Structural pharmacology and therapeutic potential of 5-methoxytryptamines.

Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders1-3. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT2A (ref. 4). However, 5-HT1A also plays a part in the behavioural effects of tryptamine hallucinogens5, particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads6. Although 5-HT1A is a validated therapeutic target7,8, little is known about how psychedelics engage 5-HT1A and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT1A, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure-activity relationship analyses of 5-methoxytryptamines at both 5-HT1A and 5-HT2A enable the characterization of molecular determinants of 5-HT1A signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT1A agonists. We show that a 5-HT1A-selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT1A-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.

The Effect of Cellulose Nanocrystal Reassembly on Latex-Based Pressure-Sensitive Adhesive Performance.

Different cellulose nanocrystal (CNC) forms (dried vs never-dried) can lead to different degrees of CNC reassembly, the formation of nanofibril-like structures, in nanocomposite latex-based pressure-sensitive adhesive (PSA) formulations. CNC reassembly is also affected by CNC sonication and loading as well as the protocol used for CNC addition to the polymerization. In this study, carboxylated CNCs (cCNCs) were incorporated into a seeded, semibatch, 2-ethylhexyl acrylate/methyl methacrylate/styrene emulsion polymerization and cast as pressure-sensitive adhesive (PSA) films. The addition of CNCs led to a simultaneous increase in tack strength, peel strength, and shear adhesion, avoiding the typical trade-off between the adhesive and cohesive strength. Increased CNC reassembly resulted from the use of dried, redispersed, and sonicated cCNCs, along with increased cCNC loading and addition of the cCNCs at the seed stage of the polymerization. The increased degree of CNC reassembly was shown to significantly increase the shear adhesion by enhancing the elastic modulus of the PSA films.

Whole genome sequencing identifies associations for nonsyndromic sagittal craniosynostosis with the intergenic region of BMP2 and noncoding RNA gene LINC01428.

Craniosynostosis (CS) is a major birth defect resulting from premature fusion of cranial sutures. Nonsyndromic CS occurs more frequently than syndromic CS, with sagittal nonsyndromic craniosynostosis (sNCS) presenting as the most common CS phenotype. Previous genome-wide association and targeted sequencing analyses of sNCS have identified multiple associated loci, with the strongest association on chromosome 20. Herein, we report the first whole-genome sequencing study of sNCS using 63 proband-parent trios. Sequencing data for these trios were analyzed using the transmission disequilibrium test (TDT) and rare variant TDT (rvTDT) to identify high-risk rare gene variants. Sequencing data were also examined for copy number variants (CNVs) and de novo variants. TDT analysis identified a highly significant locus at 20p12.3, localized to the intergenic region between BMP2 and the noncoding RNA gene LINC01428. Three variants (rs6054763, rs6054764, rs932517) were identified as potential causal variants due to their probability of being transcription factor binding sites, deleterious combined annotation dependent depletion scores, and high minor allele enrichment in probands. Morphometric analysis of cranial vault shape in an unaffected cohort validated the effect of these three single nucleotide variants (SNVs) on dolichocephaly. No genome-wide significant rare variants, de novo loci, or CNVs were identified. Future efforts to identify risk variants for sNCS should include sequencing of larger and more diverse population samples and increased omics analyses, such as RNA-seq and ATAC-seq.

GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents.

The NMDA receptor (NMDAR) antagonist ketamine has shown great potential as a rapid-acting antidepressant; however, its use is limited by poor oral bioavailability and a side effect profile that necessitates in-clinic dosing. GM-1020 is a novel NMDAR antagonist that was developed to address these limitations of ketamine as a treatment for depression. Here, we present the preclinical characterization of GM-1020 alongside ketamine, for comparison. In vitro, we profiled GM-1020 for binding to NMDAR and functional inhibition using patch-clamp electrophysiology. In vivo, GM-1020 was assessed for antidepressant-like efficacy using the Forced Swim Test (FST) and Chronic Mild Stress (CMS), while motor side effects were assessed in spontaneous locomotor activity and on the rotarod. The pharmacokinetic properties of GM-1020 were profiled across multiple preclinical species. Electroencephalography (EEG) was performed to determine indirect target engagement and provide a potentially translational biomarker. These results demonstrate that GM-1020 is an orally bioavailable NMDAR antagonist with antidepressant-like efficacy at exposures that do not produce unwanted motor effects.

