The role of ventral premotor cortex in action execution and action understanding

The human ventral premotor cortex overlaps, at least in part, with Broca's region in the dominant cerebral hemisphere, that is known to mediate the production of language and contributes to language comprehension. This region is constituted of Brodmann's areas 44 and 45 in the inferior frontal gyrus. We summarize the evidence that the motor related part of Broca's region is localized in the opercular portion of the inferior frontal cortex, mainly in area 44 of Brodmann. According to our own data, there seems to be a homology between Brodmann area 44 in humans and the monkey area F5. The non-language related motor functions of Broca's region comprise complex hand movements, associative sensorimotor learning and sensorimotor integration. Brodmann's area 44 is also a part of a specialized parieto-premotor network and interacts significantly with the neighbouring premotor areas. In the ventral premotor area F5 of monkeys, the so called mirror neurons have been found which discharge both when the animal performs a goal-directed hand action and when it observes another individual performing the same or a similar action. More recently, in the same area mirror neurons responding not only to the observation of mouth actions, but also to sounds characteristic to actions have been found. In humans, through an fMRI study, it has been shown that the observation of actions performed with the hand, the mouth and the foot leads to the activation of different sectors of Broca's area and premotor cortex, according to the effector involved in the observed action, following a somatotopic pattern which resembles the classical motor cortex homunculus. On the other hand the evidence is growing that human ventral premotor cortex, especially Brodmann's area 44, is involved in polymodal action processing. These results strongly support the existence of an execution-observation matching system (mirror neuron system). It has been proposed that this system is involved in polymodal action recognition and might represent a precursor of language processing. Experimental evidence in favour of this hypothesis both in the monkey and humans is shortly reviewed.     

Molecular understanding of aminoglycoside action and resistance

Aminoglycosides are potent bactericidal antibiotics targeting the bacterial ribosome, where they bind to the A-site and disrupt protein synthesis. They are particularly active against aerobic, Gram-negative bacteria and act synergistically against certain Gram-positive organisms. Aminoglycosides are used in the treatment of severe infections of the abdomen and urinary tract, bacteremia, and endocarditis. They are also used for prophylaxis, especially against endocarditis. Bacterial resistance to aminoglycosides continues to escalate and is widely recognized as a serious health threat. This might be the reason for the interest in understanding the mechanisms of resistance. It is now clear that the resistance occurs by different mechanisms such as prevention of drug entry, active extrusion of drugs, alteration of the drug target (mutational modification of 16S rRNA and mutational modification of ribosomal proteins), and enzymatic inactivation through the expression of enzymes, which covalently modify these antibiotics. Enzymatic inactivation is normally due to acetyltransferases, nucleotidyltransferases, and phosphotransferases. In this review, we focus on the recent concept of molecular understanding of aminoglycoside action and resistance.     

Mirroring and the development of action understanding

The discovery of mirror neurons in the monkey motor cortex has inspired wide-ranging hypotheses about the potential relationship between action control and social cognition. In this paper, we consider the hypothesis that this relationship supports the early development of a critical aspect of social understanding, the ability to analyse others’ actions in terms of goals. Recent investigations of infant action understanding have revealed rich connections between motor development and the analysis of goals in others’ actions. In particular, infants’ own goal-directed actions influence their analysis of others’ goals. This evidence indicates that the cognitive systems that drive infants’ own actions contribute to their analysis of goals in others’ actions. These effects occur at a relatively abstract level of analysis both in terms of the structure infants perceive in others’ actions and relevant structure in infants’ own actions. Although the neural bases of these effects in infants are not yet well understood, current evidence indicates that connections between action production and action perception in infancy involve the interrelated neural systems at work in generating planned, intelligent action.     

Approaches to understanding auxin action

The effects of auxin on plant growth and development have been studied for decades, but the molecular mechanisms of auxin action remain unknown. These mechanisms have primarily been investigated by characterization of auxin physiology mutants and analysis of auxin-binding proteins and auxin-regulated genes. These efforts are now converging, since some mutants have recently been shown to have altered expression of specific auxin-binding proteins and auxin-regulated genes. The features of these proteins and genes are providing the first tantalizing clues to the organization of auxin signal transduction pathways.     

