Transition state in the folding of α-lactalbumin probed by the 6-120 disulfide bond

The guanidine hydrochloride concentration dependence of the folding and unfolding rate constants of a derivative of α-lactalbumin, in which the 6-120 disulfide bond is selectively reduced and S-carboxymethylated, was measured and compared with that of disulfide-intact α-lactalbumin. The concentration dependence of the folding and unfolding rate constants was analyzed on the basis of the two alternative models, the intermediate-controlled folding model and the multiple-pathway folding model, that we had proposed previously. All of the data supported the multiple-pathway folding model. Therefore, the molten globule state that accumulates at an early stage of folding of α-lactalbumin is not an obligatory intermediate. The cleavage of the 6-120 disulfide bond resulted in acceleration of unfolding without changing the refolding rate, indicating that the loop closed by the 6-120 disulfide bond is unfolded in the transition state. It is theoretically shown that the chain entropy gain on removing the cross-link from a random coil chain with helical stretches can be comparable to that from an entirely random chain. Therefore, the present result is not inconsistent with the known structure in the molten globule intermediate. Based on this result and other knowledge obtained so far, the structure in the transition state of the folding reaction of α-lactalbumin is discussed

The right temporoparietal junction during a cooperation dilemma: An rTMS study

Cooperation enhances interpersonal communication and nurtures society. However, efforts to socially cooperate may often evoke conflict. Individuals may selfishly pursue a greater reward or success by exploiting the efforts of other individuals or taking unnecessary risk to oneself. Such a cooperation dilemma is highly prevalent in real life; thus, it has been studied in various disciplines. Although published functional magnetic resonance imaging studies have shown the involvement of the right temporoparietal junction (TPJ) in resolving a dilemma through cooperation, a causal relationship between the two has rarely been explored. Hence, we investigated this issue by combining repetitive transcranial magnetic stimulation with a priority game task (modified snowdrift game). In this game task, participants and opponent players jointly faced a problem whereby their collaboration was anticipated to defuse the situation. This conflicted with a choice in the participant's self-interest that was more rewarding but risky. We further included conditions with and without explicit social cues using figures describing elderly/pregnant passengers in the game opponent's car, and measured participants' prosocial traits to examine any cue-induced effect as well as the personality-cooperation relationship, respectively. The cooperation ratio was not statistically different in both the no-cue and with-cue conditions between the sham stimulation and inhibitory continuous theta burst stimulation (cTBS). However, after cTBS, in the no-cue condition, the strength of the association between cooperation ratio and empathy traits decreased significantly. These results add to our knowledge about the right TPJ's role in social cognition, which may be extraordinarily complex. This topic is deserving of further examination

Contribution of the 6-120 disulfide bond of α-lactalbumin to the stabilities of its native and molten globule states

The unfolding and refolding of a derivative of a-lactalbumin, in which the disulfide bond between Cys6 and Cys120 is selectively reduced and S-carboxymethylated, are investigated by equilibrium and kinetic circular dichroism measurements. The native conformation of this derivative is known to be essentially identical to that of intact α-lactalbumin. The equilibrium unfolding of the derivative involves a stable intermediate, which is also similar to the molten globule state of the disulfide intact protein. The results of stopped-flow circular dichroism experiments show that the same intermediate is formed rapidly as a transient intermediate in kinetic refolding. The conformational stabilities for the native and intermediate states have been estimated and compared with the stabilities for the corresponding states of intact α-lactalbumin. The stabilization of the native state by the disulfide has been interpreted in terms of a decrease in chain entropy in the unfolded state and elimination of the strain imposed on the disulfide bond in the native state. The molten globule state is also stabilized by the disulfide bond, although the degree of stabilization of the molten globule state is smaller than of the native state. The results suggest that, in the molten globule state, some ordered structures are present within the loop moiety formed by the 6-120 disulfide

Inflexible daily behaviour is associated with the ability to control an automatic reaction in autism spectrum disorder

Inflexible behaviours in people with autism spectrum disorder (ASD) broadly obstruct social communication. Meanwhile, flexibility implicates cognitive control to resolve socially conflicting situations; however, it remains unclear how people with ASD behave in the face of these conflicts in this respect. We used the ultimatum game (UG) and the implicit-association test (IAT) to examine goal-directed/economic flexibility, both of which involve conflict and cognitive control. In addition, we used the Detail and Flexibility Questionnaire (DFlex) to measure inflexible everyday behaviour with diminished cognitive control and attention shifting. We observed the decreased flexibility in participants with ASD (DFlex and IAT); further, their IAT scores positively correlated with DFlex. However, in the UG, contrary to our prediction, participants with ASD accepted unfair offers more frequently than TD. These results suggest that assessing the automatic/attention processing level with the IAT could be a useful approach to study behavioural flexibility among ASD compared with the UG, which might comprise multiple response strategies besides economic rationality. Overall, the severity of inflexible daily behaviours in people with ASD may be associated with a reduced flexible attitude at an automatic level, altered attention processing and decreased cognitive control

Inflexible daily behaviour is associated with the ability to control an automatic reaction in autism spectrum disorder.