Diagnostic Accuracy of Laryngeal Ultrasound for Evaluating Vocal Fold Movement Impairment in Children.

PURPOSE: Vocal fold movement impairment (VFMI) secondary to recurrent laryngeal nerve (RLN) injury is a common source of morbidity after pediatric cervical, thoracic, and cardiac procedures. Flexible laryngoscopy (FL) is the gold standard to diagnose VFMI yet can be challenging to perform and/or risks possible clinical decompensation in some children and is an aerosolizing procedure. Laryngeal ultrasound (LUS) is a potential non-invasive alternative, but limited data exists in the pediatric surgical population regarding its efficacy. We aimed to investigate the diagnostic accuracy of LUS compared to FL in evaluating VFMI. METHODS: A prospective, single-center, single-blinded (rater) cohort study was undertaken on perioperative pediatric patients at risk for RLN injury. Patients underwent FL and LUS. Cohen's kappa was used to determine chance-corrected agreement. RESULTS: Between 2021 and 2023, 85 paired evaluations were performed with patients having a median (IQR) age of 10 (4, 42) months and weight of 7.5 (5.4, 13.4) kilograms. The prevalence of VFMI was 27.1%. Absolute agreement between evaluations was 98.8% (kappa 0.97, 95% CI: 0.91-1.00, P < 0.001). The sensitivity and specificity of LUS in detecting VFMI was 95.7% and 100%, yielding a positive predictive value (PPV) of 100% and negative predictive value (NPV) of 98.4% (95% CI: 90-100%). Diagnostic accuracy was 98.8% (95% CI: 93-100%). CONCLUSION: LUS is a highly accurate modality in evaluating VFMI in children. While FL remains the gold standard for diagnosis, LUS offers a low-risk screening modality for children at risk for VFMI such that only those with an abnormal LUS or presence of clinical symptoms discordant with LUS findings should undergo FL. TYPE OF STUDY: Prospective, single-center, single blinded (rater), cohort study. LEVEL OF EVIDENCE: Level II.

CO2-Switchable colloids.

The development and design of CO2-switchable colloidal particles is described. A presentation of the principles of CO2 switching, especially as they apply to colloids, is followed by recent progress in the preparation of several types of colloidal particles (polymer nanoparticles, metal-organic frameworks (MOFs), quantum dots, graphene, cellulose nanocrystals, carbon nanotubes) for various applications (Pickering stabilizers, catalysts, latexes), and our perspective on future opportunities.

A Congenital Tongue Mass.

A 13-month-old male presents with a firm left anterior tongue mass noted since birth that has increased proportionally with the child's growth. What is your diagnosis?

CTNNB1 and APC Mutations in Sinonasal Myxoma : Expanding the Spectrum of Tumors Driven By WNT/ß-catenin Pathway.

Sinonasal myxoma (SNM) is a rare, benign mesenchymal neoplasm with distinct clinicopathologic features and aberrant nuclear localization of ß-catenin by immunohistochemistry. The molecular underpinnings have been linked to that of a "myxoid variant" of desmoid fibromatosis. Herein, we describe a series of 8 cases of SNM and propose clinical and biologic differences compared with desmoid fibromatosis. Our patient cohort is comprised of 5 males and 3 females (age range: 10 mo to 12 y), 6 of whom are aged less than or equal to 24 months. All presented with facial swelling, reflecting lesions involving the maxillary bone, and all underwent resection. All tumors were variably cellular and comprised of bland spindled to stellate cells in a profusely myxoid background with diffuse nuclear ß-catenin expression. All cases of SNM were analyzed by next-generation sequencing using the Oncopanel assay. Three cases failed sequencing, 2 of 5 successful cases exhibited exon 3 CTNNB1 alterations involving the ubiquitin recognition motif, and 3 had adenomatous polyposis coli ( APC ) deletions. One patient had APC germline testing which was negative. No germline testing was available for the remaining 7 patients. Follow-up data over a range of 1 month to 23 years was available for 7 of the 8 SNMs. One case patient had local recurrence, and all were alive without evidence of disease. This is in contrast to the high recurrence rate typically seen in desmoid fibromatosis, particularly after resection. Our findings expand the spectrum of tumors with underlying WNT/ß-catenin pathway and highlight the histologic, clinical, and genetic differences of SNM compared with desmoid fibromatosis. APC deletion raises the possibility of underlying germline alteration and familial adenomatous polyposis.

