STARGATE-X: a Python package for statistical analysis on the REACTOME network.

Many important aspects of biological knowledge at the molecular level can be represented by pathways. Through their analysis, we gain mechanistic insights and interpret lists of interesting genes from experiments (usually omics and functional genomic experiments). As a result, pathways play a central role in the development of bioinformatics methods and tools for computing predictions from known molecular-level mechanisms. Qualitative as well as quantitative knowledge about pathways can be effectively represented through biochemical networks linking the biochemical reactions and the compounds (e.g., proteins) occurring in the considered pathways. So, repositories providing biochemical networks for known pathways play a central role in bioinformatics and in systems biology. Here we focus on Reactome, a free, comprehensive, and widely used repository for biochemical networks and pathways. In this paper, we: (1) introduce a tool StARGate-X (STatistical Analysis of the Reactome multi-GrAph Through nEtworkX) to carry out an automated analysis of the connectivity properties of Reactome biochemical reaction network and of its biological hierarchy (i.e., cell compartments, namely, the closed parts within the cytosol, usually surrounded by a membrane); the code is freely available at https://github.com/marinoandrea/stargate-x; (2) show the effectiveness of our tool by providing an analysis of the Reactome network, in terms of centrality measures, with respect to in- and out-degree. As an example of usage of StARGate-X, we provide a detailed automated analysis of the Reactome network, in terms of centrality measures. We focus both on the subgraphs induced by single compartments and on the graph whose nodes are the strongly connected components. To the best of our knowledge, this is the first freely available tool that enables automatic analysis of the large biochemical network within Reactome through easy-to-use APIs (Application Programming Interfaces).

Sexual attraction to visual sexual stimuli in association with steroid hormones across menstrual cycles and fertility treatment.

BACKGROUND: Steroid hormones (i.e., estradiol, progesterone, and testosterone) are considered to play a crucial role in the regulation of women's sexual desire and sexual attraction to sexual stimuli throughout the menstrual cycle. However, the literature is inconsistent, and methodologically sound studies on the relationship between steroid hormones and women's sexual attraction are rare. METHODS: This prospective longitudinal multisite study examined estradiol, progesterone, and testosterone serum levels in association with sexual attraction to visual sexual stimuli in naturally cycling women and in women undergoing fertility treatment (in vitro fertilization, IVF). Across ovarian stimulation of fertility treatment, estradiol reaches supraphysiological levels, while other ovarian hormones remain nearly stable. Ovarian stimulation hence offers a unique quasi-experimental model to study concentration-dependent effects of estradiol. Hormonal parameters and sexual attraction to visual sexual stimuli assessed with computerized visual analogue scales were collected at four time points per cycle, i.e., during the menstrual, preovulatory, mid-luteal, and premenstrual phases, across two consecutive menstrual cycles (n = 88 and n = 68 for the first and second cycle, respectively). Women undergoing fertility treatment (n = 44) were assessed twice, at the beginning and at the end of ovarian stimulation. Sexually explicit photographs served as visual sexual stimuli. RESULTS: In naturally cycling women, sexual attraction to visual sexual stimuli did not vary consistently across two consecutive menstrual cycles. While in the first menstrual cycle sexual attraction to male bodies, couples kissing, and at intercourse varied significantly with a peak in the preovulatory phase, (all p ≤ 0.001), there was no significant variability across the second cycle. Univariable and multivariable models evaluating repeated cross-sectional relationships and intraindividual change scores revealed no consistent associations between estradiol, progesterone, and testosterone and sexual attraction to visual sexual stimuli throughout both menstrual cycles. Also, no significant association with any hormone was found when the data from both menstrual cycles were combined. In women undergoing ovarian stimulation of IVF, sexual attraction to visual sexual stimuli did not vary over time and was not associated with estradiol levels despite intraindividual changes in estradiol levels from 122.0 to 11,746.0 pmol/l with a mean (SD) of 3553.9 (2472.4) pmol/l. CONCLUSIONS: These results imply that neither physiological levels of estradiol, progesterone, and testosterone in naturally cycling women nor supraphysiological levels of estradiol due to ovarian stimulation exert any relevant effect on women's sexual attraction to visual sexual stimuli.

