Structure-Activity Relationships of the Fentanyl Scaffold: Identification of Antagonists as Potential Opioid Overdose Reversal Agents.

Opioid-related overdoses account for almost half of all drug overdose deaths in the United States and cause more preventable deaths every year than car crashes. Fentanyl, a highly potent mu opioid receptor (MOR) agonist and its analogues (fentalogues) are increasingly found in illicit drug samples, both where the primary drug of abuse is an opioid and where it is not. The prevalence of fentalogues in the illicit drug market is thought to be the primary driver of the increased number of opioid-related overdose deaths since 2016. In fact, fentanyl and its analogues are involved in more than 70% of opioid-related overdoses. The standard opioid overdose rescue therapy naloxone is often insufficient to reverse opioid overdoses caused by fentalogue agonists under current treatment paradigms. However, the pharmacology of many fentalogues is unknown. Moreover, within the fentalogue series of compounds, it is possible that antagonists could be identified that might be superior to naloxone as opioid overdose reversal agents. In this report, we explore the pharmacology of 70 fentalogues and identify compounds that behave as MOR antagonists in vitro and demonstrate with one of these reversals of fentanyl-induced respiratory depression in the mouse. Such compounds could provide leads for the development of effective agents for the reversal of opioid overdose.

Do salient abrupt onsets trigger suppression?

Many studies have indicated that abrupt onsets can capture our attention involuntarily. The present study examined whether task-irrelevant onsets trigger strong suppression of their features, to reduce the ability of the onsets to capture attention. We used a capture-probe paradigm with salient abrupt onsets as precues. Participants performed a search task (70% of the trials) with occasional probe tasks mixed in (30% of the trials). In Experiment 1, two irrelevant-color distractors appeared simultaneously with the target, one of which was always precued by the abrupt onset. The question was whether an abrupt onset cue would promote suppression of the correlated color, thereby impeding recall of probe letters at a location with that color. This did not happen. The same result was obtained in Experiment 2, despite removing the target shape from the probe display to minimize floor effects and despite presenting only one distractor color per trial to further strengthen the onset-color association. In Experiment 3, one of the two irrelevant-color distractors abruptly onsetted 50 ms before the other search elements. Despite efforts to promote suppression of the cued distractor color, probe recall accuracy was again similar for the cued and non-cued distractor colors. We conclude that distractor features are suppressed but that making them especially salient does not noticeably enhance this suppression. The suppression mechanism is therefore geared towards helping observers discriminate between target features and distractor features, not towards beating down the most threatening object.

The role of perceptual difficulty in visual hindsight bias for emotional faces.

Visual hindsight bias, also known as the "saw-it-all-along" effect, is the tendency to overestimate one's perceptual abilities with the aid of outcome knowledge. Recently, Giroux et al. (2022, Emotion, https://doi.org/10.1037/emo0001068 ) reported robust visual hindsight bias for emotional faces except for happy. We examined whether the difficulty of emotional processing could explain their finding. As in Giroux et al., participants saw a blurred image of an emotional face (happy, angry, or neutral) that progressed to clear and were instructed to stop the clearing process when they were able to identify the emotion (foresight trials). They then were shown the clearest image of each face and determined the emotion, followed by a memory task where they were asked to adjust the blur levels to indicate the point at which they had identified the emotion earlier (hindsight trials). Experiment 1 replicated Giroux et al.'s finding, showing that participants stopped the image at a higher degree of blur during the hindsight trials than they had during the foresight trials (i.e., a visual hindsight bias) for the angry and neutral faces but not happy faces. Experiment 2 manipulated the perceptual difficulty of angry and happy faces. While the easy faces replicated the results of Experiment 1, both angry and happy faces produced strong bias when made difficult. A multinomial processing tree model suggests that visual hindsight bias for emotional faces, while robust, is sensitive to perceptual processing difficulties across emotions.

The Floral Microbiome and Its Management in Agroecosystems: A Perspective.

Disease management is critical to ensuring healthy crop yields and is often targeted at flowers because of their susceptibility to pathogens and direct link to reproduction. Many disease management strategies are unsustainable however because of the potential for pathogens to evolve resistance, or nontarget effects on beneficial insects. Manipulating the floral microbiome holds some promise as a sustainable alternative to chemical means of disease control. In this perspective, we discuss the current state of research concerning floral microbiome assembly and management in agroecosystems as well as future directions aimed at improving the sustainability of disease control and insect-mediated ecosystem services.

Cross-species analysis of thyroperoxidase inhibition by xenobiotics demonstrates conservation of response between pig and rat.