Investigating action understanding: inferential processes versus action simulation

In our daily life, we continuously monitor others' behaviors and interpret them in terms of goals, intentions, and reasons. Despite their central importance for predicting and interpreting each other's actions, the functional mechanisms and neural circuits involved in action understanding remain highly controversial. Two alternative accounts have been advanced. Simulation theory assumes that we understand actions by simulating the observed behavior through a direct matching process that activates the mirror-neuron circuit. The alternative interpretive account assumes that action understanding is based on specialized inferential processes activating brain areas with no mirror properties. Although both approaches recognize the central role of contextual information in specifying action intentions, their respective accounts of this process differ in significant respects. Here, we investigated the role of context in action understanding by using functional brain imaging while participants observed an unusual action in implausible versus plausible contexts. We show that brain areas that are part of a network involved in inferential interpretive processes of rationalization and mentalization but that lack mirror properties are more active when the action occurs in an implausible context. However, no differential activation was found in the mirror network. Our findings support the assumption that action understanding in novel situations is primarily mediated by an inferential interpretive system rather than the mirror system.     

Complementary systems for understanding action intentions

How humans understand the intention of others' actions remains controversial. Some authors have suggested that intentions are recognized by means of a motor simulation of the observed action with the mirror-neuron system [1-3]. Others emphasize that intention recognition is an inferential process, often called "mentalizing" or employing a "theory of mind," which activates areas well outside the motor system [4-6]. Here, we assessed the contribution of brain regions involved in motor simulation and mentalizing for understanding action intentions via functional brain imaging. Results show that the inferior frontal gyrus (part of the mirror-neuron system) processes the intentionality of an observed action on the basis of the visual properties of the action, irrespective of whether the subject paid attention to the intention or not. Conversely, brain areas that are part of a "mentalizing" network become active when subjects reflect about the intentionality of an observed action, but they are largely insensitive to the visual properties of the observed action. This supports the hypothesis that motor simulation and mentalizing have distinct but complementary functions for the recognition of others' intentions.     

A neurocognitive model for understanding treatment action in depression

The way in which emotion is represented and processed in the human brain is an expanding area of research and has key implications for how we understand and potentially treat affective disorders such as depression. Characterizing the effects of pharmacological manipulations of key neurotransmitter systems can also help reveal the neurochemical underpinnings of emotional processing and how common antidepressant drugs may work in the treatment of depression and anxiety. This approach has revealed that depression is associated with both neural and behavioural biases towards negative over positive stimuli. Evidence from pharmacological challenge studies suggests that antidepressant treatment acts to normalize these biases early on in treatment, resulting in patients experiencing the world in a more positive way, improving their mood over time. This model is supported by evidence from both pharmacological and non-pharmacological interventions. The unique perspective on antidepressant treatment offered by this approach provides some insights into individual response to treatment, as well as novel approaches to drug development.     

Functionally referential communication in a chimpanzee

The evolutionary origins of the use of speech signals to refer to events or objects in the world have remained obscure. Although functionally referential calls have been described in some monkey species, studies with our closest living relatives, the great apes, have not generated comparable findings. These negative results have been taken to suggest that ape vocalizations are not the product of their otherwise sophisticated mentality and that ape gestural communication is more informative for theories of language evolution. We tested whether chimpanzee rough grunts, which are produced during feeding contexts, functioned as referential signals. Individuals produced acoustically distinct types of "rough grunts" when encountering different foods. In a naturalistic playback experiment, a focal subject was able to use the information conveyed by these calls produced by several group mates to guide his search for food, demonstrating that the different grunt types were meaningful to him. This study provides experimental evidence that our closest living relatives can produce and understand functionally referential calls as part of their natural communication. We suggest that these findings give support to the vocal rather than gestural theories of language evolution.     

Use of models in understanding the mechanism of action of haemoglobin

Models with three, four and eight salt-bridges have been used to study the mechanism of action of haemoglobin. Both side chains forming a salt-bridge, i.e. the proton acceptor and the proton donor, are postulated to change pK on ligation of oxygen. The eight salt-bridge model is able to predict, as a unified theory, both the degree of oxygenation and the Bohr effect at any PH and p_O2 value; this has not been done by any other published model. The predicted pK values for the Borh groups corresponde well with those measured experiemntally. This model predicts the pK values of those side chains responsible for the acid Bohr effect, suggesting that these correspond to the proton acceptors of the salt-bridges. The model also fulfils the condition of linearity between the fractional degree of oxygenation and fractional number of protons released. It is postulated that there is a gradual change in structure on going from deoxy to oxyhaemoglobin, due to the rupture of salt-bridges. The path folowed during this process will be both pH and p_O2 dependent. A formula describing the number of intact or broken salt-bridges as a function of pH and p_O2 was developed. This formula shows that the fractional number of broken salt-bridges reaches a minimum value of 0.2 at around pH 6.3 in the absence of oxygen. However, if oxygen is added, this fractional number approaches 1.0 soon after the partial pressure of oxygen goes above 40 mm Hg.     

