body? Such diverse substances as oils, polysaccharides or nectar are forced to cross the cell wall and, in fact, do so. How are chemical materials that are repelled by the cell wall or that are sufficiently viscous to not cross passively released from plant cells? Scope and Conclusions I propose a cell-cycle model developed based on observations of different secreting systems, some unpublished results and an extensive literature review, aiming to understand the processes involved in both the secretory process and the release of secretion products. In the absence of facilitated diffusion, a mechanical action of the protoplast is necessary to ensure that some substances can cross the cell wall. The mechanical action of the protoplast, in the form of successive cycles of contraction and expansion, causes the material accumulated in the periplasmic space to cross the cell wall and the cuticle. This action is particularly relevant for the release of lipids, resins and highly viscous hydrophilic secretions. The proposed cell-cycle model and the statements regarding exudate release will also apply to secretory glands not elaborated upon here. Continuous secretion of several days, as observed in extrafloral nectaries, salt glands and some mucilage-producing glands, is only possible because the process is cyclical. PMID:26929201

Eliminating mirror responses by instructions.

PubMed

Bardi, Lara; Bundt, Carsten; Notebaert, Wim; Brass, Marcel

2015-09-01

The observation of an action leads to the activation of the corresponding motor plan in the observer. This phenomenon of motor resonance has an important role in social interaction, promoting imitation, learning and action understanding. However, mirror responses not always have a positive impact on our behavior. An automatic tendency to imitate others can introduce interference in action execution and non-imitative or opposite responses have an advantage in some contexts. Previous studies suggest that mirror tendencies can be suppressed after extensive practice or in complementary joint action situations revealing that mirror responses are more flexible than previously thought. The aim of the present study was to gain insight into the mechanisms that allow response flexibility of motor mirroring. Here we show that the mere instruction of a counter-imitative mapping changes mirror responses as indexed by motor evoked potentials (MEPs) enhancement induced by transcranial magnetic stimulation (TMS). Importantly, mirror activation was measured while participants were passively watching finger movements, without having the opportunity to execute the task. This result suggests that the implementation of task instructions activates stimulus-response association that can overwrite the mirror representations. Our outcome reveals one of the crucial mechanisms that might allow flexible adjustments of mirror responses in different contexts. The implications of this outcome are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Smac mimetic enables the anticancer action of BCG-stimulated neutrophils through TNF-α but not through TRAIL and FasL.

PubMed

Jinesh G, Goodwin; Chunduru, Srinivas; Kamat, Ashish M

2012-07-01

BCG, the current gold standard immunotherapy for bladder cancer, exerts its activity via recruitment of neutrophils to the tumor microenvironment. Many patients do not respond to BCG therapy, indicating the need to understand the mechanism of action of BCG-stimulated neutrophils and to identify ways to overcome resistance to BCG therapy. Using isolated human neutrophils stimulated with BCG, we found that TNF-α is the key mediator secreted by BCG-stimulated neutrophils. RT4v6 human bladder cancer cells, which express TNFR1, CD95/Fas, CD95 ligand/FasL, DR4, and DR5, were resistant to BCG-stimulated neutrophil conditioned medium but effectively killed by the combination of conditioned medium and Smac mimetic. rhTNF-α and rhFasL, but not rhTRAIL, in combination with Smac mimetic, generated signature molecular events similar to those produced by BCG-stimulated neutrophils in combination with Smac mimetic. However, experiments using neutralizing antibodies to these death ligands showed that TNF-α secreted from BCG-stimulated neutrophils was the key mediator of anticancer action. These findings explain the mechanism of action of BCG and identified Smac mimetics as potential combination therapeutic agents for bladder cancer.

Characterization of drug-induced transcriptional modules: towards drug repositioning and functional understanding

PubMed Central

Iskar, Murat; Zeller, Georg; Blattmann, Peter; Campillos, Monica; Kuhn, Michael; Kaminska, Katarzyna H; Runz, Heiko; Gavin, Anne-Claude; Pepperkok, Rainer; van Noort, Vera; Bork, Peer

2013-01-01

In pharmacology, it is crucial to understand the complex biological responses that drugs elicit in the human organism and how well they can be inferred from model organisms. We therefore identified a large set of drug-induced transcriptional modules from genome-wide microarray data of drug-treated human cell lines and rat liver, and first characterized their conservation. Over 70% of these modules were common for multiple cell lines and 15% were conserved between the human in vitro and the rat in vivo system. We then illustrate the utility of conserved and cell-type-specific drug-induced modules by predicting and experimentally validating (i) gene functions, e.g., 10 novel regulators of cellular cholesterol homeostasis and (ii) new mechanisms of action for existing drugs, thereby providing a starting point for drug repositioning, e.g., novel cell cycle inhibitors and new modulators of α-adrenergic receptor, peroxisome proliferator-activated receptor and estrogen receptor. Taken together, the identified modules reveal the conservation of transcriptional responses towards drugs across cell types and organisms, and improve our understanding of both the molecular basis of drug action and human biology. PMID:23632384

Altered DNA methylation: a secondary mechanism involved in carcinogenesis.

PubMed

Goodman, Jay I; Watson, Rebecca E

2002-01-01

This review focuses on the role that DNA methylation plays in the regulation of normal and aberrant gene expression and on how, in a hypothesis-driven fashion, altered DNA methylation may be viewed as a secondary mechanism involved in carcinogenesis. Research aimed at discerning the mechanisms by which chemicals can transform normal cells into frank carcinomas has both theoretical and practical implications. Through an increased understanding of the mechanisms by which chemicals affect the carcinogenic process, we learn more about basic biology while, at the same time, providing the type of information required to make more rational safety assessment decisions concerning their actual potential to cause cancer under particular conditions of exposure. One key question is: does the mechanism of action of the chemical in question involve a secondary mechanism and, if so, what dose may be below its threshold?

Dynamics of action potential initiation in the GABAergic thalamic reticular nucleus in vivo.

PubMed

Muñoz, Fabián; Fuentealba, Pablo

2012-01-01

Understanding the neural mechanisms of action potential generation is critical to establish the way neural circuits generate and coordinate activity. Accordingly, we investigated the dynamics of action potential initiation in the GABAergic thalamic reticular nucleus (TRN) using in vivo intracellular recordings in cats in order to preserve anatomically-intact axo-dendritic distributions and naturally-occurring spatiotemporal patterns of synaptic activity in this structure that regulates the thalamic relay to neocortex. We found a wide operational range of voltage thresholds for action potentials, mostly due to intrinsic voltage-gated conductances and not synaptic activity driven by network oscillations. Varying levels of synchronous synaptic inputs produced fast rates of membrane potential depolarization preceding the action potential onset that were associated with lower thresholds and increased excitability, consistent with TRN neurons performing as coincidence detectors. On the other hand the presence of action potentials preceding any given spike was associated with more depolarized thresholds. The phase-plane trajectory of the action potential showed somato-dendritic propagation, but no obvious axon initial segment component, prominent in other neuronal classes and allegedly responsible for the high onset speed. Overall, our results suggest that TRN neurons could flexibly integrate synaptic inputs to discharge action potentials over wide voltage ranges, and perform as coincidence detectors and temporal integrators, supported by a dynamic action potential threshold.

Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action.

PubMed

Zhang, Chun-Lei; Feng, Ze-Jun; Liu, Yue; Ji, Xiao-Hua; Peng, Ji-Yun; Zhang, Xue-Han; Zhen, Xue-Chu; Li, Bao-Ming

2012-01-01

Methylphenidate (MPH), commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD). Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V∼VI pyramidal cells of the rat medial prefrontal cortex (PFC). To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by σ1 but not D1/5 and α2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca(2+) increase, but does not require PKA and extracellular Ca(2+) influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via σ1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects.

Methylphenidate and Atomoxetine Inhibit Social Play Behavior through Prefrontal and Subcortical Limbic Mechanisms in Rats

PubMed Central

Achterberg, E.J. Marijke; van Kerkhof, Linda W.M.; Damsteegt, Ruth; Trezza, Viviana

2015-01-01

Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development. However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used treatments for ADHD. PMID:25568111

Methylphenidate Enhances NMDA-Receptor Response in Medial Prefrontal Cortex via Sigma-1 Receptor: A Novel Mechanism for Methylphenidate Action

PubMed Central

Liu, Yue; Ji, Xiao-Hua; Peng, Ji-Yun; Zhang, Xue-Han; Zhen, Xue-Chu; Li, Bao-Ming

2012-01-01

Methylphenidate (MPH), commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD). Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V∼VI pyramidal cells of the rat medial prefrontal cortex (PFC). To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by σ1 but not D1/5 and α2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca2+ increase, but does not require PKA and extracellular Ca2+ influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via σ1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects. PMID:23284812

Membrane Protein Structure, Function, and Dynamics: a Perspective from Experiments and Theory

DOE PAGES

Cournia, Zoe; Allen, Toby W.; Andricioaei, Ioan; ...

2015-06-11

It is fundamental for the flourishing biological cells that membrane proteins mediate the process. Membrane-embedded transporters move ions and larger solutes across membranes; receptors mediate communication between the cell and its environment and membrane-embedded enzymes catalyze chemical reactions. Understanding these mechanisms of action requires knowledge of how the proteins couple to their fluid, hydrated lipid membrane environment. Here, we present here current studies in computational and experimental membrane protein biophysics, and show how they address outstanding challenges in understanding the complex environmental effects on the structure, function, and dynamics of membrane proteins.

Do we understand how botulinum toxin works and have we optimized the way it is administered to the bladder? ICI-RS 2014.

PubMed

Apostolidis, Apostolos; Rahnama'i, Mohammad S; Fry, Christopher; Dmochowski, Roger; Sahai, Arun

2016-02-01

The use of botulinum toxin A (BoNT/A) is commonplace now in the management of refractory overactive bladder and neurogenic detrusor overactivity (NDO). Despite one formulation now having a license, the full mechanism of action is not fully understood. Furthermore practice varies worldwide in the way the toxin is delivered to the bladder. At the ICI-RS 2014 Meeting in Bristol, UK a Think Tank session was conducted on the topic of "Do we understand how botulinum toxin works and have we optimized the way it is administered to the bladder?" This manuscript reflects the Think Tank's summary and opinion. An overview of the existing evidence and consensus regarding mechanism of action and practical aspects of BoNT/A administration was presented. Further avenues of potential research were suggested. BoNT/A effect in the bladder is complex with likely effects on both efferent and afferent nerves. The site of action is controversial with the relative contribution of the detrusor as opposed to the suburothelial effects remaining unclear and open to further studying. The classical concept of prevention of acetylcholine release in the bladder is not supported by a wealth of evidence on neurotransmitters although co-localization studies have suggested cholinergic nerves are the most affected by BoNT/A. There is more robust evidence for effects on the purinergic system and afferent desensitization and emerging evidence for central effects. A variety of technique studies were presented. OnabotlinumtoxinA has recently been studied in large phase III trials and with this there is a standardized injection technique which is trigone-sparing. The evidence for altering location of injection is mixed with some studies suggesting less voiding dysfunction in bladder base injections alone but others suggesting location of injection does not affect outcomes. Early pilot data and evidence of instillation either with electromotive drug administration (EMDA) or in liposomes were also presented as an alternative to injections. The mechanism of action of BoNT/A in the bladder is complex and not fully understood. There is emerging support for its role on afferent mechanisms. The technical aspects of the injection procedure have been standardized to a certain extent but further study is required in larger scale studies to assess minimizing voiding dysfunction, improving tolerability, and assessing alternatives to injections. © 2016 Wiley Periodicals, Inc.

Creatine Supplementation and Skeletal Muscle Metabolism for Building Muscle Mass- Review of the Potential Mechanisms of Action.

PubMed

Farshidfar, Farnaz; Pinder, Mark A; Myrie, Semone B

2017-01-01

Creatine, a very popular supplement among athletic populations, is of growing interest for clinical applications. Since over 90% of creatine is stored in skeletal muscle, the effect of creatine supplementation on muscle metabolism is a widely studied area. While numerous studies over the past few decades have shown that creatine supplementation has many favorable effects on skeletal muscle physiology and metabolism, including enhancing muscle mass (growth/hypertrophy); the underlying mechanisms are poorly understood. This report reviews studies addressing the mechanisms of action of creatine supplementation on skeletal muscle growth/hypertrophy. Early research proposed that the osmotic effect of creatine supplementation serves as a cellular stressor (osmosensing) that acts as an anabolic stimulus for protein synthesis signal pathways. Other reports indicated that creatine directly affects muscle protein synthesis via modulations of components in the mammalian target of rapamycin (mTOR) pathway. Creatine may also directly affect the myogenic process (formation of muscle tissue), by altering secretions of myokines, such as myostatin and insulin-like growth factor-1, and expressions of myogenic regulatory factors, resulting in enhanced satellite cells mitotic activities and differentiation into myofiber. Overall, there is still no clear understanding of the mechanisms of action regarding how creatine affects muscle mass/growth, but current evidence suggests it may exert its effects through multiple approaches, with converging impacts on protein synthesis and myogenesis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pidotimod: the past and the present

PubMed Central

2013-01-01

At the end of 1990s, acute respiratory tract infections (ARTIs) were called the 'forgotten pandemic’, with a clear dichotomy between developing and industrialised countries in mortality and morbidity, the main outcomes associated with ARTIs. This definition still applies 20 years later, when the introduction of new and safe antibiotics and vaccines has certainly contributed to controlling the most life-threatening ARTIs, but has not had a major impact on viral ARTIs in paediatric age. One functional approach to preventing and treating ARTIs is non-specifically increasing the immune response or enhancing the children’s innate defence mechanisms. Different kinds of biologically active substances – called immunostimulants – of natural and synthetic origins and with different mechanisms of action have been introduced in some countries for the prevention of ARTIs in children. Recently, research focused on one of these compounds, Pidotimod, has attempted to better clarify and define its mechanisms of action both in vitro and in vivo. In this paper, we critically examine the most recent findings on Pidotimod. Certainly the improvement of research methodology in the last 20 years and the acquired knowledge in various fields of clinical immunology should be the starting point for research on Pidotimod. Preclinical research will be essential to better understand the mechanisms of action of this compound. However, in vivo studies, especially randomised control trials, will be necessary to establish the real efficacy of Pidotimod in the prevention of ARTIs in paediatric age. PMID:24314100

Retinoid-xenobiotic interactions: the Ying and the Yang

PubMed Central

2015-01-01

The literature provides compelling evidence pointing to tight metabolic interactions between retinoids and xenobiotics. These are extensive and important for understanding xenobiotic actions in the body. Within the body, retinoids affect xenobiotic metabolism and actions and conversely, xenobiotics affect retinoid metabolism and actions. This article summarizes data that establish the importance of retinoid-dependent metabolic pathways for sustaining the body’s responses to xenobiotic exposure, including the roles of all-trans- and 9-cis-retinoic acid for protecting mammals from harmful xenobiotic effects and for ensuring xenobiotic elimination from the body. This review will also consider molecular mechanisms underlying xenobiotic toxicity focusing on how this may contribute to retinoid deficiency and disruption of normal retinoid homeostasis. Special attention is paid to xenobiotic molecular targets (nuclear receptors, regulatory proteins, enzymes, and transporters) which affect retinoid metabolism and signaling. PMID:26311625

Dexrazoxane for the prevention of cardiac toxicity and treatment of extravasation injury from the anthracycline antibiotics.

PubMed

Doroshow, James H

2012-08-01

The cumulative cardiac toxicity of the anthracycline antibiotics and their propensity to produce severe tissue injury following extravasation from a peripheral vein during intravenous administration remain significant problems in clinical oncologic practice. Understanding of the free radical metabolism of these drugs and their interactions with iron proteins led to the development of dexrazoxane, an analogue of EDTA with intrinsic antineoplastic activity as well as strong iron binding properties, as both a prospective cardioprotective therapy for patients receiving anthracyclines and as an effective treatment for anthracycline extravasations. In this review, the molecular mechanisms by which the anthracyclines generate reactive oxygen species and interact with intracellular iron are examined to understand the cardioprotective mechanism of action of dexrazoxane and its ability to protect the subcutaneous tissues from anthracycline-induced tissue necrosis.

The Three Bacterial Lines of Defense against Antimicrobial Agents.

PubMed

Zhou, Gang; Shi, Qing-Shan; Huang, Xiao-Mo; Xie, Xiao-Bao

2015-09-09

Antimicrobial agents target a range of extra- and/or intracellular loci from cytoplasmic wall to membrane, intracellular enzymes and genetic materials. Meanwhile, many resistance mechanisms employed by bacteria to counter antimicrobial agents have been found and reported in the past decades. Based on their spatially distinct sites of action and distribution of location, antimicrobial resistance mechanisms of bacteria were categorized into three groups, coined the three lines of bacterial defense in this review. The first line of defense is biofilms, which can be formed by most bacteria to overcome the action of antimicrobial agents. In addition, some other bacteria employ the second line of defense, the cell wall, cell membrane, and encased efflux pumps. When antimicrobial agents permeate the first two lines of defense and finally reach the cytoplasm, many bacteria will make use of the third line of defense, including alterations of intracellular materials and gene regulation to protect themselves from harm by bactericides. The presented three lines of defense theory will help us to understand the bacterial resistance mechanisms against antimicrobial agents and design efficient strategies to overcome these resistances.

Toward innovative combinational immunotherapy: A systems biology perspective.

PubMed

Li, Xue-Tao; Yang, Jin-Ji; Wu, Yi-Long; Hou, Jun

2018-05-08

The treatment of non-small-cell lung cancer (NSCLC) has advanced significantly in the last decades. Especially immune checkpoint inhibitors have shown inconceivable effect on enhancing host anti-tumor activity in NSCLC. However, the limitation of checkpoint blockade monotherapy seems unavoidable in most of the NSCLC patients and only ∼20% of them achieved response to monotherapy with immune checkpoint inhibitors. Thus combining immune checkpoint inhibitors with other agents with different action mechanisms holds a promise to revitalize NSCLC treatment, such as the combination of checkpoint inhibitors with angiogenesis inhibitors, or with chemotherapy, as well as the combination of two checkpoint inhibitors. Recently, various combinational strategies have been explored to setup promising combination regimens and to understand the action mechanisms. In this review, we summarize the suspected synergistic mechanisms of several combinational approaches by reviewing the available preclinical and clinical data. Then we discuss in light of the current knowledge of cancer biology and systems biology the important facets to be examined when setting up a framework for developing immunotherapy-based combination strategies. Copyright © 2018. Published by Elsevier Ltd.

Bioactivity and the First Transmission Electron Microscopy Immunogold Studies of Short De Novo-Designed Antimicrobial Peptides▿

PubMed Central

Azad, Marisa Ann; Huttunen-Hennelly, Heidi Esther Katrina; Ross Friedman, Cynthia

2011-01-01

In light of the era of microbial drug resistance, the current study aimed to better understand the relationships between sequence, higher-order structure, and mechanism of action for five designed peptides against multidrug-resistant (MDR) pathogens. All peptides studied were 15 residues long, were polycationic, adopted alpha-helical structures within hydrophobic environments (excluding the d-amino acid-substituted peptide MA-d), and contained N-terminal glycine residues, a novel antimicrobial peptide (AMP) design principle. Increasing hydrophobicity enhanced MICs (≤500 μg/ml to ≤7.4 μg/ml) without significantly increasing hemolytic activity (18% maximum hemolysis at 3,400 μg/ml). To the best of our knowledge, this is the first study to have successfully adapted and used a transmission electron microscopy (TEM) immunogold method to investigate the mechanism of action of short (∼15 residues long) AMPs within bacteria. We propose a “floodgate” mechanism to possibly explain membrane deformation and the relative absence of membrane-associated peptides 10 h into incubation. PMID:21300831

A hidden Markov model to assess drug-induced sleep fragmentation in the telemetered rat.

PubMed

Diack, C; Ackaert, O; Ploeger, B A; van der Graaf, P H; Gurrell, R; Ivarsson, M; Fairman, D

2011-12-01

Drug-induced sleep fragmentation can cause sleep disturbances either via their intended pharmacological action or as a side effect. Examples of disturbances include excessive daytime sleepiness, insomnia and nightmares. Developing drugs without these side effects requires insight into the mechanisms leading to sleep disturbance. The characterization of the circadian sleep pattern by EEG following drug exposure has improved our understanding of these mechanisms and their translatability across species. The EEG shows frequent transitions between specific sleep states leading to multiple correlated sojourns in these states. We have developed a Markov model to consider the high correlation in the data and quantitatively compared sleep disturbance in telemetered rats induced by methylphenidate, which is known to disturb sleep, and of a new chemical entity (NCE). It was assumed that these drugs could either accelerate or decelerate the transitions between the sleep states. The difference in sleep disturbance of methylphenidate and the NCE were quantitated and different mechanisms of action on rebound sleep were identified. The estimated effect showed that both compounds induce sleep fragmentation with methylphenidate being fivefold more potent compared to the NCE.

Identification of diverse nerve growth factor-regulated genes by serial analysis of gene expression (SAGE) profiling

PubMed Central

Angelastro, James M.; Klimaschewski, Lars; Tang, Song; Vitolo, Ottavio V.; Weissman, Tamily A.; Donlin, Laura T.; Shelanski, Michael L.; Greene, Lloyd A.

2000-01-01

Neurotrophic factors such as nerve growth factor (NGF) promote a wide variety of responses in neurons, including differentiation, survival, plasticity, and repair. Such actions often require changes in gene expression. To identify the regulated genes and thereby to more fully understand the NGF mechanism, we carried out serial analysis of gene expression (SAGE) profiling of transcripts derived from rat PC12 cells before and after NGF-promoted neuronal differentiation. Multiple criteria supported the reliability of the profile. Approximately 157,000 SAGE tags were analyzed, representing at least 21,000 unique transcripts. Of these, nearly 800 were regulated by 6-fold or more in response to NGF. Approximately 150 of the regulated transcripts have been matched to named genes, the majority of which were not previously known to be NGF-responsive. Functional categorization of the regulated genes provides insight into the complex, integrated mechanism by which NGF promotes its multiple actions. It is anticipated that as genomic sequence information accrues the data derived here will continue to provide information about neurotrophic factor mechanisms. PMID:10984536

The Three Bacterial Lines of Defense against Antimicrobial Agents

PubMed Central

Zhou, Gang; Shi, Qing-Shan; Huang, Xiao-Mo; Xie, Xiao-Bao

2015-01-01

Antimicrobial agents target a range of extra- and/or intracellular loci from cytoplasmic wall to membrane, intracellular enzymes and genetic materials. Meanwhile, many resistance mechanisms employed by bacteria to counter antimicrobial agents have been found and reported in the past decades. Based on their spatially distinct sites of action and distribution of location, antimicrobial resistance mechanisms of bacteria were categorized into three groups, coined the three lines of bacterial defense in this review. The first line of defense is biofilms, which can be formed by most bacteria to overcome the action of antimicrobial agents. In addition, some other bacteria employ the second line of defense, the cell wall, cell membrane, and encased efflux pumps. When antimicrobial agents permeate the first two lines of defense and finally reach the cytoplasm, many bacteria will make use of the third line of defense, including alterations of intracellular materials and gene regulation to protect themselves from harm by bactericides. The presented three lines of defense theory will help us to understand the bacterial resistance mechanisms against antimicrobial agents and design efficient strategies to overcome these resistances. PMID:26370986

The Potential and Action Mechanism of Polyphenols in the Treatment of Liver Diseases

PubMed Central

Li, Sha; Cheung, Fan

2018-01-01

Liver disease, involving a wide range of liver pathologies from fatty liver, hepatitis, and fibrosis to cirrhosis and hepatocellular carcinoma, is a serious health problem worldwide. In recent years, many natural foods and herbs with abundant phytochemicals have been proposed as health supplementation for patients with hepatic disorders. As an important category of phytochemicals, natural polyphenols have attracted increasing attention as potential agents for the prevention and treatment of liver diseases. The striking capacities in remitting oxidative stress, lipid metabolism, insulin resistance, and inflammation put polyphenols in the spotlight for the therapies of liver diseases. It has been reported that many polyphenols from a wide range of foods and herbs exert therapeutic effects on liver injuries via complicated mechanisms. Therefore, it is necessary to have a systematical review to sort out current researches to help better understand the potentials of polyphenols in liver diseases. In this review, we aim to summarize and update the existing evidence of natural polyphenols in the treatment of various liver diseases by in vitro, in vivo, and clinical studies, while special attention is paid to the action mechanisms. PMID:29507653

Unity in diversity: Shared mechanism of entry among paramyxoviruses

PubMed Central

Palgen, Jean-Louis; Jurgens, Eric M.; Moscona, Anne; Palermo, Laura M.; Porotto, Matteo

2015-01-01

The Paramyxoviridae family includes many viruses that are pathogenic in humans, including parainfluenza viruses, measles virus, respiratory syncytial virus and the emerging zoonotic Henipaviruses. No effective treatments are currently available for these viruses, and there is a need for efficient antiviral therapies. Paramyxoviruses enter the target cell by binding to a cell surface receptor and then fusing the viral envelope with the target cell membrane, allowing the release of the viral genome into the cytoplasm. Blockage of these crucial steps prevents infection and disease. Binding and fusion are driven by two virus encoded glycoproteins, the receptor-binding protein and the fusion protein, that together form the viral “fusion machinery”. The development of efficient antiviral drugs requires a deeper understanding of the mechanism of action of the Paramyxoviridae fusion machinery, which is still controversial. Here we review recent structural and functional data on these proteins and the current understanding of the mechanism of the paramyxovirus cell entry process. PMID:25595799

Open questions in current models of antidepressant action

PubMed Central

Tanti, A; Belzung, C

2010-01-01

Research on depression and antidepressant drugs is necessary, as many patients display poor response to therapy. Different symptomatic and pathophysiological features have been proposed as end points of the depressive phenotype and of the antidepressant action, including anhedonia, depressed mood, alterations in morphology and activity of some brain areas (amygdala, nucleus accumbens, hippocampus, prefrontal cortex and cingulate cortex), modifications in the connectivity between brain structures, changes in neurotransmitters (serotonin, noradrenaline, glutamate and neuropeptides), brain plasticity (neurogenesis, neurotrophins) and abnormal function of the hypothalamic-pituitary adrenal axis. However, few models have been proposed to describe how these end points could induce the depressive phenotype and are involved in the mechanism of action of antidepressants. Here we propose a connectionist-inspired network of depression and antidepressant action, in which the different aetiological factors participating in the release of a depressive episode are represented by input nodes, the different symptomatic as well as pathophysiological end points are represented by an intermediate layer, and the onset of depression or of comorbid disease is represented by the output node. The occurrence of depression and the mechanism of the antidepressant action thus depend upon the weight of the interactions between the different end points, none of them being per se crucial to the onset of a depressive phenotype or to the antidepressant action. This model is heuristic to draw future lines of research concerning new antidepressant therapies, designing new animal models of depression and for a better understanding of the depressive pathology and of its comorbid pathology such as anxiety disorders. PMID:20132212

Building and Breaking the Cell Wall in Four Acts: A Kinesthetic and Tactile Role-Playing Exercise for Teaching Beta-Lactam Antibiotic Mechanism of Action and Resistance †

PubMed Central

Popovich, John; Stephens, Michelle; Celaya, Holly; Suwarno, Serena; Barclay, Shizuka; Yee, Emily; Dean, David A.; Farris, Megan; Haydel, Shelley E.

2018-01-01

“Building and breaking the cell wall” is designed to review the bacterial cell envelope, previously learned in lower-division biology classes, while introducing new topics such as antibiotics and bacterial antibiotic resistance mechanisms. We developed a kinesthetic and tactile modeling activity where students act as cellular components and construct the cell wall. In the first two acts, students model a portion of the gram-positive bacterial cell envelope and then demonstrate in detail how the peptidoglycan is formed. Act III involves student demonstration of the addition of β-lactam antibiotics to the environment and how they inhibit the formation of peptidoglycan, thereby preventing bacterial replication. Using Staphylococcus aureus as a model for gram-positive bacteria, students finish the activity (Act IV) by acting out how S. aureus often becomes resistant to β-lactam antibiotics. A high level of student engagement was observed, and the activity received positive feedback. In an assessment administered prior to and two months after the activity, significant improvements in scores were observed (p < 0.0001), demonstrating increased understanding and retention. This activity allows students to (i) visualize, role play, and kinesthetically “build” the cell envelope and form the peptidoglycan layer, (ii) understand the mechanism of action for β-lactam antibiotics, as well as how gene acquisition and protein changes result in resistance, and (iii) work cooperatively and actively to promote long-term retention of the subject material. PMID:29904519

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.