Inflexible behaviours in people with autism spectrum disorder (ASD) broadly obstruct social communication. Meanwhile, flexibility implicates cognitive control to resolve socially conflicting situations; however, it remains unclear how people with ASD behave in the face of these conflicts in this respect. We used the ultimatum game (UG) and the implicit-association test (IAT) to examine goal-directed/economic flexibility, both of which involve conflict and cognitive control. In addition, we used the Detail and Flexibility Questionnaire (DFlex) to measure inflexible everyday behaviour with diminished cognitive control and attention shifting. We observed the decreased flexibility in participants with ASD (DFlex and IAT); further, their IAT scores positively correlated with DFlex. However, in the UG, contrary to our prediction, participants with ASD accepted unfair offers more frequently than TD. These results suggest that assessing the automatic/attention processing level with the IAT could be a useful approach to study behavioural flexibility among ASD compared with the UG, which might comprise multiple response strategies besides economic rationality. Overall, the severity of inflexible daily behaviours in people with ASD may be associated with a reduced flexible attitude at an automatic level, altered attention processing and decreased cognitive contro

Egocentric biases and atypical generosity in autistic individuals.

Individuals with autism spectrum conditions (ASCs) often experience difficulty and confusion in acknowledging others\u27 perspectives and arguably exhibit egocentricity. However, whether this egocentricity necessarily results in selfish behavior during social situations remains a matter of debate. To study this relationship, we used computerized visuospatial perspective-taking task (VPT) and social-discounting task (SDT), derived from cognitive psychology and behavioral economics, and examined egocentric and other-oriented judgments in participants with ASCs (mean age 29.0 ± 4.2 years) and a group of matched typically developing (TD) controls (30.8 ± 8.5). The response time in VPT showed altered perspective-taking in the ASCs group compared with the TD group that involved in enhanced self-other intrusion and condition-insensitive response. Regardless of self/other perspective judgments, responses were relatively slower and consistent in duration in the ASCs group compared with the TD group. Social discounting was attenuated rather than steep discounting in the ASCs group. Their discounting was comparatively more consistent, irrespective of the task condition (i.e., self-other closeness-level). In effect, ASCs group exhibited more generous decisions than the TD group in this task. Finally, those with more egocentric perspective intrusion in VPT paradoxically showed more generous behaviors in SDT in the ASCs group. Our findings suggest that having ASCs does not always exhibit selfish behavior during interpersonal communication. Reduced flexibility in distinguishing self/other perspective and shifting decision-rules might account for this unique relationship between egocentricity and apparently generous behaviors. These results extend the recent suggestion that more careful attention should be paid to the idea of egocentricity in individuals with ASCs. Autism Res 2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We aimed to examine whether seeing the world from another person\u27s point of view and being generous toward other people are related in autistic and nonautistic people. We used a visual perspective-taking task and a social task in which individuals made decisions about how to divide a sum of money with others. Our results suggest that being autistic does not always make someone bad at seeing the world from another\u27s viewpoint, and that autistic people may make fairer social decisions toward unfamiliar people because of lower bias

Role of the right temporoparietal junction in intergroup bias in trust decisions

Intergroup bias, which is the tendency to behave more positively toward an in-group member than toward an out-group member, is pervasive in real life. In particular, intergroup bias in trust decisions substantially influences multiple areas of life and thus better understanding of this tendency can provide significant insights into human social behavior. Although previous functional magnetic resonance imaging studies showed the involvement of the right temporoparietal junction (TPJ) in intergroup trust bias, a causal relationship between the two has rarely been explored. By combining repetitive transcranial magnetic stimulation and a newly developed trust game task, we investigated the causal role of the right TPJ in intergroup bias in trust decisions. In the trust game task, the counterpart\u27s group membership (in-group or out-group) and reciprocity were manipulated. We applied either neuronavigated inhibitory continuous theta burst stimulation (cTBS) or sham stimulation over theright TPJ before performing the trust game task in healthy volunteers. After the sham stimulation, the participants\u27 degrees of investments with in-group members were significantly higher than those with out-group members. However, after cTBS to the right TPJ, this difference was not observed. The current results extend previous findings by showing that the causal roles of the right TPJ can be observed in intergroup bias in trust decisions. Our findings add to our understanding of the mechanisms of human social behavior

