Prader–Willi syndrome (PWS) is a rare imprinting-related neurodevelopmental disorder caused by loss of paternally expressed genes within the chromosome 15q11–q13 region, including SNORD116, MAGEL2, and NDN. It provides a natural model for examining how genomic imprinting disruptions shape neural development and psychiatric vulnerability. This review synthesizes current evidence to clarify the mechanistic pathways linking imprinting defects and epigenetic dysregulation to neuropsychiatric outcomes in PWS. Published studies—including patient-derived induced pluripotent stem cell (iPSC) models, animal knockout systems (e.g., Magel2-null models), transcriptomic and DNA methylation datasets, and human neuroimaging research—were identified through targeted searches of PubMed and Web of Science and integrated narratively rather than through systematic procedures. Across these data sources, deletion-type PWS is primarily associated with impaired neuronal maturation, altered serotonergic signaling, and locus-specific transcriptional dysregulation. Maternal uniparental disomy (mUPD) is characterized by broader epigenetic alterations within the imprinted domain, genome-wide transcriptional effects, dopaminergic pathway alterations, and disrupted prefrontal–limbic connectivity linked to increased psychosis risk. Importantly, available evidence supports substantial phenotypic and mechanistic overlap between PWS subtypes, with genotype–phenotype associations reflecting probabilistic tendencies rather than categorical distinctions. Collectively, convergent findings across molecular, neurochemical, and systems-level studies support a mechanistic continuum extending from imprinting defects to behavioral phenotypes. These insights position PWS as a translational model for understanding how epigenetic dysregulation contributes to psychiatric risk and highlight the need for genotype-informed, mechanistically grounded research to advance biomarker development and targeted therapeutic strategies.

Background: Esketamine, an intranasally administered N-methyl-D-aspartate (NMDA) receptor antagonist, represents a significant advancement in the treatment of Major Depressive Disorder (MDD), particularly among patients with Treatment-Resistant Depression (TRD). Its therapeutic effects are associated with rapid enhancement of glutamatergic neurotransmission and downstream activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor–Brain-Derived Neurotrophic Factor (BDNF)–mechanistic Target Of Rapamycin (mTOR) signaling pathway, which is implicated in synaptic plasticity. This mini-review aims to synthesize current clinical and translational evidence on intranasal esketamine in TRD. Methods: This mini-review provides an integrative overview of clinically relevant and translational studies on intranasal esketamine, based on a focused search of the PubMed and Scopus databases. Peer-reviewed clinical trials, meta-analyses, mechanistic studies, and regulatory documents were included. Results: Evidence from randomized controlled trials demonstrates a rapid onset of antidepressant effects, often within hours of administration, with consistent reductions in depressive symptom severity. Effects on clinician-rated suicidality were variable across studies. The most common adverse events include transient dissociation, dizziness, and modest increases in blood pressure, which are generally self-limiting. Discussion: Overall, the available evidence supports intranasal esketamine as an effective rapid-acting treatment for TRD, with a favorable benefit–risk profile under supervised clinical use. However, important considerations remain regarding optimal patient selection, maintenance strategies, and long-term outcomes. Conclusion: Esketamine offers a clinically meaningful option for patients unresponsive to conventional monoaminergic treatments. Key unresolved issues include the development of predictive biomarkers, optimization of maintenance regimens, integration with psychotherapy, and evaluation of long-term cognitive and functional outcomes.

Oral nanocarrier development for inflammatory bowel disease (IBD) is complicated by inflammation-dependent changes in mucus, epithelial integrity, and immune-cell interactions. This critical narrative review examines comparative evidence from in vitro systems, animal models, and human intestinal tissue, alongside clinical studies, to assess how barrier state modifies formulation performance. Across the reviewed studies, particle size alone does not consistently predict lesion accumulation, while surface chemistry, coating, geometry, and stability in gastrointestinal fluids influence mucus interaction, cellular access, and payload release. Tissue-associated fluorescence, increased permeability, and cellular uptake do not independently establish intact-carrier transport or productive delivery. Clinical trials of selected oral nano-enabled formulations report improvements in some disease outcomes but do not establish inflammation-selective delivery as the underlying mechanism. We propose an evidence-informed benchmarking framework linking characterization in biological media to mucus transport or retention, epithelial–immune responses, spatial localization, target engagement, and safety. Matched healthy and inflamed comparators are central to testing selectivity, and preclinical findings must be distinguished from clinical validation. Artificial intelligence may support barrier-state-aware formulation optimization but requires standardized datasets and prospective experimental validation. Given the heterogeneous evidence base and limited direct human delivery studies, prospective validation should prioritize local payload delivery and therapeutic benefit without exacerbating intestinal barrier injury.

Sex-chromosome dosage and pubertal hormone exposure exert powerful but temporally distinct influences on human brain development, yet their interaction has rarely been formalized within a unified mechanistic framework. Variation in X-chromosome dosage provides a unique opportunity to dissociate early organizational constraints from later modulatory processes shaping cognitive circuits. Here, we synthesize genetic, neuroimaging, neuroendocrine, and neuropsychological evidence to propose a hierarchical gene-hormone-circuit framework of cognitive development. Using Turner syndrome as a biologically constrained model system, we argue that haploinsufficiency of X-linked genes escaping inactivation imposes early, front-loaded constraints on cortical patterning and parietal-frontoparietal connectivity, establishing a neural scaffold that persists across development. Pubertal estrogen signaling subsequently acts as a modulatory influence, refining prefrontal and fronto-limbic circuits that retain plasticity into adolescence, but operating within the limits imposed by earlier gene-dosage-defined architecture. Importantly, this framework departs from prior models by explicitly distinguishing organizational constraints from modulatory influences across developmental timescales. The interaction of these processes yields a domain-specific neurobehavioral organization characterized by persistent visuospatial and executive vulnerabilities alongside variable socio-emotional outcomes. By explicitly integrating sex-chromosome dosage effects with hormone-dependent circuit tuning, this framework advances a generalizable model of hierarchical constraint and modulation in brain development, offering mechanistic insight into sex-linked variation in cognitive and affective circuit maturation and generating testable predictions for future longitudinal neurogenetic and neuroimaging studies.