Transient extracellular application of gold nanostars increases hippocampal neuronal activity.

PubMed

Salinas, Kirstie; Kereselidze, Zurab; DeLuna, Frank; Peralta, Xomalin G; Santamaria, Fidel

2014-08-20

With the increased use of nanoparticles in biomedical applications there is a growing need to understand the effects that nanoparticles may have on cell function. Identifying these effects and understanding the mechanism through which nanoparticles interfere with the normal functioning of a cell is necessary for any therapeutic or diagnostic application. The aim of this study is to evaluate if gold nanoparticles can affect the normal function of neurons, namely their activity and coding properties. We synthesized star shaped gold nanoparticles of 180 nm average size. We applied the nanoparticles to acute mouse hippocampal slices while recording the action potentials from single neurons in the CA3 region. Our results show that CA3 hippocampal neurons increase their firing rate by 17% after the application of gold nanostars. The increase in excitability lasted for as much as 50 minutes after a transient 5 min application of the nanoparticles. Further analyses of the action potential shape and computational modeling suggest that nanoparticles block potassium channels responsible for the repolarization of the action potentials, thus allowing the cell to increase its firing rate. Our results show that gold nanoparticles can affect the coding properties of neurons by modifying their excitability.

Cytoprotection of Human Endothelial Cells Against Oxidative Stress by 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im): Application of Systems Biology to Understand the Mechanism of Action

DTIC Science & Technology

2014-04-03

and exogenous oxidants, electrophiles , and toxicants. Activation of this pathway was reported to facilitate the induction of HMOX1 (Heiss et al., 2009...cytoprotective effect of caffeic acid phenethyl ester (CAPE) and fluorinated derivatives: effects on heme oxygenase-1 induction and antioxidant

The science behind vitamins.

PubMed

Linder, Jennifer

2012-01-01

The use of topically applied vitamins has become a ubiquitous part of clinical skin care. While a part of the skin's antioxidant system that assists in protecting it from oxidative damage, vitamins A, C, and E have also proven their ability to treat photoaging, acne, cutaneous inflammation, and hyperpigmentation ((Burgess, 2008). Understanding these vitamins' unique mechanisms of action and how they work in concert helps the clinician select the appropriate topicals for their patients.

DNA synthesis inhibitors for the treatment of gastrointestinal cancer.

PubMed

Yasui, Hiroshi; Tsurita, Giichiro; Imai, Kohzoh

2014-11-01

Intensive laboratory, preclinical and clinical studies have identified and validated molecular targets in cancers, leading to a shift toward the development of novel, rationally designed and specific therapeutic agents. However, gastrointestinal cancers continue to have a poor prognosis, largely due to drug resistance. Here, we discuss the current understanding of DNA synthesis inhibitors and their mechanisms of action for the treatment of gastrointestinal malignancies. Conventional agents, including DNA synthesis inhibitors such as fluoropyrimidines and platinum analogs, remain the most effective therapeutics and are the standards against which new drugs are compared. Novel DNA synthesis inhibitors for the treatment of gastrointestinal malignancies include a combination of the antimetabolite TAS-102, which consists of trifluorothymidine with a thymidine phosphorylase inhibitor, and a novel micellar formulation of cisplatin NC-6004 that uses a nanotechnology-based drug delivery system. The challenges of translational cancer research using DNA synthesis inhibitors include the identification of drugs that are specific to tumor cells to reduce toxicity and increase antitumor efficacy, biomarkers to predict pharmacological responses to chemotherapeutic drugs, identification of ways to overcome drug resistance and development of novel combination therapies with DNA synthesis inhibitors and other cancer therapies, such as targeted molecular therapeutics. Here, we discuss the current understanding of DNA synthesis inhibitors and their mechanisms of action for the treatment of gastrointestinal malignancies.

Does mechanism of drug action matter to inform rational polytherapy in epilepsy?

PubMed

Giussani, Giorgia; Beghi, Ettore

2013-05-01

When monotherapy for epilepsy fails, add-on therapy is an alternative option. There are several possible antiepileptic drug combinations based on their different and multiple mechanisms of action and pharmacokinetic interactions. However, only when benefits of drug combinations outweigh the harms, polytherapy can be defined as "rational". In the past 20 years, second generation AEDs have been marketed, some of which have better defined mechanisms of action and better pharmacokinetic profile. The mechanisms of action of AEDs involve, among others, blockade of voltage-gated sodium channels, blockade of voltage-gated calcium channel, activation of the ionotropic GABAA receptor and increase of GABA levels at the synaptic cleft, blockade of glutamate receptors, binding to synaptic vesicle protein 2A, and opening of KCNQ (Kv7) potassium channels. Aim of this review was to examine published reports on AEDs combinations in animal models and humans focusing on mechanisms of action and pharmacokinetic interactions. Studies in animals have shown that AED combinations are more effective when using drugs with different mechanisms of action. The most effective combination was found using a drug with a single mechanism of action and another with multiple mechanisms of action. In humans some combinations between a blocker of voltage-gated sodium channels and a drug with multiple mechanisms of action may be synergistic. Future studies are necessary to better define rational combinations and complementary mechanisms of action, considering also pharmacokinetic interactions and measures of toxicity and not only drug efficacy.

Simulation of action potential propagation in plants.

PubMed

Sukhov, Vladimir; Nerush, Vladimir; Orlova, Lyubov; Vodeneev, Vladimir

2011-12-21

Action potential is considered to be one of the primary responses of a plant to action of various environmental factors. Understanding plant action potential propagation mechanisms requires experimental investigation and simulation; however, a detailed mathematical model of plant electrical signal transmission is absent. Here, the mathematical model of action potential propagation in plants has been worked out. The model is a two-dimensional system of excitable cells; each of them is electrically coupled with four neighboring ones. Ion diffusion between excitable cell apoplast areas is also taken into account. The action potential generation in a single cell has been described on the basis of our previous model. The model simulates active and passive signal transmission well enough. It has been used to analyze theoretically the influence of cell to cell electrical conductivity and H(+)-ATPase activity on the signal transmission in plants. An increase in cell to cell electrical conductivity has been shown to stimulate an increase in the length constant, the action potential propagation velocity and the temperature threshold, while the membrane potential threshold being weakly changed. The growth of H(+)-ATPase activity has been found to induce the increase of temperature and membrane potential thresholds and the reduction of the length constant and the action potential propagation velocity. Copyright © 2011 Elsevier Ltd. All rights reserved.

Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward

PubMed Central

Khan, Mohammad Aslam; Azim, Shafquat; Zubair, Haseeb; Bhardwaj, Arun; Patel, Girijesh Kumar; Khushman, Moh’d; Singh, Seema; Singh, Ajay Pratap

2017-01-01

Pancreatic cancer (PC) continues to rank among the most lethal cancers. The consistent increase in incidence and mortality has made it the seventh leading cause of cancer-associated deaths globally and the third in the United States. The biggest challenge in combating PC is our insufficient understanding of the molecular mechanism(s) underlying its complex biology. Studies during the last several years have helped identify several putative factors and events, both genetic and epigenetic, as well as some deregulated signaling pathways, with implications in PC onset and progression. In this review article, we make an effort to summarize our current understanding of molecular and cellular events involved in the pathogenesis of pancreatic malignancy. Specifically, we provide up-to-date information on the genetic and epigenetic changes that occur during the initiation and progression of PC and their functional involvement in the pathogenic processes. We also discuss the impact of the tumor microenvironment on the molecular landscape of PC and its role in aggressive disease progression. It is envisioned that a better understanding of these molecular factors and the mechanisms of their actions can help unravel novel diagnostic and prognostic biomarkers and can also be exploited for future targeted therapies. PMID:28383487

A network pharmacology approach to determine the synergetic mechanisms of herb couple for treating rheumatic arthritis.

PubMed

Xu, Xi-Xi; Bi, Jian-Ping; Ping, Li; Li, Ping; Li, Fei

2018-01-01

The purpose of this study was to investigate the therapeutic mechanism(s) of Clematis chinensis Osbeck/ Notopterygium incisum K.C. Ting ex H.T (CN). A network pharmacology approach integrating prediction of ingredients, target exploration, network construction, module partition and pathway analysis was used. This approach successfully helped to identify 12 active ingredients of CN, interacting with 13 key targets (Akt1, STAT3, TNFsf13, TP53, EPHB2, IL-10, IL-6, TNF, MAPK8, IL-8, RELA, ROS1 and STAT4). Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that CN-regulated pathways were mainly classified into signal transduction and immune system. The present work may help to illustrate the mechanism(s) of action of CN, and it may provide a better understanding of antirheumatic effects.

Molecular analysis of Hsp70 mechanisms in plants and their function in response to stress.

PubMed

Usman, Magaji G; Rafii, Mohd Y; Martini, Mohammad Y; Yusuff, Oladosu A; Ismail, Mohd R; Miah, Gous

2017-04-01

Studying the strategies of improving abiotic stress tolerance is quite imperative and research under this field will increase our understanding of response mechanisms to abiotic stress such as heat. The Hsp70 is an essential regulator of protein having the tendency to maintain internal cell stability like proper folding protein and breakdown of unfolded proteins. Hsp70 holds together protein substrates to help in movement, regulation, and prevent aggregation under physical and or chemical pressure. However, this review reports the molecular mechanism of heat shock protein 70 kDa (Hsp70) action and its structural and functional analysis, research progress on the interaction of Hsp70 with other proteins and their interaction mechanisms as well as the involvement of Hsp70 in abiotic stress responses as an adaptive defense mechanism.

On the globality of motor suppression: unexpected events and their influence on behavior and cognition

PubMed Central

Wessel, Jan R.; Aron, Adam R.

2016-01-01

SUMMARY Unexpected events are part of everyday experience. They come in several varieties – action errors, unexpected action outcomes, and unexpected perceptual events – and they lead to motor slowing and cognitive distraction. While different varieties of unexpected events have been studied largely independently, and many different mechanisms are thought to explain their effects on action and cognition, we suggest a unifying theory. We propose that unexpected events recruit a fronto-basal-ganglia network for stopping. This network includes specific prefrontal cortical nodes and is posited to project to the subthalamic nucleus, with a putative global suppressive effect on basal-ganglia output. We argue that unexpected events interrupt action and impact cognition, partly at least, by recruiting this global suppressive network. This provides a common mechanistic basis for different types of unexpected events, links the literatures on motor inhibition, performance-monitoring, attention, and working memory, and is relevant for understanding clinical symptoms of distractibility and mental inflexibility. PMID:28103476

Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes.

PubMed

Lum, Pek Yee; Armour, Christopher D; Stepaniants, Sergey B; Cavet, Guy; Wolf, Maria K; Butler, J Scott; Hinshaw, Jerald C; Garnier, Philippe; Prestwich, Glenn D; Leonardson, Amy; Garrett-Engele, Philip; Rush, Christopher M; Bard, Martin; Schimmack, Greg; Phillips, John W; Roberts, Christopher J; Shoemaker, Daniel D

2004-01-09

Modern medicine faces the challenge of developing safer and more effective therapies to treat human diseases. Many drugs currently in use were discovered without knowledge of their underlying molecular mechanisms. Understanding their biological targets and modes of action will be essential to design improved second-generation compounds. Here, we describe the use of a genome-wide pool of tagged heterozygotes to assess the cellular effects of 78 compounds in Saccharomyces cerevisiae. Specifically, lanosterol synthase in the sterol biosynthetic pathway was identified as a target of the antianginal drug molsidomine, which may explain its cholesterol-lowering effects. Further, the rRNA processing exosome was identified as a potential target of the cell growth inhibitor 5-fluorouracil. This genome-wide screen validated previously characterized targets or helped identify potentially new modes of action for over half of the compounds tested, providing proof of this principle for analyzing the modes of action of clinically relevant compounds.

On the Globality of Motor Suppression: Unexpected Events and Their Influence on Behavior and Cognition.

PubMed

Wessel, Jan R; Aron, Adam R

2017-01-18

Unexpected events are part of everyday experience. They come in several varieties-action errors, unexpected action outcomes, and unexpected perceptual events-and they lead to motor slowing and cognitive distraction. While different varieties of unexpected events have been studied largely independently, and many different mechanisms are thought to explain their effects on action and cognition, we suggest a unifying theory. We propose that unexpected events recruit a fronto-basal-ganglia network for stopping. This network includes specific prefrontal cortical nodes and is posited to project to the subthalamic nucleus, with a putative global suppressive effect on basal-ganglia output. We argue that unexpected events interrupt action and impact cognition, partly at least, by recruiting this global suppressive network. This provides a common mechanistic basis for different types of unexpected events; links the literatures on motor inhibition, performance monitoring, attention, and working memory; and is relevant for understanding clinical symptoms of distractibility and mental inflexibility. Copyright © 2017 Elsevier Inc. All rights reserved.

Neurodevelopment in Schizophrenia: The Role of the Wnt Pathways

PubMed Central

Panaccione, Isabella; Napoletano, Flavia; Forte, Alberto Maria; Kotzalidis, Giorgio D.; Del Casale, Antonio; Rapinesi, Chiara; Brugnoli, Chiara; Serata, Daniele; Caccia, Federica; Cuomo, Ilaria; Ambrosi, Elisa; Simonetti, Alessio; Savoja, Valeria; De Chiara, Lavinia; Danese, Emanuela; Manfredi, Giovanni; Janiri, Delfina; Motolese, Marta; Nicoletti, Ferdinando; Girardi, Paolo; Sani, Gabriele

2013-01-01

Objectives. To review the role of Wnt pathways in the neurodevelopment of schizophrenia. Methods: Systematic PubMed search, using as keywords all the terms related to the Wnt pathways and crossing them with each of the following areas: normal neurodevelopment and physiology, neurodevelopmental theory of schizophrenia, schizophrenia, and antipsychotic drug action. Results: Neurodevelopmental, behavioural, genetic, and psychopharmacological data point to the possible involvement of Wnt systems, especially the canonical pathway, in the pathophysiology of schizophrenia and in the mechanism of antipsychotic drug action. The molecules most consistently found to be associated with abnormalities or in antipsychotic drug action are Akt1, glycogen synthase kinase3beta, and beta-catenin. However, the extent to which they contribute to the pathophysiology of schizophrenia or to antipsychotic action remains to be established. Conclusions: The study of the involvement of Wnt pathway abnormalities in schizophrenia may help in understanding this multifaceted clinical entity; the development of Wnt-related pharmacological targets must await the collection of more data. PMID:24403877

The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse.

PubMed

Glennon, Richard A

2017-04-13

The phenylalkylamine, particularly the phenylethylamine, moiety is a common structural feature found embedded in many clinically approved agents. Greater still is its occurrence in drugs of abuse. The simplest phenylethylamine, 2-phenylethylamine itself, is without significant central action when administered at moderate doses, but fairly simple structural modifications profoundly impact its pharmacology and result in large numbers of useful pharmacological tools, agents with therapeutic potential, and in drugs of abuse (e.g., hallucinogens, central stimulants, empathogens), the latter of which are the primary focus here. In vivo drug discrimination techniques and in vitro receptor/transporter methods have been applied to understand the actions of these phenylalkylamines and their mechanisms of action. Thus far, depending upon pendent substituents, certain receptors (e.g., serotonin receptors) and monoamine transporters (i.e., serotonin, dopamine, and norepinephrine transporters) have been implicated as playing major roles in the actions of these abused agents in a complex and, at times, interwoven manner.

3D visualization software to analyze topological outcomes of topoisomerase reactions

PubMed Central

Darcy, I. K.; Scharein, R. G.; Stasiak, A.

2008-01-01

The action of various DNA topoisomerases frequently results in characteristic changes in DNA topology. Important information for understanding mechanistic details of action of these topoisomerases can be provided by investigating the knot types resulting from topoisomerase action on circular DNA forming a particular knot type. Depending on the topological bias of a given topoisomerase reaction, one observes different subsets of knotted products. To establish the character of topological bias, one needs to be aware of all possible topological outcomes of intersegmental passages occurring within a given knot type. However, it is not trivial to systematically enumerate topological outcomes of strand passage from a given knot type. We present here a 3D visualization software (TopoICE-X in KnotPlot) that incorporates topological analysis methods in order to visualize, for example, knots that can be obtained from a given knot by one intersegmental passage. The software has several other options for the topological analysis of mechanisms of action of various topoisomerases. PMID:18440983

Allergoids for allergy treatment.

PubMed

Carnes, Jeronimo; Gallego, Maria T; Moya, Raquel; Iraola, Victor

2018-02-21

Background Chemically modified allergen extracts, known as allergoids, are commonly used for treating allergic patients. In general terms, the concept of allergoids implies allergen extracts with a reduction of their allergenicity maintaining their immunogenicity. Different methods to obtain allergoids have been developed in the past years, opening attractive lines of research. Objective To review the different approaches to allergoid development as well as their characterization, mechanism of action and efficacy and safety issues. Methods A revision and analysis of the different types of allergoids has been performed, with special attention to patents submitted and granted in the last years. Additionally, updated information about the mechanism of action and clinical evidence and safety of allergoids has been discussed. Results Principally, allergoids are obtained by the polymerization of native allergen extracts with aldehydes, including formaldehyde or glutaraldehyde. However, recent patents and publications about different chemical modifications have been presented, as well as about the use of new adjuvants with allergoids. Regarding the characterization, allergoids require more sophisticated analytical methods than native extracts, as a consequence of their properties and characteristics. Conclusion In the last years, the partial understanding of the mechanism of action and the generation of clinical evidence of different types of allergoids, linked to their excellent safety profile and their convenience for a quick build up phase, have made of allergoids an excellent product for allergy treatment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Molecular mechanism of action of oxazolinoanthracyclines in cells derived from human solid tumors. Part 2.

PubMed

Denel-Bobrowska, Marta; Łukawska, Małgorzata; Bukowska, Barbara; Gajek, Arkadiusz; Oszczapowicz, Irena; Marczak, Agnieszka

2018-02-01

Oxazolinodoxorubicin (O-DOX) and oxazolinodaunorubicin (O-DAU) are derivatives of anthracyclines (DOX and DAU) with a modified daunosamine moiety. We aimed to clarify their mechanisms of action by investigating intracellular accumulation and effects on the cell cycle, phosphatidylserine externalization, and proteasome 20S activity. Experimental model consisted of SKOV-3, A549 and HepG2 cells. Compounds were used at the concentration of 80nM. Intracellular accumulation, drug uptake, and proteasome 20S activity were evaluated by fluorimetric methods. The effects on the cell cycle and phosphatidylserine externalization were measured by flow cytometry. O-DOX was equivalent to DOX in terms of inducing G2/M arrest, but O-DAU was less potent in SKOV-3, HepG2, and A549 cells. O-DOX had the greatest effect on initiating apoptosis in all tested cells. Externalization of phosphatidylserine was significantly higher following O-DOX treatment compared with control cells and cells incubated with DOX. The intracellular accumulation and uptake of the derivatives were similar to those of the reference drugs. Tested compounds are able to activate proteasome 20S activity. Our results extended the understanding of the toxicity, mechanism of action, and biochemical properties of oxazoline derivatives of doxorubicin and daunorubicin, including their effects on cell cycle, apoptosis and DNA degradation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bench-to-bedside review: Inhaled nitric oxide therapy in adults

PubMed Central

Creagh-Brown, Benedict C; Griffiths, Mark JD; Evans, Timothy W

2009-01-01

Nitric oxide (NO) is an endogenous mediator of vascular tone and host defence. Inhaled nitric oxide (iNO) results in preferential pulmonary vasodilatation and lowers pulmonary vascular resistance. The route of administration delivers NO selectively to ventilated lung units so that its effect augments that of hypoxic pulmonary vasoconstriction and improves oxygenation. This 'Bench-to-bedside' review focuses on the mechanisms of action of iNO and its clinical applications, with emphasis on acute lung injury and the acute respiratory distress syndrome. Developments in our understanding of the cellular and molecular actions of NO may help to explain the hitherto disappointing results of randomised controlled trials of iNO. PMID:19519946

Identifying biologically relevant putative mechanisms in a given phenotype comparison

PubMed Central

Hanoudi, Samer; Donato, Michele; Draghici, Sorin

2017-01-01

A major challenge in life science research is understanding the mechanism involved in a given phenotype. The ability to identify the correct mechanisms is needed in order to understand fundamental and very important phenomena such as mechanisms of disease, immune systems responses to various challenges, and mechanisms of drug action. The current data analysis methods focus on the identification of the differentially expressed (DE) genes using their fold change and/or p-values. Major shortcomings of this approach are that: i) it does not consider the interactions between genes; ii) its results are sensitive to the selection of the threshold(s) used, and iii) the set of genes produced by this approach is not always conducive to formulating mechanistic hypotheses. Here we present a method that can construct networks of genes that can be considered putative mechanisms. The putative mechanisms constructed by this approach are not limited to the set of DE genes, but also considers all known and relevant gene-gene interactions. We analyzed three real datasets for which both the causes of the phenotype, as well as the true mechanisms were known. We show that the method identified the correct mechanisms when applied on microarray datasets from mouse. We compared the results of our method with the results of the classical approach, showing that our method produces more meaningful biological insights. PMID:28486531

Molecular and Neuroendocrine Approaches to Understanding Trade-offs: Food, Sex, Aggression, Stress, and Longevity-An Introduction to the Symposium.

PubMed

Schneider, Jill E; Deviche, Pierre

2017-12-01

Life history strategies are composed of multiple fitness components, each of which incurs costs and benefits. Consequently, organisms cannot maximize all fitness components simultaneously. This situation results in a dynamic array of trade-offs in which some fitness traits prevail at the expense of others, often depending on context. The identification of specific constraints and trade-offs has helped elucidate physiological mechanisms that underlie variation in behavioral and physiological life history strategies. There is general recognition that trade-offs are made at the individual and population level, but much remains to be learned concerning the molecular neuroendocrine mechanisms that underlie trade-offs. For example, we still do not know whether the mechanisms that underlie trade-offs at the individual level relate to trade-offs at the population level. To advance our understanding of trade-offs, we organized a group of speakers who study neuroendocrine mechanisms at the interface of traits that are not maximized simultaneously. Speakers were invited to represent research from a wide range of taxa including invertebrates (e.g., worms and insects), fish, nonavian reptiles, birds, and mammals. Three general themes emerged. First, the study of trade-offs requires that we investigate traditional endocrine mechanisms that include hormones, neuropeptides, and their receptors, and in addition, other chemical messengers not traditionally included in endocrinology. The latter group includes growth factors, metabolic intermediates, and molecules of the immune system. Second, the nomenclature and theory of neuroscience that has dominated the study of behavior is being re-evaluated in the face of evidence for the peripheral actions of so-called neuropeptides and neurotransmitters and the behavioral repercussions of these actions. Finally, environmental and ecological contexts continue to be critical in unmasking molecular mechanisms that are hidden when study animals are housed in enclosed spaces, with unlimited food, without competitors or conspecifics, and in constant ambient conditions. © The Author 2017. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology.

Women and postfertilization effects of birth control: consistency of beliefs, intentions and reported use.

PubMed

Dye, Huong M; Stanford, Joseph B; Alder, Stephen C; Kim, Han S; Murphy, Patricia A

2005-11-28

This study assesses the consistency of responses among women regarding their beliefs about the mechanisms of actions of birth control methods, beliefs about when human life begins, the intention to use or not use birth control methods that they believe may act after fertilization or implantation, and their reported use of specific methods. A questionnaire was administered in family practice and obstetrics and gynecology clinics in Salt Lake City, Utah, and Tulsa, Oklahoma. Participants included women ages 18-50 presenting for any reason and women under age 18 presenting for family planning or pregnancy care. Analyses were based on key questions addressing beliefs about whether specific birth control methods may act after fertilization, beliefs about when human life begins, intention to use a method that may act after fertilization, and reported use of specific methods. The questionnaire contained no information about the mechanism of action of any method of birth control. Responses were considered inconsistent if actual use contradicted intentions, if one intention contradicted another, or if intentions contradicted beliefs. Of all respondents, 38% gave consistent responses about intention to not use or to stop use of any birth control method that acted after fertilization, while 4% gave inconsistent responses. The corresponding percentages for birth control methods that work after implantation were 64% consistent and 2% inconsistent. Of all respondents, 34% reported they believed that life begins at fertilization and would not use any birth control method that acts after fertilization (a consistent response), while 3% reported they believed that life begins at fertilization but would use a birth control method that acts after fertilization (inconsistent). For specific methods of birth control, less than 1% of women gave inconsistent responses. A majority of women (68% or greater) responded accurately about the mechanism of action of condoms, abstinence, sterilization, and abortion, but a substantial percentage of women (between 19% and 57%) were uncertain about the mechanisms of action of oral contraceptives, intrauterine devices (IUDs), Depo-Provera, or natural family planning. Women who believe that life begins at fertilization may not intend to use a birth control method that could have postfertilization effects. More research is needed to understand the relative importance of postfertilization effects for women in other populations, and in relation to other properties of and priorities for birth control methods. However, many women were uncertain about the mechanisms of action of specific methods. To respect the principles of informed consent, some women may need more education about what is known and not known about the mechanisms of action of birth control methods.

Non-communicable diseases and human rights: Global synergies, gaps and opportunities.

PubMed

Ferguson, Laura; Tarantola, Daniel; Hoffmann, Michael; Gruskin, Sofia

2017-10-01

The incorporation of human rights in health policy and programmes is known to strengthen responses to health problems and help address disparities created or exacerbated by illness yet this remains underexplored in relation to non-communicable diseases (NCDs). Aiming to understand existing synergies and how they might be further strengthened, we assessed the extent to which human rights are considered in global NCD policies and strategies and the degree of attention given to NCDs by select United Nations human rights mechanisms. Across global NCD policies and strategies, rhetorical assertions regarding human rights appear more often than actionable statements, thus limiting their implementation and impact. Although no human rights treaty explicitly mentions NCDs, some human rights monitoring mechanisms have been paying increasing attention to NCDs. This provides important avenues for promoting the incorporation of human rights norms and standards into NCD responses as well as for accountability. Linking NCDs and human rights at the global level is critical for encouraging national-level action to promote better outcomes relating to both health and human rights. The post-2015 development agenda constitutes a key entry point for highlighting these synergies and strengthening opportunities for health and rights action at global, national and local levels.

Banishing the Control Homunculi in Studies of Action Control and Behavior Change

PubMed Central

Verbruggen, Frederick; McLaren, Ian P. L.; Chambers, Christopher D.

