Modelling the Phosphorylation of Glucose by Human hexokinase I

In this paper, we develop a comprehensive mathematical model to describe the phosphorylation of glucose by the enzyme hexokinase I. Glucose phosphorylation is the first step of the glycolytic pathway, and as such, it is carefully regulated in cells. Hexokinase I phosphorylates glucose to produce glucose-6-phosphate, and the cell regulates the phosphorylation rate by inhibiting the action of this enzyme. The cell uses three inhibitory processes to regulate the enzyme: an allosteric product inhibitory process, a competitive product inhibitory process, and a competitive inhibitory process. Surprisingly, the cellular regulation of hexokinase I is not yet fully resolved, and so, in this study, we developed a detailed mathematical model to help unpack the behaviour. Numerical simulations of the model produced results that were consistent with the experimentally determined behaviour of hexokinase I. In addition, the simulations provided biological insights into the abstruse enzymatic behaviour, such as the dependence of the phosphorylation rate on the concentration of inorganic phosphate or the concentration of the product glucose-6-phosphate. A global sensitivity analysis of the model was implemented to help identify the key mechanisms of hexokinase I regulation. The sensitivity analysis also enabled the development of a simpler model that produced an output that was very close to that of the full model. Finally, the potential utility of the model in assisting experimental studies is briefly indicated.

Impairment of a cyanobacterial glycosyltransferase that modifies a pilin results in biofilm development

A biofilm inhibiting mechanism operates in the cyanobacterium Synechococcus elongatus. Here, we demonstrate that the glycosyltransferase homolog, Ogt, participates in the inhibitory process. inactivation of ogt results in robust biofilm formation. Furthermore, a mutational approach shows requirement of the glycosyltransferase activity for biofilm inhibition. This enzyme is necessary for glycosylation of the pilus subunit and for adequate pilus formation. In contrast to wild type culture in which most cells exhibit several pili, only 25% of the mutant cells are piliated, half of which possess a single pilus. In spite of this poor piliation, natural DNA competence was similar to that of wild type, therefore, we propose that the unglycosylated pili facilitate DNA transformation. Additionally, conditioned medium from wild-type culture, which contains a biofilm inhibiting substance(s), only partially blocks biofilm development by the ogt mutant. Thus, we suggest that inactivation of ogt affects multiple processes including production or secretion of the inhibitor as well as the ability to sense or respond to it.

Computational Mechanisms Mediating Inhibitory Control of Coordinated Eye-Hand Movements

Significant progress has been made in understanding the computational and neural mechanisms that mediate eye and hand movements made in isolation. However, less is known about the mechanisms that control these movements when they are coordinated. Here, we outline our computational approaches using accumulation-to-threshold and race-to-threshold models to elucidate the mechanisms that initiate and inhibit these movements. We suggest that, depending on the behavioral context, the initiation and inhibition of coordinated eye-hand movements can operate in two modes—coupled and decoupled. The coupled mode operates when the task context requires a tight coupling between the effectors; a common command initiates both effectors, and a unitary inhibitory process is responsible for stopping them. Conversely, the decoupled mode operates when the task context demands weaker coupling between the effectors; separate commands initiate the eye and hand, and separate inhibitory processes are responsible for stopping them. We hypothesize that the higher-order control processes assess the behavioral context and choose the most appropriate mode. This computational mechanism can explain the heterogeneous results observed across many studies that have investigated the control of coordinated eye-hand movements and may also serve as a general framework to understand the control of complex multi-effector movements.

Computational Architecture Mediating Inhibitory Control of Coordinated Eye-Hand Movements

Significant progress has been made in understanding the computational and neural architecture that mediates eye and hand movements made in isolation. However, less is known about the mechanisms that control these movements when they are coordinated. Here, we outline our computational approaches using accumulation-to-threshold and race-to-threshold models to elucidate the mechanisms that initiate and inhibit these movements. We suggest that, depending on the behavioral context, the initiation and inhibition of coordinated eye-hand movements can operate in two modes- coupled and decoupled. The coupled-mode operates when the task context requires a tight coupling between the effectors; a common command initiates both effectors, and a unitary inhibitory process is responsible for stopping them. Conversely, the decoupled mode operates when the task context demands weaker coupling between the effectors; separate commands initiate the eye and hand, and separate inhibitory processes are responsible for stopping them. We hypothesize that higher-order control processes assess the behavioral context and choose the most appropriate mode. This computational architecture can explain heterogeneous results observed across many studies that have investigated the control of coordinated eye-hand movements and may also serve as a general framework to understand the control of complex multi-effector movements.

