DARTpaths, an in silico platform to investigate molecular mechanisms of compounds.

SUMMARY: Xpaths is a collection of algorithms that allow for the prediction of compound-induced molecular mechanisms of action by integrating phenotypic endpoints of different species; and proposes follow-up tests for model organisms to validate these pathway predictions. The Xpaths algorithms are applied to predict developmental and reproductive toxicity (DART) and implemented into an in silico platform, called DARTpaths. AVAILABILITY AND IMPLEMENTATION: All code is available on GitHub https://github.com/Xpaths/dartpaths-app under Apache license 2.0, detailed overview with demo is available at https://www.vivaltes.com/dartpaths/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The gonadal response to social stress and its relationship to cortisol.

The cortisol response to social evaluative stress has been well characterized. However, data regarding changes in gonadal hormones after stress are still scarce and inconsistent. The majority of studies have focused on testosterone reactivity to stress in men, while estradiol responses or gonadal stress responses in women have hardly been investigated. Furthermore, it has not been evaluated whether sex hormone reactivity to stress differs between men and women and the relationship between cortisol and gonadal reactivity to stress is still unclear. To address these questions, we re-analyzed saliva samples collected from 37 men and 30 women in their luteal cycle phase before and repeatedly after social-evaluative stress. Both, testosterone and estradiol levels were assessed. In both men and women, testosterone was significantly reduced after stress. Testosterone levels were at their lowest after 20 minutes, but did not return to baseline until 35 minutes after stress. Across the whole sample, estradiol was significantly increased after stress with two separate peaks after 15 and 30 minutes. Follow-up analyses revealed that 41 participants actually responded with a decrease in estradiol levels to stress, with lowest levels after 20 min, while the remaining participants responded with an increase in estradiol levels. These gonadal stress responses appear to be largely independent of the cortisol response to stress. These results demonstrate that the endocrinological stress response is not restricted to the HPA axis and stress responsivity of gonadal hormones is not simply driven by cortisol. Accordingly, the stress responsivity of gonadal hormones and their association to psychological variables is an additional avenue to explore in both men and women.

Frontal delta-beta cross-frequency coupling in high and low social anxiety: An index of stress regulation?

Cross-frequency coupling (CFC) between frontal delta (1-4 Hz) and beta (14-30 Hz) oscillations has been suggested as a candidate neural correlate of social anxiety disorder, a disorder characterized by fear and avoidance of social and performance situations. Prior studies have used amplitude-amplitude correlation (AAC) as a CFC measure and hypothesized it as a candidate neural mechanism of affective control. However, using this metric has yielded inconsistent results regarding the direction of CFC, and the functional significance of coupling strength is uncertain. To offer a better understanding of CFC in social anxiety, we compared frontal delta-beta AAC with phase-amplitude coupling (PAC) - a mechanism for information transfer through neural circuits. Twenty high socially anxious (HSA) and 32 low socially anxious (LSA) female undergraduates participated in a social performance task (SPT). Delta-beta PAC and AAC were estimated during the resting state, as well as the anticipation and recovery conditions. Results showed significantly more AAC in LSA than HSA participants during early anticipation, as well as significant values during all conditions in LSA participants only. PAC did not distinguish between LSA and HSA participants, and instead was found to correlate with state nervousness during early anticipation, but in LSA participants only. Together, these findings are interpreted to suggest that delta-beta AAC is a plausible neurobiological index of adaptive stress regulation and can distinguish between trait high and low social anxiety during stress, while delta-beta PAC might be sensitive enough to reflect mild state anxiety in LSA participants.

In the anticipation of threat: Neural regulatory activity indicated by delta-beta correlation and its relation to anxiety.

The anticipation of oncoming threats is emotionally challenging and related to anxiety. The current study aimed to investigate the neural regulatory processes during the anticipatory preparations in stressful situations in relation to trait anxiety, especially in an uncertainty-related stressful situation. To this end, we measured within-subjects delta-beta amplitude-amplitude correlation (AAC) and phase-amplitude coupling (PAC) with electroencephalography using a well-defined stress-inducing paradigm in 28 high-trait-anxiety (HTA) and 29 low-trait-anxiety (LTA) college students. Specifically, a threat probability task was conducted, where participants anticipated the future stimuli under the uncertain (i.e., an average of 50% electric shocks), certain (i.e., 100% electric shocks) and no threat conditions, as well as a resting state task. Results showed a generally larger delta-beta AAC in the LTA group relative to the HTA group across conditions, supporting the hypothesis that delta-beta AAC reflects the efficiency of stress regulation and trait anxiety could compromise this adaptive regulatory activity. Furthermore, a larger delta-beta PAC was found under the uncertain threat condition relative to the no threat condition, indicating the sensitivity of delta-beta PAC in reflecting state anxiety. These findings indicate that while delta-beta AAC is more related to trait anxiety and could distinguish between high and low trait anxiety irrespective of conditions, delta-beta PAC is more related to state anxiety and is sensitive enough to detect the uncertainty-related anxious state.

Delta-beta cross-frequency coupling as an index of stress regulation during social-evaluative threat.

Coupling between delta (1-4 Hz) and beta (14-30 Hz) oscillations is posited to reflect subcortico-cortical communication and stress regulation. To validate delta-beta coupling (DBC) as an index of neural stress regulation, we investigated whether DBC changes during stress and whether these changes are associated with established stress responses. We induced stress using a social-evaluative threat (impromptu speech) task and measured frontal and parietal delta-beta amplitude-amplitude correlation (AAC) and phase-amplitude coupling (PAC), as well as cardiovascular, affective, and endocrine stress responses. Results showed no significant changes in either AAC or PAC in response to stress and no correlations with stress responses. However, baseline AAC tended to be related to more adaptive endocrine stress responses. Our results suggest that delta-beta AAC or PAC are not valid neural indices of stress regulation itself, but rather traits that relate to differences in neuroendocrine stress responses.