2014-01-01

For centuries, human self-control has fascinated scientists and nonscientists alike. Current theories often attribute it to an executive control system. But even though executive control receives a great deal of attention across disciplines, most aspects of it are still poorly understood. Many theories rely on an ill-defined set of “homunculi” doing jobs like “response inhibition” or “updating” without explaining how they do so. Furthermore, it is not always appreciated that control takes place across different timescales. These two issues hamper major advances. Here we focus on the mechanistic basis for the executive control of actions. We propose that at the most basic level, action control depends on three cognitive processes: signal detection, action selection, and action execution. These processes are modulated via error-correction or outcome-evaluation mechanisms, preparation, and task rules maintained in working and long-term memory. We also consider how executive control of actions becomes automatized with practice and how people develop a control network. Finally, we discuss how the application of this unified framework in clinical domains can increase our understanding of control deficits and provide a theoretical basis for the development of novel behavioral change interventions. PMID:25419227

Molecular mechanisms responsible for interaction or differentiation between hydrotropism and gravitropism in roots

NASA Astrophysics Data System (ADS)

Takahashi, Hideyuki; Morohashi, Keita; Kobayashi, Akie; Miyazawa, Yutaka; Fujii, Nobuharu

Roots display hydrotropism in response to moisture gradient, but it is often interfered by gravitropic response on Earth. We demonstrated that roots of cucumber seedlings showed positive hydrotropism when exposed to moisture gradient and rotated on a two-axis clinostat. Under stationary conditions, however, gravitropic response overcame hydrotropic response. Using this experimental system, we examined the role of auxin in hydrotropism. Cucumber roots showed severely reduced hydrotropic response when treated with inhibitors of auxin transport (efflux) or auxin action. mRNA accumulation of auxin-inducible gene, CsIAA1, became more abundant in the concave side of the hydrotropically responding roots, compared with that of the convex side. To understand the auxin dynamics in cucumber roots, we isolated cDNAs of auxin efflux carriers, CsPINs, and examined the localization of their mRNAs and proteins. Of these CsPINs, CsPIN5 was localized peripherally in the region between lateral root cap and elongation zone of cucumber roots. In hydrotropically responding roots, CsPIN5 proteins decreased in the convex side while it was maintained in the concave side. These results suggest that auxin dynamics and action play important roles in inducing hydrotropism, similarly to the case of gravitropism in roots. In cucumber roots, therefore, hydrotropism interacts with gravitropism, possibly by competitive manner in auxin dynamics. We are currently preparing spaceflight experiment for separating the hydrotropic response mechanism from that of gravitropism to understand the regulatory mechanisms of root growth orientation and determine whether hydrotropic response can be used for controlling growth orientation of roots in microgravity. On the other hand, we identified MIZ1 gene essential for hydrotropism but not gravitropism in Arabidopsis roots. Thus, there exist molecular mechanisms shared and differed in the two tropisms.

New mechanisms and targets in the treatment of bone fragility.

PubMed

Martin, T John; Seeman, Ego

2007-01-01

Bone modelling and remodelling are cell-mediated processes responsible for the construction and reconstruction of the skeleton throughout life. These processes are chiefly mediated by locally generated cytokines and growth factors that regulate the differentiation, activation, work and life span of osteoblasts and osteoclasts, the cells that co-ordinate the volumes of bone resorbed and formed. In this way, the material composition and structural design of bone is regulated in accordance with its loading requirements. Abnormalities in this regulatory system compromise the material and structural determinants of bone strength producing bone fragility. Understanding the intercellular control processes that regulate bone modelling and remodelling is essential in planning therapeutic approaches to prevention and treatment of bone fragility. A great deal has been learnt in the last decade. Clinical trials carried out exclusively with drugs that inhibit bone resorption have identified the importance of reducing the rate of bone remodelling and so the progression of bone fragility to achieved fracture reductions of approx. 50%. These trials have also identified limitations that should be placed upon interpretation of bone mineral density changes in relation to treatment. New resorption inhibitors are being developed, based on mechanisms of action that are different from existing drugs. Some of these might offer resorption inhibition without reducing bone formation. More recent research has provided the first effective anabolic therapy for bone reconstruction. Daily injections of PTH (parathyroid hormone)-(1-34) have been shown in preclinical studies and in a large clinical trial to increase bone tissue mass and reduce the risk of fractures. The action of PTH differs from that of the resorption inhibitors, but whether it is more effective in fracture reduction is not known. Understanding the cellular and molecular mechanisms of PTH action, particularly its interactions with other pathways in determining bone formation, is likely to lead to new therapeutic developments. The recent discovery through mouse genetics that PTHrP (PTH-related protein) is a crucial bone-derived paracrine regulator of remodelling offers new and interesting therapeutic targets.

From Movements to Actions: Two Mechanisms for Learning Action Sequences

ERIC Educational Resources Information Center

Endress, Ansgar D.; Wood, Justin N.

2011-01-01

When other individuals move, we interpret their movements as discrete, hierarchically-organized, goal-directed actions. However, the mechanisms that integrate visible movement features into actions are poorly understood. Here, we consider two sequence learning mechanisms--transitional probability-based (TP) and position-based encoding…

Progress in high-level exploratory vision

NASA Astrophysics Data System (ADS)

Brand, Matthew

1993-08-01

We have been exploring the hypothesis that vision is an explanatory process, in which causal and functional reasoning about potential motion plays an intimate role in mediating the activity of low-level visual processes. In particular, we have explored two of the consequences of this view for the construction of purposeful vision systems: Causal and design knowledge can be used to (1) drive focus of attention, and (2) choose between ambiguous image interpretations. An important result of visual understanding is an explanation of the scene's causal structure: How action is originated, constrained, and prevented, and what will happen in the immediate future. In everyday visual experience, most action takes the form of motion, and most causal analysis takes the form of dynamical analysis. This is even true of static scenes, where much of a scene's interest lies in how possible motions are arrested. This paper describes our progress in developing domain theories and visual processes for the understanding of various kinds of structured scenes, including structures built out of children's constructive toys and simple mechanical devices.

Physicochemical structural changes of cellulosic substrates during enzymatic saccharification

DOE PAGES

Meng, Xianzhi; Yoo, Chang Geun; Li, Mi; ...

2016-12-30

Enzymatic hydrolysis represents one of the major steps and barriers in the commercialization process of converting cellulosic substrates into biofuels and other value added products. It is usually achieved by a synergistic action of enzyme mixture typically consisting of multiple enzymes such as glucanase, cellobiohydrolase and β-glucosidase with different mode of actions. Due to the innate biomass recalcitrance, enzymatic hydrolysis normally starts with an initial fast rate of hydrolysis followed by a rapid decrease of rate toward the end of hydrolysis. With majority of literature studies focusing on the effect of key substrate characteristics on the initial rate or finalmore » yield of enzymatic hydrolysis, information about physicochemical structural changes of cellulosic substrates during enzymatic hydrolysis is still quite limited. Consequently, what slows down the reaction rate toward the end of hydrolysis is not well understood. Lastly, this review highlights recent advances in understanding the structural changes of cellulosic substrates during the hydrolysis process, to better understand the fundamental mechanisms of enzymatic hydrolysis.« less

Physicochemical structural changes of cellulosic substrates during enzymatic saccharification

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

Meng, Xianzhi; Yoo, Chang Geun; Li, Mi

Enzymatic hydrolysis represents one of the major steps and barriers in the commercialization process of converting cellulosic substrates into biofuels and other value added products. It is usually achieved by a synergistic action of enzyme mixture typically consisting of multiple enzymes such as glucanase, cellobiohydrolase and β-glucosidase with different mode of actions. Due to the innate biomass recalcitrance, enzymatic hydrolysis normally starts with an initial fast rate of hydrolysis followed by a rapid decrease of rate toward the end of hydrolysis. With majority of literature studies focusing on the effect of key substrate characteristics on the initial rate or finalmore » yield of enzymatic hydrolysis, information about physicochemical structural changes of cellulosic substrates during enzymatic hydrolysis is still quite limited. Consequently, what slows down the reaction rate toward the end of hydrolysis is not well understood. Lastly, this review highlights recent advances in understanding the structural changes of cellulosic substrates during the hydrolysis process, to better understand the fundamental mechanisms of enzymatic hydrolysis.« less

Modulation of gastrointestinal vagal neurocircuits by hyperglycemia

PubMed Central

Browning, Kirsteen N.

2013-01-01

Glucose sensing within autonomic neurocircuits is critical for the effective integration and regulation of a variety of physiological homeostatic functions including the co-ordination of vagally-mediated reflexes regulating gastrointestinal (GI) functions. Glucose regulates GI functions via actions at multiple sites of action, from modulating the activity of enteric neurons, endocrine cells, and glucose transporters within the intestine, to regulating the activity and responsiveness of the peripheral terminals, cell bodies and central terminals of vagal sensory neurons, to modifying both the activity and synaptic responsiveness of central brainstem neurons. Unsurprisingly, significant impairment in GI functions occurs in pathophysiological states where glucose levels are dysregulated, such as diabetes. A substantial obstacle to the development of new therapies to modify the disease, rather than treat the symptoms, are the gaps in our understanding of the mechanisms by which glucose modulates GI functions, particularly vagally-mediated responses and a more complete understanding of disease-related plasticity within these neurocircuits may open new avenues and targets for research. PMID:24324393

A Network Pharmacology Approach to Understanding the Mechanisms of Action of Traditional Medicine: Bushenhuoxue Formula for Treatment of Chronic Kidney Disease

PubMed Central

Zheng, Xiao-yong; Cao, Dong-sheng; Ye, Fa-qing; Xiang, Zheng

2014-01-01

Traditional Chinese medicine (TCM) has unique therapeutic effects for complex chronic diseases. However, for the lack of an effective systematic approach, the research progress on the effective substances and pharmacological mechanism of action has been very slow. In this paper, by incorporating network biology, bioinformatics and chemoinformatics methods, an integrated approach was proposed to systematically investigate and explain the pharmacological mechanism of action and effective substances of TCM. This approach includes the following main steps: First, based on the known drug targets, network biology was used to screen out putative drug targets; Second, the molecular docking method was used to calculate whether the molecules from TCM and drug targets related to chronic kidney diseases (CKD) interact or not; Third, according to the result of molecular docking, natural product-target network, main component-target network and compound-target network were constructed; Finally, through analysis of network characteristics and literature mining, potential effective multi-components and their synergistic mechanism were putatively identified and uncovered. Bu-shen-Huo-xue formula (BSHX) which was frequently used for treating CKD, was used as the case to demonstrate reliability of our proposed approach. The results show that BSHX has the therapeutic effect by using multi-channel network regulation, such as regulating the coagulation and fibrinolytic balance, and the expression of inflammatory factors, inhibiting abnormal ECM accumulation. Tanshinone IIA, rhein, curcumin, calycosin and quercetin may be potential effective ingredients of BSHX. This research shows that the integration approach can be an effective means for discovering active substances and revealing their pharmacological mechanisms of TCM. PMID:24598793

Understanding the Complexity of Teacher Reflection in Action Research

ERIC Educational Resources Information Center

Luttenberg, Johan; Meijer, Paulien; Oolbekkink-Marchand, Helma

2017-01-01

Reflection in action research is a complex matter, as is action research itself. In recent years, complexity science has regularly been called upon in order to more thoroughly understand the complexity of action research. The present article investigates the benefits that complexity science may yield for reflection in action research. This article…

Antimicrobial Action and Cell Agglutination by the Eosinophil Cationic Protein Are Modulated by the Cell Wall Lipopolysaccharide Structure

PubMed Central

Pulido, David; Moussaoui, Mohammed; Andreu, David; Nogués, M. Victòria

2012-01-01

Antimicrobial proteins and peptides (AMPs) are essential effectors of innate immunity, acting as a first line of defense against bacterial infections. Many AMPs exhibit high affinity for cell wall structures such as lipopolysaccharide (LPS), a potent endotoxin able to induce sepsis. Hence, understanding how AMPs can interact with and neutralize LPS endotoxin is of special relevance for human health. Eosinophil cationic protein (ECP) is an eosinophil secreted protein with high activity against both Gram-negative and Gram-positive bacteria. ECP has a remarkable affinity for LPS and a distinctive agglutinating activity. By using a battery of LPS-truncated E. coli mutant strains, we demonstrate that the polysaccharide moiety of LPS is essential for ECP-mediated bacterial agglutination, thereby modulating its antimicrobial action. The mechanism of action of ECP at the bacterial surface is drastically affected by the LPS structure and in particular by its polysaccharide moiety. We have also analyzed an N-terminal fragment that retains the whole protein activity and displays similar cell agglutination behavior. Conversely, a fragment with further minimization of the antimicrobial domain, though retaining the antimicrobial capacity, significantly loses its agglutinating activity, exhibiting a different mechanism of action which is not dependent on the LPS composition. The results highlight the correlation between the protein's antimicrobial activity and its ability to interact with the LPS outer layer and promote bacterial agglutination. PMID:22330910

Antimicrobial action and cell agglutination by the eosinophil cationic protein are modulated by the cell wall lipopolysaccharide structure.

PubMed

Pulido, David; Moussaoui, Mohammed; Andreu, David; Nogués, M Victòria; Torrent, Marc; Boix, Ester

2012-05-01

Antimicrobial proteins and peptides (AMPs) are essential effectors of innate immunity, acting as a first line of defense against bacterial infections. Many AMPs exhibit high affinity for cell wall structures such as lipopolysaccharide (LPS), a potent endotoxin able to induce sepsis. Hence, understanding how AMPs can interact with and neutralize LPS endotoxin is of special relevance for human health. Eosinophil cationic protein (ECP) is an eosinophil secreted protein with high activity against both Gram-negative and Gram-positive bacteria. ECP has a remarkable affinity for LPS and a distinctive agglutinating activity. By using a battery of LPS-truncated E. coli mutant strains, we demonstrate that the polysaccharide moiety of LPS is essential for ECP-mediated bacterial agglutination, thereby modulating its antimicrobial action. The mechanism of action of ECP at the bacterial surface is drastically affected by the LPS structure and in particular by its polysaccharide moiety. We have also analyzed an N-terminal fragment that retains the whole protein activity and displays similar cell agglutination behavior. Conversely, a fragment with further minimization of the antimicrobial domain, though retaining the antimicrobial capacity, significantly loses its agglutinating activity, exhibiting a different mechanism of action which is not dependent on the LPS composition. The results highlight the correlation between the protein's antimicrobial activity and its ability to interact with the LPS outer layer and promote bacterial agglutination.

Dynamics of Action Potential Initiation in the GABAergic Thalamic Reticular Nucleus In Vivo

PubMed Central

Muñoz, Fabián; Fuentealba, Pablo

2012-01-01

Understanding the neural mechanisms of action potential generation is critical to establish the way neural circuits generate and coordinate activity. Accordingly, we investigated the dynamics of action potential initiation in the GABAergic thalamic reticular nucleus (TRN) using in vivo intracellular recordings in cats in order to preserve anatomically-intact axo-dendritic distributions and naturally-occurring spatiotemporal patterns of synaptic activity in this structure that regulates the thalamic relay to neocortex. We found a wide operational range of voltage thresholds for action potentials, mostly due to intrinsic voltage-gated conductances and not synaptic activity driven by network oscillations. Varying levels of synchronous synaptic inputs produced fast rates of membrane potential depolarization preceding the action potential onset that were associated with lower thresholds and increased excitability, consistent with TRN neurons performing as coincidence detectors. On the other hand the presence of action potentials preceding any given spike was associated with more depolarized thresholds. The phase-plane trajectory of the action potential showed somato-dendritic propagation, but no obvious axon initial segment component, prominent in other neuronal classes and allegedly responsible for the high onset speed. Overall, our results suggest that TRN neurons could flexibly integrate synaptic inputs to discharge action potentials over wide voltage ranges, and perform as coincidence detectors and temporal integrators, supported by a dynamic action potential threshold. PMID:22279567

Altered Brain Activation During Action Imitation and Observation in Schizophrenia: A Translational Approach to Investigating Social Dysfunction in Schizophrenia

PubMed Central

Thakkar, Katharine N.; Peterman, Joel S.; Park, Sohee

2015-01-01

Objective Social impairments are a key feature of schizophrenia, but their underlying mechanisms are poorly understood. Imitation, a process through which we understand the minds of others, involves the so-called mirror neuron system, a network comprising the inferior parietal lobe, inferior frontal gyrus, and posterior superior temporal sulcus. The authors examined mirror neuron system function in schizophrenia. Method Sixteen medicated schizophrenia patients and 16 healthy comparison subjects performed an action imitation/ observation task during functional MRI. Participants saw a video of a moving hand or spatial cue and were instructed to either execute finger movements associated with the stimulus or simply observe. Activation in the mirror neuron system was measured during imitative versus nonimitative actions and observation of a moving hand versus a moving spatial cue. These contrasts were compared across groups. Results Activation in the mirror neuron system was less specific for imitation in schizophrenia. Relative to healthy subjects, patients had reduced activity in the posterior superior temporal sulcus during imitation and greater activity in the posterior superior temporal sulcus and inferior parietal lobe during nonimitative action. Patients also showed reduced activity in these regions during action observation. Mirror neuron system activation was related to symptom severity and social functioning in patients and to schizotypal syndrome in comparison subjects. Conclusions Given the role of the inferior parietal lobe and posterior superior temporal sulcus in imitation and social cognition, impaired imitative ability in schizophrenia may stem from faulty perception of biological motion and transformations from perception to action. These findings extend our understanding of social dysfunction in schizophrenia. PMID:24626638

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

"Unwilling" versus "Unable": Chimpanzees' Understanding of Human Intentional Action

ERIC Educational Resources Information Center

Call, Josep; Hare, Brian; Carpenter, Malinda; Tomasello, Michael

2004-01-01

Understanding the intentional actions of others is a fundamental part of human social cognition and behavior. An important question is therefore whether other animal species, especially our nearest relatives the chimpanzees, also understand the intentional actions of others. Here we show that chimpanzees spontaneously (without training) behave…

Toxicodynamics of Mycotoxins in the Framework of Food Risk Assessment—An In Silico Perspective

PubMed Central

Dall’Asta, Chiara

2018-01-01

Mycotoxins severely threaten the health of humans and animals. For this reason, many countries have enforced regulations and recommendations to reduce the dietary exposure. However, even though regulatory actions must be based on solid scientific knowledge, many aspects of their toxicological activity are still poorly understood. In particular, deepening knowledge on the primal molecular events triggering the toxic stimulus may be relevant to better understand the mechanisms of action of mycotoxins. The present work presents the use of in silico approaches in studying the mycotoxins toxicodynamics, and discusses how they may contribute in widening the background of knowledge. A particular emphasis has been posed on the methods accounting the molecular initiating events of toxic action. In more details, the key concepts and challenges of mycotoxins toxicology have been introduced. Then, topical case studies have been presented and some possible practical implementations of studying mycotoxins toxicodynamics have been discussed. PMID:29360783

Human androgen deficiency: insights gained from androgen receptor knockout mouse models

PubMed Central

Rana, Kesha; Davey, Rachel A; Zajac, Jeffrey D

2014-01-01

The mechanism of androgen action is complex. Recently, significant advances have been made into our understanding of how androgens act via the androgen receptor (AR) through the use of genetically modified mouse models. A number of global and tissue-specific AR knockout (ARKO) models have been generated using the Cre-loxP system which allows tissue- and/or cell-specific deletion. These ARKO models have examined a number of sites of androgen action including the cardiovascular system, the immune and hemopoetic system, bone, muscle, adipose tissue, the prostate and the brain. This review focuses on the insights that have been gained into human androgen deficiency through the use of ARKO mouse models at each of these sites of action, and highlights the strengths and limitations of these Cre-loxP mouse models that should be considered to ensure accurate interpretation of the phenotype. PMID:24480924

Electropharmacological effects of antiarrhythmic drugs on atrial fibrillation termination. Part I: Molecular and ionic fundamentals of antiarrhythmic drug actions.

PubMed

Calò, Leonardo; Sciarra, Luigi; Lamberti, Filippo; Loricchio, Maria Luisa; Castro, Antonio; Bianconi, Leopoldo; Pandozi, Claudio; Gaita, Fiorenzo; Santini, Massimo

2003-07-01

In the last few years many studies have been performed with the aim of gaining a better understanding of the pathophysiological nature of atrial fibrillation. These recent observations provide new insights into the initiation and perpetuation of atrial fibrillation, underlying the importance of the pulmonary veins as major sources of atrial triggers and introducing new concepts such as the atrial electrical remodeling and the spatial heterogeneity of the electrophysiological characteristics of this arrhythmia. The increasing knowledge about the cardiac ion channel structure and function and about the electrophysiological actions of the antiarrhythmic drugs may contribute to a better comprehension of the mechanisms of the pharmacological termination of the arrhythmia. In part I of the review we try to give a unified vision of the old models and new concepts about the molecular and ionic fundamentals of antiarrhythmic drug actions.

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.

Nanoscale monitoring of drug actions on cell membrane using atomic force microscopy

PubMed Central

Li, Mi; Liu, Lian-qing; Xi, Ning; Wang, Yue-chao

2015-01-01

Knowledge of the nanoscale changes that take place in individual cells in response to a drug is useful for understanding the drug action. However, due to the lack of adequate techniques, such knowledge was scarce until the advent of atomic force microscopy (AFM), which is a multifunctional tool for investigating cellular behavior with nanometer resolution under near-physiological conditions. In the past decade, researchers have applied AFM to monitor the morphological and mechanical dynamics of individual cells following drug stimulation, yielding considerable novel insight into how the drug molecules affect an individual cell at the nanoscale. In this article we summarize the representative applications of AFM in characterization of drug actions on cell membrane, including topographic imaging, elasticity measurements, molecular interaction quantification, native membrane protein imaging and manipulation, etc. The challenges that are hampering the further development of AFM for studies of cellular activities are aslo discussed. PMID:26027658

Theory of mind: mechanisms, methods, and new directions

PubMed Central

Byom, Lindsey J.; Mutlu, Bilge

2013-01-01

Theory of Mind (ToM) has received significant research attention. Traditional ToM research has provided important understanding of how humans reason about mental states by utilizing shared world knowledge, social cues, and the interpretation of actions; however, many current behavioral paradigms are limited to static, “third-person” protocols. Emerging experimental approaches such as cognitive simulation and simulated social interaction offer opportunities to investigate ToM in interactive, “first-person” and “second-person” scenarios while affording greater experimental control. The advantages and limitations of traditional and emerging ToM methodologies are discussed with the intent of advancing the understanding of ToM in socially mediated situations. PMID:23964218

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.

Understanding Collagen Organization in Breast Tumors to Predict and Prevent Metastasis

DTIC Science & Technology

2012-09-01

metastasis. Specific Aim 2. Determine the role of Th1, Th2, and Tregs in governing collagen ordering in tumors, and their mechanism of action. (Months...surrounding tissue by penetrating through the basement membrane of the duct. Invasive Lobular Carcinoma ( ILC ) is the invasive growth of cancer...not as a predecessor to ILC , but rather a benign growth of abnormal cells that are commonly undetectable by mammograms but if detected (usually in

Molecular simulation aspects of amyloid peptides at membrane interface.

PubMed

Liu, Yonglan; Ren, Baiping; Zhang, Yanxian; Sun, Yan; Chang, Yung; Liang, Guizhao; Xu, Lijian; Zheng, Jie

2018-02-06

The interactions of amyloid peptides with cell membranes play an important role in maintaining the integrity and functionality of cell membrane. A thorough molecular-level understanding of the structure, dynamics, and interactions between amyloid peptides and cell membranes is critical to amyloid aggregation and toxicity mechanisms for the bench-to-bedside applications. Here we review the most recent computational studies of amyloid peptides at model cell membranes. Different mechanisms of action of amyloid peptides on/in cell membranes, targeted by different computational techniques at different lengthscales and timescales, are rationally discussed. Finally, we have proposed some new insights into the remaining challenges and perspectives for future studies to improve our understanding of the activity of amyloid peptides associated with protein-misfolding diseases. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy. Copyright © 2018 Elsevier B.V. All rights reserved.

Shared neural processes support semantic control and action understanding

PubMed Central

Davey, James; Rueschemeyer, Shirley-Ann; Costigan, Alison; Murphy, Nik; Krieger-Redwood, Katya; Hallam, Glyn; Jefferies, Elizabeth

2015-01-01

Executive–semantic control and action understanding appear to recruit overlapping brain regions but existing evidence from neuroimaging meta-analyses and neuropsychology lacks spatial precision; we therefore manipulated difficulty and feature type (visual vs. action) in a single fMRI study. Harder judgements recruited an executive–semantic network encompassing medial and inferior frontal regions (including LIFG) and posterior temporal cortex (including pMTG). These regions partially overlapped with brain areas involved in action but not visual judgements. In LIFG, the peak responses to action and difficulty were spatially identical across participants, while these responses were overlapping yet spatially distinct in posterior temporal cortex. We propose that the co-activation of LIFG and pMTG allows the flexible retrieval of semantic information, appropriate to the current context; this might be necessary both for semantic control and understanding actions. Feature selection in difficult trials also recruited ventral occipital–temporal areas, not implicated in action understanding. PMID:25658631

Mechanism underlying impaired cardiac pacemaking rhythm during ischemia: A simulation study

NASA Astrophysics Data System (ADS)

Bai, Xiangyun; Wang, Kuanquan; Yuan, Yongfeng; Li, Qince; Dobrzynski, Halina; Boyett, Mark R.; Hancox, Jules C.; Zhang, Henggui

2017-09-01

Ischemia in the heart impairs function of the cardiac pacemaker, the sinoatrial node (SAN). However, the ionic mechanisms underlying the ischemia-induced dysfunction of the SAN remain elusive. In order to investigate the ionic mechanisms by which ischemia causes SAN dysfunction, action potential models of rabbit SAN and atrial cells were modified to incorporate extant experimental data of ischemia-induced changes to membrane ion channels and intracellular ion homeostasis. The cell models were incorporated into an anatomically detailed 2D model of the intact SAN-atrium. Using the multi-scale models, the functional impact of ischemia-induced electrical alterations on cardiac pacemaking action potentials (APs) and their conduction was investigated. The effects of vagal tone activity on the regulation of cardiac pacemaker activity in control and ischemic conditions were also investigated. The simulation results showed that at the cellular level ischemia slowed the SAN pacemaking rate, which was mainly attributable to the altered Na+-Ca2+ exchange current and the ATP-sensitive potassium current. In the 2D SAN-atrium tissue model, ischemia slowed down both the pacemaking rate and the conduction velocity of APs into the surrounding atrial tissue. Simulated vagal nerve activity, including the actions of acetylcholine in the model, amplified the effects of ischemia, leading to possible SAN arrest and/or conduction exit block, which are major features of the sick sinus syndrome. In conclusion, this study provides novel insights into understanding the mechanisms by which ischemia alters SAN function, identifying specific conductances as contributors to bradycardia and conduction block.

Epigenetic Interactions between Alcohol and Cannabinergic Effects: Focus on Histone Modification and DNA Methylation

PubMed Central

Parira, Tiyash; Laverde, Alejandra; Agudelo, Marisela

2017-01-01

Epigenetic studies have led to a more profound understanding of the mechanisms involved in chronic conditions. In the case of alcohol addiction, according to the National Institute on Alcohol Abuse and Alcoholism, 16 million adults suffer from Alcohol Use Disorders (AUDs). Even though therapeutic interventions like behavioral therapy and medications to prevent relapse are currently available, no robust cure exists, which stems from the lack of understanding the mechanisms of action of alcohol and the lack of development of precision medicine approaches to treat AUDs. Another common group of addictive substance, cannabinoids, have been studied extensively to reveal they work through cannabinoid receptors. Therapeutic applications have been found for the cannabinoids and a deeper understanding of the endocannabinoid system has been gained over the years. Recent reports of cannabinergic mechanisms in AUDs has opened an exciting realm of research that seeks to elucidate the molecular mechanisms of alcohol-induced end organ diseases and hopefully provide insight into new therapeutic strategies for the treatment of AUDs. To date, several epigenetic mechanisms have been associated with alcohol and cannabinoids independently. Therefore, the scope of this review is to compile the most recent literature regarding alcohol and cannabinoids in terms of a possible epigenetic connection between the endocannabinoid system and alcohol effects. First, we will provide an overview of epigenetics, followed by an overview of alcohol and epigenetic mechanisms with an emphasis on histone modifications and DNA methylations. Then, we will provide an overview of cannabinoids and epigenetic mechanisms. Lastly, we will discuss evidence of interactions between alcohol and cannabinergic pathways and possible insights into the novel epigenetic mechanisms underlying alcohol-cannabinergic pathway activity. Finalizing the review will be a discussion of future directions and therapeutic applications. PMID:28730160

Silver nanoparticles are broad-spectrum bactericidal and virucidal compounds

PubMed Central

2011-01-01

The advance in nanotechnology has enabled us to utilize particles in the size of the nanoscale. This has created new therapeutic horizons, and in the case of silver, the currently available data only reveals the surface of the potential benefits and the wide range of applications. Interactions between viral biomolecules and silver nanoparticles suggest that the use of nanosystems may contribute importantly for the enhancement of current prevention of infection and antiviral therapies. Recently, it has been suggested that silver nanoparticles (AgNPs) bind with external membrane of lipid enveloped virus to prevent the infection. Nevertheless, the interaction of AgNPs with viruses is a largely unexplored field. AgNPs has been studied particularly on HIV where it was demonstrated the mechanism of antiviral action of the nanoparticles as well as the inhibition the transmission of HIV-1 infection in human cervix organ culture. This review discusses recent advances in the understanding of the biocidal mechanisms of action of silver Nanoparticles. PMID:21812950

[Cyclic phosphatidic acids and their analogues--unique lipid mediators].