Isolated frontosphenoidal craniosynostosis: An argument for genetic testing.

Isolated frontosphenoidal craniosynostosis (IFSC) is a rare congenital defect defined as premature fusion of the frontosphenoidal suture in the absence of other suture fusion. Until now, IFSC was regarded as a phenomenon with an unclear genetic etiology. We have identified three cases with IFSC with underlying syndromic diagnoses that were attributable to pathogenic mutations involving FGFR3 and MN1, as well as 22q11.2 deletion syndrome. These findings suggest a genetic predisposition to IFSC may exist, thereby justifying the recommendation for genetic evaluation and testing in this population. Furthermore, due to improved imaging resolution, cases of IFSC are now readily identified. With the identification of IFSC with underlying genetic diagnoses, in combination with significant improvements in imaging resolution, we recommend genetic evaluation in children with IFSC.

PINNED: identifying characteristics of druggable human proteins using an interpretable neural network.

The identification of human proteins that are amenable to pharmacologic modulation without significant off-target effects remains an important unsolved challenge. Computational methods have been devised to identify features which distinguish between "druggable" and "undruggable" proteins, finding that protein sequence, tissue and cellular localization, biological role, and position in the protein-protein interaction network are all important discriminant factors. However, many prior efforts to automate the assessment of protein druggability suffer from low performance or poor interpretability. We developed a neural network-based machine learning model capable of generating druggability sub-scores based on each of four distinct categories, combining them to form an overall druggability score. The model achieves an excellent performance in separating drugged and undrugged proteins in the human proteome, with an area under the receiver operating characteristic (AUC) of 0.95. Our use of multiple sub-scores allows the assessment of potential protein targets of interest based on distinct contributors to druggability, leading to a more interpretable and holistic model to identify novel targets.

Spencer's phenomenological variant of ecological systems theory (PVEST): Charting its origin and impact.

This article examines the origin and scholarly impact of Dr. Margaret Beale Spencer's phenomenological variant of ecological systems theory (PVEST). We expound on her early foundational work replicating the Clark and Clark (1950) doll study and research during the period of "Atlanta's missing and murdered children." As a conceptual template, we anchor the theoretical contribution as introducing phenomenology and "net vulnerability" as factors that inform "emerging identities." Highlighted research focuses on synergistic themes associated with identity intersectionality, pubertal development, and education as a context for net vulnerability. We end with suggestions for future directions for PVEST. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

CO2-responsive gels.

CO2-responsive materials undergo a change in chemical or physical properties in response to the introduction or removal of CO2. The use of CO2 as a stimulus is advantageous as it is abundant, benign, inexpensive, and it does not accumulate in a system. Many CO2-responsive materials have already been explored including polymers, latexes, surfactants, and catalysts. As a sub-set of CO2-responsive polymers, the study of CO2-responsive gels (insoluble, cross-linked polymers) is a unique discipline due to the unique set of changes in the gels brought about by CO2 such as swelling or a transformed morphology. In the past 15 years, CO2-responsive gels and self-assembled gels have been investigated for a variety of emerging potential applications, reported in 90 peer-reviewed publications. The two most widely exploited properties include the control of flow (fluids) via CO2-triggered aggregation and their capacity for reversible CO2 absorption-desorption, leading to applications in Enhanced Oil Recovery (EOR) and CO2 sequestration, respectively. In this paper, we review the preparation, properties, and applications of these CO2-responsive gels, broadly classified by particle size as nanogels, microgels, aerogels, and macrogels. We have included a section on CO2-induced self-assembled gels (including poly(ionic liquid) gels).

Perceived parenting practices associated with African American adolescents' future expectations.

The current chapter investigated perceived parenting practices associated with future expectations in a sample of African American adolescents and how these relations varied across self-processes (i.e., hope, self-esteem, racial identity). Specifically, 358 low-income, African American high school students were surveyed to examine the role of perceived parenting practices in youth's aspirations and expectations. Structural equation modeling (SEM) revealed that general parenting practices (i.e., support, monitoring, and consistent discipline) and racial socialization (i.e., preparation for bias, cultural socialization) significantly predicted positive future expectations, particularly for adolescents with low self-esteem. Implications of these results and directions for future research are discussed. Importantly, the results contribute to understanding of the developmental cascades of parenting practices and racial socialization in the everyday experiences of African American populations.

