Atherothrombosis is a leading cause of cardiovascular mortality and morbidity worldwide. The underlying mechanisms of atherothrombosis comprise plaque disruption and subsequent thrombus formation. ...Arterial thrombi are thought to mainly comprise aggregated platelets as a result of high blood velocity. However, thrombi that develop on disrupted plaques comprise not only aggregated platelets, but also large amounts of fibrin, because plaques contain large amount of tissue factor that activate the coagulation cascade. Since not all thrombi grow large enough to occlude the vascular lumen, the propagation of thrombi is also critical in the onset of adverse vascular events. Various factors such as vascular wall thrombogenicity, local hemorheology, systemic thrombogenicity and fibrinolytic activity modulate thrombus formation and propagation. Although the activation mechanisms of platelets and the coagulation cascade have been intensively investigated, the underlying mechanisms of occlusive thrombus formation on disrupted plaques remain obscure. Pathological findings derived from humans and animal models of human atherothrombosis have uncovered pathophysiological processes during thrombus formation and propagation after plaque disruption, and novel factors have been identified that modulate the activation of platelets and the coagulation cascade. These findings have also provided insights into the development of novel drugs for atherothrombosis.
Thrombosis remains a leading cause of death worldwide despite technological advances in prevention, diagnosis, and treatment. The traditional view of arterial thrombus formation is that it is a ...platelet‐dependent process, whereas that of venous thrombus formation is a coagulation‐dependent process. Current pathological and basic studies on atherothrombosis and venous thrombosis have revealed the diverse participation of platelet and coagulation activation mechanisms in both thrombus initiation and growth processes during clinical thrombotic events. Atherosclerotic plaque cell‐derived tissue factor contributes to fibrin formation and platelet aggregation. The degree of plaque disruption and a blood flow alteration promote atherothrombotic occlusion. While blood stasis/turbulent flow due to luminal stenosis itself initiates venous thrombus formation. The coagulation factor XI‐driven propagation phase of blood coagulation plays a major role in venous thrombus growth, but a minor role in hemostasis. These lines of evidence indicate that atherothrombosis onset is affected by the thrombogenic potential of atherosclerotic plaques, the plaque disruption size, and an alteration in blood flow. Upon onset of venous thrombosis, enhancement of the propagation phase of blood coagulation under blood stasis and a hypercoagulable state contribute to large thrombus formation.
Ischemic cardiovascular disease is a major cause of morbidity and mortality worldwide and thrombus formation on disrupted atherosclerotic plaques is considered to trigger its onset. Although the ...activation of platelets and coagulation pathways has been investigated intensively, the mechanisms of thrombus formation on disrupted plaques have not been understood in detail. Platelets are thought to play a central role in the formation of arterial thrombus because of rapid flow conditions; however, thrombus that develops on disrupted plaques consistently includes large amounts of fibrin in addition to aggregated platelets. While, thrombus does not always become large enough to completely occlude the vascular lumen, indicating that the propagation of thrombus is also critical for the onset of cardiovascular events. Various factors, such as vascular wall thrombogenicity, altered blood flow and imbalanced blood hemostasis, modulate thrombus formation and propagation on disrupted plaques. Pathological findings derived from humans and experimental animal models of atherothrombosis have identified important factors that affect thrombus formation and propagation, namely platelets, extrinsic and intrinsic coagulation factors, proinflammatory factors, plaque hypoxia and blood flow alteration. These findings might provide insight into the mechanisms of thrombus formation and propagation on disrupted plaques that lead to the onset of cardiovascular events.
•We examined the influence of action-outcome delay on sense of agency and binding.•Delay impaired self-reported sense of agency, but not binding.•We also examined the influence of arousal.•Arousal ...enhanced binding but had no influence on the self-reported agency.•Self-reported agency and binding reflect different aspects of the sense of agency.
The sense of agency refers to the feeling of being able to initiate and control events through one’s actions. The “intentional binding” effect (Haggard, Clark, & Kalogeras, 2002), refers to a subjective compression of the temporal interval between actions and their effects. The present study examined the influence of action-outcome delays and arousal on both the subjective judgment of agency and the intentional binding effect. In the experiment, participants pressed a key to trigger a central square to jump after various delays. A red central square was used in the high-arousal condition. Results showed that a longer interval between actions and their effects was associated with a lower sense of agency but a stronger intentional binding effect. Furthermore, although arousal enhanced the intentional binding effect, it did not influence the judgment of agency.
The sense of agency refers to the feeling that one is controlling events through one's own behavior. This study examined how task performance and the delay of events influence one's sense of agency ...during continuous action accompanied by a goal. The participants were instructed to direct a moving dot into a square as quickly as possible by pressing the left and right keys on a keyboard to control the direction in which the dot traveled. The interval between the key press and response of the dot (i.e., direction change) was manipulated to vary task difficulty. Moreover, in the assisted condition, the computer ignored participants' erroneous commands, resulting in improved task performance but a weaker association between the participants' commands and actual movements of the dot relative to the condition in which all of the participants' commands were executed (i.e., self-control condition). The results showed that participants' sense of agency increased with better performance in the assisted condition relative to the self-control condition, even though a large proportion of their commands were not executed. We concluded that, when the action-feedback association was uncertain, cognitive inference was more dominant relative to the process of comparing predicted and perceived information in the judgment of agency.