PubMed

Grzelczyk, Anna; Koziołkiewicz, Maria

2012-01-01

Lysophosphatidic acid (1-acyl-2-sn-glycerol-3-phosphate; LPA) and its naturally occurring analog, cyclic phosphatidic acid (1-acyl-sn-glycerol-2,3-cyclic phosphate; cPA) belong to a group of bioactive glycerophospholipids, which attract attention of many scientists because of their biological functions. Among these two compounds LPA is known better; information about unique biological properties of cPA appeared for the first time in the 90's. The synthesis of various, chemically modified analogues of cPA was performed to highlight mechanisms of the compound actions. Both native cPA and its derivatives emerge into the limelight because of their anti-cancer activities. Knowledge about pathways of biosynthesis and biodegradation of LPA and cPA as well as understanding of mechanisms of their action are increasing gradually. Previous studies have shown that both the metabolism and signaling cascades of these compounds have numerous common points. What is even more interesting, LPA and cPA seem to induce opposite biological activities.

Antioxidant property of coffee components: assessment of methods that define mechanisms of action.

PubMed

Liang, Ningjian; Kitts, David D

2014-11-19

Coffee is a rich source of dietary antioxidants, and this property, coupled with the fact that coffee is one of the world's most popular beverages, has led to the understanding that coffee is a major contributor to dietary antioxidant intake. Brewed coffee is a complex food matrix with numerous phytochemical components that have antioxidant activity capable of scavenging free radicals, donating hydrogen and electrons, providing reducing activity and also acting as metal ion pro-oxidant chelators. More recent studies have shown that coffee components can trigger tissue antioxidant gene expression and protect against gastrointestinal oxidative stress. This paper will describe different in vitro, cell-free and cell-based assays that both characterize and compare the antioxidant capacity and mechanism of action of coffee and its bioactive constituents. Moreover, evidence of cellular antioxidant activity and correlated specific genomic events induced by coffee components, which are relevant to antioxidant function in both animal and human studies, will be discussed.

Cellular and Molecular Mechanisms of Action of Transcranial Direct Current Stimulation: Evidence from In Vitro and In Vivo Models

PubMed Central

Pelletier, Simon J.

2015-01-01

Transcranial direct current stimulation is a noninvasive technique that has been experimentally tested for a number of psychiatric and neurological conditions. Preliminary observations suggest that this approach can indeed influence a number of cellular and molecular pathways that may be disease relevant. However, the mechanisms of action underlying its beneficial effects are largely unknown and need to be better understood to allow this therapy to be used optimally. In this review, we summarize the physiological responses observed in vitro and in vivo, with a particular emphasis on cellular and molecular cascades associated with inflammation, angiogenesis, neurogenesis, and neuroplasticity recruited by direct current stimulation, a topic that has been largely neglected in the literature. A better understanding of the neural responses to transcranial direct current stimulation is critical if this therapy is to be used in large-scale clinical trials with a view of being routinely offered to patients suffering from various conditions affecting the central nervous system. PMID:25522391

Comparative Systems Analyses Reveal Molecular Signatures of Clinically tested Vaccine Adjuvants

NASA Astrophysics Data System (ADS)

Olafsdottir, Thorunn A.; Lindqvist, Madelene; Nookaew, Intawat; Andersen, Peter; Maertzdorf, Jeroen; Persson, Josefine; Christensen, Dennis; Zhang, Yuan; Anderson, Jenna; Khoomrung, Sakda; Sen, Partho; Agger, Else Marie; Coler, Rhea; Carter, Darrick; Meinke, Andreas; Rappuoli, Rino; Kaufmann, Stefan H. E.; Reed, Steven G.; Harandi, Ali M.

2016-12-01

A better understanding of the mechanisms of action of human adjuvants could inform a rational development of next generation vaccines for human use. Here, we exploited a genome wide transcriptomics analysis combined with a systems biology approach to determine the molecular signatures induced by four clinically tested vaccine adjuvants, namely CAF01, IC31, GLA-SE and Alum in mice. We report signature molecules, pathways, gene modules and networks, which are shared by or otherwise exclusive to these clinical-grade adjuvants in whole blood and draining lymph nodes of mice. Intriguingly, co-expression analysis revealed blood gene modules highly enriched for molecules with documented roles in T follicular helper (TFH) and germinal center (GC) responses. We could show that all adjuvants enhanced, although with different magnitude and kinetics, TFH and GC B cell responses in draining lymph nodes. These results represent, to our knowledge, the first comparative systems analysis of clinically tested vaccine adjuvants that may provide new insights into the mechanisms of action of human adjuvants.

Estradiol is a protective factor in the adult and aging brain: understanding of mechanisms derived from in vivo and in vitro studies.

PubMed

Wise, P M; Dubal, D B; Wilson, M E; Rau, S W; Böttner, M; Rosewell, K L

2001-11-01

We have shown that 17beta-estradiol exerts profound protective effects against stroke-like ischemic injury in female rats. These effects are evident using physiological levels of estradiol replacement in ovariectomized rats and require hormone treatment prior to the time of injury. The protective actions of estradiol appear to be most prominent in the cerebral cortex, where cell death is not apparent until at least 4 h after the initiation of ischemic injury and where cell death is thought to be apoptotic in nature. Middle-aged rats remain equally responsive to the protective actions of estradiol. The maintenance of responsiveness of the cerebral cortex to the neuroprotective actions of estradiol was unexpected since responsiveness of the hypothalamus to estradiol decreases dramatically by the time animals are middle-aged. We believe that the protective actions of estradiol require the estrogen receptor-alpha, since estradiol does not protect in estrogen receptor-alpha knockout mice. We have also implemented a method of culturing cerebral cortical explants to assess the protective effects of estradiol in vitro. This model exhibits remarkable parallelisms with our in vivo model of brain injury. We have found that 17beta-estradiol decreases the extent of cell death and that this protective effect requires hormone pretreatment. Finally, 17alpha-estradiol, which does not interact effectively with the estrogen receptor, does not protect; and addition of ICI 182,780, an estrogen receptor antagonist, blocks the protective actions of estradiol. We have begun to explore the molecular and cellular mechanisms of estradiol-mediated protection. In summary, our findings demonstrate that estradiol exerts powerful protective effects both in vivo and in vitro and suggest that these actions are mediated by estrogen receptors.

Effects of action observation on corticospinal excitability: Muscle specificity, direction, and timing of the mirror response.

PubMed

Naish, Katherine R; Houston-Price, Carmel; Bremner, Andrew J; Holmes, Nicholas P

2014-11-01

Many human behaviours and pathologies have been attributed to the putative mirror neuron system, a neural system that is active during both the observation and execution of actions. While there are now a very large number of papers on the mirror neuron system, variations in the methods and analyses employed by researchers mean that the basic characteristics of the mirror response are not clear. This review focuses on three important aspects of the mirror response, as measured by modulations in corticospinal excitability: (1) muscle specificity; (2) direction; and (3) timing of modulation. We focus mainly on electromyographic (EMG) data gathered following single-pulse transcranial magnetic stimulation (TMS), because this method provides precise information regarding these three aspects of the response. Data from paired-pulse TMS paradigms and peripheral nerve stimulation (PNS) are also considered when we discuss the possible mechanisms underlying the mirror response. In this systematic review of the literature, we examine the findings of 85 TMS and PNS studies of the human mirror response, and consider the limitations and advantages of the different methodological approaches these have adopted in relation to discrepancies between their findings. We conclude by proposing a testable model of how action observation modulates corticospinal excitability in humans. Specifically, we propose that action observation elicits an early, non-specific facilitation of corticospinal excitability (at around 90ms from action onset), followed by a later modulation of activity specific to the muscles involved in the observed action (from around 200ms). Testing this model will greatly advance our understanding of the mirror mechanism and provide a more stable grounding on which to base inferences about its role in human behaviour. Copyright © 2014. Published by Elsevier Ltd.

The Potentials and Caveats of Mesenchymal Stromal Cell-Based Therapies in the Preterm Infant

PubMed Central

Shahzad, Tayyab; Radajewski, Sarah; Chao, Cho-Ming; Morty, Rory E.; Reicherzer, Tobias

2018-01-01

Preponderance of proinflammatory signals is a characteristic feature of all acute and resulting long-term morbidities of the preterm infant. The proinflammatory actions are best characterized for bronchopulmonary dysplasia (BPD) which is the chronic lung disease of the preterm infant with lifelong restrictions of pulmonary function and severe consequences for psychomotor development and quality of life. Besides BPD, the immature brain, eye, and gut are also exposed to inflammatory injuries provoked by infection, mechanical ventilation, and oxygen toxicity. Despite the tremendous progress in the understanding of disease pathologies, therapeutic interventions with proven efficiency remain restricted to a few drug therapies with restricted therapeutic benefit, partially considerable side effects, and missing option of applicability to the inflamed brain. The therapeutic potential of mesenchymal stromal cells (MSCs)—also known as mesenchymal stem cells—has attracted much attention during the recent years due to their anti-inflammatory activities and their secretion of growth and development-promoting factors. Based on a molecular understanding, this review summarizes the positive actions of exogenous umbilical cord-derived MSCs on the immature lung and brain and the therapeutic potential of reprogramming resident MSCs. The pathomechanistic understanding of MSC actions from the animal model is complemented by the promising results from the first phase I clinical trials testing allogenic MSC transplantation from umbilical cord blood. Despite all the enthusiasm towards this new therapeutic option, the caveats and outstanding issues have to be critically evaluated before a broad introduction of MSC-based therapies. PMID:29765429

Shared Mechanisms in the Estimation of Self-Generated Actions and the Prediction of Other's Actions by Humans.

PubMed

Ikegami, Tsuyoshi; Ganesh, Gowrishankar

2017-01-01

The question of how humans predict outcomes of observed motor actions by others is a fundamental problem in cognitive and social neuroscience. Previous theoretical studies have suggested that the brain uses parts of the forward model (used to estimate sensory outcomes of self-generated actions) to predict outcomes of observed actions. However, this hypothesis has remained controversial due to the lack of direct experimental evidence. To address this issue, we analyzed the behavior of darts experts in an understanding learning paradigm and utilized computational modeling to examine how outcome prediction of observed actions affected the participants' ability to estimate their own actions. We recruited darts experts because sports experts are known to have an accurate outcome estimation of their own actions as well as prediction of actions observed in others. We first show that learning to predict the outcomes of observed dart throws deteriorates an expert's abilities to both produce his own darts actions and estimate the outcome of his own throws (or self-estimation). Next, we introduce a state-space model to explain the trial-by-trial changes in the darts performance and self-estimation through our experiment. The model-based analysis reveals that the change in an expert's self-estimation is explained only by considering a change in the individual's forward model, showing that an improvement in an expert's ability to predict outcomes of observed actions affects the individual's forward model. These results suggest that parts of the same forward model are utilized in humans to both estimate outcomes of self-generated actions and predict outcomes of observed actions.

Resistance of Bacteria to Biocides.

PubMed

Maillard, Jean-Yves

2018-04-01

Biocides and formulated biocides are used worldwide for an increasing number of applications despite tightening regulations in Europe and in the United States. One concern is that such intense usage of biocides could lead to increased bacterial resistance to a product and cross-resistance to unrelated antimicrobials including chemotherapeutic antibiotics. Evidence to justify such a concern comes mostly from the use of health care-relevant bacterial isolates, although the number of studies of the resistance characteristics of veterinary isolates to biocides have increased the past few years. One problem remains the definition of "resistance" and how to measure resistance to a biocide. This has yet to be addressed globally, although the measurement of resistance is becoming more pressing, with regulators both in Europe and in the United States demanding that manufacturers provide evidence that their biocidal products will not impact on bacterial resistance. Alongside in vitro evidence of potential antimicrobial cross-resistance following biocide exposure, our understanding of the mechanisms of bacterial resistance and, more recently, our understanding of the effect of biocides to induce a mechanism(s) of resistance in bacteria has improved. This article aims to provide an understanding of the development of antimicrobial resistance in bacteria following a biocide exposure. The sections provide evidence of the occurrence of bacterial resistance and its mechanisms of action and debate how to measure bacterial resistance to biocides. Examples pertinent to the veterinary field are used where appropriate.

The origins and mechanisms of karrikin signalling.

PubMed

Waters, Mark T; Scaffidi, Adrian; Flematti, Gavin R; Smith, Steven M

2013-10-01

Karrikins are butenolides in smoke and char that stimulate seed germination. Karrikin action in Arabidopsis requires the F-box protein MAX2 and the α/β-hydrolase KAI2, a paralogue of D14 that is required for perception of strigolactones (SL). SL response involves hydrolysis by D14, whereas karrikins bind to KAI2 without apparent hydrolysis. We discuss the current understanding of the mechanisms of karrikin perception and response. The usual function of KAI2 is unclear, but we hypothesise that the similarity between karrikins and the endogenous ligand for KAI2 made adaptation of some plants to karrikins possible. Copyright © 2013 Elsevier Ltd. All rights reserved.

Amygdala-Dependent Molecular Mechanisms of the Tac2 Pathway in Fear Learning

PubMed Central

Andero, Raül; Daniel, Sarah; Guo, Ji-Dong; Bruner, Robert C; Seth, Shivani; Marvar, Paul J; Rainnie, Donald; Ressler, Kerry J

2016-01-01

Recently we determined that activation of the tachykinin 2 (Tac2) pathway in the central amygdala (CeA) is necessary and sufficient for the modulation of fear memories. The Tac2 pathway includes the Tac2 gene, which encodes the neuropeptide neurokinin B and its corresponding receptor neurokinin 3 receptor (NK3R). In this study, using Tac2–cre and Tac2–GFP mice, we applied a combination of in vivo (optogenetics) and multiple in vitro techniques to further explore the mechanisms of action within the Tac2 pathway. In transgenic mice that express ChR2 solely in Tac2 neurons, in vivo optogenetic stimulation of CeA Tac2-expressing neurons during fear acquisition enhanced fear memory consolidation and drove action potential firing in vitro. In addition, Tac2–CeA neurons were shown to co-express striatal-enriched protein tyrosine phosphatase, which may have an important role in regulating Nk3R signaling during fear conditioning. These data extend our current understanding for the underlying mechanism(s) for the role of the Tac2 pathway in the regulation of fear memory, which may serve as a new therapeutic target in the treatment of fear-related disorders. PMID:27238620

Mono- and Dinuclear Phosphorescent Rhenium(I) Complexes: Impact of Subcellular Localization on Anticancer Mechanisms.

PubMed

Ye, Rui-Rong; Tan, Cai-Ping; Chen, Mu-He; Hao, Liang; Ji, Liang-Nian; Mao, Zong-Wan

2016-06-01

Elucidation of relationship among chemical structure, cellular uptake, localization, and biological activity of anticancer metal complexes is important for the understanding of their mechanisms of action. Organometallic rhenium(I) tricarbonyl compounds have emerged as potential multifunctional anticancer drug candidates that can integrate therapeutic and imaging capabilities in a single molecule. Herein, two mononuclear phosphorescent rhenium(I) complexes (Re1 and Re2), along with their corresponding dinuclear complexes (Re3 and Re4), were designed and synthesized as potent anticancer agents. The subcellular accumulation of Re1-Re4 was conveniently analyzed by confocal microscopy in situ in live cells by utilizing their intrinsic phosphorescence. We found that increased lipophilicity of the bidentate ligands could enhance their cellular uptake, leading to improved anticancer efficacy. The dinuclear complexes were more potent than the mononuclear counterparts. The molecular anticancer mechanisms of action evoked by Re3 and Re4 were explored in detail. Re3 with a lower lipophilicity localizes to lysosomes and induces caspase-independent apoptosis, whereas Re4 with higher lipophilicity specially accumulates in mitochondria and induces caspase-independent paraptosis in cancer cells. Our study demonstrates that subcellular localization is crucial for the anticancer mechanisms of these phosphorescent rhenium(I) complexes. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Understanding Actions of Others: The Electrodynamics of the Left and Right Hemispheres. A High-Density EEG Neuroimaging Study

PubMed Central

Ortigue, Stephanie; Sinigaglia, Corrado; Rizzolatti, Giacomo; Grafton, Scott T.

2010-01-01

Background When we observe an individual performing a motor act (e.g. grasping a cup) we get two types of information on the basis of how the motor act is done and the context: what the agent is doing (i.e. grasping) and the intention underlying it (i.e. grasping for drinking). Here we examined the temporal dynamics of the brain activations that follow the observation of a motor act and underlie the observer's capacity to understand what the agent is doing and why. Methodology/Principal Findings Volunteers were presented with two-frame video-clips. The first frame (T0) showed an object with or without context; the second frame (T1) showed a hand interacting with the object. The volunteers were instructed to understand the intention of the observed actions while their brain activity was recorded with a high-density 128-channel EEG system. Visual event-related potentials (VEPs) were recorded time-locked with the frame showing the hand-object interaction (T1). The data were analyzed by using electrical neuroimaging, which combines a cluster analysis performed on the group-averaged VEPs with the localization of the cortical sources that give rise to different spatio-temporal states of the global electrical field. Electrical neuroimaging results revealed four major steps: 1) bilateral posterior cortical activations; 2) a strong activation of the left posterior temporal and inferior parietal cortices with almost a complete disappearance of activations in the right hemisphere; 3) a significant increase of the activations of the right temporo-parietal region with simultaneously co-active left hemispheric sources, and 4) a significant global decrease of cortical activity accompanied by the appearance of activation of the orbito-frontal cortex. Conclusions/Significance We conclude that the early striking left hemisphere involvement is due to the activation of a lateralized action-observation/action execution network. The activation of this lateralized network mediates the understanding of the goal of object-directed motor acts (mirror mechanism). The successive right hemisphere activation indicates that this hemisphere plays an important role in understanding the intention of others. PMID:20730095

Unexpected cross-reactivity of anti-cathepsin B antibodies leads to uncertainties regarding the mechanism of action of anti-CD20 monoclonal antibody GA101.

PubMed

Chien, Wei Wen; Niogret, Charlène; Jugé, Romain; Lionnard, Loïc; Cornut-Thibaut, Aurélie; Kucharczak, Jérôme; Savina, Ariel; Salles, Gilles; Aouacheria, Abdel

2017-04-01

GA101, also known as obinutuzumab or Gazyva (Gazyvaro), is a glycoengineered type II humanized antibody that targets the CD20 antigen expressed at the surface of B-cells. This novel anti-CD20 antibody is currently assessed in clinical trials with promising results as a single agent or as part of therapeutic combinations for the treatment of B-cell malignancies. Detailed understanding of the mechanisms of GA101-induced cell death is needed to get insight into possible resistance mechanisms occurring in patients. Although multiple in vitro and in vivo mechanisms have been suggested to describe the effects of GA101 on B-cells, currently available data are ambiguous. The aim of our study was to clarify the cellular mechanisms involved in GA101-induced cell death in vitro, and more particularly the respective roles played by lysosomal and mitochondrial membrane permeabilization. Our results confirm previous reports suggesting that GA101 triggers homotypic adhesion and caspase-independent cell death, two processes that are dependent on actin remodeling and involve the production of reactive oxygen species. With respect to lysosomal membrane permeabilization (LMP), our data suggest that lack of specificity of available antibodies directed against cathepsin B may have confounded previously published results, possibly challenging current LMP-driven model of GA101 action mode. Copyright © 2017 Elsevier Ltd. All rights reserved.

Why is your spouse so predictable? Connecting mirror neuron system and self-expansion model of love.

PubMed

Ortigue, Stephanie; Bianchi-Demicheli, Francesco

2008-12-01

The simulation theory assumes we understand actions and intentions of others through a direct matching process. This matching process activates a complex brain network involving the mirror neuron system (MNS), which is self-related and active when one does something or observes someone else acting. Because social psychology admits that mutual intention's understanding grows in close relationship as love grows, we hypothesize that mirror mechanisms take place in love relationships. The similarities between the mirror matching process and the mutual intention's understanding that occurs when two persons are in love suggest that exposure to love might affect functional and neural mechanisms, thus facilitating the understanding of the beloved's intentions. Congruent with our hypothesis, our preliminary results from 38 subjects strongly suggest a significant facilitation effect of love on understanding the intentions of the beloved (as opposed to control stimuli). Based on these phenomenological, and neurofunctional findings we suggest that the mirror mechanisms are involved in the facilitation effects of love for understanding intentions, and might further be extended to any types of love (e.g., passionate love, maternal love). Love experiences are important not only to the beloved himself, but also to any societal, cultural, and institutional patterns that relate to love. Yet, concerning its subjective character, love experiences are difficult to access. The modern procedures and techniques of socio-cognitive neuroscience make it possible to understand love and self-related experiences not only by the analysis of subjective self-reported questionnaires, but also by approaching the automatic (non-conscious) mirror experiences of love in healthy subjects, and neurological patients with a brain damage within the mirror neuron system. Although the psychology of love is now well admitted, the systematic study of the automatic facilitation effect of love through mirror mechanisms might open a new avenue towards the social mind and also self consciousness.

Lipoic acid stimulates cAMP production via G protein coupled receptor dependent and independent mechanisms

PubMed Central

Salinthone, Sonemany; Schillace, Robynn V.; Tsang, Catherine; Regan, John W.; Bourdette, Dennis N.; Carr, Daniel W.

2010-01-01

Lipoic acid (LA) is a naturally occurring fatty acid that exhibits anti-oxidant and anti-inflammatory properties and is being pursued as a therapeutic for many diseases including multiple sclerosis, diabetic polyneuropathy and Alzheimer’s disease. We previously reported on the novel finding that racemic LA (50:50 mixture of R and S LA) stimulates cAMP production, activates prostanoid EP2 and EP4 receptors and adenylyl cyclases (AC), and suppresses activation and cytotoxicity in NK cells. In this study we present evidence that furthers our understanding of the mechanisms of action of LA. Using various LA derivatives, dihydrolipoic acid (DHLA), S,S-dimethyl lipoic acid (DMLA) and lipoamide (LPM), we discovered that only LA is capable of stimulating cAMP production in NK cells. Furthermore, there is no difference in cAMP production after stimulation with either R-LA, S-LA or racemic LA. Competition and synergistic studies indicate that LA may also activate AC independent of the EP2 and EP4 receptors. Pretreatment of PBMCc with KH7 (a specific peptide inhibitor of soluble AC) and the calcium inhibitor (Bapta) prior to LA treatment resulted in reduced cAMP levels, suggesting that soluble AC and calcium signaling mediate LA stimulation of cAMP production. In addition, pharmacological inhibitor studies demonstrate that LA also activates other G- protein coupled receptors, including histamine and adenosine, but not the beta adrenergic receptors. These novel findings provide information to better understand the mechanisms of action of LA, which can help facilitate the use of LA as a therapeutic for various diseases. PMID:21036588

Deconstructing the roles of glucocorticoids in adipose tissue biology and the development of central obesity.

PubMed

Lee, Mi-Jeong; Pramyothin, Pornpoj; Karastergiou, Kalypso; Fried, Susan K

2014-03-01

Central obesity is associated with insulin resistance and dyslipidemia. Thus, the mechanisms that control fat distribution and its impact on systemic metabolism have importance for understanding the risk for diabetes and cardiovascular disease. Hypercortisolemia at the systemic (Cushing's syndrome) or local levels (due to adipose-specific overproduction via 11β-hydroxysteroid dehydrogenase 1) results in the preferential expansion of central, especially visceral fat depots. At the same time, peripheral subcutaneous depots can become depleted. The biochemical and molecular mechanisms underlying the depot-specific actions of glucocorticoids (GCs) on adipose tissue function remain poorly understood. GCs exert pleiotropic effects on adipocyte metabolic, endocrine and immune functions, and dampen adipose tissue inflammation. GCs also regulate multiple steps in the process of adipogenesis. Acting synergistically with insulin, GCs increase the expression of numerous genes involved in fat deposition. Variable effects of GC on lipolysis are reported, and GC can improve or impair insulin action depending on the experimental conditions. Thus, the net effect of GC on fat storage appears to depend on the physiologic context. The preferential effects of GC on visceral adipose tissue have been linked to higher cortisol production and glucocorticoid receptor expression, but the molecular details of the depot-dependent actions of GCs are only beginning to be understood. In addition, increasing evidence underlines the importance of circadian variations in GCs in relationship to the timing of meals for determining their anabolic actions on the adipocyte. In summary, although the molecular mechanisms remain to be fully elucidated, there is increasing evidence that GCs have multiple, depot-dependent effects on adipocyte gene expression and metabolism that promote central fat deposition. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. Copyright © 2013 Elsevier B.V. All rights reserved.

Nitrates and Nitrites in the Treatment of Ischemic Cardiac Disease

PubMed Central

Nossaman, Vaughn E.; Nossaman, Bobby D.; Kadowitz, Philip J.

2010-01-01

The organic nitrite, amyl of nitrite, was initially used as a therapeutic agent in the treatment of angina pectoris in 1867, but was replaced over a decade later by the organic nitrate, nitroglycerin (NTG), due to the ease of administration and longer duration of action. The administration of organic nitrate esters, such as NTG, continues to be used in the treatment of angina pectoris and heart failure during the birth of modern pharmacology. The clinical effectiveness is due to vasodilator activity in large veins and arteries through an as yet unidentified method of delivering nitric oxide (NO), or a NO-like compound to vascular smooth muscle cells. The major drawback with NTG administration is the rapid development of tolerance; and with amyl of nitrite, the duration and route of administration. Although amyl of nitrite are no longer used in the treatments of hypertension or ischemic heart disease, the nitrite anion has recently been discovered to possess novel pharmacologic actions such as modulating hypoxic vasodilation and providing cytoprotection in ischemia-reperfusion injury. Although the actions of these two similar chemical classes (nitrites and organic nitrates) have often been considered to be alike, we still do not understand their mechanism of action. However, the recent discovery that the nitrite anion, derived from either sodium nitrite or an intermediate NTG form, may act as a storage form for NO and provides support for investigating the use of these agents in the treatment of ischemic cardiovascular states. We review what is presently known about the use of nitrites and nitrates, the potential uses of these agents, and their mechanisms of action. PMID:20539102

Hopes for the Future of Pain Control.

PubMed

Bannister, Kirsty; Kucharczyk, Mateusz; Dickenson, Anthony H

2017-12-01

Here we aim to present an accessible review of the pharmacological targets for pain management, and succinctly discuss the newest trends in pain therapy. A key task for current pain pharmacotherapy is the identification of receptors and channels orchestrating nociception. Notwithstanding peripheral alterations in the receptors and channels following pathophysiological events, the modulatory mechanisms in the central nervous system are also fundamental to the regulation of pain perception. Bridging preclinical and clinical studies of peripheral and central components of pain modulation, we present the different types of pain and relate these to pharmacological interventions. We firstly highlight the roles of several peripheral nociceptors, such as NGF, CGRP, sodium channels, and TRP-family channels that may become novel targets for therapies. In the central nervous system, the roles of calcium channels and gabapentinoids as well as NMDA receptors in generating excitability are covered including ideas on central sensitization. We then turn to central modulatory systems and discuss opioids and monoamines. We aim to explain the importance of central sensitization and the dialogue of the spinal circuits with the brain descending modulatory controls before discussing a mechanism-based effectiveness of antidepressants in pain therapy and their potential to modulate the descending controls. Emphasizing the roles of conditioned pain modulation and its animal's equivalent, diffuse noxious inhibitory controls, we discuss these unique descending modulations as a potential tool for understanding mechanisms in patients suffering from pain. Mechanism-based therapy is the key to picking the correct treatments and recent clinical studies using sensory symptoms of patients as surrogates for underlying mechanisms can be used to subgroup patients and reveal actions of drugs that may be lost when studying heterogenous groups of patients. Key advances in the understanding of basic pain principles will impact our thinking about therapy targets. The complexity of pain syndromes will require tailored pharmacological drugs, often in combination or through drugs with more than one action, and often psychotherapy, to fully control pain.