Expansion of the sagittal suture induces proliferation of skeletal stem cells and sustains endogenous calvarial bone regeneration.

In newborn humans, and up to approximately 2 y of age, calvarial bone defects can naturally regenerate. This remarkable regeneration potential is also found in newborn mice and is absent in adult mice. Since previous studies showed that the mouse calvarial sutures are reservoirs of calvarial skeletal stem cells (cSSCs), which are the cells responsible for calvarial bone regeneration, here we hypothesized that the regenerative potential of the newborn mouse calvaria is due to a significant amount of cSSCs present in the newborn expanding sutures. Thus, we tested whether such regenerative potential can be reverse engineered in adult mice by artificially inducing an increase of the cSSCs resident within the adult calvarial sutures. First, we analyzed the cellular composition of the calvarial sutures in newborn and in older mice, up to 14-mo-old mice, showing that the sutures of the younger mice are enriched in cSSCs. Then, we demonstrated that a controlled mechanical expansion of the functionally closed sagittal sutures of adult mice induces a significant increase of the cSSCs. Finally, we showed that if a calvarial critical size bone defect is created simultaneously to the mechanical expansion of the sagittal suture, it fully regenerates without the need for additional therapeutic aids. Using a genetic blockade system, we further demonstrate that this endogenous regeneration is mediated by the canonical Wnt signaling. This study shows that controlled mechanical forces can harness the cSSCs and induce calvarial bone regeneration. Similar harnessing strategies may be used to develop novel and more effective bone regeneration autotherapies.

Juvenile Nasopharyngeal Angiofibroma: Outcomes Analysis Based Upon Hospital Volume.

OBJECTIVE: To evaluate the management of juvenile nasopharyngeal angiofibroma (JNA) from a national perspective with outcomes comparison based on hospital volume. STUDY DESIGN: Ten-year Pediatric Health Information Systems (PHIS) data analysis. METHODS: The PHIS database was queried for the diagnosis of JNA. Data regarding demographics, surgical approach, embolization, length of stay, charges, readmission, and revision surgery was collected and analyzed. Hospitals were classified as low volume if fewer than 10 cases and high volume if greater than or equal to 10 cases during the study period. A random effects model compared outcomes based on hospital volume. RESULTS: A total of 287 JNA patients were identified with a mean age of 13.8 (± 2.7) years. Nine hospitals were classified as high volume, accounting for a total of 121 patients. The mean length of hospitalization, blood transfusion rate, and 30-day readmissions did not differ significantly by hospital volume. Patients cared for at high-volume institutions were less likely to require postoperative mechanical ventilation (8.3% vs. 25.0%; adjusted RR = 0.32; 95% CI 0.14-0.73; p < 0.01) or return to the operating room for residual disease than patients admitted to low-volume hospitals (7.4% vs. 20.5%; adjusted RR = 0.38; 95% CI 0.18-0.79; p = 0.01). CONCLUSIONS: The management of JNA is complex from both an operative and perioperative management standpoint. Over the past decade, nearly half (42.2%) of JNA patients have been managed at nine institutions in the United States. These centers have significantly lower rates of postoperative mechanical ventilation and the need for revision surgery. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:3216-3220, 2023.

Transcriptomic Signatures of Single-Suture Craniosynostosis Phenotypes.

Craniosynostosis is a birth defect where calvarial sutures close prematurely, as part of a genetic syndrome or independently, with unknown cause. This study aimed to identify differences in gene expression in primary calvarial cell lines derived from patients with four phenotypes of single-suture craniosynostosis, compared to controls. Calvarial bone samples (N = 388 cases/85 controls) were collected from clinical sites during reconstructive skull surgery. Primary cell lines were then derived from the tissue and used for RNA sequencing. Linear models were fit to estimate covariate adjusted associations between gene expression and four phenotypes of single-suture craniosynostosis (lambdoid, metopic, sagittal, and coronal), compared to controls. Sex-stratified analysis was also performed for each phenotype. Differentially expressed genes (DEGs) included 72 genes associated with coronal, 90 genes associated with sagittal, 103 genes associated with metopic, and 33 genes associated with lambdoid craniosynostosis. The sex-stratified analysis revealed more DEGs in males (98) than females (4). There were 16 DEGs that were homeobox (HOX) genes. Three TFs (SUZ12, EZH2, AR) significantly regulated expression of DEGs in one or more phenotypes. Pathway analysis identified four KEGG pathways associated with at least one phenotype of craniosynostosis. Together, this work suggests unique molecular mechanisms related to craniosynostosis phenotype and fetal sex.

Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs.

Ariadne is a non-hallucinogenic analog in the phenylalkylamine chemical class of psychedelics that is closely related to an established synthetic hallucinogen, 2,5-dimethoxy-4-methyl-amphetamine (DOM), differing only by one methylene group in the α-position to the amine. Ariadne has been tested in humans including clinical trials at Bristol-Myers Company that indicate a lack of hallucinogenic effects and remarkable therapeutic effects, such as rapid remission of psychotic symptoms in schizophrenics, relaxation in catatonics, complete remission of symptoms in Parkinson's disease (PD), and improved cognition in geriatric subjects. Despite these provocative clinical results, the compound has been abandoned as a drug candidate and its molecular pharmacology remained unknown. Here, we report a detailed examination of the in vitro and in vivo pharmacology of Ariadne and its analogs, and propose a molecular hypothesis for the lack of hallucinogenic effects and the therapeutic potential of this compound class. We also provide a summary of previous clinical and preclinical results to contextualize the molecular signaling data. Our results show that Ariadne is a serotonin 5-HT2 receptor agonist, exhibits modest selectivity over 5-HT1 receptors, has no relevant activity at 5-HT4,5,7 and other aminergic receptors, and no substantial affinity at plasma membrane monoamine transporters. Compared to DOM, Ariadne shows lower signaling potency and efficacy in multiple signaling pathways examined (Gq, G11, and ß-arrestin2) coupled to 5-HT2A receptors. We confirmed the shift in signaling for an α-propyl analog and provide a molecular docking rationale for the progressive decrease in signaling potency with the growing length of the α-substituent. Ariadne versus DOM exhibits no apparent change in the relative preference between Gq/11 activation and ß-arrestin2 recruitment; instead, there is a small but consistent drop in efficacy in these signaling channels. Ariadne acts as a 5-HT2A agonist in vivo in mice and shows markedly attenuated head twitch response (HTR) in comparison to its hallucinogenic analogs, consistent with previous studies in rabbits, cats, and dogs. Hence, we propose the lower 5-HT2A receptor signaling efficacy of this compound class as an explanatory model for the lack of hallucinogenic effects of Ariadne in humans and the dramatically attenuated hallucinosis-like effects in animals (5-HT2A signaling efficacy hypothesis). In terms of reverse translation of the noted clinical therapeutic effects, we used an auxilin knockout model of Parkinson's disease where Ariadne rescued severe motor deficits in this mouse line, on par with the effects of l-DOPA, a notable finding considering Ariadne's lack of activity at dopamine receptors and transporters. Ariadne emerges as a prototype of a new drug class, non-hallucinogenic 5-HT2A agonists, with considerable therapeutic potential across psychiatric and neurological indications.

Damaging variants in FOXI3 cause microtia and craniofacial microsomia.

PURPOSE: Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown. METHODS: We performed genome sequencing and linkage analysis in patients and families with microtia and CFM of unknown genetic etiology. The functional consequences of damaging missense variants were evaluated through expression of wild-type and mutant proteins in vitro. RESULTS: We studied a 5-generation kindred with microtia, identifying a missense variant in FOXI3 (p.Arg236Trp) as the cause of disease (logarithm of the odds = 3.33). We subsequently identified 6 individuals from 3 additional kindreds with microtia-CFM spectrum phenotypes harboring damaging variants in FOXI3, a regulator of ectodermal and neural crest development. Missense variants in the nuclear localization sequence were identified in cases with isolated microtia with aural atresia and found to affect subcellular localization of FOXI3. Loss of function variants were found in patients with microtia and mandibular hypoplasia (CFM), suggesting dosage sensitivity of FOXI3. CONCLUSION: Damaging variants in FOXI3 are the second most frequent genetic cause of CFM, causing 1% of all cases, including 13% of familial cases in our cohort.