Attitudes toward risk and ambiguity in patients with autism spectrum disorder

Although the ability to make optimal decisions under uncertainty is an integral part of everyday life, individuals with autism spectrum disorder (ASD) frequently report that they experience difficulties with this skill. In behavioral economics, researchers distinguish two types of uncertainty to understand decision-making in this setting: risk (known probabilities) and ambiguity (unknown probabilities). However, it remains unclear how individuals with ASD behave under risk and ambiguity, despite growing evidence of their altered decision-making under uncertainty. We therefore extended previous research by studying the attitudes of those with ASD toward risk and ambiguity in both positive and negative contexts (i.e., gain and loss). In gain contexts, no significant difference was observed between the groups in risk attitudes, but ambiguity aversion was attenuated in ASD. In loss contexts, ambiguity attitudes did not significantly differ between the groups, but the ASD participants were less risk-seeking compared with the controls. In addition, insensitivity to the context change under risk and ambiguity in ASD was both significantly associated with poor social skills. These results improve our understanding of altered decision-making under uncertainty by disentangling the attitudes toward risk and ambiguity in ASD individuals. Applying behavioral economics tools may provide insights into the mechanisms underlying behavioral disturbances in ASD

Transdiagnostic subtyping of males with developmental disorders using cortical characteristics

Background: autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are biologically heterogeneous and often co-occur. As within-diagnosis heterogeneity and overlapping diagnoses are challenging for researchers and clinicians, identifying biologically homogenous subgroups, independent of diagnosis, is an urgent need. Methods: MRI data from 148 adult males with developmental disorders (99 primary ASD；mean age = 31.7±8.0, 49 primary ADHD; mean age = 31.7±9.6) and 105 neurotypical controls (NTC; mean age = 30.6±6.8) were analyzed. We extracted mean cortical thickness (CT) and surface area (SA) values using a functional atlas. Then, we conducted HeterogeneitY through DiscRiminant Analysis (HYDRA) to transdiagnostically cluster and classify individuals. Differences in diagnostic likelihood and clinical symptoms between subtypes were tested. Sensitivity analyses tested the stability of the number of subtypes and their membership by excluding 13 participants diagnosed with both ASD and ADHD and by using a different atlas. Results: in relation to both CT and SA, HYDRA identified two subtypes. The likelihood of ASD or ADHD was not significantly different from the chance of belonging to any of these two subtypes. Clinical characteristics did not differ between subtypes in either CT or SA based analyses. The high consistency in membership was replicated when utilizing a different atlas or excluding people with dual diagnoses in CT (dice coefficients > 0.94) and in SA (>0.88). Conclusion: although the brain-derived subtypes do not match diagnostic groups, individuals with developmental disorders were successfully and stably subtyped using either CT or SA

Impact of past experiences on decision-making in autism spectrum disorder.

People are often influenced by past costs in their current decision-making, thus succumbing to a well-known bias recognized as the sunk cost effect. A recent study showed that the sunk cost effect is attenuated in individuals with autism spectrum disorder (ASD). However, the study only addressed one situation of utilization decision by focusing on the choice between similar attractive alternatives with different levels of sunk costs. Thus, it remains unclear how individuals with ASD behave under sunk costs in different types of decision situations, particularly progress decisions, in which the decision-maker allocates additional resources to an initially chosen alternative. The sunk cost effect in progress decisions was estimated using an economic task designed to assess the effect of the past investments on current decision-making. Twenty-four individuals with ASD and 21 age-, sex-, smoking status-, education-, and intelligence quotient-level-matched typical development (TD) subjects were evaluated. The TD participants were more willing to make the second incremental investment if a previous investment was made, indicating that their decisions were influenced by sunk costs. However, unlike the TD group, the rates of investments were not significantly increased after prior investments in the ASD group. The results agree with the previous evidence of a reduced sensitivity to context stimuli in individuals with ASD and help us obtain a broader picture of the impact of sunk costs on their decision-making. Our findings will contribute to a better understanding of ASD and may be useful in addressing practical implications of their socioeconomic behavior