Low, but not high, dose caffeine is a readily available probe for adenosine actions.

PubMed

Fredholm, Bertil B; Yang, Jiangning; Wang, Yingqing

2017-06-01

Caffeine is very widely used and knowledge of its mode of action can be used to gain an understanding of basal physiological regulation. This review makes the point that caffeine is - in low doses - an antagonist of adenosine acting at A 1 , A 2A and A 2B receptors. We use published and unpublished data to make the point that high dose effects of caffeine are not only qualitatively different but have a different underlying mechanism. Therefore one must be careful in only using epidemiological or experimental data where rather low doses of caffeine are used to draw conclusions about the physiology and pathophysiology of adenosine. Copyright © 2016 Elsevier Ltd. All rights reserved.

How do humans affect wildlife nematodes?

USGS Publications Warehouse

Weinstein, Sara B.; Lafferty, Kevin D.

2015-01-01

Human actions can affect wildlife and their nematode parasites. Species introductions and human-facilitated range expansions can create new host–parasite interactions. Novel hosts can introduce parasites and have the potential to both amplify and dilute nematode transmission. Furthermore, humans can alter existing nematode dynamics by changing host densities and the abiotic conditions that affect larval parasite survival. Human impacts on wildlife might impair parasites by reducing the abundance of their hosts; however, domestic animal production and complex life cycles can maintain transmission even when wildlife becomes rare. Although wildlife nematodes have many possible responses to human actions, understanding host and parasite natural history, and the mechanisms behind the changing disease dynamics might improve disease control in the few cases where nematode parasitism impacts wildlife.

Current gaps in basic science knowledge of botulinum neurotoxin biological actions.

PubMed

Rossetto, Ornella; Pirazzini, Marco; Montecucco, Cesare

2015-12-01

Botulinum neurotoxins are produced by anaerobic spore-forming bacteria of the genus Clostridium in several dozens of variants that inactivate neurotransmitter release owing to their metalloprotease activity. This results in a persistent paralysis of peripheral nerve terminals known as botulism. They are the most potent toxins known and are classified as one of the six highest-risk threat agents of bioterrorism. Despite their high toxicity, two of them are used as valuable pharmaceutical for the therapy of many neurological and non-neurological disorders. Notwithstanding the many advances in our understanding of the genetics and structure of botulinum neurotoxins, there are still many gaps in knowledge of toxin mechanism of action that will be discussed here. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Birth of Social Intelligence

PubMed Central

Henderson, Annette M. E.; Gerson, Sarah; Woodward, Amanda L.

2013-01-01

The ability to make sense out of the actions of others is critical to people’s daily functioning. Adults are social experts: They understand that people’s actions are directed at goals and are driven by intentions. In this article, the authors highlight key findings from studies examining infants’ understanding of human action. These findings suggest that infants come to understand that intentions and attention guide human action within the first few months of their lives. By 13 months, infants understand that intentions are specific to individuals, yet there are some actions that are shared by all individuals within a group. Taken together, the evidence suggests that infants are well on their way to becoming social experts by their second birthdays. PMID:25278644

Alteration of the mode of antibacterial action of a defensin by the amino-terminal loop substitution

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

Gao, Bin; Zhu, Shunyi, E-mail: Zhusy@ioz.ac.cn

Highlights: Black-Right-Pointing-Pointer Al-M is an engineered fungal defensin with the n-loop of an insect defensin. Black-Right-Pointing-Pointer Al-M adopts a native defensin-like structure with high antibacterial potency. Black-Right-Pointing-Pointer Al-M kills bacteria through a membrane disruptive mechanism. Black-Right-Pointing-Pointer This work sheds light on the functional evolution of CS{alpha}{beta}-type defensins. -- Abstract: Ancient invertebrate-type and classical insect-type defensins (AITDs and CITDs) are two groups of evolutionarily related antimicrobial peptides (AMPs) that adopt a conserved cysteine-stabilized {alpha}-helical and {beta}-sheet (CS{alpha}{beta}) fold with a different amino-terminal loop (n-loop) size and diverse modes of antibacterial action. Although they both are identified as inhibitors of cell wallmore » biosynthesis, only CITDs evolved membrane disruptive ability by peptide oligomerization to form pores. To understand how this occurred, we modified micasin, a fungus-derived AITDs with a non-membrane disruptive mechanism, by substituting its n-loop with that of an insect-derived CITDs. After air oxidization, the synthetic hybrid defensin (termed Al-M) was structurally identified by circular dichroism (CD) and functionally evaluated by antibacterial and membrane permeability assays and electronic microscopic observation. Results showed that Al-M folded into a native-like defensin structure, as determined by its CD spectrum that is similar to that of micasin. Al-M was highly efficacious against the Gram-positive bacterium Bacillus megaterium with a lethal concentration of 1.76 {mu}M. As expected, in contrast to micasin, Al-M killed the bacteria through a membrane disruptive mechanism of action. The alteration in modes of action supports a key role of the n-loop extension in assembling functional surface of CITDs for membrane disruption. Our work provides mechanical evidence for evolutionary relationship between AITDs and CITDs.« less

Identification and validation nucleolin as a target of curcumol in nasopharyngeal carcinoma cells.

PubMed

Wang, Juan; Wu, Jiacai; Li, Xumei; Liu, Haowei; Qin, Jianli; Bai, Zhun; Chi, Bixia; Chen, Xu

2018-06-30

Identification of the specific protein target(s) of a drug is a critical step in unraveling its mechanisms of action (MOA) in many natural products. Curcumol, isolated from well known Chinese medicinal plant Curcuma zedoary, has been shown to possess multiple biological activities. It can inhibit nasopharyngeal carcinoma (NPC) proliferation and induce apoptosis, but its target protein(s) in NPC cells remains unclear. In this study, we employed a mass spectrometry-based chemical proteomics approach reveal the possible protein targets of curcumol in NPC cells. Cellular thermal shift assay (CETSA), molecular docking and cell-based assay was used to validate the binding interactions. Chemical proteomics capturing uncovered that NCL is a target of curcumol in NPC cells, Molecular docking showed that curcumol bound to NCL with an -7.8 kcal/mol binding free energy. Cell function analysis found that curcumol's treatment leads to a degradation of NCL in NPC cells, and it showed slight effects on NP69 cells. In conclusion, our results providing evidences that NCL is a target protein of curcumol. We revealed that the anti-cancer effects of curcumol in NPC cells are mediated, at least in part, by NCL inhibition. Many natural products showed high bioactivity, while their mechanisms of action (MOA) are very poor or completely missed. Understanding the MOA of natural drugs can thoroughly exploit their therapeutic potential and minimize their adverse side effects. Identification of the specific protein target(s) of a drug is a critical step in unraveling its MOA. Compound-centric chemical proteomics is a classic chemical proteomics approach which integrates chemical synthesis with cell biology and mass spectrometry (MS) to identify protein targets of natural products determine the drug mechanism of action, describe its toxicity, and figure out the possible cause of off-target. It is an affinity-based chemical proteomics method to identify small molecule-protein interactions through affinity chromatography approach coupled with mass spectrometry, has been conventionally used to identify target proteins and has yielded good results. Curcumol, has shown effective inhibition on Nasopharyngeal Carcinoma (NPC) Cells, interacted with NCL and then initiated the anti-tumor biological effect. This research demonstrated the effectiveness of chemical proteomics approaches in natural drugs molecular target identification, revealing and understanding of the novel mechanism of actions of curcumol is crucial for cancer prevention and treatment in nasopharynx cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma

PubMed Central

Fedorenko, Inna V.; Paraiso, Kim H. T.; Smalley, Keiran S. M.

2014-01-01

The discovery of activating BRAF V600E mutations in 50% of all cutaneous melanomas has revolutionized the understanding of melanoma biology and provided new strategies for the therapeutic management of this deadly disease. Highly potent small molecule inhibitors of BRAF are now showing great promise as a novel therapeutic strategy for melanomas harboring activating BRAF V600E mutations and are associated with high levels of response. This commentary article discusses the latest data on the role of mutated BRAF in the development and progression of melanoma as the basis for understanding the mechanism of action of BRAF inhibitors in the preclinical and clinical settings. We further address the issue of BRAF inhibitor resistance and outline the latest insights into the mechanisms of therapeutic escape as well as describing approaches to prevent and abrogate the onset of both intrinsic and acquired drug resistance. It is likely that our evolving understanding of melanoma genetics and signaling will allow for the further personalization of melanoma therapy with the goal of improving clinical responses. PMID:21635872

Behavioral responses in structured populations pave the way to group optimality.

PubMed

Akçay, Erol; Van Cleve, Jeremy

2012-02-01

An unresolved controversy regarding social behaviors is exemplified when natural selection might lead to behaviors that maximize fitness at the social-group level but are costly at the individual level. Except for the special case of groups of clones, we do not have a general understanding of how and when group-optimal behaviors evolve, especially when the behaviors in question are flexible. To address this question, we develop a general model that integrates behavioral plasticity in social interactions with the action of natural selection in structured populations. We find that group-optimal behaviors can evolve, even without clonal groups, if individuals exhibit appropriate behavioral responses to each other's actions. The evolution of such behavioral responses, in turn, is predicated on the nature of the proximate behavioral mechanisms. We model a particular class of proximate mechanisms, prosocial preferences, and find that such preferences evolve to sustain maximum group benefit under certain levels of relatedness and certain ecological conditions. Thus, our model demonstrates the fundamental interplay between behavioral responses and relatedness in determining the course of social evolution. We also highlight the crucial role of proximate mechanisms such as prosocial preferences in the evolution of behavioral responses and in facilitating evolutionary transitions in individuality.

Cellular dynamical mechanisms for encoding the time and place of events along spatiotemporal trajectories in episodic memory.

PubMed

Hasselmo, Michael E; Giocomo, Lisa M; Brandon, Mark P; Yoshida, Motoharu

2010-12-31

Understanding the mechanisms of episodic memory requires linking behavioral data and lesion effects to data on the dynamics of cellular membrane potentials and population interactions within brain regions. Linking behavior to specific membrane channels and neurochemicals has implications for therapeutic applications. Lesions of the hippocampus, entorhinal cortex and subcortical nuclei impair episodic memory function in humans and animals, and unit recording data from these regions in behaving animals indicate episodic memory processes. Intracellular recording in these regions demonstrates specific cellular properties including resonance, membrane potential oscillations and bistable persistent spiking that could underlie the encoding and retrieval of episodic trajectories. A model presented here shows how intrinsic dynamical properties of neurons could mediate the encoding of episodic memories as complex spatiotemporal trajectories. The dynamics of neurons allow encoding and retrieval of unique episodic trajectories in multiple continuous dimensions including temporal intervals, personal location, the spatial coordinates and sensory features of perceived objects and generated actions, and associations between these elements. The model also addresses how cellular dynamics could underlie unit firing data suggesting mechanisms for coding continuous dimensions of space, time, sensation and action. Copyright © 2010 Elsevier B.V. All rights reserved.

ACTH Action on StAR Biology

PubMed Central

Clark, Barbara J.

2016-01-01

Adrenocorticotropin hormone (ACTH) produced by the anterior pituitary stimulates glucocorticoid synthesis by the adrenal cortex. The first step in glucocorticoid synthesis is the delivery of cholesterol to the mitochondrial matrix where the first enzymatic reaction in the steroid hormone biosynthetic pathway occurs. A key response of adrenal cells to ACTH is activation of the cAMP-protein kinase A (PKA) signaling pathway. PKA activation results in an acute increase in expression and function of the Steroidogenic Acute Regulatory protein (StAR). StAR plays an essential role in steroidogenesis- it controls the hormone-dependent movement of cholesterol across the mitochondrial membranes. Currently StAR's mechanism of action remains a major unanswered question in the field. However, some insight may be gained from understanding the mechanism(s) controlling the PKA-dependent phosphorylation of StAR at S194/195 (mouse/human StAR), a modification that is required for function. This mini-review provides a background on StAR's biology with a focus on StAR phosphorylation. The model for StAR translation and phosphorylation at the outer mitochondrial membrane, the location for StAR function, is presented to highlight a unifying theme emerging from diverse studies. PMID:27999527

ACTH Action on StAR Biology.

PubMed

Clark, Barbara J

2016-01-01

Adrenocorticotropin hormone (ACTH) produced by the anterior pituitary stimulates glucocorticoid synthesis by the adrenal cortex. The first step in glucocorticoid synthesis is the delivery of cholesterol to the mitochondrial matrix where the first enzymatic reaction in the steroid hormone biosynthetic pathway occurs. A key response of adrenal cells to ACTH is activation of the cAMP-protein kinase A (PKA) signaling pathway. PKA activation results in an acute increase in expression and function of the Steroidogenic Acute Regulatory protein (StAR). StAR plays an essential role in steroidogenesis- it controls the hormone-dependent movement of cholesterol across the mitochondrial membranes. Currently StAR's mechanism of action remains a major unanswered question in the field. However, some insight may be gained from understanding the mechanism(s) controlling the PKA-dependent phosphorylation of StAR at S194/195 (mouse/human StAR), a modification that is required for function. This mini-review provides a background on StAR's biology with a focus on StAR phosphorylation. The model for StAR translation and phosphorylation at the outer mitochondrial membrane, the location for StAR function, is presented to highlight a unifying theme emerging from diverse studies.

Cellular dynamical mechanisms for encoding the time and place of events along spatiotemporal trajectories in episodic memory

PubMed Central

Hasselmo, Michael E.; Giocomo, Lisa M.; Yoshida, Motoharu

2010-01-01

Understanding the mechanisms of episodic memory requires linking behavioural data and lesion effects to data on the dynamics of cellular membrane potentials and population interactions within these brain regions. Linking behavior to specific membrane channels and neurochemicals has implications for therapeutic applications. Lesions of the hippocampus, entorhinal cortex and subcortical nuclei impair episodic memory function in humans and animals, and unit recording data from these regions in behaving animals indicate episodic memory processes. Intracellular recording in these regions demonstrates specific cellular properties including resonance, membrane potential oscillations and bistable persistent spiking that could underlie the encoding and retrieval of episodic trajectories. A model presented here shows how intrinsic dynamical properties of neurons could mediate the encoding of episodic memories as complex spatiotemporal trajectories. The dynamics of neurons allow encoding and retrieval of unique episodic trajectories in multiple continuous dimensions including temporal intervals, personal location, the spatial coordinates and sensory features of perceived objects and generated actions, and associations between these elements. The model also addresses how cellular dynamics could underlie unit firing data suggesting mechanisms for coding continuous dimensions of space, time, sensation and action. PMID:20018213

[Prostate cancer and new hormonal treatments: mechanism of action and main clinical results].

PubMed

Neuzillet, Y; Flamand, V; Lebdai, S; Villers, A; Lebret, T

2013-10-01

New drugs have recently been developed, through a better understanding of the mechanisms involved in the progression of prostate cancer, including castration-resistant ones (CRPC). This article aims to describe the mechanisms of action of these new hormonal treatments and their major clinical outcomes and development programs. A bibliographic research in French and English using Medline(®) and Embase(®) using the keywords "castration-resistant prostate cancer", "abiraterone acetate", "orteronel", "enzalutamide", and "clinical trials" was performed. the androgen signaling pathway remains the cornerstone of advanced cancers management. Hence, some molecules target the androgen biosynthesis, as abiraterone acetate and orteronel, which are selective inhibitors of the enzyme CYP17. Others act as antagonists of the androgen receptor: the enzalutamide, RNA-509 and ODM201. Finally, galeterone combines the two effects. Progress conferred by these molecules in terms of overall survival and quality of life in patients with metastatic CRPC, suggest that their use at earlier stages of the disease could reduce morbidity and mortality from prostate cancer. Determining the best strategy for sequence or combination therapy to optimize the use of these new molecules should be investigated. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

An Overview of the Mechanism of Action of the Monoclonal Antibody Vedolizumab.

PubMed

Wyant, Tim; Fedyk, Eric; Abhyankar, Brihad

2016-12-01

Vedolizumab is a novel therapeutic monoclonal antibody recently approved for the treatment of moderately to severely active ulcerative colitis and Crohn's disease in adults who have failed at least one conventional therapy. An integrin antagonist, vedolizumab binds to the α 4 β 7 integrin which is expressed specifically by a subset of gastrointestinal-homing T lymphocytes. The binding of α 4 β 7 integrin to mucosal addressin cell adhesion molecule-1 expressed on the surface of mucosal endothelial cells is a crucial component of the gut-selective homing mechanism for lymphocytes.In contrast, other monoclonal antibodies approved for the treatment of inflammatory bowel diseases, such as tumour necrosis factor α antagonists and the integrin antagonist natalizumab, act systemically or on multiple targets to reduce inflammation.The unique gut selectivity of vedolizumab may contribute to the favourable benefit-risk profile observed in vedolizumab clinical trials. In this review, we summarise data from the preclinical development of vedolizumab and describe the current understanding of the mechanism of action as it relates to other biological therapies for inflammatory bowel disease. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

1H NMR-based metabolic profiling reveals the effects of fluoxetine on lipid and amino acid metabolism in astrocytes.

PubMed

Bai, Shunjie; Zhou, Chanjuan; Cheng, Pengfei; Fu, Yuying; Fang, Liang; Huang, Wen; Yu, Jia; Shao, Weihua; Wang, Xinfa; Liu, Meiling; Zhou, Jingjing; Xie, Peng

2015-04-15

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is a prescribed and effective antidepressant and generally used for the treatment of depression. Previous studies have revealed that the antidepressant mechanism of fluoxetine was related to astrocytes. However, the therapeutic mechanism underlying its mode of action in astrocytes remains largely unclear. In this study, primary astrocytes were exposed to 10 µM fluoxetine; 24 h post-treatment, a high-resolution proton nuclear magnetic resonance (1H NMR)-based metabolomic approach coupled with multivariate statistical analysis was used to characterize the metabolic variations of intracellular metabolites. The orthogonal partial least-squares discriminant analysis (OPLS-DA) score plots of the spectra demonstrated that the fluoxetine-treated astrocytes were significantly distinguished from the untreated controls. In total, 17 differential metabolites were identified to discriminate the two groups. These key metabolites were mainly involved in lipids, lipid metabolism-related molecules and amino acids. This is the first study to indicate that fluoxetine may exert antidepressant action by regulating the astrocyte's lipid and amino acid metabolism. These findings should aid our understanding of the biological mechanisms underlying fluoxetine therapy.

1H NMR-Based Metabolic Profiling Reveals the Effects of Fluoxetine on Lipid and Amino Acid Metabolism in Astrocytes

PubMed Central

Bai, Shunjie; Zhou, Chanjuan; Cheng, Pengfei; Fu, Yuying; Fang, Liang; Huang, Wen; Yu, Jia; Shao, Weihua; Wang, Xinfa; Liu, Meiling; Zhou, Jingjing; Xie, Peng

2015-01-01

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is a prescribed and effective antidepressant and generally used for the treatment of depression. Previous studies have revealed that the antidepressant mechanism of fluoxetine was related to astrocytes. However, the therapeutic mechanism underlying its mode of action in astrocytes remains largely unclear. In this study, primary astrocytes were exposed to 10 µM fluoxetine; 24 h post-treatment, a high-resolution proton nuclear magnetic resonance (1H NMR)-based metabolomic approach coupled with multivariate statistical analysis was used to characterize the metabolic variations of intracellular metabolites. The orthogonal partial least-squares discriminant analysis (OPLS-DA) score plots of the spectra demonstrated that the fluoxetine-treated astrocytes were significantly distinguished from the untreated controls. In total, 17 differential metabolites were identified to discriminate the two groups. These key metabolites were mainly involved in lipids, lipid metabolism-related molecules and amino acids. This is the first study to indicate that fluoxetine may exert antidepressant action by regulating the astrocyte’s lipid and amino acid metabolism. These findings should aid our understanding of the biological mechanisms underlying fluoxetine therapy. PMID:25884334

Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects.

PubMed

Yuan, Chun-Su

2007-06-01

To review the mechanisms of action of methylnaltrexone and its effects on opioid bowel dysfunction, as well as its effects on other opioid-induced adverse effects (ADEs), and its potential roles in clinical practice. A literature search using the MEDLINE and Cochrane Collaboration databases for articles published between 1966 and March 2007 was performed. Additional data sources were obtained from manual searches of recent journal articles, book chapters, and monographs. An updated literature search showed no additional publications. Abstracts and original preclinical and clinical research reports published in the English language were identified for review. Review articles, commentaries, and news reports of this compound were excluded. Literature related to opioids, opioid receptors, opioid antagonists, methylnaltrexone, opioid-induced bowel dysfunction, constipation, nausea, and vomiting was evaluated and selected based on consideration of the support shown for the proof of concept, mechanistic findings, and timeliness. Fifty-eight original articles from preclinical studies and clinical trials using methylnaltrexone were identified. Pharmacologic action, benefits, and ADEs of methylnaltrexone were reviewed, with a focus on its effects on bowel dysfunction after opioids. Emphases were placed on its receptor binding activities and therapeutically relevant sites of action (peripheral vs central), in which peripheral opioid receptors in the body contribute to physiological and drug-induced effects. Morphine and related opioids are associated with a number of limiting ADEs, including opioid-induced bowel dysfunction. Methylnaltrexone, a quaternary derivative of naltrexone, blocks peripheral effects of opioids while sparing central analgesic effects. It is currently under late-stage clinical investigation for the treatment of opioid-induced constipation in patients with advanced illness. Reported results showed the drug to be generally well-tolerated. The rapid reversal of constipation is very encouraging. Hastening postoperative discharge may also be possible. Methylnaltrexone has the potential to prevent or treat opioid-induced peripherally mediated ADEs on bowel dysfunction without interfering with central analgesia. The study of methylnaltrexone leads to a greater understanding of the mechanisms of action of opioid pharmacology.

Interacting With Robots to Investigate the Bases of Social Interaction.

PubMed

Sciutti, Alessandra; Sandini, Giulio

2017-12-01

Humans show a great natural ability at interacting with each other. Such efficiency in joint actions depends on a synergy between planned collaboration and emergent coordination, a subconscious mechanism based on a tight link between action execution and perception. This link supports phenomena as mutual adaptation, synchronization, and anticipation, which cut drastically the delays in the interaction and the need of complex verbal instructions and result in the establishment of joint intentions, the backbone of social interaction. From a neurophysiological perspective, this is possible, because the same neural system supporting action execution is responsible of the understanding and the anticipation of the observed action of others. Defining which human motion features allow for such emergent coordination with another agent would be crucial to establish more natural and efficient interaction paradigms with artificial devices, ranging from assistive and rehabilitative technology to companion robots. However, investigating the behavioral and neural mechanisms supporting natural interaction poses substantial problems. In particular, the unconscious processes at the basis of emergent coordination (e.g., unintentional movements or gazing) are very difficult-if not impossible-to restrain or control in a quantitative way for a human agent. Moreover, during an interaction, participants influence each other continuously in a complex way, resulting in behaviors that go beyond experimental control. In this paper, we propose robotics technology as a potential solution to this methodological problem. Robots indeed can establish an interaction with a human partner, contingently reacting to his actions without losing the controllability of the experiment or the naturalness of the interactive scenario. A robot could represent an "interactive probe" to assess the sensory and motor mechanisms underlying human-human interaction. We discuss this proposal with examples from our research with the humanoid robot iCub, showing how an interactive humanoid robot could be a key tool to serve the investigation of the psychological and neuroscientific bases of social interaction.

Krüppel-like factors are effectors of nuclear receptor signaling

PubMed Central

Knoedler, Joseph R.; Denver, Robert J.

2015-01-01

Binding of steroid and thyroid hormones to their cognate nuclear receptors (NRs) impacts virtually every aspect of postembryonic development, physiology and behavior, and inappropriate signaling by NRs may contribute to disease. While NRs regulate genes by direct binding to hormone response elements in the genome, their actions may depend on the activity of other transcription factors (TFs) that may or may not bind DNA. The Krüppel-like family of transcription factors (KLF) is an evolutionarily conserved class of DNA-binding proteins that influence many aspects of development and physiology. Several members of this family have been shown to play diverse roles in NR signaling. For example, KLFs 1) act as accessory transcription factors for NR actions, 2) regulate expression of NR genes, and 3) as gene products of primary NR response genes function as key players in NR-dependent transcriptional networks. In mouse models, deletion of different KLFs leads to aberrant transcriptional and physiological responses to hormones, underscoring the importance of these proteins in the regulation of hormonal signaling. Understanding the functional relationships between NRs and KLFs will yield important insights into mechanisms of NR signaling. In this review we present a conceptual framework for understanding how KLFs participate in NR signaling, and we provide examples of how these proteins function to effect hormone action. PMID:24642391

Neural basis of understanding communicative actions: Changes associated with knowing the actor's intention and the meanings of the actions.

PubMed

Möttönen, Riikka; Farmer, Harry; Watkins, Kate E

2016-01-29

People can communicate by using hand actions, e.g., signs. Understanding communicative actions requires that the observer knows that the actor has an intention to communicate and the meanings of the actions. Here, we investigated how this prior knowledge affects processing of observed actions. We used functional MRI to determine changes in action processing when non-signers were told that the observed actions are communicative (i.e., signs) and learned the meanings of half of the actions. Processing of hand actions activated the left and right inferior frontal gyrus (IFG, BA 44 and 45) when the communicative intention of the actor was known, even when the meanings of the actions remained unknown. These regions were not active when the observers did not know about the communicative nature of the hand actions. These findings suggest that the left and right IFG play a role in understanding the intention of the actor, but do not process visuospatial features of the communicative actions. Knowing the meanings of the hand actions further enhanced activity in the anterior part of the IFG (BA 45), the inferior parietal lobule and posterior inferior and middle temporal gyri in the left hemisphere. These left-hemisphere language regions could provide a link between meanings and observed actions. In sum, the findings provide evidence for the segregation of the networks involved in the neural processing of visuospatial features of communicative hand actions and those involved in understanding the actor's intention and the meanings of the actions. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

LANL Transfers Glowing Bio Technology to Sandia Biotech

ScienceCinema

Nakhla, Tony; Pino, Tony; Hadley, David

2018-03-02

Partnering with Los Alamos National Laboratory, an Albuquerque-based company is seeking to transform the way protein and peptide analysis is conducted around the world. Sandia Biotech is using a biological technology licensed from Los Alamos called split green fluorescent protein (sGFP), as a detecting and tracking tool for the protein and peptide industry, valuable in the fields of Alzheimer's research, drug development and other biotechnology fields using protein folding to understand protein expression and mechanisms of action.

Development of Coactivator-Dependent, First-in-Class Therapies for Breast Cancer

DTIC Science & Technology

2014-09-01

star: AMP-activated protein kinase stimulates fat absorption. Cell Metab. 13:1–2 53. Reineke EL, York B, Stashi E, et al. 2012. SRC-2 coactivator...receptor/SRC-3 protein complexes achieved by our group are providing powerful new insights into understanding the conformation of intact, full...length proteins in a complex and should provide valuable new information on the mechanism of action of SRC SMIs as well. 15. SUBJECT TERMS Breast

Ionic mechanisms subserving mechanosensory transduction and neural integration in statocyst hair cells of Hermissenda

NASA Technical Reports Server (NTRS)

Farley, Joseph

1988-01-01

The neural processing of gravitational-produced sensory stimulation of statocyst hair cells in the nudibranch mollusk Hermissenda was studied. The goal in these studies was to understand how: gravireceptor neurons sense or transduce gravitational forces, gravitational stimulation is integrated so as to produce a graded receptor potential, and ultimately the generation of an action potential, and various neural adaptation phenomena which hair cells exhibit arise. The approach to these problems was primarily electrophysical.