Pyruvate decarboxylating action of L-cycloserine. The significance of this in understanding its metabolic inhibitory action

We present evidence which demonstrates that L-cycloserine, structural analog of L-alanine, which is known to be an effective aminotransferase inhibitor, is also a potent inhibitor of cellular pyruvate metabolism. This effect was found to be related to its almost instantaneous action in decreasing pyruvate concentrations in a dose-dependent manner. 1H nuclear magnetic resonance studies clearly demonstrate that the irreversible removal of pyruvate induced by L-cycloserine is caused by the decarboxylating action of the latter. Pyruvate disappearance induced by L-cycloserine can be stoichiometrically accounted for as acetate. The process does not involve any chemically detected transformation of L-cycloserine. These observations lead to two main considerations regarding the known action of L-cycloserine. First, its inhibitory effect on gluconeogenesis from lactate could be explained only on the basis of its ability to reduce pyruvate availability with no apparent need for transaminase inhibition. Second, its ability as a transaminase inhibitor should be reconsidered in view of its potent decarboxylating action on pyruvate and probably other oxoacids.     

Familial glucocorticoid deficiency: advances in the molecular understanding of ACTH action

Familial glucocorticoid deficiency (FGD), otherwise known as hereditary unresponsiveness to ACTH, is a rare autosomal recessive disease characterized by glucocorticoid deficiency in the absence of mineralocorticoid deficiency. Mutations of the ACTH receptor, also known as the melanocortin-2 receptor (MC2R), account for approximately 25% of FGD cases. More recently a second gene, MRAP (melanocortin-2 receptor accessory protein), was identified and found to account for a further 15-20%. MRAP encodes a small single transmembrane domain protein, which is essential in the trafficking of the MC2R to the cell surface. In this review, we will firstly summarize the clinical presentation and genetic aetiology of this condition. Secondly, we will discuss how the discovery of MRAP has enhanced our understanding of the mechanisms of ACTH/MC2R action. Finally, we will explore future developments in this field.     

The evolution of functionally referential meaning in a structured world

Animal communication systems serve to transfer both motivational information--about the intentions or emotional state of the signaler--and referential information--about external objects. Although most animal calls seem to deal primarily with motivational information, those with a substantial referential component are particularly interesting because they invite comparison with words in human language. We present a game-theoretic model of the evolution of communication in a "structured world", where some situations may be more similar to one another than others, and therefore require similar responses. We find that breaking the symmetry in this way creates the possibility for a diverse array of evolutionarily stable communication systems. When the number of signals is limited, as in alarm calling, the system tends to evolve to group together situations which require similar responses. We use this observation to make some predictions about the situations in which primarily motivational or referential communication systems will evolve.     

Systems pharmacology and enhanced pharmacodynamic models for understanding antibody-based drug action and toxicity

Pharmacokinetic (PK) and pharmacodynamic (PD) models seek to describe the temporal pattern of drug exposures and their associated pharmacological effects produced at micro- and macro-scales of organization. Antibody-based drugs have been developed for a large variety of diseases, with effects exhibited through a comprehensive range of mechanisms of action. Mechanism-based PK/PD and systems pharmacology models can play a major role in elucidating and integrating complex antibody pharmacological properties, such as nonlinear disposition and dynamical intracellular signaling pathways triggered by ligation to their cognate targets. Such complexities can be addressed through the use of robust computational modeling techniques that have proven powerful tools for pragmatic characterization of experimental data and for theoretical exploration of antibody efficacy and adverse effects. The primary objectives of such multi-scale mathematical models are to generate and test competing hypotheses and to predict clinical outcomes. In this review, relevant systems pharmacology and enhanced PD (ePD) models that are used as predictive tools for antibody-based drug action are reported. Their common conceptual features are highlighted, along with approaches used for modeling preclinical and clinically available data. Key examples illustrate how systems pharmacology and ePD models codify the interplay among complex biology, drug concentrations, and pharmacological effects. New hybrid modeling concepts that bridge cutting-edge systems pharmacology models with established PK/ePD models will be needed to anticipate antibody effects on disease in subpopulations and individual patients.