Mind-wandering impedes response inhibition by affecting the triggering of the inhibitory process

Mind-wandering is a state where our mental focus shifts towards task-unrelated thoughts. While it is known that mind-wandering has a detrimental effect on concurrent task performance, e.g., decreased accuracy, its effect on executive functions is poorly studied. Yet, the latter question is relevant to many real-world situations, e.g., rapid stopping during driving. Here we studied how mind-wandering would affect the requirement to subsequently stop an incipient motor response. We tested, first, whether mind-wandering affected stopping, and second, which component of stopping was affected: the triggering of the inhibitory brake or the implementation of the brake following triggering. We observed that during mind-wandering, stopping-latency increased as did the proportion of trials with failed triggering. Indeed, 67% of the variance of the increase in stopping-latency was explained by the increased trigger failures. Thus, mind-wandering affects stopping, primarily by affecting the triggering of the brake.

Stopping timed actions.

The ability to inhibit ongoing responses that suddenly become inappropriate is essential for safe and effective interaction with an ever-changing and unpredictable world. Response inhibition is quantified by the unobservablestop-signal reaction time (SSRT), the completion time of an inhibitory process triggered by a signal to stop responding. SSRTs can be inferred based on a model in which inhibitory and response processes race with each other to control behavior. Inhibition is usually studied in the context of choice responses, but there has been increasing interest in what is often a key component of skilled behavior, stopping a response that is timed to coincide with an anticipated event. We show that SSRT measurement via the standard race model fails for anticipated responses because the stop signal changes the perception of the passage of time, due to the long-known “filled-interval illusion”. We propose a computational model of anticipated response inhibitionthat takes account of this distortion of time perception and show that this model produces valid estimates of not only SSRT, but also another key process that determines inhibitory ability, lapses in attention. Our new modeland accompanying Bayesian estimation procedures provide a solid basis for the burgeoning study of timed-action control.

Removal of information from working memory is not related to inhibition

Working memory (WM) is a system for maintenance of and access to a limited number of goal-relevant representations in the service of higher cognition. Because of its limited capacity, WM requires interference-control processes, allowing us to avoid being distracted by irrelevant information. Recent research has proposed two interference-control processes, which are conceptually similar: (1) an active, item-wise removal process assumed to remove no-longer relevant information from WM, and (2) an inhibitory process assumed to suppress the activation of distractors against competing, goal-relevant representations. The purpose of this study was to determine the extent to which removal and inhibition are the same construct. Results showed acceptable to good reliabilities for nearly all measures. Similar to previous studies, a structural equation modeling approach identified a reliable latent variable of removal. However, also similar to some previous studies, no latent variable of inhibition could be established. This was the case even when the correlation matrix used to compute the latent variable of inhibition was disattenuated for imperfect reliability. Critically, the individual measures of inhibition were unrelated to the latent variable of removal. These results provide tentative support for the notion that removal is not an inhibitory process. This suggests that the removal process should be conceptualized as a process independent of inhibition, as proposed in computational WM models that implement removal as the “unbinding” of a WM item from the context in which it occurred.

Neuronal dynamics of signal selective motor plan cancellation in the macaque dorsal premotor cortex

Primates adopt various strategies to interact with the environment. Yet, no study has examined the effects of behavioral strategies with regard to how movement inhibition is implemented at the neuronal level. We modified a classical approach to study movement control (stop-task) by adding an extra signal – termed the Ignore signal – which influenced movement inhibition only under a specific strategy. We simultaneously recorded multisite neuronal activity from the dorsal premotor (PMd) cortex of macaque monkeys during a task and applied a state-space approach. As a result, we found that movement generation is characterized by neuronal dynamics that evolve between subspaces. When the movement is halted, this evolution is arrested and inverted. Conversely, when the Ignore signal is presented, inversion of the evolution is observed briefly and only when a specific behavioral strategy is adopted. Moreover, neuronal signatures during the inhibitory process were predictive of how PMd processes inhibitory signals, allowing the classification of the resulting behavioral strategy. Our data corroborate the PMd as a critical node in movement inhibition.

Emotional Stop Cues Facilitate Inhibitory Control in Schizophrenia

Objective:Inhibitory control is a key deficit in patients with schizophrenia. This study aims to test whether emotions can facilitate inhibition in patients with schizophrenia when they increase attention to inhibitory process.Method:A total of 36 patients with schizophrenia and 36 healthy controls completed an emotional stop-signal task. The task involved selective responses to “Go” stimuli and stopped response when emotional or neutral stop cues occurred.Results:In all conditions, patients with schizophrenia took longer time to inhibit response compared with healthy controls, indicating an overall impairment in response inhibition. Importantly, patients with schizophrenia and controls acquired similar size of benefit from the negative stop cues, showing as reduced reaction time to negative than neutral stop cues. However, the negative stop cues impaired subsequent Go performance only in patients with schizophrenia, indicating additional cost of the negative stop cues for patients with schizophrenia. In both groups, the positive stop cues did not have any significant influence on response inhibition.Conclusions:These findings provide novel evidence for the benefit of emotional stop cues on inhibitory control in patients with schizophrenia and reveal different after-effects of emotional enhancement effect in patients and healthy populations. The findings may help develop effective interventions for improving inhibitory control in patients with schizophrenia and other clinical populations.