LANL Transfers Glowing Bio Technology to Sandia Biotech

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

Nakhla, Tony; Pino, Tony; Hadley, David

2012-05-21

Partnering with Los Alamos National Laboratory, an Albuquerque-based company is seeking to transform the way protein and peptide analysis is conducted around the world. Sandia Biotech is using a biological technology licensed from Los Alamos called split green fluorescent protein (sGFP), as a detecting and tracking tool for the protein and peptide industry, valuable in the fields of Alzheimer's research, drug development and other biotechnology fields using protein folding to understand protein expression and mechanisms of action.

Mechanisms of Anesthetic Action and Neurotoxicity: Lessons from Molluscs

PubMed Central

Armstrong, Ryden; Riaz, Saba; Hasan, Sean; Iqbal, Fahad; Rice, Tiffany; Syed, Naweed

2018-01-01

Anesthesia is a prerequisite for most surgical procedures in both animals and humans. Significant strides have been made in search of effective and safer compounds that elicit rapid induction and recovery from anesthesia. However, recent studies have highlighted possible negative effects of several anesthetic agents on the developing brain. The precise nature of this cytotoxicity remains to be determined mainly due to the complexity and the intricacies of the mammalian brain. Various invertebrates have contributed significantly toward our understanding of how both local and general anesthetics affect intrinsic membrane and synaptic properties. Moreover, the ability to reconstruct in vitro synapses between individually identifiable pre- and postsynaptic neurons is a unique characteristic of molluscan neurons allowing us to ask fundamental questions vis-à-vis the long-term effects of anesthetics on neuronal viability and synaptic connectivity. Here, we highlight some of the salient aspects of various molluscan organisms and their contributions toward our understanding of the fundamental mechanisms underlying the actions of anesthetic agents as well as their potential detrimental effects on neuronal growth and synaptic connectivity. We also present some novel preliminary data regarding a newer anesthetic agent, dexmedetomidine, and its effects on synaptic transmission between Lymnaea neurons. The findings presented here underscore the importance of invertebrates for research in the field of anesthesiology while highlighting their relevance to both vertebrates and humans. PMID:29410627

Enuresis and encopresis: ten years of progress.

PubMed

Mikkelsen, E J

2001-10-01

To review the progress made over the past decade with regard to the treatment of enuresis and encopresis, as well as advances in the understanding of etiological mechanisms. Separate computerized literature (English language only) searches of Medline and PsycINFO databases were conducted under the parameter of enuresis and children-adolescents, as well as encopresis and children-adolescents. There has been a substantial decrease in published research concerning the use of imipramine to treat enuresis compared with the prior two decades, accompanied by a corresponding increase in the number of papers concerning desmopressin acetate (DDAVP), which has become the primary pharmacological treatment. Genetic studies of large pedigrees have further confirmed the importance of heritable factors. With regard to encopresis, the research has focused primarily on pathophysiological factors related to the colon and anal sphincter. The widespread use of DDAVP has been the primary addition to treatment strategies over the past decade. The bell-and-pad method of conditioning, the only major treatment that has enduring benefit after being withdrawn, is the most cost-effective and appears to be underutilized. Research into etiological mechanisms has focused primarily on the mechanism of action of DDAVP and advances in the understanding of genetic factors. Advances in the treatment and etiological understanding of encopresis have been less impressive.

Understanding the mechanisms behind deficits in imitation: do individuals with autism know 'what' to imitate and do they know 'how' to imitate?

PubMed

Vanvuchelen, Marleen; Van Schuerbeeck, Lise; Roeyers, Herbert; De Weerdt, Willy

2013-01-01

Although imitation problems have been associated with autism for many years, the underlying mechanisms of these problems remain subject to debate. In this article, the question whether imitation problems are caused by selection or correspondence problems is explored and discussed. This review revealed that hypotheses on the nature of imitation problems in autism are complicated and inconclusive at the present time. There is some evidence for impaired selection, especially implicating poor preferential attention to biological motion and poor ascription of intention to action. There is also some evidence that both transformations of perspectives and mapping of visual to motor information are impaired, characterized as correspondence problems. However, it is not yet clear how poor selection processes contribute to correspondence problems and vice versa. Insight in this interaction may provide a valuable contribution to our understanding of imitation problems in autism. For further research we recommend that tasks should be constrained to target as few mechanisms as possible in given experiments. Copyright © 2012 Elsevier Ltd. All rights reserved.

The Paradox of Oestradiol-Induced Breast Cancer Cell Growth and Apoptosis.

PubMed

Maximov, Philipp Y; Lewis-Wambi, Joan S; Jordan, V Craig

2009-05-01

High dose oestrogen therapy was used as a treatment for postmenopausal patients with breast cancer from the 1950s until the introduction of the safer antioestrogen, tamoxifen in the 1970s. The anti-tumour mechanism of high dose oestrogen therapy remained unknown. There was no enthusiasm to study these signal transduction pathways as oestrogen therapy has almost completely been eliminated from the treatment paradigm. Current use of tamoxifen and the aromatase inhibitors seek to create oestrogen deprivation that prevents the growth of oestrogen stimulated oestrogen receptor (ER) positive breast cancer cells. However, acquired resistance to antihormonal therapy does occur, but it is through investigation of laboratory models that a vulnerability of the cancer cell has been discovered and is being investigated to provide new opportunities in therapy with the potential for discovering new cancer-specific apoptotic drugs. Laboratory models of resistance to raloxifene and tamoxifen, the selective oestrogen receptor modulators (SERMs) and aromatase inhibitors demonstrate an evolution of drug resistance so that after many years of oestrogen deprivation, the ER positive cancer cell reconfigures the survival signal transduction pathways so oestrogen now becomes an apoptotic trigger rather than a survival signal. Current efforts are evaluating the mechanisms of oestrogen-induced apoptosis and how this new biology of oestrogen action can be amplified and enhanced, thereby increasing the value of this therapeutic opportunity for the treatment of breast cancer. Several synergistic approaches to therapeutic enhancement are being advanced which involve drug combinations to impair survival signaling with the use of specific agents and to impair bcl-2 that protects the cancer cell from apoptosis. We highlight the historical understanding of oestrogen's role in cell survival and death and specifically illustrate the progress that has been made in the last five years to understand the mechanisms of oestrogen-induced apoptosis. There are opportunities to harness knowledge from this new signal transduction pathway to discover the precise mechanism of this oestrogen-induced apoptotic trigger. Indeed, the new biology of oestrogen action also has significance for understanding the physiology of bone remodeling. Thus, the pathway has a broad appeal in both physiology and cancer research.

Two different streams form the dorsal visual system: anatomy and functions.

PubMed

Rizzolatti, Giacomo; Matelli, Massimo

2003-11-01

There are two radically different views on the functional role of the dorsal visual stream. One considers it as a system involved in space perception. The other is of a system that codes visual information for action organization. On the basis of new anatomical data and a reconsideration of previous functional and clinical data, we propose that the dorsal stream and its recipient parietal areas form two distinct functional systems: the dorso-dorsal stream (d-d stream) and the ventro-dorsal stream (v-d stream). The d-d stream is formed by area V6 (main d-d extrastriate visual node) and areas V6A and MIP of the superior parietal lobule. Its major functional role is the control of actions "on line". Its damage leads to optic ataxia. The v-d stream is formed by area MT (main v-d extrastriate visual node) and by the visual areas of the inferior parietal lobule. As the d-d stream, v-d stream is responsible for action organization. It, however, also plays a crucial role in space perception and action understanding. The putative mechanisms linking action and perception in the v-d stream is discussed.

Cytochrome P450 and Lipoxygenase Metabolites on Renal Function

PubMed Central

Imig, John D.; Hye Khan, Md. Abdul

2018-01-01

Arachidonic acid metabolites have a myriad of biological actions including effects on the kidney to alter renal hemodynamics and tubular transport processes. Cyclooxygenase metabolites are products of an arachidonic acid enzymatic pathway that has been extensively studied in regards to renal function. Two lesser-known enzymatic pathways of arachidonic acid metabolism are the lipoxygenase (LO) and cytochrome P450 (CYP) pathways. The importance of LO and CYP metabolites to renal hemodynamics and tubular transport processes is now being recognized. LO and CYP metabolites have actions to alter renal blood flow and glomerular filtration rate. Proximal and distal tubular sodium transport and fluid and electrolyte homeostasis are also significantly influenced by renal CYP and LO levels. Metabolites of the LO and CYP pathways also have renal actions that influence renal inflammation, proliferation, and apoptotic processes at vascular and epithelial cells. These renal LO and CYP pathway actions occur through generation of specific metabolites and cell-signaling mechanisms. Even though the renal physiological importance and actions for LO and CYP metabolites are readily apparent, major gaps remain in our understanding of these lipid mediators to renal function. Future studies will be needed to fill these major gaps regarding LO and CYP metabolites on renal function. PMID:26756638

Women and postfertilization effects of birth control: consistency of beliefs, intentions and reported use

PubMed Central

Dye, Huong M; Stanford, Joseph B; Alder, Stephen C; Kim, Han S; Murphy, Patricia A

2005-01-01

Background This study assesses the consistency of responses among women regarding their beliefs about the mechanisms of actions of birth control methods, beliefs about when human life begins, the intention to use or not use birth control methods that they believe may act after fertilization or implantation, and their reported use of specific methods. Methods A questionnaire was administered in family practice and obstetrics and gynecology clinics in Salt Lake City, Utah, and Tulsa, Oklahoma. Participants included women ages 18–50 presenting for any reason and women under age 18 presenting for family planning or pregnancy care. Analyses were based on key questions addressing beliefs about whether specific birth control methods may act after fertilization, beliefs about when human life begins, intention to use a method that may act after fertilization, and reported use of specific methods. The questionnaire contained no information about the mechanism of action of any method of birth control. Responses were considered inconsistent if actual use contradicted intentions, if one intention contradicted another, or if intentions contradicted beliefs. Results Of all respondents, 38% gave consistent responses about intention to not use or to stop use of any birth control method that acted after fertilization, while 4% gave inconsistent responses. The corresponding percentages for birth control methods that work after implantation were 64% consistent and 2% inconsistent. Of all respondents, 34% reported they believed that life begins at fertilization and would not use any birth control method that acts after fertilization (a consistent response), while 3% reported they believed that life begins at fertilization but would use a birth control method that acts after fertilization (inconsistent). For specific methods of birth control, less than 1% of women gave inconsistent responses. A majority of women (68% or greater) responded accurately about the mechanism of action of condoms, abstinence, sterilization, and abortion, but a substantial percentage of women (between 19% and 57%) were uncertain about the mechanisms of action of oral contraceptives, intrauterine devices (IUDs), Depo-Provera, or natural family planning. Conclusion Women who believe that life begins at fertilization may not intend to use a birth control method that could have postfertilization effects. More research is needed to understand the relative importance of postfertilization effects for women in other populations, and in relation to other properties of and priorities for birth control methods. However, many women were uncertain about the mechanisms of action of specific methods. To respect the principles of informed consent, some women may need more education about what is known and not known about the mechanisms of action of birth control methods. PMID:16313677

“Rapid Estrogen Signaling in the Brain: Implications for the Fine-Tuning of Neuronal Circuitry”

PubMed Central

Srivastava, Deepak P.; Waters, Elizabeth M.; Mermelstein, Paul G.; Kramár, Enikö A.; Shors, Tracey J.; Liu, Feng

2011-01-01

Rapid actions of estrogens were first described over 40 years ago. However, the importance of rapid estrogen-mediated actions in the central nervous system (CNS) has only now becoming apparent. Several lines of evidence demonstrate that rapid estrogen-mediated signaling elicits potent effects on molecular and cellular events, resulting in the fine-tuning of neuronal circuitry. At an ultrastructural level, the details of estrogen receptor localization and how these are regulated by the circulating hormone and age, are now becoming evident. Furthermore, the mechanisms that allow membrane-associated estrogen receptors to couple with intracellular signaling pathways are also now being revealed. Elucidation of complex actions of rapid estrogen-mediated signaling on synaptic proteins, connectivity and synaptic function in pyramidal neurons has demonstrated that this neurosteroid engage specific mechanisms in different areas of the brain. The regulation of synaptic properties most likely underlies the ‘fine-tuning’ of neuronal circuitry. This in turn may influence how learned behaviors are encoded by different circuitry in male and female subjects. Importantly, as estrogens have been suggested as potential treatments of a number of disorders of the CNS, advancements in our understanding of rapid estrogen signaling in the brain will serve to aid in the development of potential novel estrogen-based treatments. PMID:22072656

A Module Analysis Approach to Investigate Molecular Mechanism of TCM Formula: A Trial on Shu-feng-jie-du Formula

PubMed Central

Zhang, Fangbo; Tang, Shihuan; Liu, Xi; Gao, Yibo; Wang, Yanping

2013-01-01

At the molecular level, it is acknowledged that a TCM formula is often a complex system, which challenges researchers to fully understand its underlying pharmacological action. However, module detection technique developed from complex network provides new insight into systematic investigation of the mode of action of a TCM formula from the molecule perspective. We here proposed a computational approach integrating the module detection technique into a 2-class heterogeneous network (2-HN) which models the complex pharmacological system of a TCM formula. This approach takes three steps: construction of a 2-HN, identification of primary pharmacological units, and pathway analysis. We employed this approach to study Shu-feng-jie-du (SHU) formula, which aimed at discovering its molecular mechanism in defending against influenza infection. Actually, four primary pharmacological units were identified from the 2-HN for SHU formula and further analysis revealed numbers of biological pathways modulated by the four pharmacological units. 24 out of 40 enriched pathways that were ranked in top 10 corresponding to each of the four pharmacological units were found to be involved in the process of influenza infection. Therefore, this approach is capable of uncovering the mode of action underlying a TCM formula via module analysis. PMID:24376467

Nutrigenomics of essential oils and their potential domestic use for improving health.

PubMed

Cayuela Sánchez, José Antonio; Elamrani, Abdelaziz

2014-11-01

The use of essential oils as industrial food additives is notorious, like their medicinal properties. However, their use in household food spicing is for now limited. In this work, we have made a review to reveal the nutrigenomic actions exerted by their bioactive components, to promote awareness of their modulating gene expression ability and the potential that this implies. Also considered is how essential oils can be used as flavoring and seasoning after cooking and before consumption, such as diet components which can improve human health. Genetic mechanisms involved in the medicinal properties of essential oils for food use are identified from literature. These genetic mechanisms reveal nutrigenomic actions. Reviews on the medicinal properties of essential oils have been particularly considered. A wide diversity of nutrigenomic effects from essential oils useful potentially for food spicing is reviewed. General ideas are discussed about essential oils and their properties, such as anti-inflammatory, analgesic, immunomodulatory, anticancer, hepatoprotective, hypolipidemic, anti-diabetic, antioxidant, bone-reparation, anti-depressant and mitigatory for Alzheimer's disease. The essential oils for food use are potentially promoting health agents, and, therefore, worth using as flavoring and condiments. Becoming aware of the modulating gene expression actions from essential oils is important for understanding their potential for use in household dishes as spices to improve health.

The Roles and Mechanisms of Actions of Vitamin C in Bone: New Developments.

PubMed

Aghajanian, Patrick; Hall, Susan; Wongworawat, Montri D; Mohan, Subburaman

2015-11-01

Vitamin C is an important antioxidant and cofactor that is involved in the regulation of development, function, and maintenance of several cell types in the body. Deficiencies in vitamin C can lead to conditions such as scurvy, which, among other ailments, causes gingivia, bone pain, and impaired wound healing. This review examines the functional importance of vitamin C as it relates to the development and maintenance of bone tissues. Analysis of several epidemiological studies and genetic mouse models regarding the effect of vitamin C shows a positive effect on bone health. Overall, vitamin C exerts a positive effect on trabecular bone formation by influencing expression of bone matrix genes in osteoblasts. Recent studies on the molecular pathway for vitamin C actions that include direct effects of vitamin C on transcriptional regulation of target genes by influencing the activity of transcription factors and by epigenetic modification of key genes involved in skeletal development and maintenance are discussed. With an understanding of mechanisms involved in the uptake and metabolism of vitamin C and knowledge of precise molecular pathways for vitamin C actions in bone cells, it is possible that novel therapeutic strategies can be developed or existing therapies can be modified for the treatment of osteoporotic fractures. © 2015 American Society for Bone and Mineral Research.

The Roles and Mechanisms of Actions of Vitamin C in Bone: New Developments

PubMed Central

Aghajanian, Patrick; Hall, Susan; Wongworawat, Montri D.; Mohan, Subburaman

2016-01-01

Vitamin C is an important antioxidant and cofactor which is involved in the regulation of development, function and maintenance of several cell types in the body. Deficiencies in vitamin C can lead to conditions such as scurvy, which, among other ailments, causes gingivia, bone pain and impaired wound healing. This review examines the functional importance of vitamin C as it relates to the development and maintenance of bone tissues. Analysis of several epidemiological studies and genetic mouse models regarding the effect of vitamin C shows a positive effect on bone health. Overall, vitamin C exerts a positive effect on trabecular bone formation by influencing expression of bone matrix genes in osteoblasts. Recent studies on the molecular pathway for vitamin C actions that include direct effects of vitamin C on transcriptional regulation of target genes by influencing the activity of transcription factors and by epigenetic modification of key genes involved in skeletal development and maintenance are discussed. With an understanding of mechanisms involved in the uptake and metabolism of vitamin C and knowledge of precise molecular pathways for vitamin C actions in bone cells, it is possible that novel therapeutic strategies can be developed or existing therapies can be modified for the treatment of osteoporotic fractures. PMID:26358868

Effects of methotrexate on the viscoelastic properties of single cells probed by atomic force microscopy.

PubMed

Li, Mi; Liu, Lianqing; Xiao, Xiubin; Xi, Ning; Wang, Yuechao

2016-10-01

Methotrexate is a commonly used anti-cancer chemotherapy drug. Cellular mechanical properties are fundamental parameters that reflect the physiological state of a cell. However, so far the role of cellular mechanical properties in the actions of methotrexate is still unclear. In recent years, probing the behaviors of single cells with the use of atomic force microscopy (AFM) has contributed much to the field of cell biomechanics. In this work, with the use of AFM, the effects of methotrexate on the viscoelastic properties of four types of cells were quantitatively investigated. The inhibitory and cytotoxic effects of methotrexate on the proliferation of cells were observed by optical and fluorescence microscopy. AFM indenting was used to measure the changes of cellular viscoelastic properties (Young's modulus and relaxation time) by using both conical tip and spherical tip, quantitatively showing that the stimulation of methotrexate resulted in a significant decrease of both cellular Young's modulus and relaxation times. The morphological changes of cells induced by methotrexate were visualized by AFM imaging. The study improves our understanding of methotrexate action and offers a novel way to quantify drug actions at the single-cell level by measuring cellular viscoelastic properties, which may have potential impacts on developing label-free methods for drug evaluation.

Antibacterial action mode of quaternized carboxymethyl chitosan/poly(amidoamine) dendrimer core-shell nanoparticles against Escherichia coli correlated with molecular chain conformation.

PubMed

Wen, Yan; Yao, Fanglian; Sun, Fang; Tan, Zhilei; Tian, Liang; Xie, Lei; Song, Qingchao

2015-03-01

The action mode of quaternized carboxymethyl chitosan/poly(amidoamine) dendrimer core-shell nanoparticles (CM-HTCC/PAMAM) against Escherichia coli (E. coli) was investigated via a combination of approaches including measurements of cell membrane integrity, outer membrane (OM) and inner membrane (IM) permeability, and scanning electron microscopy (SEM). CM-HTCC/PAMAM dendrimer nanoparticles likely acted in a sequent event-driven mechanism, beginning with the binding of positively charged groups from nanoparticle surface with negative cell surface, thereby causing the disorganization of cell membrane, and subsequent leakage of intracellular components which might ultimately lead to cell death. Moreover, the chain conformation of polymers was taken into account for a better understanding of the antibacterial action mode by means of viscosity and GPC measurements. High utilization ratio of positive charge and large specific surface area generated from a compacted conformation of CM-HTCC/PAMAM, significantly different from the extended conformation of HTCC, were proposed to be involved in the antibacterial action. Copyright © 2014 Elsevier B.V. All rights reserved.

[Homeostasis and Disorder of Musculoskeletal System.Molecular mechanism of bone metabolism and future therapeutic strategies.

PubMed

Nakashima, Tomoki

Recent studies of mouse genetics and human gene mutations has greatly contributed to clarifying the molecular mechanism of bone metabolism. Bone is constantly renewed by the balanced action of osteoblastic bone formation and osteoclastic bone resorption both of which mainly occur at the bone surface. This restructuring process called "bone remodeling" is important not only for normal bone mass and strength, but also for mineral homeostasis. Bone remodeling is stringently regulated by communication among bone component cells such as osteoclasts, osteoblasts, osteocytes and endothelial cells. An imbalance of this process is often linked to various bone diseases. Thus, the elucidation of the molecular mechanisms involved in bone remodeling is critical for a deeper understanding of the maintenance of healthy skeleton and bone disease.

The Role of Lactate-Mediated Metabolic Coupling between Astrocytes and Neurons in Long-Term Memory Formation

PubMed Central

Steinman, Michael Q.; Gao, Virginia; Alberini, Cristina M.

2016-01-01

Long-term memory formation, the ability to retain information over time about an experience, is a complex function that affects multiple behaviors, and is an integral part of an individual’s identity. In the last 50 years many scientists have focused their work on understanding the biological mechanisms underlying memory formation and processing. Molecular studies over the last three decades have mostly investigated, or given attention to, neuronal mechanisms. However, the brain is composed of different cell types that, by concerted actions, cooperate to mediate brain functions. Here, we consider some new insights that emerged from recent studies implicating astrocytic glycogen and glucose metabolisms, and particularly their coupling to neuronal functions via lactate, as an essential mechanism for long-term memory formation. PMID:26973477

Global gene expression analysis of early response to chemotherapy treatment in ovarian cancer spheroids.

PubMed

L'Espérance, Sylvain; Bachvarova, Magdalena; Tetu, Bernard; Mes-Masson, Anne-Marie; Bachvarov, Dimcho

2008-02-26

Chemotherapy (CT) resistance in ovarian cancer (OC) is broad and encompasses diverse unrelated drugs, suggesting more than one mechanism of resistance. To better understand the molecular mechanisms controlling the immediate response of OC cells to CT exposure, we have performed gene expression profiling in spheroid cultures derived from six OC cell lines (OVCAR3, SKOV3, TOV-112, TOV-21, OV-90 and TOV-155), following treatment with 10,0 microM cisplatin, 2,5 microM paclitaxel or 5,0 microM topotecan for 72 hours. Exposure of OC spheroids to these CT drugs resulted in differential expression of genes associated with cell growth and proliferation, cellular assembly and organization, cell death, cell cycle control and cell signaling. Genes, functionally involved in DNA repair, DNA replication and cell cycle arrest were mostly overexpressed, while genes implicated in metabolism (especially lipid metabolism), signal transduction, immune and inflammatory response, transport, transcription regulation and protein biosynthesis, were commonly suppressed following all treatments. Cisplatin and topotecan treatments triggered similar alterations in gene and pathway expression patterns, while paclitaxel action was mainly associated with induction of genes and pathways linked to cellular assembly and organization (including numerous tubulin genes), cell death and protein synthesis. The microarray data were further confirmed by pathway and network analyses. Most alterations in gene expression were directly related to mechanisms of the cytotoxics actions in OC spheroids. However, the induction of genes linked to mechanisms of DNA replication and repair in cisplatin- and topotecan-treated OC spheroids could be associated with immediate adaptive response to treatment. Similarly, overexpression of different tubulin genes upon exposure to paclitaxel could represent an early compensatory effect to this drug action. Finally, multicellular growth conditions that are known to alter gene expression (including cell adhesion and cytoskeleton organization), could substantially contribute in reducing the initial effectiveness of CT drugs in OC spheroids. Results described in this study underscore the potential of the microarray technology for unraveling the complex mechanisms of CT drugs actions in OC spheroids and early cellular response to treatment.

Space for action: How practitioners influence environmental assessment

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

Kågström, Mari, E-mail: mari.kagstrom@slu.se; Richardson, Tim, E-mail: tim.richardson@nmbu.no

2015-09-15

Highlights: • The concept of ‘space for action’ offers an important new lens on EA practice. • Focuses on the relation between practitioner's understanding and their actions • Environmental assessment practice is decisively shaped by practitioners. • Practitioners may underestimate their potential to make a difference. • Contributes to understanding change in the environmental assessment field. This article contributes to understanding of how change occurs in the field of environmental assessment (EA). It argues that the integration of new issues in EA, such as human health, is significantly influenced by how practitioners' understandings shape their actions, and by what happensmore » when those, possibly different, interpretations of appropriate action are acted out. The concept of space for action is developed as a means of investigating this relation between understanding and action. Frame theory is also used, to develop a sharper focus on how ‘potential spaces for action’ are created, what these imply for (individuals') preferred choices and actions in certain situations, and what happens in practice when these are acted out and ‘actual spaces for action’ are created. This novel approach is then applied in a Swedish case study of transport planning. The analysis reveals the important work done by practitioners, revealing just how EA practice is decisively shaped by practitioners. Analysis of practice using the lens of spaces for action offers an important new perspective in understanding how the field adapts to new challenges.« less

Fluorescent Antibiotics: New Research Tools to Fight Antibiotic Resistance.

PubMed

Stone, M Rhia L; Butler, Mark S; Phetsang, Wanida; Cooper, Matthew A; Blaskovich, Mark A T

2018-05-01

Better understanding how multidrug-resistant (MDR) bacteria can evade current and novel antibiotics requires a better understanding of the chemical biology of antibiotic action. This necessitates using new tools and techniques to advance our knowledge of bacterial responses to antibiotics, ideally in live cells in real time, to selectively investigate bacterial growth, division, metabolism, and resistance in response to antibiotic challenge. In this review, we discuss the preparation and biological evaluation of fluorescent antibiotics, focussing on how these reporters and assay methods can help elucidate resistance mechanisms. We also examine the potential utility of such probes for real-time in vivo diagnosis of infections. Copyright © 2018 Elsevier Ltd. All rights reserved.

The modulatory action of harmane on serotonergic neurotransmission in rat brain.

PubMed

Abu Ghazaleh, Haya; Lalies, Maggie D; Nutt, David J; Hudson, Alan L

2015-02-09

The naturally occurring β-carboline, harmane, has been implicated in various physiological and psychological conditions. Some of these effects are attributed to its interaction with monoaminergic systems. Previous literature indicates that certain β-carbolines including harmane modulate central monoamine levels partly through monoamine oxidase (MAO) inhibition. However, this is not always the case and thus additional mechanisms may be involved. This study set to assess the potential modulatory role of harmane on the basal or K(+) stimulated release of preloaded radiolabelled noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in rat brain cortex in vitro in the presence of the MAO inhibitor pargyline. Harmane displayed an overt elevation in K(+) -evoked [(3)H]5-HT release; whilst little and no effect was reported with [(3)H]DA and [(3)H]NA respectively. The effect of harmane on [(3)H]5-HT efflux was partially compensated in K(+)-free medium. Further analyses demonstrated that removal of Ca(2+) ions and addition of 1.2mM EGTA did not alter the action of harmane on [(3)H]5-HT release from rat brain cortex. The precise mechanism of action however remains unclear but is unlikely to reflect an involvement of MAO inhibition. The current finding aids our understanding on the modulatory action of harmane on monoamine levels and could potentially be of therapeutic use in psychiatric conditions such as depression and anxiety. Copyright © 2014 Elsevier B.V. All rights reserved.

