Predicting estrogen receptor binding of chemicals using a suite of in silico methods - Complementary approaches of (Q)SAR, molecular docking and molecular dynamics.

With the aim of obtaining reliable estimates of Estrogen Receptor (ER) binding for diverse classes of compounds, a weight of evidence approach using estimates from a suite of in silico models was assessed. The predictivity of a simple Majority Consensus of (Q)SAR models was assessed using a test set of compounds with experimental Relative Binding Affinity (RBA) data. Molecular docking was also carried out and the binding energies of these compounds to the ERα receptor were determined. For a few selected compounds, including a known full agonist and antagonist, the intrinsic activity was determined using low-mode molecular dynamics methods. Individual (Q)SAR model predictivity varied, as expected, with some models showing high sensitivity, others higher specificity. However, the Majority Consensus (Q)SAR prediction showed a high accuracy and reasonably balanced sensitivity and specificity. Molecular docking provided quantitative information on strength of binding to the ERα receptor. For the 50 highest binding affinity compounds with positive RBA experimental values, just 5 of them were predicted to be non-binders by the Majority QSAR Consensus. Furthermore, agonist-specific assay experimental values for these 5 compounds were negative, which indicates that they may be ER antagonists. We also showed different scenarios of combining (Q)SAR results with Molecular docking classification of ER binding based on cut-off values of binding energies, providing a rational combined strategy to maximize terms of toxicological interest.

Healing from weight stigma in community: A thematic analysis of a group intervention for large-bodied individuals.

Discrimination against and negative beliefs about large-bodied individuals, known as weight stigma, is pervasive and harmful. While previous research has focused on the negative consequences of weight stigma, the present study aims to highlight the lived experience of large-bodied individuals while also exploring the process of healing from harmful experiences of weight stigma. Ten adult (9/10 White, 8/10 cisgender women), large-bodied individuals recruited via snowball sampling through a nonprofit, grassroots, eating disorder advocacy organization participated in a 10-week, counselor-facilitated support group with the shared goal of healing from the impact of weight stigma. Researchers used reflexive thematic analysis to analyze video recordings and transcripts of group sessions to answer the following question: how did participants make sense of their weight stigma experiences and engage with the process of healing in community? Four primary themes were generated: (a) Community is Essential, (b) Storying, (c) Deprogramming and Changing Mindset, and (d) Expansive Healing. These results underscore the impact of weight stigma in the lives of large-bodied individuals and provide insight into how clinicians might support such individuals engaging in collective healing from these painful experiences. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Sequential modulation of cardiac autonomic control induced by cardiopulmonary and arterial baroreflex mechanisms.

BACKGROUND: Nonhypotensive lower body negative pressure (LBNP) induces a reflex increase in forearm vascular resistance and muscle sympathetic neural discharge without affecting mean heart rate. We tested the hypothesis that a reflex change of the autonomic modulation of heartbeat might arise during low intensity LBNP without changes of mean heart rate. METHODS AND RESULTS: Ten healthy volunteers underwent plasma catecholamine evaluation and a continuous recording of ECG, finger blood pressure, respiratory activity, and central venous pressure (CVP) during increasing levels of LBNP up to -40 mm Hg. Spectrum and cross-spectrum analyses assessed the changes in the spontaneous variability of R-R interval, respiration, systolic arterial pressure (SAP), and CVP and in the gain (alpha(LF)) of arterial baroreflex control of heart rate. Baroreceptor sensitivity was also evaluated by the SAP/R-R spontaneous sequences technique. LBNP began decreasing significantly: CVP at -10, R-R interval at -20, SAP at -40, and the indexes alpha(LF) and baroreceptor sensitivity at -30 and -20 mm Hg, compared with baseline conditions. Plasma norepinephrine increased significantly at -20 mm Hg. The normalized low-frequency component of R-R variability (LF(R-R)) progressively increased and was significantly higher than in the control condition at -15 mm Hg. CONCLUSIONS: Nonhypotensive LBNP elicits a reflex increase of cardiac sympathetic modulation, as evaluated by LF(R-R), which precedes the changes in the hemodynamics and in the indexes of arterial baroreflex control.

Orthostatic intolerance: different abnormalities in the neural sympathetic response to a gravitational stimulus.

In this paper we shall focus on the different abnormalities in the neural sympathetic response to a gravitational stimulus, characterising syndromes with symptoms of orthostatic intolerance. In Vaso vagal Syncope, an increase or a reduction of cardiac and vascular sympathetic modulation have been described in occasional and habitual fainters, respectively. Pure Autonomic Failure (PAF) is characterized by a global cardiovascular denervation. Accordingly, the spectral markers of cardiac and vascular sympathetic modulation are absent or reduced. However, a concomitant vagal diminished activity is present. In Chronic Orthostatic Intolerance (COI), the most common form of dysautonomia in young female, an abnormal regional distribution of sympathetic discharge has been hypothesized during standing. Indeed, an overall increased sympathetic activity is present in recumbent position; during tilt a blunted vascular sympathetic discharge, with a concomitant exaggerated cardiac sympathetic modulation, is evident. Baroreflex Failure is a syndrome that may result from neck surgery or irradiation due to different forms of regional cancer. It is characterized by a volatility of blood pressure and heart rate, without habitual orthostatic hypotension. In the present paper, we describe a case of Baroreflex Failure with marked orthostatic hypotension in spite of a huge muscle sympathetic nerve activity (MSNA) and high levels of plasma cathecolamines. The most relevant finding was the absence of any coordinate rythmicity in blood pressure, heart rate and MSNA, both at rest and during tilt, particularly in the frequency band likely to be related with sympathetic modulation, i.e. at 0.1 Hz. We hypothesize that the absence of 0.1 Hz spontaneous fluctuations might play a role in sustaining orthostatic hypotension.

Dissociation of the effects of acute chlomipramine on morphine analgesia and plasma concentrations.

Morphine-induced analgesia and plasma concentrations were evaluated in rats after the administration of the opiate alone or together with chlomipramine, a tricyclic antidepressant drug. As expected, chlomipramine increased antinociceptive thresholds, but also increased morphine-induced analgesia in a dose-related fashion. Plasma concentrations of free morphine were higher in rats that had been administered chlomipramine, but the increase in plasma concentrations was not related to the increase in analgesic thresholds. In conclusion, the data reported indicate that chlomipramine increases the analgesic effect of morphine, but this is not related to plasma concentrations of the opiate.