Self-related stimuli are important cues for people to recognize themselves in the external world and hold a special status in our perceptual system. Self-voice plays an important role in daily social ...communication and is also a frequent input for self-identification. Although many studies have been conducted on the acoustic features of self-voice, no research has ever examined the spatial aspect, although the spatial perception of voice is important for humans. This study proposes a novel perspective for studying self-voice. We investigated people's distance perception of their own voice when the voice was heard from an external position. Participants heard their own voice from one of four speakers located either 90 or 180 cm from their sitting position, either immediately after uttering a short vowel (i.e., active session) or hearing the replay of their own pronunciation (i.e., replay session). They were then asked to indicate which speaker they heard the voice from. Their voices were either pitch-shifted by ± 4 semitones (i.e., other-voice condition) or unaltered (i.e., self-voice condition). The results of spatial judgment showed that self-voice from the closer speakers was misattributed to that from the speakers further away at a significantly higher proportion than other-voice. This phenomenon was also observed when the participants remained silent and heard prerecorded voices. Additional structural equation modeling using participants' schizotypal scores showed that the effect of self-voice on distance perception was significantly associated with the score of delusional thoughts (Peters Delusion Inventory) and distorted body image (Perceptual Aberration Scale) in the active speaking session but not in the replay session. The findings of this study provide important insights for understanding how people process self-related stimuli when there is a small distortion and how this may be linked to the risk of psychosis.
The ABCD1 protein, one of the four ATP-binding cassette (ABC) proteins in subfamily D, is located on the peroxisomal membrane and is involved in the transport of very long chain fatty acid ...(VLCFA)-CoA into peroxisomes. Its mutation causes X-linked adrenoleukodystophy (X-ALD): an inborn error of peroxisomal β-oxidation of VLCFA. Whether ABCD1 transports VLCFA-CoA as a CoA ester or free fatty acid is controversial. Recently, Comatose (CTS), a plant homologue of human ABCD1, has been shown to possess acyl-CoA thioesterase (ACOT) activity, and it is suggested that this activity is required for transport of acyl-CoA into peroxisomes. However, the precise transport mechanism is unknown. Here, we expressed human His-tagged ABCD1 in methylotrophic yeast, and characterized its ACOT activity and transport mechanism. The expressed ABCD1 possessed both ATPase and ACOT activities. The ACOT activity of ABCD1 was inhibited by p-chloromercuribenzoic acid (pCMB), a cysteine-reactive compound. Furthermore, we performed a transport assay with ABCD1-containing liposomes using 7-nitro-2-1,3-benzoxadiazol-4-yl (NBD)-labeled acyl-CoA as the substrate. The results showed that the fatty acid produced from VLCFA-CoA by ABCD1 is transported into liposomes and that ACOT activity is essential during this transport process. We propose a detailed mechanism of VLCFA-CoA transport by ABCD1.
GPR55 is an orphan G protein-coupled receptor. In this study, we explored a possible endogenous ligand for GPR55 using HEK293 cells which expressed GPR55. We found that lysophosphatidylinositol ...induced rapid phosphorylation of the extracellular signal-regulated kinase in transiently or stably GPR55-expressing cells. On the other hand, lysophosphatidylinositol did not induce phosphorylation of the extracellular signal-regulated kinase in vector-transfected cells. Lysophosphatidic acid and sphingosine 1-phosphate also induced phosphorylation of the extracellular signal-regulated kinase in GPR55-expressing cells. However, these lipid phosphoric acids elicited similar responses in vector-transfected cells. Various types of other lysolipids as well as the cannabinoid receptor ligands did not induce phosphorylation of the extracellular signal-regulated kinase. We also found that lysophosphatidylinositol elicited a rapid Ca
2+ transient in GPR55-expressing cells. Lysophosphatidylinositol also stimulated the binding of GTPγS to the GPR55-expressing cell membranes. These results strongly suggest that GPR55 is a specific and functional receptor for lysophosphatidylinositol.
The sense of agency refers to the feeling of control over one's own actions, and through them, the external events. This study examined the effect of modified visual feedback on the sense of agency ...over one's body movements using virtual reality in healthy individuals whose motor control was disturbed. Participants moved a virtual object using their right hand to trace a trajectory (Experiment 1) or a leading target (Experiment 2). Their motor control was disturbed by a delay in visual feedback (Experiment 1) or a 1-kg weight attached to their wrist (Experiment 2). In the offset conditions, the virtual object was presented at the median point between the desired position and the participants' actual hand position. In both experiments, participants reported improved sense of agency in the offset condition compared to the aligned condition where the visual feedback reflected their actual body movements, despite their motion being less precise in the offset condition. The results show that sense of agency can be enhanced by modifying feedback to motor tasks according to the goal of the task, even when visual feedback is discrepant from the actual body movements. The present study sheds light on the possibility of artificially enhancing body agency to improve voluntary motor control.
Adaptive motor learning refers to the ability to adjust to novel disturbances in the environment as a way of minimizing sensorimotor errors. It is known that such processes show large individual ...differences and are linked to multiple perceptual and cognitive processes. On the other hand, the sense of agency refers to the subjective feeling of control during voluntary motor control. Is the sense of agency just a by-product of the control outcome, or is it actually important for motor control and learning? To answer this question, this study takes an approach based on individual differences to investigate the relationship between the sense of agency and learnability in sensorimotor adaptation. Specifically, we use an adaptive motor learning task to measure individual differences in the efficiency of motor learning. Regarding the sense of agency, we measure the perceptual sensitivity of detecting an increase or a decrease in control when the actual level of control gradually increases or decreases, respectively. The results of structure equation modelling reveal a significant influence of perceptual sensitivity to increased control on motor learning efficiency. On the other hand, the link between perceptual sensitivity to decreased control and motor learning is nonsignificant. The results show that the sense of agency in detecting increased control is associated with the actual ability of sensorimotor adaptation: people who are more sensitive in detecting their control in the environment can also more quickly adjust their behaviors to novel disturbances to acquire better control, compared to people who have a less sensitive sense of agency. Finally, the results also reveal that the processes of increasing control and decreasing control may be partially independent.
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