Additive and Synergistic Membrane Permeabilization by Antimicrobial (Lipo)Peptides and Detergents

PubMed Central

Patel, Hiren; Huynh, Quang; Bärlehner, Dominik; Heerklotz, Heiko

2014-01-01

Certain antibiotic peptides are thought to permeabilize membranes of pathogens by effects that are also observed for simple detergents, such as membrane thinning and disordering, asymmetric bilayer expansion, toroidal pore formation, and micellization. Here we test the hypothesis that such peptides act additively with detergents when applied in parallel. Additivity is defined analogously to a fractional inhibitory concentration index of unity, and the extent and mechanism of leakage is measured by the fluorescence lifetime-based vesicle leakage assay using calcein-loaded vesicles. Good additivity was found for the concerted action of magainin 2, the fungicidal lipopeptide class of surfactins from Bacillus subtilis QST713, and the detergent octyl glucoside, respectively, with the detergent C12EO8. Synergistic or superadditive action was observed for fengycins from B. subtilis, as well as the detergent CHAPS, when combined with C12EO8. The results illustrate two mechanisms of synergistic action: First, maximal leakage requires an optimum degree of heterogeneity in the system that may be achieved by mixing a graded with an all-or-none permeabilizer. (The optimal perturbation should be focused to certain defect structures, yet not to the extent that some vesicles are not affected at all.) Second, a cosurfactant may enhance the bioavailability of a poorly soluble peptide. The results are important for understanding the concerted action of membrane-permeabilizing compounds in biology as well as for optimizing formulations of such antimicrobials for medical applications or crop protection. PMID:24853740

Probiotics as beneficial microbes in aquaculture: an update on their multiple modes of action: a review.

PubMed

Zorriehzahra, Mohammad Jalil; Delshad, Somayeh Torabi; Adel, Milad; Tiwari, Ruchi; Karthik, K; Dhama, Kuldeep; Lazado, Carlo C

2016-12-01

Wide and discriminate use of antibiotics has resulted in serious biological and ecological concerns, especially the emergence of antibiotic resistance. Probiotics, known as beneficial microbes, are being proposed as an effective and eco-friendly alternative to antibiotics. They were first applied in aquaculture species more than three decades ago, but considerable attention had been given only in the early 2000s. Probiotics are defined as live or dead, or even a component of the microorganisms that act under different modes of action in conferring beneficial effects to the host or to its environment. Several probiotics have been characterized and applied in fish and a number of them are of host origin. Unlike some disease control alternatives being adapted and proposed in aquaculture where actions are unilateral, the immense potential of probiotics lies on their multiple mechanisms in conferring benefits to the host fish and the rearing environment. The staggering number of probiotics papers in aquaculture highlights the multitude of advantages from these microorganisms and conspicuously position them in the dynamic search for health-promoting alternatives for cultured fish. This paper provides an update on the use of probiotics in finfish aquaculture, particularly focusing on their modes of action. It explores the contemporary understanding of their spatial and nutritional competitiveness, inhibitory metabolites, environmental modification capability, immunomodulatory potential and stress-alleviating mechanism. This timely update affirms the importance of probiotics in fostering sustainable approaches in aquaculture and provides avenues in furthering its research and development.

[Mechanism of action of antiepileptic drugs].

PubMed

Saidón, Patricia

2003-01-01

Antiepileptic drugs (DAEs) act through different mechanisms of action: increase in central inhibition, inhibition of excitatorios mechanisms and modification of the excitability through their action on the ionic channels. Epilepsy is characterized by an abnormal and hypersynchronic unloading of a neuronal population. The activity of numerous drugs is associated to increase in gabaergic activity. Another group of drugs decreases excitatory mechanisms, through the inhibition of ionic channels, or through a decrease in the activity of the excitatory neurotransmitters. There are some of antiepileptic drugs, especially within the group of drugs of recent appearance, for wich the mechanism of action remains unknown.

Developing Critical Understanding by Teaching Action Research to Undergraduate Psychology Students

ERIC Educational Resources Information Center

Jacobs, Gaby; Murray, Michael

2010-01-01

Action research assumes the active engagement of the stakeholders, such as the community, in the research, and a multiple-level process of reflection in order to evaluate and monitor the actions taken. This makes action research a suitable methodology to increase the critical understanding of the participants. In this paper we describe the…

Shared Mechanisms in the Estimation of Self-Generated Actions and the Prediction of Other’s Actions by Humans

PubMed Central

Ganesh, Gowrishankar

2017-01-01

Abstract The question of how humans predict outcomes of observed motor actions by others is a fundamental problem in cognitive and social neuroscience. Previous theoretical studies have suggested that the brain uses parts of the forward model (used to estimate sensory outcomes of self-generated actions) to predict outcomes of observed actions. However, this hypothesis has remained controversial due to the lack of direct experimental evidence. To address this issue, we analyzed the behavior of darts experts in an understanding learning paradigm and utilized computational modeling to examine how outcome prediction of observed actions affected the participants’ ability to estimate their own actions. We recruited darts experts because sports experts are known to have an accurate outcome estimation of their own actions as well as prediction of actions observed in others. We first show that learning to predict the outcomes of observed dart throws deteriorates an expert’s abilities to both produce his own darts actions and estimate the outcome of his own throws (or self-estimation). Next, we introduce a state-space model to explain the trial-by-trial changes in the darts performance and self-estimation through our experiment. The model-based analysis reveals that the change in an expert’s self-estimation is explained only by considering a change in the individual’s forward model, showing that an improvement in an expert’s ability to predict outcomes of observed actions affects the individual’s forward model. These results suggest that parts of the same forward model are utilized in humans to both estimate outcomes of self-generated actions and predict outcomes of observed actions. PMID:29340300

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.

A Discrete Electromechanical Model for Human Cardiac Tissue: Effects of Stretch-Activated Currents and Stretch Conditions on Restitution Properties and Spiral Wave Dynamics

PubMed Central

Weise, Louis D.; Panfilov, Alexander V.

2013-01-01

We introduce an electromechanical model for human cardiac tissue which couples a biophysical model of cardiac excitation (Tusscher, Noble, Noble, Panfilov, 2006) and tension development (adjusted Niederer, Hunter, Smith, 2006 model) with a discrete elastic mass-lattice model. The equations for the excitation processes are solved with a finite difference approach, and the equations of the mass-lattice model are solved using Verlet integration. This allows the coupled problem to be solved with high numerical resolution. Passive mechanical properties of the mass-lattice model are described by a generalized Hooke's law for finite deformations (Seth material). Active mechanical contraction is initiated by changes of the intracellular calcium concentration, which is a variable of the electrical model. Mechanical deformation feeds back on the electrophysiology via stretch-activated ion channels whose conductivity is controlled by the local stretch of the medium. We apply the model to study how stretch-activated currents affect the action potential shape, restitution properties, and dynamics of spiral waves, under constant stretch, and dynamic stretch caused by active mechanical contraction. We find that stretch conditions substantially affect these properties via stretch-activated currents. In constantly stretched medium, we observe a substantial decrease in conduction velocity, and an increase of action potential duration; whereas, with dynamic stretch, action potential duration is increased only slightly, and the conduction velocity restitution curve becomes biphasic. Moreover, in constantly stretched medium, we find an increase of the core size and period of a spiral wave, but no change in rotation dynamics; in contrast, in the dynamically stretching medium, we observe spiral drift. Our results may be important to understand how altered stretch conditions affect the heart's functioning. PMID:23527160

A discrete electromechanical model for human cardiac tissue: effects of stretch-activated currents and stretch conditions on restitution properties and spiral wave dynamics.

PubMed

Weise, Louis D; Panfilov, Alexander V

2013-01-01

We introduce an electromechanical model for human cardiac tissue which couples a biophysical model of cardiac excitation (Tusscher, Noble, Noble, Panfilov, 2006) and tension development (adjusted Niederer, Hunter, Smith, 2006 model) with a discrete elastic mass-lattice model. The equations for the excitation processes are solved with a finite difference approach, and the equations of the mass-lattice model are solved using Verlet integration. This allows the coupled problem to be solved with high numerical resolution. Passive mechanical properties of the mass-lattice model are described by a generalized Hooke's law for finite deformations (Seth material). Active mechanical contraction is initiated by changes of the intracellular calcium concentration, which is a variable of the electrical model. Mechanical deformation feeds back on the electrophysiology via stretch-activated ion channels whose conductivity is controlled by the local stretch of the medium. We apply the model to study how stretch-activated currents affect the action potential shape, restitution properties, and dynamics of spiral waves, under constant stretch, and dynamic stretch caused by active mechanical contraction. We find that stretch conditions substantially affect these properties via stretch-activated currents. In constantly stretched medium, we observe a substantial decrease in conduction velocity, and an increase of action potential duration; whereas, with dynamic stretch, action potential duration is increased only slightly, and the conduction velocity restitution curve becomes biphasic. Moreover, in constantly stretched medium, we find an increase of the core size and period of a spiral wave, but no change in rotation dynamics; in contrast, in the dynamically stretching medium, we observe spiral drift. Our results may be important to understand how altered stretch conditions affect the heart's functioning.

Utilizing induced pluripotent stem cells (iPSCs) to understand the actions of estrogens in human neurons

PubMed Central

Shum, Carole; Macedo, Sara C.; Warre-Cornish, Katherine; Cocks, Graham; Price, Jack; Srivastava, Deepak P.

2015-01-01

This article is part of a Special Issue “Estradiol and Cognition”. Over recent years tremendous progress has been made towards understanding the molecular and cellular mechanism by which estrogens exert enhancing effects on cognition, and how they act as a neuroprotective or neurotrophic agent in disease. Currently, much of this work has been carried out in animal models with only a limited number of studies using native human tissue or cells. Recent advances in stem cell technology now make it possible to reprogram somatic cells from humans into induced pluripotent stem cells (iPSCs), which can subsequently be differentiated into neurons of specific lineages. Importantly, the reprogramming of cells allows for the generation of iPSCs that retain the genetic “makeup” of the donor. Therefore, it is possible to generate iPSC-derived neurons from patients diagnosed with specific diseases, that harbor the complex genetic background associated with the disorder. Here, we review the iPSC technology and how it's currently being used to model neural development and neurological diseases. Furthermore, we explore whether this cellular system could be used to understand the role of estrogens in human neurons, and present preliminary data in support of this. We further suggest that the use of iPSC technology offers a novel system to not only further understand estrogens' effects in human cells, but also to investigate the mechanism by which estrogens are beneficial in disease. Developing a greater understanding of these mechanisms in native human cells will also aid in the development of safer and more effective estrogen-based therapeutics. PMID:26143621

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.

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

What Are You Doing with That Object? Comparing the Neural Responses of Action Understanding in Adolescents with and without Autism

ERIC Educational Resources Information Center

Pokorny, Jennifer J.; Hatt, Naomi V.; Rogers, Sally J.; Rivera, Susan M.

2018-01-01

Understanding another's actions, including what they are doing and why they are doing it, can be difficult for individuals with autism spectrum disorder (ASD). This understanding is supported by the action observation (AON) and mentalizing (MZN) networks, as well as the superior temporal sulcus. We examined these areas in children with ASD and…

Decoding the network of Trypanosoma brucei proteins that determines sensitivity to apolipoprotein-L1

PubMed Central

MacLeod, Annette

2018-01-01

In contrast to Trypanosoma brucei gambiense and T. b. rhodesiense (the causative agents of human African trypanosomiasis), T. b. brucei is lysed by apolipoprotein-L1 (apoL1)-containing human serum trypanolytic factors (TLF), rendering it non-infectious to humans. While the mechanisms of TLF1 uptake, apoL1 membrane integration, and T. b. gambiense and T. b. rhodesiense apoL1-resistance have been extensively characterised, our understanding of the range of factors that drive apoL1 action in T. b. brucei is limited. Selecting our bloodstream-form T. b. brucei RNAi library with recombinant apoL1 identified an array of factors that supports the trypanocidal action of apoL1, including six putative ubiquitin modifiers and several proteins putatively involved in membrane trafficking; we also identified the known apoL1 sensitivity determinants, TbKIFC1 and the V-ATPase. Most prominent amongst the novel apoL1 sensitivity determinants was a putative ubiquitin ligase. Intriguingly, while loss of this ubiquitin ligase reduces parasite sensitivity to apoL1, its loss enhances parasite sensitivity to TLF1-dominated normal human serum, indicating that free and TLF1-bound apoL1 have contrasting modes-of-action. Indeed, loss of the known human serum sensitivity determinants, p67 (lysosomal associated membrane protein) and the cathepsin-L regulator, ‘inhibitor of cysteine peptidase’, had no effect on sensitivity to free apoL1. Our findings highlight a complex network of proteins that influences apoL1 action, with implications for our understanding of the anti-trypanosomal action of human serum. PMID:29346416

Learning to understand others' actions.

PubMed

Press, Clare; Heyes, Cecilia; Kilner, James M

2011-06-23

Despite nearly two decades of research on mirror neurons, there is still much debate about what they do. The most enduring hypothesis is that they enable 'action understanding'. However, recent critical reviews have failed to find compelling evidence in favour of this view. Instead, these authors argue that mirror neurons are produced by associative learning and therefore that they cannot contribute to action understanding. The present opinion piece suggests that this argument is flawed. We argue that mirror neurons may both develop through associative learning and contribute to inferences about the actions of others.

The function and failure of sensory predictions.

PubMed

Bansal, Sonia; Ford, Judith M; Spering, Miriam

2018-04-23

Humans and other primates are equipped with neural mechanisms that allow them to automatically make predictions about future events, facilitating processing of expected sensations and actions. Prediction-driven control and monitoring of perceptual and motor acts are vital to normal cognitive functioning. This review provides an overview of corollary discharge mechanisms involved in predictions across sensory modalities and discusses consequences of predictive coding for cognition and behavior. Converging evidence now links impairments in corollary discharge mechanisms to neuropsychiatric symptoms such as hallucinations and delusions. We review studies supporting a prediction-failure hypothesis of perceptual and cognitive disturbances. We also outline neural correlates underlying prediction function and failure, highlighting similarities across the visual, auditory, and somatosensory systems. In linking basic psychophysical and psychophysiological evidence of visual, auditory, and somatosensory prediction failures to neuropsychiatric symptoms, our review furthers our understanding of disease mechanisms. © 2018 New York Academy of Sciences.

Cell Signaling Experiments Driven by Optical Manipulation

PubMed Central

Difato, Francesco; Pinato, Giulietta; Cojoc, Dan

2013-01-01

Cell signaling involves complex transduction mechanisms in which information released by nearby cells or extracellular cues are transmitted to the cell, regulating fundamental cellular activities. Understanding such mechanisms requires cell stimulation with precise control of low numbers of active molecules at high spatial and temporal resolution under physiological conditions. Optical manipulation techniques, such as optical tweezing, mechanical stress probing or nano-ablation, allow handling of probes and sub-cellular elements with nanometric and millisecond resolution. PicoNewton forces, such as those involved in cell motility or intracellular activity, can be measured with femtoNewton sensitivity while controlling the biochemical environment. Recent technical achievements in optical manipulation have new potentials, such as exploring the actions of individual molecules within living cells. Here, we review the progress in optical manipulation techniques for single-cell experiments, with a focus on force probing, cell mechanical stimulation and the local delivery of active molecules using optically manipulated micro-vectors and laser dissection. PMID:23698758

Gene expression metadata analysis reveals molecular mechanisms employed by Phanerochaete chrysosporium during lignin degradation and detoxification of plant extractives.

PubMed

Kameshwar, Ayyappa Kumar Sista; Qin, Wensheng

2017-10-01

Lignin, most complex and abundant biopolymer on the earth's surface, attains its stability from intricate polyphenolic units and non-phenolic bonds, making it difficult to depolymerize or separate from other units of biomass. Eccentric lignin degrading ability and availability of annotated genome make Phanerochaete chrysosporium ideal for studying lignin degrading mechanisms. Decoding and understanding the molecular mechanisms underlying the process of lignin degradation will significantly aid the progressing biofuel industries and lead to the production of commercially vital platform chemicals. In this study, we have performed a large-scale metadata analysis to understand the common gene expression patterns of P. chrysosporium during lignin degradation. Gene expression datasets were retrieved from NCBI GEO database and analyzed using GEO2R and Bioconductor packages. Commonly expressed statistically significant genes among different datasets were further considered to understand their involvement in lignin degradation and detoxification mechanisms. We have observed three sets of enzymes commonly expressed during ligninolytic conditions which were later classified into primary ligninolytic, aromatic compound-degrading and other necessary enzymes. Similarly, we have observed three sets of genes coding for detoxification and stress-responsive, phase I and phase II metabolic enzymes. Results obtained in this study indicate the coordinated action of enzymes involved in lignin depolymerization and detoxification-stress responses under ligninolytic conditions. We have developed tentative network of genes and enzymes involved in lignin degradation and detoxification mechanisms by P. chrysosporium based on the literature and results obtained in this study. However, ambiguity raised due to higher expression of several uncharacterized proteins necessitates for further proteomic studies in P. chrysosporium.

Molecular approaches to treatments for cocaine abuse

NASA Astrophysics Data System (ADS)

Flippen-Anderson, Judith L.; George, Clifford; Deschamps, Jeffrey R.

2003-02-01

Cocaine is a potent stimulant of the central nervous system with severe addiction potential. Its abuse is a major problem worldwide. The exact mechanism of action of cocaine is still uncertain but it is known that its reinforcing and stimulant effects are related to its ability to inhibit the membrane bound dopamine transporter (DAT). This paper discusses efforts that are underway to identify ligands for possible use in the treatment of cocaine abuse. Much of this effort has been focussed on understanding cocaine interactions at DAT receptor sites.

Understanding Collagen Organization in Breast Tumors to Predict and Prevent Metastasis

DTIC Science & Technology

2015-11-01

and their mechanism of action. We have explored stromal effects of macrophages in the E0771 murine mammary adenocarcinoma grown in the mammary fat ...and impacted tumor progression in breast tumor cell lines grown in the mammary fat pad (Figure 2 in Madden K, et al. 2013, Figure 9 here). We then...expression of TNF-α. To test this hypothesis, we grew mammary fat pad (MFP) tumors using a breast tumor cell line (E0771, a mammary adenocarcinoma derived from

Src-JNK Potentiation of Estrogen Receptor AF-1; Mechanism, and Role in Estrogen Action in Breast Cancer

DTIC Science & Technology

2002-08-01

an increase in estrogen receptor activity. A second objective is to understand the potential role of Src in estrogen induced mammary ductal development ...bPcis i on to The Ser-ilS-dependent link wt GR- t KaroBio AB, a Swedish pharmaceutical development company with CBP is in addition to the Ser-1l8...the ECL detection kit (Amersham Pharmacia Biotech ). phoresis, stained with Coomassic Blue to monitor expression, and sub- Fluorescence Microscopy

The mirror neuron system.

PubMed

Cattaneo, Luigi; Rizzolatti, Giacomo

2009-05-01

Mirror neurons are a class of neurons, originally discovered in the premotor cortex of monkeys, that discharge both when individuals perform a given motor act and when they observe others perform that same motor act. Ample evidence demonstrates the existence of a cortical network with the properties of mirror neurons (mirror system) in humans. The human mirror system is involved in understanding others' actions and their intentions behind them, and it underlies mechanisms of observational learning. Herein, we will discuss the clinical implications of the mirror system.

Lessons of Abu Ghraib: Understanding and Preventing Prisoner Abuse in Military Operations

DTIC Science & Technology

2008-11-01

was real. See Stanley Milgram, Obedience to Authority: An Experimental View (New York: Harper-Collins, 1983). 49 According to Albert Bandura , moral...responsibility, as when a group of people share in the deci- sions and actions leading to harm. See Albert Bandura et al., “Mechanisms of moral disengagement in...the exercise of moral agency,” Journal of Personality and Social Psychology 71 (1996), 364–374; and also Albert Bandura , “Moral disengagement in the

Structural insights into microtubule doublet interactions inaxonemes

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

Downing, Kenneth H.; Sui, Haixin

2007-06-06

Coordinated sliding of microtubule doublets, driven by dynein motors, produces periodic beating of the axoneme. Recent structural studies of the axoneme have used cryo-electron tomography to reveal new details of the interactions among some of the multitude of proteins that form the axoneme and regulate its movement. Connections among the several sets of dyneins, in particular, suggest ways in which their actions may be coordinated. Study of the molecular architecture of isolated doublets has provided a structural basis for understanding the doublet's mechanical properties that are related to the bending of the axoneme, and has also offered insight into itsmore » potential role in the mechanism of dynein activity regulation.« less

Lights, Camera, Action! Antimicrobial Peptide Mechanisms Imaged in Space and Time

PubMed Central

Choi, Heejun; Rangarajan, Nambirajan; Weisshaar, James C.

2015-01-01

Deeper understanding of the bacteriostatic and bactericidal mechanisms of antimicrobial peptides (AMPs) should help in the design of new antibacterial agents. Over several decades, a variety of biochemical assays have been applied to bulk bacterial cultures. While some of these bulk assays provide time resolution on the order of 1 min, they do not capture faster mechanistic events. Nor can they provide subcellular spatial information or discern cell-to-cell heterogeneity within the bacterial population. Single-cell, time-resolved imaging assays bring a completely new spatiotemporal dimension to AMP mechanistic studies. We review recent work that provides new insights into the timing, sequence, and spatial distribution of AMP-induced effects on bacterial cells. PMID:26691950

Contextual signals in visual cortex.

PubMed

Khan, Adil G; Hofer, Sonja B

2018-06-05

Vision is an active process. What we perceive strongly depends on our actions, intentions and expectations. During visual processing, these internal signals therefore need to be integrated with the visual information from the retina. The mechanisms of how this is achieved by the visual system are still poorly understood. Advances in recording and manipulating neuronal activity in specific cell types and axonal projections together with tools for circuit tracing are beginning to shed light on the neuronal circuit mechanisms of how internal, contextual signals shape sensory representations. Here we review recent work, primarily in mice, that has advanced our understanding of these processes, focusing on contextual signals related to locomotion, behavioural relevance and predictions. Copyright © 2018 Elsevier Ltd. All rights reserved.

Predictive role of computer simulation in assessing signaling pathways of crizotinib-treated A549 lung cancer cells.

PubMed

Xia, Pu; Mou, Fei-Fei; Wang, Li-Wei

2012-01-01

Non-small-cell lung cancer (NSCLC) is a leading cause of cancer deaths worldwide. Crizotinib has been approved by the U.S. Food and Drug Administration for the treatment of patients with advanced NSCLC. However, understanding of mechanisms of action is still limited. In our studies, we confirmed crizotinib-induced apoptosis in A549 lung cancer cells. In order to assess mechanisms, small molecular docking technology was used as a preliminary simulation of signaling pathways. Interesting, our results of experiments were consistent with the results of computer simulation. This indicates that small molecular docking technology should find wide use for its reliability and convenience.

Current Knowledge on Endocrine Disrupting Chemicals (EDCs) from Animal Biology to Humans, from Pregnancy to Adulthood: Highlights from a National Italian Meeting.

PubMed

Street, Maria Elisabeth; Angelini, Sabrina; Bernasconi, Sergio; Burgio, Ernesto; Cassio, Alessandra; Catellani, Cecilia; Cirillo, Francesca; Deodati, Annalisa; Fabbrizi, Enrica; Fanos, Vassilios; Gargano, Giancarlo; Grossi, Enzo; Iughetti, Lorenzo; Lazzeroni, Pietro; Mantovani, Alberto; Migliore, Lucia; Palanza, Paola; Panzica, Giancarlo; Papini, Anna Maria; Parmigiani, Stefano; Predieri, Barbara; Sartori, Chiara; Tridenti, Gabriele; Amarri, Sergio

2018-06-02

Wildlife has often presented and suggested the effects of endocrine disrupting chemicals (EDCs). Animal studies have given us an important opportunity to understand the mechanisms of action of many chemicals on the endocrine system and on neurodevelopment and behaviour, and to evaluate the effects of doses, time and duration of exposure. Although results are sometimes conflicting because of confounding factors, epidemiological studies in humans suggest effects of EDCs on prenatal growth, thyroid function, glucose metabolism and obesity, puberty, fertility, and on carcinogenesis mainly through epigenetic mechanisms. This manuscript reviews the reports of a multidisciplinary national meeting on this topic.

15 CFR 700.63 - Letters of Understanding.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Letters of Understanding. 700.63... DEFENSE PRIORITIES AND ALLOCATIONS SYSTEM Official Actions § 700.63 Letters of Understanding. (a) A Letter of Understanding is an official action which may be issued in resolving special priorities assistance...

Endocrine disrupting chemicals in fish: developing exposure indicators and predictive models of effects based on mechanism of action.

PubMed

Ankley, Gerald T; Bencic, David C; Breen, Michael S; Collette, Timothy W; Conolly, Rory B; Denslow, Nancy D; Edwards, Stephen W; Ekman, Drew R; Garcia-Reyero, Natalia; Jensen, Kathleen M; Lazorchak, James M; Martinović, Dalma; Miller, David H; Perkins, Edward J; Orlando, Edward F; Villeneuve, Daniel L; Wang, Rong-Lin; Watanabe, Karen H

2009-05-05

Knowledge of possible toxic mechanisms (or modes) of action (MOA) of chemicals can provide valuable insights as to appropriate methods for assessing exposure and effects, thereby reducing uncertainties related to extrapolation across species, endpoints and chemical structure. However, MOA-based testing seldom has been used for assessing the ecological risk of chemicals. This is in part because past regulatory mandates have focused more on adverse effects of chemicals (reductions in survival, growth or reproduction) than the pathways through which these effects are elicited. A recent departure from this involves endocrine-disrupting chemicals (EDCs), where there is a need to understand both MOA and adverse outcomes. To achieve this understanding, advances in predictive approaches are required whereby mechanistic changes caused by chemicals at the molecular level can be translated into apical responses meaningful to ecological risk assessment. In this paper we provide an overview and illustrative results from a large, integrated project that assesses the effects of EDCs on two small fish models, the fathead minnow (Pimephales promelas) and zebrafish (Danio rerio). For this work a systems-based approach is being used to delineate toxicity pathways for 12 model EDCs with different known or hypothesized toxic MOA. The studies employ a combination of state-of-the-art genomic (transcriptomic, proteomic, metabolomic), bioinformatic and modeling approaches, in conjunction with whole animal testing, to develop response linkages across biological levels of organization. This understanding forms the basis for predictive approaches for species, endpoint and chemical extrapolation. Although our project is focused specifically on EDCs in fish, we believe that the basic conceptual approach has utility for systematically assessing exposure and effects of chemicals with other MOA across a variety of biological systems.

Reafferent copies of imitated actions in the right superior temporal cortex

PubMed Central

Iacoboni, Marco; Koski, Lisa M.; Brass, Marcel; Bekkering, Harold; Woods, Roger P.; Dubeau, Marie-Charlotte; Mazziotta, John C.; Rizzolatti, Giacomo

2001-01-01

Imitation is a complex phenomenon, the neural mechanisms of which are still largely unknown. When individuals imitate an action that already is present in their motor repertoire, a mechanism matching the observed action onto an internal motor representation of that action should suffice for the purpose. When one has to copy a new action, however, or to adjust an action present in one's motor repertoire to a different observed action, an additional mechanism is needed that allows the observer to compare the action made by another individual with the sensory consequences of the same action made by himself. Previous experiments have shown that a mechanism that directly matches observed actions on their motor counterparts exists in the premotor cortex of monkeys and humans. Here we report the results of functional magnetic resonance experiments, suggesting that in the superior temporal sulcus, a higher order visual region, there is a sector that becomes active both during hand action observation and during imitation even in the absence of direct vision of the imitator's hand. The motor-related activity is greater during imitation than during control motor tasks. This newly identified region has all the requisites for being the region at which the observed actions, and the reafferent motor-related copies of actions made by the imitator, interact. PMID:11717457

Understanding avoidant leadership in health care: findings from a secondary analysis of two qualitative studies.

