Classic serotonergic psychedelics such as psilocybin act as agonists at cortical serotonin (5-HT) 2A receptors (5-HT2AR), inducing psychedelic effects in humans and head-twitch responses (HTRs) in rodents. Another class of psychedelic drugs called entactogens, exemplified by MDMA, function primarily as monoamine releasers and typically evoke minimal HTR despite causing serotonin release. The polypharmacology of psychedelic drugs at receptors other than 5-HT2AR may modulate their behavioral effects. Here, we report that MDMA, but not psilocybin, induces robust elevations of both 5-HT and norepinephrine (NE) in the medial prefrontal cortex. Blocking the release of extracellular NE unmasks MDMA-evoked HTR, suggesting that polypharmacology involving noradrenergic receptors may oppose the 5-HT2A-mediated effects of MDMA. Artificially elevating NE also attenuates psilocybin-induced HTR, supporting this hypothesis. Selective agonism of the noradrenergic α2 receptor (α2R) is sufficient to suppress 5-HT2A-mediated HTR, and also suppresses the HTR in locus coeruleus-ablated mice, suggesting that this effect is mediated by heteroreceptors. Moreover, psilocybin-induced effects in the forced swim test persisted in the presence of α₂R activation. Thus, these findings support a model in which some forms of 5-HT2A signaling can be attenuated by α2R activation without interfering with antidepressant-like effects. The ability to reduce potential side effects of 5-HT2A activation while preserving antidepressant-like effects via α2R and other analogous receptors may be relevant to therapeutic development.

PURPOSE:Pigment dispersion syndrome and pigmentary glaucoma are important causes of ocular hypertension and glaucomatous optic neuropathy, yet their genetic determinants remain incompletely defined, particularly across diverse ancestries. This study aimed to use a large multi-ancestry cohort from the All of Us Research Program to investigate the genetic basis of pigment dispersion syndrome and pigmentary glaucoma. DESIGN:Case-control study. PARTICIPANTS:In total, 572 cases and 37 808 controls with array genotyping and 537 cases and 35 493 controls with whole-genome sequencing. METHODS:Using electronic health record phenotyping in the All of Us Research Program, we performed multi-ancestry genome-wide association analyses using both array-based data and whole-genome sequencing-based data, comparing patients with pigment dispersion syndrome or pigmentary glaucoma to those without either condition. We also performed Firth penalized regression and Fisher analyses, and we performed principal component analyses to assess effect sizes across genetic ancestries. We applied statistical fine-mapping, examined for cross-trait overlap, and assessed expression quantitative trait locus associations for lead variants. MAIN OUTCOME MEASURES:P values and odds ratios of lead loci from genome-wide association analyses; size of credible sets determined from fine-mapping; allele frequency of lead variants in cases, controls, and the general population; expression quantitative trait loci effect size and P values linking lead variants to gene expression. RESULTS:We identified 4 loci reaching genome-wide significance across analyses, including signals near EPHA7 (which mediates cell-cell signaling), within TYR (involved in melanin synthesis and replicated from prior studies), within LINC01138, and near OTX2. Statistical fine-mapping refined 3 of these loci to single-variant 95% credible sets and narrowed the TYR locus to small credible sets, prioritizing possible causal variants. Effect estimates were broadly consistent across genetic ancestry clusters. Lead variants showed regulatory evidence in expression quantitative trait locus, including reduced EPHA7 expression. CONCLUSIONS:These findings implicate both melanogenesis and cell-cell adhesion and signaling pathways in pigment dispersion syndrome and pigmentary glaucoma. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Classic serotonergic psychedelics such as psilocybin act as agonists at cortical serotonin (5-HT) 2A receptors (5-HT2AR), inducing psychedelic effects in humans and head-twitch responses (HTRs) in rodents. Another class of psychedelic drugs called entactogens, exemplified by MDMA, function primarily as monoamine releasers and typically evoke minimal HTR despite causing serotonin release. The polypharmacology of psychedelic drugs at receptors other than 5-HT2AR may modulate their behavioral effects. Here, we report that MDMA, but not psilocybin, induces robust elevations of both 5-HT and norepinephrine (NE) in the medial prefrontal cortex. Blocking the release of extracellular NE unmasks MDMA-evoked HTR, suggesting that polypharmacology involving noradrenergic receptors may oppose the 5-HT2A-mediated effects of MDMA. Artificially elevating NE also attenuates psilocybin-induced HTR, supporting this hypothesis. Selective agonism of the noradrenergic alpha 2 receptor (alpha 2R) is sufficient to suppress 5-HT2A-mediated HTR, and also suppresses the HTR in locus coeruleus-ablated mice, suggesting that this effect is mediated by heteroreceptors. Moreover, psilocybin-induced effects in the forced swim test persisted in the presence of alpha R-2 activation. Thus, these findings support a model in which some forms of 5-HT2A signaling can be attenuated by alpha 2R activation without interfering with antidepressant-like effects. The ability to reduce potential side effects of 5-HT2A activation while preserving antidepressant-like effects via alpha 2R and other analogous receptors may be relevant to therapeutic development.