Reflecting on Existential Threats Elicits Self-Reported Negative Affect but No Physiological Arousal.

There is mixed evidence whether reflecting on an existential threat increases negative affect and thereby elicits subjective arousal and physiological activation. Additionally, it is debated whether different existential and non-existential threats elicit different arousal responses, although systematic comparisons are lacking. The current study explored affective, subjective, and physiological arousal responses while comparing several existential threats with a non-existential threat and with a control condition. One-hundred-and-seventy-one undergraduate students were randomly allocated to one of four existential threat conditions: mortality salience (MS), freedom restriction, uncontrollability, and uncertainty; or to the non-existential threat condition: social-evaluative threat (SET); or to a control condition (TV salience). Self-reported positive/negative affect was measured before and after reflection, while subjective arousal and physiological activation (electrodermal, cardiovascular, and respiratory) were measured on a high time-scale during baseline and reflection. Results showed larger increases in self-reported negative affect, as compared to the control condition, for all existential threat conditions, while there were no differences between the control condition and threat conditions regarding positive affect, subjective arousal, skin conductance, respiratory rate, and respiratory sinus arrythmia. There were subtle differences between existential and non-existential threat conditions, most notably in affective responses. Correlations showed positive associations between negative affect and subjective arousal and between trait avoidance and subjective arousal. This study is the first to systematically compare affective, subjective, and physiological changes in arousal due to reflecting on different existential threats, as well as one non-existential threat. We showed that, as compared to a control condition, reflecting on threats has a large impact on negative affect, but no significant impact on positive affect, subjective arousal, and physiological activation.

Data for "Social-evaluative threat: Stress response stages and influences of biological sex and neuroticism".

This Data In Brief article contains supplementary materials to the article "Social-evaluative threat: stress response stages and influences of biological sex and neuroticism" [1], and describes analysis results of an open dataset [2]. Additional information is provided regarding the methods, particularly: the analysis of individual stress response peak times per stress system, and the statistical analysis. Importantly, correlation tables are presented between the different stress systems, both for baseline stress levels as well as for stress responses, and significant associations are displayed in scatter plots.

Social-evaluative threat: Stress response stages and influences of biological sex and neuroticism.

Social-evaluative threat (SET) - when the self could be negatively judged by others - can cause pronounced responses in the different stress systems: threat/challenge appraisal, the sympathetic (SNS) and parasympathetic (PNS) nervous systems, experienced motivation and affect, and the hypothalamus-pituitary-adrenal (HPA) axis. Here, we utilize a four-stage stress response model to shed light on the complex associations between different stress responses, where earlier stages are hypothesized to predict later stages. Additionally, we take into account important moderators, such as biological sex (controlling for menstrual cycle phase), personality traits (neuroticism and extraversion), and baseline stress levels. Thirty-seven men and 30 women in their luteal phase participated in an impromptu public speaking task to induce SET. Stress responses in four different stages were measured using: self-reported appraisal (threat or challenge, stage 1: S1), cardiovascular measures (pre-ejection period as SNS index, respiratory sinus arrhythmia as PNS index, S2), self-reported motivation and affect (state approach motivation, state anxiety, S3) and endocrine measures (cortisol as HPA index, S4). Stress reactivity was calculated by subtracting individual peaks from baseline. Results showed that SET induced pronounced stress reactivity in stages two to four. Against expectations, self-reported appraisal (S1) or motivation and affect (S3) did not predict later stress reactivity. As hypothesized, increased SNS (but not PNS) reactivity (S2) predicted increased HPA reactivity (S4). Bayesian model comparison confirmed the absence of sex differences in stress reactivity, likely due to controlling for menstrual cycle phase and sex differences in neuroticism levels. Higher trait neuroticism predicted blunted SNS (S2) and HPA (S4) reactivity, while higher baseline stress levels predicted blunted stages two and three reactivity overall. In conclusion, this rigorously controlled experiment partly supports and partly contradicts previous findings regarding associations between stress response stages, and offers new insight into the causes of blunted HPA responses in women.

Fear of negative evaluation modulates electrocortical and behavioral responses when anticipating social evaluative feedback.

Cognitive models posit that the fear of negative evaluation (FNE) is a hallmark feature of social anxiety. As such, individuals with high FNE may show biased information processing when faced with social evaluation. The aim of the current study was to examine the neural underpinnings of anticipating and processing social-evaluative feedback, and its correlates with FNE. We used a social judgment paradigm in which female participants (N = 31) were asked to indicate whether they believed to be socially accepted or rejected by their peers. Anticipatory attention was indexed by the stimulus preceding negativity (SPN), while the feedback-related negativity and P3 were used to index the processing of social-evaluative feedback. Results provided evidence of an optimism bias in social peer evaluation, as participants more often predicted to be socially accepted than rejected. Participants with high levels of FNE needed more time to provide their judgments about the social-evaluative outcome. While anticipating social-evaluative feedback, SPN amplitudes were larger for anticipated social acceptance than for social rejection feedback. Interestingly, the SPN during anticipated social acceptance was larger in participants with high levels of FNE. None of the feedback-related brain potentials correlated with the FNE. Together, the results provided evidence of biased information processing in individuals with high levels of FNE when anticipating (rather than processing) social-evaluative feedback. The delayed response times in high FNE individuals were interpreted to reflect augmented vigilance imposed by the upcoming social-evaluative threat. Possibly, the SPN constitutes a neural marker of this vigilance in females with higher FNE levels, particularly when anticipating social acceptance feedback.