The androgen system across the menstrual cycle: Hormonal, (epi-)genetic and psychometric alterations.

The menstrual cycle is characterized by various hormonal alterations and associations with mental and physical conditions have been postulated. Among endocrine factors, the androgen system has been a target of major interest in males and to a lesser extent in females and may influence emotion, cognition, behavior and somatic factors. Only few studies investigated alterations of these parameters throughout the menstrual cycle and there is a lack of studies exploring a link towards epigenetic and genetic regulation. This multisite longitudinal study examines behavioral parameters including affectivity, stress perception and various diary parameters of mental and physical well-being in conjunction with testosterone and LH plasma levels in 87 menstruating women. Additionally, Cysteine-Adenenine-Guanin (CAG) repeat length and methylation of the androgen receptor gene collected at four time points across two cycles comprising the menstrual, pre-ovulatory, mid-luteal and premenstrual phase were assesed. There was a significant increase of LH and testosterone plasma levels during the pre-ovulatory phase as well as a decrease of methylation of the androgen receptor at mid-luteal phase. Subjective ratings of physical condition and sexual interest peaked during the pre-ovulatory phase and the former correlated negatively with the androgen receptor gene methylation level. This longitudinal study shows alterations of the androgen system including epigenetic measurements throughout the menstrual cycle. While a link between peripheral testosterone and sexual activity and between increased physical condition and an upregulation of testosterone receptor protein expression can be assumed, the majority of parameters remained unchanged. These initial findings need validation by subsequent studies.

Food preferences throughout the menstrual cycle - A computer-assisted neuro-endocrino-psychological investigation.

BACKGROUND: As eating behavior changes in relation to the menstrual cycle and weight changes with menopausal transition, ovarian hormones appear to be involved in regulating eating behavior. However, observations are contradictory and are difficult to compare, due to methodological problems related to nutritional epidemiology. To better understand the relationship between ovarian steroid hormones and eating behavior, our study evaluates women's responses to visual food cues at different points in the menstrual cycle with their specific serum estrogen/progesterone levels and women's responses in the case of strong estrogen changes in the context of fertility treatments. METHODS: We collected data from 129 women, 44 of whom received in vitro fertilization (IVF) at the Department of Reproductive Endocrinology, University Hospital Zurich. A total of 85 women with natural cycles were recruited at the University Hospital Zurich (n = 37) and at the Hannover Medical School (n = 48). Our observational study used 4 different measurement time points across the natural cycle and 2 measurement time points in women with supraphysiological estradiol levels during fertility treatments. Using a second cycle, we then tested our results for replication. At these predefined time points, women were shown pictures of 11 categories of food, with 4 items for each category and blood samples for measurement of hormone levels were taken. Food preferences registered at the time of the investigation were indicated on a visual analogue scale (0-100). RESULTS: We did not find any statistically significant association between women's serum hormone levels and the rating of visually presented food, either during the menstrual cycle or during fertility treatments after controlling for multiple testing (all p > 0.005). Ratings for fruits, vegetables, and carbohydrates showed a significant linear decline throughout the first menstrual cycle (p < 0.01), which did not replicate in the second cycle (p > 0.05). In contrast, the ratings for sweets showed a significant linear decline in both cycles (both p < 0.01), with a mean rating of 54.2 and 48.8 in the menstrual phase of the first and second cycle, respectively, to a mean rating of 47.7 and 43.4 in the premenstrual phase of the first and second cycle, respectively. During fertility treatments, no food rating showed a significant change (all p > 0.05). Mood such as negative and positive affects did not influence ratings for visual food cues neither throughout the menstrual cycles nor during fertility treatment. CONCLUSIONS: Serum levels of estradiol and progesterone do not correlate with food ratings in women, even when estradiol levels are above the physiological level of a natural menstrual cycle. Since, except for sweets, significant changes in food ratings in a first cycle did not replicate in a second menstrual cycle, significant findings from the literature based on animal or human studies focusing on a single-cycle have to be interpreted with caution.

Mathematical Modeling and Simulation Provides Evidence for New Strategies of Ovarian Stimulation.