PubMed

Jackson, Debra; Hutchinson, Marie; Peters, Kath; Luck, Lauretta; Saltman, Deborah

2013-04-01

To illuminate ways that avoidant leadership can be enacted in contemporary clinical settings. Avoidance is identified in relation to laissez-faire leadership and passive avoidant leadership. However, the nature and characteristics of avoidance and how it can be enacted in a clinical environment are not detailed. This paper applied secondary analysis to data from two qualitative studies. We have identified three forms of avoidant leader response: placating avoidance, where leaders affirmed concerns but abstained from action; equivocal avoidance, where leaders were ambivalent in their response; and hostile avoidance, where the failure of leaders to address concerns escalated hostility towards the complainant. Through secondary analysis of two existing sets of data, we have shed new light on avoidant leaderships and how it can be enacted in contemporary clinical settings. Further work needs to be undertaken to better understand this leadership style. We recommend that organizations ensure that all nurse leaders are aware of how best to respond to concerns of wrongdoing and that mechanisms are created to ensure timely feedback is provided about the actions taken. © 2012 Blackwell Publishing Ltd.

Non-Accidental Health Impacts of Wildfire Smoke

PubMed Central

Youssouf, Hassani; Liousse, Catherine; Roblou, Laurent; Assamoi, Eric-Michel; Salonen, Raimo O.; Maesano, Cara; Banerjee, Soutrik; Annesi-Maesano, Isabella

2014-01-01

Wildfires take a heavy toll on human health worldwide. Climate change may increase the risk of wildfire frequency. Therefore, in view of adapted preventive actions, there is an urgent need to further understand the health effects and public awareness of wildfires. We conducted a systematic review of non-accidental health impacts of wildfire and incorporated lessons learned from recent experiences. Based on the literature, various studies have established the relationship between one of the major components of wildfire, particulate matter (particles with diameter less than 10 µm (PM10) and less than 2.5 µm (PM2.5)) and cardiorespiratory symptoms in terms of Emergency Rooms visits and hospital admissions. Associations between wildfire emissions and various subclinical effects have also been established. However, few relationships between wildfire emissions and mortality have been observed. Certain segments of the population may be particularly vulnerable to smoke-related health risks. Among them, people with pre-existing cardiopulmonary conditions, the elderly, smokers and, for professional reasons, firefighters. Potential action mechanisms have been highlighted. Overall, more research is needed to better understand health impact of wildfire exposure. PMID:25405597

Non-accidental health impacts of wildfire smoke.

PubMed

Youssouf, Hassani; Liousse, Catherine; Roblou, Laurent; Assamoi, Eric-Michel; Salonen, Raimo O; Maesano, Cara; Banerjee, Soutrik; Annesi-Maesano, Isabella

2014-11-14

Wildfires take a heavy toll on human health worldwide. Climate change may increase the risk of wildfire frequency. Therefore, in view of adapted preventive actions, there is an urgent need to further understand the health effects and public awareness of wildfires. We conducted a systematic review of non-accidental health impacts of wildfire and incorporated lessons learned from recent experiences. Based on the literature, various studies have established the relationship between one of the major components of wildfire, particulate matter (particles with diameter less than 10 µm (PM10) and less than 2.5 µm (PM2.5)) and cardiorespiratory symptoms in terms of Emergency Rooms visits and hospital admissions. Associations between wildfire emissions and various subclinical effects have also been established. However, few relationships between wildfire emissions and mortality have been observed. Certain segments of the population may be particularly vulnerable to smoke-related health risks. Among them, people with pre-existing cardiopulmonary conditions, the elderly, smokers and, for professional reasons, firefighters. Potential action mechanisms have been highlighted. Overall, more research is needed to better understand health impact of wildfire exposure.

Structural and molecular brain sexual differences: A tool to understand sex differences in health and disease.

PubMed

Panzica, GianCarlo; Melcangi, Roberto C

2016-08-01

Sex differences are present both in the genotype and in the phenotype of all vertebrates, and they have been evidenced also within the central and peripheral nervous system. Earlier studies on brain sex differences suggested a relatively simple view based on (1) the presence of sexually dimorphic circuits in the hypothalamus (or in regions related to reproductive behaviors), (2) the action of gonadal hormones to masculinize the brain, and (3) the gonadal steroids' action to modulate gene transcription through nuclear receptors. These assumptions are today contradicted by the findings accumulated in the last 20 years. We know now that mechanisms determining sexual dimorphisms may vary according to location and species, and may involve several factors, as genes, epigenetic factors, gonadal hormones and neurosteroids. Sex differences were also revealed by epidemiological studies in several neural pathologies. This suggests that the approach to understand the genesis of these pathologies, should involve specific attention to interactions among genes, gonadal and brain-born steroid hormones, epigenetic and environmental factors. Copyright © 2016 Elsevier Ltd. All rights reserved.

Endogenous Modulators and Pharmacological Inhibitors of Histone Deacetylases in Cancer Therapy

PubMed Central

Spiegel, Sarah; Milstien, Sheldon; Grant, Steven

2012-01-01

The class I histone deacetylases HDAC1 and HDAC2 belong to a family of 11 zinc-dependent human HDACs and are overexpressed in many cancers. Inhibitors of these HDACs now in clinical trials show activity against several types of cancers. This review is focuse on recent advances in both clinical and preclinical efforts to understand the basis for HDACi actions, with an emphasis on implications for rational combinations with conventional or other targeted agents. We will address new perspectives on the molecular mechanisms by which HDACs act and how these actions relate to cancer. We will also review new evidence demonstrating that HDACs are direct intracellular targets of the potent sphingolipid mediator sphingosine-1-phosphate (S1P), the first identified endogenous nuclear regulator of these enzymes, linking sphingolipid metabolism in the nucleus to remodeling of chromatin and epigenetic regulation of gene expression. Understanding how endogenous molecules regulate HDAC activity in vivo may facilitate the search for safer and more effective anti-cancer drugs capable of interfering with HDAC functions in a highly specific manner. PMID:21725353

Nonthermal effects of therapeutic ultrasound: the frequency resonance hypothesis.

PubMed

Johns, Lennart D

2002-07-01

To present the frequency resonance hypothesis, a possible mechanical mechanism by which treatment with non-thermal levels of ultrasound stimulates therapeutic effects. The review encompasses a 4-decade history but focuses on recent reports describing the effects of nonthermal therapeutic levels of ultrasound at the cellular and molecular levels. A search of MEDLINE from 1965 through 2000 using the terms ultrasound and therapeutic ultrasound. The literature provides a number of examples in which exposure of cells to therapeutic ultrasound under nonthermal conditions modified cellular functions. Nonthermal levels of ultrasound are reported to modulate membrane properties, alter cellular proliferation, and produce increases in proteins associated with inflammation and injury repair. Combined, these data suggest that nonthermal effects of therapeutic ultrasound can modify the inflammatory response. The concept of the absorption of ultrasonic energy by enzymatic proteins leading to changes in the enzymes activity is not novel. However, recent reports demonstrating that ultrasound affects enzyme activity and possibly gene regulation provide sufficient data to present a probable molecular mechanism of ultrasound's nonthermal therapeutic action. The frequency resonance hypothesis describes 2 possible biological mechanisms that may alter protein function as a result of the absorption of ultrasonic energy. First, absorption of mechanical energy by a protein may produce a transient conformational shift (modifying the 3-dimensional structure) and alter the protein's functional activity. Second, the resonance or shearing properties of the wave (or both) may dissociate a multimolecular complex, thereby disrupting the complex's function. This review focuses on recent studies that have reported cellular and molecular effects of therapeutic ultrasound and presents a mechanical mechanism that may lead to a better understanding of how the nonthermal effects of ultrasound may be therapeutic. Moreover, a better understanding of ultrasound's mechanical mechanism could lead to a better understanding of how and when ultrasound should be employed as a therapeutic modality.

Proteomic and metallomic strategies for understanding the mode of action of anticancer metallodrugs.

PubMed

Gabbiani, Chiara; Magherini, Francesca; Modesti, Alessandra; Messori, Luigi

2010-05-01

Since the discovery of cisplatin and its introduction in the clinics, metal compounds have been intensely investigated in view of their possible application in cancer therapy. In this frame, a deeper understanding of their mode of action, still rather obscure, might turn crucial for the design and the obtainment of new and better anticancer agents. Due to the extreme complexity of the biological systems, it is now widely accepted that innovative and information-rich methods are absolutely needed to afford such a goal. Recently, both proteomic and metallomic strategies were successfully implemented for the elucidation of specific mechanistic features of anticancer metallodrugs within an innovative "Systems Biology" perspective. Particular attention was paid to the following issues: i) proteomic studies of the molecular basis of platinum resistance; ii) proteomic analysis of cellular responses to cytotoxic metallodrugs; iii) metallomic studies of the transformation and fate of metallodrugs in cellular systems. Notably, those pioneering studies, that are reviewed here, allowed a significant progress in the understanding of the molecular mechanisms of metal based drugs at the cellular level. A further extension of those studies and a closer integration of proteomic and metallomic strategies and technologies might realistically lead to rapid and significant advancements in the mechanistic knowledge of anticancer metallodrugs.

Safety of diabetes drugs in patients with heart failure.

PubMed

Carrasco-Sánchez, F J; Ostos-Ruiz, A I; Soto-Martín, M

2018-03-01

Heart failure (HF) and diabetes mellitus are 2 clinical conditions that often coexist, particularly in patients older than 65 years. Diabetes mellitus promotes the development of HF and confers a poorer prognosis. Hypoglycaemic agents (either by their mechanism of action, hypoglycaemic action or adverse effects) can be potentially dangerous for patients with HF. In this study, we performed a review of the available evidence on the safety of diabetes drugs in HF, focused on the main observational and experimental studies. Recent studies on cardiovascular safety have evaluated, although as a secondary objective, the impact of new hypoglycaemic agents on HF, helping us understand the neutrality, risks and potential benefits of these agents. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Actions of Acute and Chronic Ethanol on Presynaptic Terminals

PubMed Central

Roberto, Marisa; Treistman, Steven N.; Pietrzykowski, Andrzej Z.; Weiner, Jeff; Galindo, Rafael; Mameli, Manuel; Valenzuela, Fernando; Zhu, Ping Jun; Lovinger, David; Zhang, Tao A.; Hendricson, Adam H.; Morrisett, Richard; Siggins, George Robert

2014-01-01

This article presents the proceedings of a symposium entitled “The Tipsy Terminal: Presynaptic Effects of Ethanol” (held at the annual meeting of the Research Society on Alcoholism, in Santa Barbara, CA, June 27, 2005). The objective of this symposium was to focus on a cellular site of ethanol action underrepresented in the alcohol literature, but quickly becoming a “hot” topic. The chairs of the session were Marisa Roberto and George Robert Siggins. Our speakers were chosen on the basis of the diverse electrophysiological and other methods used to discern the effects of acute and chronic ethanol on presynaptic terminals and on the basis of significant insights that their data provide for understanding ethanol actions on neurons in general, as mechanisms underlying problematic behavioral effects of alcohol. The 5 presenters drew from their recent studies examining the effects of acute and chronic ethanol using a range of sophisticated methods from electrophysiological analysis of paired-pulse facilitation and spontaneous and miniature synaptic currents (Drs. Weiner, Valenzuela, Zhu, and Morrisett), to direct recording of ion channel activity and peptide release from acutely isolated synaptic terminals (Dr. Treistman), to direct microscopic observation of vesicular release (Dr. Morrisett). They showed that ethanol administration could both increase and decrease the probability of release of different transmitters from synaptic terminals. The effects of ethanol on synaptic terminals could often be correlated with important behavioral or developmental actions of alcohol. These and other novel findings suggest that future analyses of synaptic effects of ethanol should attempt to ascertain, in multiple brain regions, the role of presynaptic terminals, relevant presynaptic receptors and signal transduction linkages, exocytotic mechanisms, and their involvement in alcohol’s behavioral actions. Such studies could lead to new treatment strategies for alcohol intoxication, alcohol abuse, and alcoholism. PMID:16441271

Computerized approaches to enhance understanding of organic reaction mechanisms: CAN reaction mechanisms and CPLEX prelaboratory methodology

NASA Astrophysics Data System (ADS)

Al-Shammari, Abdulrahman G. Alhamzani

2008-10-01

Two approaches to enhance the understanding of organic reaction mechanisms are described. First, a new method for teaching organic reaction mechanisms that can be used in a Computer-Assisted Instruction (CAI) environment is proposed and tested (Chapter 1). The method concentrates upon the important intermediate structures, which are assumed to be on the reaction coordinate, and which can be evaluated and graded by currently available computer techniques. At the same time, the "curved arrows" that show the electron flow in a reaction mechanism are neglected, since they cannot be evaluated and graded with currently available computer techniques. By allowing student practice for learning organic reaction mechanisms using the Curved Arrow Neglect (CAN) method within a "Practice Makes Perfect" CAI method, student performance in the drawing of traditional reaction mechanisms, in which students had to include the "curved arrows" on their written classroom exams, was significantly enhanced. Second, computerized prelaboratory experiments (CPLEX) for organic chemistry laboratory 1 & 2 courses have been created, used, and evaluated (Chapters 2 and 3). These computerized prelabs are unique because they combine both "dry lab" actions with detailed animations of the actual chemistry occurring at the molecular level. The "dry lab" serves to simulate the actual physical manipulations of equipment and chemicals that occur in the laboratory experiment through the use of drag-and-drop computer technology. At the same time, these physical actions are accompanied on a separate part of the computer screen by animations showing the chemistry at the molecular level that is occurring in the experiment. These CPLEX modules were made into Internet accessible modules. The students were allowed to access the CPLEX modules prior to performing the actual laboratory experiment. A detailed evaluation of students' perception of the modules was accomplished via survey methodology during the entire implementation process over the course of three semesters. Results of the survey data indicate that students thought that they better understood the chemical principles and procedures of the laboratory experiment. Interestingly, students prefer the CPLEX prelaboratory materials, compared to the traditional textbooks, by a wide margin (Chapter 2). The utility of CPLEX was further demonstrated by enabling a study of the effectiveness of animated reaction mechanisms to promote student learning. While most instructors believe that animated mechanisms aid student understanding of reactions, there has been no quantitative data to-date to support this view. In this work, a quantitative study, using an experimental/control group study, was conducted to provide data on the effectiveness of animated reaction mechanisms to promote student learning. Analysis of student answers, using an appropriate rubric, demonstrated that there was a statistically significant improvement in students' scores in the mechanistic question of a pre-laboratory quiz in the post-treatment results of the experimental group which had had access to the animated reaction mechanisms (Chapter 3).

The Role of AhR in Autoimmune Regulation and Its Potential as a Therapeutic Target against CD4 T Cell Mediated Inflammatory Disorder

PubMed Central

Zhu, Conghui; Xie, Qunhui; Zhao, Bin

2014-01-01

AhR has recently emerged as a critical physiological regulator of immune responses affecting both innate and adaptive systems. Since the AhR signaling pathway represents an important link between environmental stimulators and immune-mediated inflammatory disorder, it has become the object of great interest among researchers recently. The current review discusses new insights into the mechanisms of action of a select group of inflammatory autoimmune diseases and the ligand-activated AhR signaling pathway. Representative ligands of AhR, both exogenous and endogenous, are also reviewed relative to their potential use as tools for understanding the role of AhR and as potential therapeutics for the treatment of various inflammatory autoimmune diseases, with a focus on CD4 helper T cells, which play important roles both in self-immune tolerance and in inflammatory autoimmune diseases. Evidence indicating the potential use of these ligands in regulating inflammation in various diseases is highlighted, and potential mechanisms of action causing immune system effects mediated by AhR signaling are also discussed. The current review will contribute to a better understanding of the role of AhR and its signaling pathway in CD4 helper T cell mediated inflammatory disorder. Considering the established importance of AhR in immune regulation and its potential as a therapeutic target, we also think that both further investigation into the molecular mechanisms of immune regulation that are mediated by the ligand-specific AhR signaling pathway, and integrated research and development of new therapeutic drug candidates targeting the AhR signaling pathway should be pursued urgently. PMID:24905409

Aberrant dopamine D2-like receptor function in a rodent model of schizophrenia.

PubMed

Perez, Stephanie M; Lodge, Daniel J

2012-11-01

Based on the observation that antipsychotic medications display antagonist properties at dopamine D2-like receptors, aberrant dopamine signaling has been proposed to underlie psychosis in patients with schizophrenia. Thus, it is not surprising that considerable research has been devoted to understanding the mechanisms involved in the antipsychotic action of these compounds. It is important to note that the majority of these studies have been performed in "normal" experimental animals. Given that these animals do not possess the aberrant neuronal information processing typically associated with schizophrenia, the aim of the current study was to examine the dopamine D2 receptor system in a rodent model of schizophrenia. Here, we demonstrate that methylazoxymethanol acetate (MAM)-treated rats display an enhanced effect of quinpirole on dopamine neuron activity and an aberrant locomotor response to D2-like receptor activation, suggesting changes in postsynaptic D2-like receptor function. To better understand the mechanisms underlying the enhanced response to D2-like ligands in MAM-treated rats, we examined the expression of D2, D3, and dopamine transporter mRNA in the nucleus accumbens and ventral tegmental area by quantitative reverse transcription-polymerase chain reaction. MAM-treated rats displayed a significant increase in dopamine D3 receptor mRNA expression in the nucleus accumbens with no significant changes in the expression of the D2 receptor. Taken together, these data demonstrate robust alterations in dopamine D2-like receptor function in a rodent model of schizophrenia and provide evidence that preclinical studies examining the mechanisms of antipsychotic drug action should be performed in animal models that mirror aspects of the abnormal neuronal transmission thought to underlie symptoms of schizophrenia.

Toward a better understanding of the lignin isolation process from wood.

PubMed

Guerra, Anderson; Filpponen, Ilari; Lucia, Lucian A; Saquing, Carl; Baumberger, Stephanie; Argyropoulos, Dimitris S

2006-08-09

The recently developed protocol for isolating enzymatic mild acidolysis lignins (EMAL) coupled with the novel combination of derivatization followed by reductive cleavage (DFRC) and quantitative (31)P NMR spectroscopy were used to better understand the lignin isolation process from wood. The EMAL protocol is shown to offer access at lignin samples that are more representative of the overall lignin present in milled wood. The combination of DFRC/(31)P NMR provided a detailed picture on the effects of the isolation conditions on the lignin structure. More specifically, we have used vibratory and ball milling as the two methods of wood pulverization and have compared their effects on the lignin structures and molecular weights. Vibratory-milling conditions cause substantial lignin depolymerization. Lignin depolymerization occurs via the cleavage of uncondensed beta-aryl ether linkages, while condensed beta-aryl ethers and dibenzodioxocins were found to be resistant to such mechanical action. Condensation and side chain oxidations were induced mechanochemically under vibratory-milling conditions as evidenced by the increased amounts of condensed phenolic hydroxyl and carboxylic acid groups. Alternatively, the mild mechanical treatment offered by ball milling was found not to affect the isolated lignin macromolecular structure. However, the overall lignin yields were found to be compromised when the mechanical action was less intense, necessitating longer milling times under ball-milling conditions. As compared to other lignin preparations isolated from the same batch of milled wood, the yield of EMAL was about four times greater than the corresponding milled wood lignin (MWL) and about two times greater as compared to cellulolytic enzyme lignin (CEL). Molecular weight distribution analyses also pointed out that the EMAL protocol allows the isolation of lignin fractions that are not accessed by any other lignin isolation procedures.

Bacterial genome engineering and synthetic biology: combating pathogens.

PubMed

Krishnamurthy, Malathy; Moore, Richard T; Rajamani, Sathish; Panchal, Rekha G

2016-11-04

The emergence and prevalence of multidrug resistant (MDR) pathogenic bacteria poses a serious threat to human and animal health globally. Nosocomial infections and common ailments such as pneumonia, wound, urinary tract, and bloodstream infections are becoming more challenging to treat due to the rapid spread of MDR pathogenic bacteria. According to recent reports by the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC), there is an unprecedented increase in the occurrence of MDR infections worldwide. The rise in these infections has generated an economic strain worldwide, prompting the WHO to endorse a global action plan to improve awareness and understanding of antimicrobial resistance. This health crisis necessitates an immediate action to target the underlying mechanisms of drug resistance in bacteria. The advent of new bacterial genome engineering and synthetic biology (SB) tools is providing promising diagnostic and treatment plans to monitor and treat widespread recalcitrant bacterial infections. Key advances in genetic engineering approaches can successfully aid in targeting and editing pathogenic bacterial genomes for understanding and mitigating drug resistance mechanisms. In this review, we discuss the application of specific genome engineering and SB methods such as recombineering, clustered regularly interspaced short palindromic repeats (CRISPR), and bacterial cell-cell signaling mechanisms for pathogen targeting. The utility of these tools in developing antibacterial strategies such as novel antibiotic production, phage therapy, diagnostics and vaccine production to name a few, are also highlighted. The prevalent use of antibiotics and the spread of MDR bacteria raise the prospect of a post-antibiotic era, which underscores the need for developing novel therapeutics to target MDR pathogens. The development of enabling SB technologies offers promising solutions to deliver safe and effective antibacterial therapies.

Role and mechanism of action of Sclerostin in bone

PubMed Central

Delgado-Calle, Jesus; Sato, Amy Y.; Bellido, Teresita

2016-01-01

After discovering that lack of Sost/sclerostin expression is the cause of the high bone mass human syndromes Van Buchem disease and sclerosteosis, extensive animal experimentation and clinical studies demonstrated that sclerostin plays a critical role in bone homeostasis and that its deficiency or pharmacological neutralization increases bone formation. Dysregulation of sclerostin expression also underlies the pathophysiology of skeletal disorders characterized by loss of bone mass as well as the damaging effects of some cancers in bone. Thus, sclerostin has quickly become a promising molecular target for the treatment of osteoporosis and other skeletal diseases, and beneficial skeletal outcomes are observed in animal studies and clinical trials using neutralizing antibodies against sclerostin. However, the anabolic effect of blocking sclerostin decreases with time, bone mass accrual is also accompanied by anti-catabolic effects, and there is bone loss over time after therapy discontinuation. Further, the cellular source of sclerostin in the bone/bone marrow microenvironment under physiological and pathological conditions, the pathways that regulate sclerostin expression and the mechanisms by which sclerostin modulates the activity of osteocytes, osteoblasts, and osteoclasts remain unclear. In this review, we highlight the current knowledge on the regulation of Sost/sclerotin expression and its mechanism(s) of action, discuss novel observations regarding its role in signaling pathways activated by hormones and mechanical stimuli in bone, and propose future research needed to understand the full potential of therapeutic interventions that modulate Sost/sclerostin expression. PMID:27742498

Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action.

PubMed

Wong, Yin Kwan; Xu, Chengchao; Kalesh, Karunakaran A; He, Yingke; Lin, Qingsong; Wong, W S Fred; Shen, Han-Ming; Wang, Jigang

2017-11-01

Artemisinin and its derivatives (collectively termed as artemisinins) are among the most important and effective antimalarial drugs, with proven safety and efficacy in clinical use. Beyond their antimalarial effects, artemisinins have also been shown to possess selective anticancer properties, demonstrating cytotoxic effects against a wide range of cancer types both in vitro and in vivo. These effects appear to be mediated by artemisinin-induced changes in multiple signaling pathways, interfering simultaneously with multiple hallmarks of cancer. Great strides have been taken to characterize these pathways and to reveal their anticancer mechanisms of action of artemisinin. Moreover, encouraging data have also been obtained from a limited number of clinical trials to support their anticancer property. However, there are several key gaps in knowledge that continue to serve as significant barriers to the repurposing of artemisinins as effective anticancer agents. This review focuses on important and emerging aspects of this field, highlighting breakthroughs in unresolved questions as well as novel techniques and approaches that have been taken in recent studies. We discuss the mechanism of artemisinin activation in cancer, novel and significant findings with regards to artemisinin target proteins and pathways, new understandings in artemisinin-induced cell death mechanisms, as well as the practical issues of repurposing artemisinin. We believe these will be important topics in realizing the potential of artemisinin and its derivatives as safe and potent anticancer agents. © 2017 Wiley Periodicals, Inc.

Revisiting Theories of Humidity Transduction: A Focus on Electrophysiological Data.

PubMed

Tichy, Harald; Hellwig, Maria; Kallina, Wolfgang

2017-01-01

Understanding the mechanism of humidity transduction calls for experimental data and a theory to interpret the data and design new experiments. A comprehensive theory of humidity transduction must start with agreement on what humidity parameters are measured by hygroreceptors and processed by the brain. Hygroreceptors have been found in cuticular sensilla of a broad range of insect species. Their structural features are far from uniform. Nevertheless, these sensilla always contain an antagonistic pair of a moist cell and a dry cell combined with a thermoreceptive cold cell. The strategy behind this arrangement remains unclear. Three main models of humidity transduction have been proposed. Hygroreceptors could operate as mechanical hygrometers, psychrometers or evaporation detectors. Each mode of action measures a different humidity parameter. Mechanical hygrometers measure the relative humidity, psychrometers indicate the wet-bulb temperature, and evaporimeters refer to the saturation deficit of the air. Here we assess the validity of the different functions by testing specific predictions drawn from each of the models. The effect of air temperature on the responses to humidity stimulation rules out the mechanical hygrometer function, but it supports the psychrometer function and highlights the action as evaporation rate detector. We suggest testing the effect of the flow rate of the air stream used for humidity stimulation. As the wind speed strongly affects the power of evaporation, experiments with changing saturation deficit at different flow rates would improve our knowledge on humidity transduction.

Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction.

PubMed

Belin, David; Jonkman, Sietse; Dickinson, Anthony; Robbins, Trevor W; Everitt, Barry J

2009-04-12

In this review we discuss the evidence that drug addiction, defined as a maladaptive compulsive habit, results from the progressive subversion by addictive drugs of striatum-dependent operant and Pavlovian learning mechanisms that are usually involved in the control over behaviour by stimuli associated with natural reinforcement. Although mainly organized through segregated parallel cortico-striato-pallido-thalamo-cortical loops involved in motor or emotional functions, the basal ganglia, and especially the striatum, are key mediators of the modulation of behavioural responses, under the control of both action-outcome and stimulus-response mechanisms, by incentive motivational processes and Pavlovian associations. Here we suggest that protracted exposure to addictive drugs recruits serial and dopamine-dependent, striato-nigro-striatal ascending spirals from the nucleus accumbens to more dorsal regions of the striatum that underlie a shift from action-outcome to stimulus-response mechanisms in the control over drug seeking. When this progressive ventral to dorsal striatum shift is combined with drug-associated Pavlovian influences from limbic structures such as the amygdala and the orbitofrontal cortex, drug seeking behaviour becomes established as an incentive habit. This instantiation of implicit sub-cortical processing of drug-associated stimuli and instrumental responding might be a key mechanism underlying the development of compulsive drug seeking and the high vulnerability to relapse which are hallmarks of drug addiction.

What does the electroencephalogram tell us about the mechanisms of action of ECT in major depressive disorders?

PubMed

Farzan, Faranak; Boutros, Nash N; Blumberger, Daniel M; Daskalakis, Zafiris J

2014-06-01

Electroconvulsive therapy (ECT) remains to be one of the most effective treatment options in treatment-resistant major depressive disorder (MDD). From the early days, researchers have embarked on extracting information from electroencephalography (EEG) recordings before, during, and after ECT to identify neurophysiological targets of ECT and discover EEG predictors of response to ECT in patients with MDD. In this article, we provide an overview of visually detected and quantitative EEG features that could help in furthering our understanding of the mechanisms of action of ECT in MDD. We further discuss the EEG findings in the context of postulated hypotheses of ECT therapeutic pathways. We introduce an alternative and unifying hypothesis suggesting that ECT may exert its therapeutic efficacy through resetting the aberrant functional connectivity and promoting the generation of new and healthy connections in brain regions implicated in MDD pathophysiology, a mechanism that may be in part mediated by the ECT-induced activation of inhibitory and neuroplasticity mechanisms. We further discuss the added value of EEG markers in the larger context of ECT research and as complementary to neuroimaging and genetic markers. We conclude by drawing attention to the need for longitudinal studies in large cohort of patients and the need for standardization and validation of EEG algorithms of functional connectivity across studies to facilitate the translation of EEG correlates of ECT response in routine clinical practice.