Purpose:This prospective observational study assesses the efficacy of using portable next-generation sequencing directly on tear samples to identify bacterial pathogens in corneal ulcers. Methods:Tear samples were collected from ulcerated and contralateral eyes using Schirmer strips. Corneal scrapings and cultures were performed as medically indicated. The 16S rRNA gene was amplified from tear samples using polymerase chain reaction (PCR), and Nanopore sequencing was used for bacterial species identification and taxonomic classification. Results:Bacterial DNA was identified in 8 of 10 samples using the tear-based sequencing method. Nanopore sequencing accurately identified the causative bacteria in all four samples that exhibited bacterial growth on culture and detected bacterial pathogens in two of the four ulcers that did not show bacterial growth on culture. In two cases where cultures could not be obtained due to the ulcer's small size, tear sequencing successfully identified bacterial species. Among the nine contralateral tear samples collected, Nanopore sequencing identified commensal bacteria in four samples. Conclusions:PCR amplification of 16S rRNA directly from tears followed by Nanopore sequencing is an effective, noninvasive method to identify bacterial pathogens in corneal ulcers, offering noninferior results to traditional culture methods. Translational Relevance:By eliminating the need for corneal scrapings and nucleic acid extraction, this tear-based method improves the timing and accuracy of bacterial pathogen diagnosis in corneal ulcers, allowing for prompt detection of causative organisms and enabling earlier targeted antimicrobial therapy, thereby improving patient outcomes.

Psilocybin, ketamine, and MDMA are psychoactive compounds that exert behavioral effects with distinguishable but also overlapping features. The growing interest in using these compounds as therapeutics necessitates preclinical assays that can accurately screen psychedelics and related analogs. We posit that a promising approach may be to measure drug action on markers of neural plasticity in native brain tissues. We therefore developed a pipeline for drug classification using light sheet fluorescence microscopy of immediate early gene expression at cellular resolution followed by machine learning. We tested male and female mice with a panel of drugs, including psilocybin, ketamine, 5-MeO-DMT, 6-fluoro-DET, MDMA, acute fluoxetine, chronic fluoxetine, and vehicle. In one-versus-rest classification, the exact drug was identified with 67% accuracy, significantly above the chance level of 12.5%. In one-versus-one classifications, psilocybin was discriminated from 5-MeO-DMT, ketamine, MDMA, or acute fluoxetine with >95% accuracy. We used Shapley additive explanation to pinpoint the brain regions driving the machine learning predictions. Our results suggest a unique approach for characterizing and validating psychoactive drugs with psychedelic properties.

Serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses. Compounds with short-lived subjective effects may be clinically useful because dosing time would be reduced, which may improve patient access. One short-acting psychedelic is 5-MeO-DMT, which has been associated with improvement in depression and anxiety symptoms in early phase clinical studies. However, relatively little is known about the behavioral and neural mechanisms of 5-MeO-DMT, particularly the durability of its long-term effects. Here we characterized the effects of 5-MeO-DMT on innate behaviors and dendritic architecture in mice. We showed that 5-MeO-DMT induces a dose-dependent increase in head-twitch response that is shorter in duration than that induced by psilocybin at all doses tested. 5-MeO-DMT also substantially suppresses social ultrasonic vocalizations produced during mating behavior. 5-MeO-DMT produces long-lasting increases in dendritic spine density in the mouse medial frontal cortex that are driven by an elevated rate of spine formation. However, unlike psilocybin, 5-MeO-DMT did not affect the size of dendritic spines. These data provide insights into the behavioral and neural consequences underlying the action of 5-MeO-DMT and highlight similarities and differences with those of psilocybin.

Serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses. Compounds with short-lived subjective effects may be clinically useful because dosing time would be reduced, improving patient access. The short-acting psychedelic is 5-MeO-DMT has been associated with improvement in depression and anxiety symptoms in early clinical studies. However relatively little is known about the behavioral effects and neural mechanisms of 5-MeO-DMT in mice.

In this paper, we develop a density dependent model to describe sperm whale population dynamics in the Gulf of Mexico. For this model, we consider the stability of the extinction equilibrium and prove the existence and uniqueness of a positive equilibrium. We then examine the stability of the positive equilibrium and substantiate the results with numerical simulations using Matlab. Next, we consider the effect of a disturbance, such as the Deepwater Horizon oil spill, on the sperm whale population in the Gulf of Mexico. Describing a disturbance as an event that results in reductions in survival rates for a certain period of time, we examine the recovery time of a sperm whale population following a disturbance, which we define to be the length of time it takes the population to return to a certain percentage of its asymptotic equilibrium value. Through testing various recovery threshold values, reductions in survival rates, and lengths of time over which the survival rates are reduced, we find that the recovery time is sensitive to each of these variables; depending on the values of these three quantities, the recovery time can last anywhere between a few years and many centuries.