New approaches to ovarian stimulation protocols, such as luteal start, random start or double stimulation, allow for flexibility in ovarian stimulation at different phases of the menstrual cycle. It has been proposed that the success of these methods is based on the continuous growth of multiple cohorts ("waves") of follicles throughout the menstrual cycle which leads to the availability of ovarian follicles for ovarian controlled stimulation at several time points. Though several preliminary studies have been published, their scientific evidence has not been considered as being strong enough to integrate these results into routine clinical practice. This work aims at adding further scientific evidence about the efficiency of variable-start protocols and underpinning the theory of follicular waves by using mathematical modeling and numerical simulations. For this purpose, we have modified and coupled two previously published models, one describing the time course of hormones and one describing competitive follicular growth in a normal menstrual cycle. The coupled model is used to test ovarian stimulation protocols in silico. Simulation results show the occurrence of follicles in a wave-like manner during a normal menstrual cycle and qualitatively predict the outcome of ovarian stimulation initiated at different time points of the menstrual cycle.

Cognitive function in association with high estradiol levels resulting from fertility treatment.

The putative association between hormones and cognitive performance is controversial. While there is evidence that estradiol plays a neuroprotective role, hormone treatment has not been shown to improve cognitive performance. Current research is flawed by the evaluation of combined hormonal effects throughout the menstrual cycle or in the menopausal transition. The stimulation phase of a fertility treatment offers a unique model to study the effect of estradiol on cognitive function. This quasi-experimental observational study is based on data from 44 women receiving IVF in Zurich, Switzerland. We assessed visuospatial working memory, attention, cognitive bias, and hormone levels at the beginning and at the end of the stimulation phase of ovarian superstimulation as part of a fertility treatment. In addition to inter-individual differences, we examined intra-individual change over time (within-subject effects). The substantial increases in estradiol levels resulting from fertility treatment did not relate to any considerable change in cognitive functioning. As the tests applied represent a broad variety of cognitive functions on different levels of complexity and with various brain regions involved, we can conclude that estradiol does not show a significant short-term effect on cognitive function.

Neuroprediction and A.I. in Forensic Psychiatry and Criminal Justice: A Neurolaw Perspective.

Advances in the use of neuroimaging in combination with A.I., and specifically the use of machine learning techniques, have led to the development of brain-reading technologies which, in the nearby future, could have many applications, such as lie detection, neuromarketing or brain-computer interfaces. Some of these could, in principle, also be used in forensic psychiatry. The application of these methods in forensic psychiatry could, for instance, be helpful to increase the accuracy of risk assessment and to identify possible interventions. This technique could be referred to as 'A.I. neuroprediction,' and involves identifying potential neurocognitive markers for the prediction of recidivism. However, the future implications of this technique and the role of neuroscience and A.I. in violence risk assessment remain to be established. In this paper, we review and analyze the literature concerning the use of brain-reading A.I. for neuroprediction of violence and rearrest to identify possibilities and challenges in the future use of these techniques in the fields of forensic psychiatry and criminal justice, considering legal implications and ethical issues. The analysis suggests that additional research is required on A.I. neuroprediction techniques, and there is still a great need to understand how they can be implemented in risk assessment in the field of forensic psychiatry. Besides the alluring potential of A.I. neuroprediction, we argue that its use in criminal justice and forensic psychiatry should be subjected to thorough harms/benefits analyses not only when these technologies will be fully available, but also while they are being researched and developed.

Associations Between Natural Physiological and Supraphysiological Estradiol Levels and Stress Perception.