Thyroperoxidase (TPO), the enzyme that catalyzes the synthesis of thyroid hormone, is a known target for thyroid-disrupting chemicals. In vivo toxicological evidence supporting TPO-inhibition as one molecular-initiating event that leads to thyroid disruption is derived largely from rat models; however, a significant fraction of research on the inhibition of TPO by xenobiotics has been conducted using porcine TPO. The current work tested the hypothesis that porcine and rat thyroid microsomes exposed to TPO-inhibiting chemicals would demonstrate different responses in a guaiacol oxidation assay. A primary objective of this work is to establish the degree of concordance between rat and porcine TPO inhibition data. Microsomes were isolated from both rat and pig thyroid glands, and the guaiacol oxidation assay was performed for a training set of 12 chemicals, including previously reported TPO inhibitors, thyroid-disrupting chemicals thought to perturb other targets, and several previously untested chemicals, to determine the relative TPO inhibition responses across species. Concentration-response curves were derived for methimazole (MMI), dibutylphthalate (DBP), diethylhexylphthalate (DEHP), diethylphthalate (DEP), 3,5-dimethylpyrazole-1-methanol (DPM), iopanoic acid (IOA), 2-mercaptobenzothiazole (MBT), sodium perchlorate (PERC), p-nonylphenol (PNP), 4-propoxyphenol (4POP), 6-propylthiouracil (PTU), and triclosan (TCS). MMI, PTU, MBT, DPM, 4POP, and at extremely high concentrations, PERC, inhibited TPO activity. Results demonstrated a strong qualitative concordance of response between the two species. All chemicals that inhibited TPO in porcine microsomes also inhibited TPO in rat microsomes. Hill model-derived IC50 values revealed approximate 1.5- to 50-fold differences in relative potency to MMI between species for positive chemicals. DPM, MBT, 4POP, and PTU exhibited greater relative potency to MMI using rat TPO versus porcine TPO, but rank order potency for inhibition was similar for the other test chemicals, with: PTU>MBT>DPM>4POP>PERC for rat TPO and MBT>PTU>DPM>4POP>PERC for porcine TPO. These data support the extrapolation of porcine TPO data to potential thyroid-disrupting activity in rodent models to evaluate TPO-inhibiting chemicals.

Inhibition of the thyroid hormone pathway in Xenopus laevis by 2-mercaptobenzothiazole.

Determining the effects of chemicals on the thyroid system is an important aspect of evaluating chemical safety from an endocrine disrupter perspective. Since there are numerous chemicals to test and limited resources, prioritizing chemicals for subsequent in vivo testing is critical. 2-Mercaptobenzothiazole (MBT), a high production volume chemical, was tested and shown to inhibit thyroid peroxidase (TPO) enzyme activity in vitro, a key enzyme necessary for the synthesis of thyroid hormone. To determine the thyroid disrupting activity of MBT in vivo, Xenopus laevis larvae were exposed using 7- and 21-day protocols. The 7-day protocol used 18-357 µg/L MBT concentrations and evaluated: metamorphic development, thyroid histology, circulating T4, circulating thyroid stimulating hormone, thyroidal sodium-iodide symporter gene expression, and thyroidal T4, T3, and related iodo-amino acids. The 21-day protocol used 23-435 µg/L MBT concentrations and evaluated metamorphic development and thyroid histology. Both protocols demonstrated that MBT is a thyroid disrupting chemical at the lowest concentrations tested. These studies complement the in vitro study used to identify MBT as a high priority for in vivo testing, supporting the utility/predictive potential of a tiered approach to testing chemicals for TPO activity inhibition. The 7-day study, with more comprehensive, sensitive, and diagnostic endpoints, provides information at intermediate biological levels that enables linking various endpoints in a robust and integrated pathway for thyroid hormone disruption associated with TPO inhibition.

Trenbolone causes mortality and altered sexual differentiation in Xenopus tropicalis during larval development.

Trenbolone is an androgen agonist used in cattle production and has been measured in aquatic systems associated with concentrated animal-feeding operations. In this study, the authors characterized the effects of aqueous exposure to 17ß-trenbolone during larval Xenopus tropicalis development. Trenbolone exposure resulted in increased mortality of post-Nieuwkoop-Faber stage 58 tadpoles at concentrations ≥100 ng/L. Morphological observations and the timing of this mortality are consistent with hypertrophy of the larynx. Development of nuptial pads, a male secondary sex characteristic, was induced in tadpoles of both sexes at 100 ng/L. Effects on time to complete metamorphosis or body sizes were not observed; however, grow-outs placed in clean media for six weeks were significantly smaller in body size at 78 ng/L. Effects on sex ratios were equivocal, with the first experiment showing a significant shift in sex ratio toward males at 78 ng/L. In the second experiment, no significant effects were observed up to 100 ng/L, although overall sex ratios were similar. Histological assessment of gonads at metamorphosis showed half with normal male phenotypes and half that possessed a mixed-sex phenotype at 100 ng/L. Hypertrophy of the Wolffian ducts was also observed at this concentration. These results indicate that larval 17ß-trenbolone exposure results in effects down to 78 ng/L, illustrating potential effects from exposure to androgenic compounds in anurans.