Stress is a risk factor for impaired general, mental, and reproductive health. The role of physiological and supraphysiological estradiol concentrations in stress perception and stress processing is less well understood. We, therefore, conducted a prospective observational study to investigate the association between estradiol, stress perception, and stress-related cognitive performance within serial measurements either during the natural menstrual cycle or during fertility treatment, where estradiol levels are strongly above the physiological level of a natural cycle, and consequently, represent a good model to study dose-dependent effects of estradiol. Data from 44 women receiving in vitro fertilization (IVF) at the Department of Reproductive Endocrinology in Zurich, Switzerland was compared to data from 88 women with measurements during their natural menstrual cycle. The German version of the Perceived Stress Questionnaire (PSQ) and the Cognitive Bias Test (CBT), in which cognitive performance is tested under time stress were used to evaluate subjective and functional aspects of stress. Estradiol levels were investigated at four different time points during the menstrual cycle and at two different time points during a fertility treatment. Cycle phases were associated with PSQ worry and cognitive bias in normally cycling women, but different phases of fertility treatment were not associated with subjectively perceived stress and stress-related cognitive bias. PSQ lack of joy and PSQ demands related to CBT in women receiving fertility treatment but not in women with a normal menstrual cycle. Only strong changes of the estradiol level during fertility treatment were weakly associated with CBT, but not with subjectively experienced stress. Our research emphasizes the multidimensional character of stress and the necessity to adjust stress research to the complex nature of stress perception and processing. Infertility is associated with an increased psychological burden in patients. However, not all phases of the process to overcome infertility do significantly increase patient stress levels. Also, research on the psychological burden of infertility should consider that stress may vary during the different phases of fertility treatment. Clinical trial registration: ClinicalTrials.gov # NCT02098668.

Negative affect is unrelated to fluctuations in hormone levels across the menstrual cycle: Evidence from a multisite observational study across two successive cycles.

BACKGROUND: Female sex hormones may play a crucial role in the occurrence of cycle-related mood disorders. However, the literature is inconsistent and methodologically stringent observational studies on the relationship between sex hormones and negative affect are lacking. METHODS: In this longitudinal multisite study from Hannover, Germany, and Zurich, Switzerland, we examined oestrogen, progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone serum levels in association with negative affect as measured with the Positive and Negative Affect Schedule (PANAS). Negative affect and hormone assays were collected at four consecutive time points comprising menstrual, pre-ovulatory, mid-luteal and premenstrual phase across two cycles (n=87 and n=67 for the first and second cycles). The Beck Depression Inventory (BDI) was assessed once prior to the first cycle and included as a secondary measure. RESULTS: Mean negative affect scores did not significantly fluctuate across both cycles and there was in particular no symptom increase premenstrually. No sex hormone consistently related to repeated measures of negative affect across two consecutive cycles. The BDI sum-score assessed at baseline was not related to hormone levels across the first cycle. CONCLUSIONS: This is the first multisite longitudinal study on the association between negative affect and sex hormone levels encompassing two consecutive menstrual cycles. Negative affect did not fluctuate across the cycle and there was no direct and uniform association between sex hormones and self-reported negative affect. These findings suggest that moderators such as personality traits and epigenetics should be considered in future research.

Lack of Associations between Female Hormone Levels and Visuospatial Working Memory, Divided Attention and Cognitive Bias across Two Consecutive Menstrual Cycles.

Background: Interpretation of observational studies on associations between prefrontal cognitive functioning and hormone levels across the female menstrual cycle is complicated due to small sample sizes and poor replicability. Methods: This observational multisite study comprised data of n = 88 menstruating women from Hannover, Germany, and Zurich, Switzerland, assessed during a first cycle and n = 68 re-assessed during a second cycle to rule out practice effects and false-positive chance findings. We assessed visuospatial working memory, attention, cognitive bias and hormone levels at four consecutive time-points across both cycles. In addition to inter-individual differences we examined intra-individual change over time (i.e., within-subject effects). Results: Estrogen, progesterone and testosterone did not relate to inter-individual differences in cognitive functioning. There was a significant negative association between intra-individual change in progesterone and change in working memory from pre-ovulatory to mid-luteal phase during the first cycle, but that association did not replicate in the second cycle. Intra-individual change in testosterone related negatively to change in cognitive bias from menstrual to pre-ovulatory as well as from pre-ovulatory to mid-luteal phase in the first cycle, but these associations did not replicate in the second cycle. Conclusions: There is no consistent association between women's hormone levels, in particular estrogen and progesterone, and attention, working memory and cognitive bias. That is, anecdotal findings observed during the first cycle did not replicate in the second cycle, suggesting that these are false-positives attributable to random variation and systematic biases such as practice effects. Due to methodological limitations, positive findings in the published literature must be interpreted with reservation.