Direct modulation of human GABA-A α1β2γ2 receptors by the endocannabinoid 2-arachidonoylglycerol: implications for cannabinoid-related ligands and limitations for anxiolytic drug development
Anxiety disorders are associated with impaired inhibitory neurotransmission mediated by γ-aminobutyric acid type A (GABA-A) receptors. Although benzodiazepines remain effective anxiolytics, their clinical utility is limited by sedation, cognitive impairment, tolerance, and dependence, prompting the search for mechanistically distinct GABAergic modulators. Among cannabinoid-related molecules, the strongest evidence for direct GABA-A receptor modulation concerns the endocannabinoid 2-arachidonoylglycerol (2-AG), which potentiates recombinant human α1β2γ2 receptors through residues located in the M4 helix of the β2 subunit. Here, we review the structural architecture, biophysical properties, and pharmacological profile of the human GABA-A α1β2γ2 isoform as the relevant molecular framework for evaluating this mechanism, while discussing the broader relevance of cannabinoid-related ligands and selected phytocannabinoids without assuming mechanistic equivalence. We further assess the hypothesis that 2-AG reaches the β2-M4 site through a membrane-access route and identify five conceptual barriers that currently limit translation of this mechanism into anxiolytic drug development: supraphysiological effective concentrations, unresolved synaptic-versus-extrasynaptic actions, uncertain subtype selectivity, incomplete validation of lipid-environment effects, and lack of clinical evidence linking this mechanism to anxiolysis in humans. We conclude that direct modulation through β2-M4 defines a mechanistically intriguing allosteric pathway distinct from benzodiazepine action; however, its location on a shared β2 subunit and the micromolar concentrations required for modulation represent substantial obstacles to the rational design of anxioselective agents based on this mechanism.
Romanian male patients with the dual diagnosis of schizophrenia and alcohol use disorder: a prospective study of clinical, social, and treatment-related factors affecting quality of life
BackgroundSchizophrenia frequently co-occurs with alcohol use disorder (AUD), resulting in a complex clinical profile associated with poor functional outcomes and reduced quality of life (QoL). Although both conditions independently impair psychosocial functioning, few studies have examined the combined effects of clinical, social, and treatment-related factors on QoL in patients with this dual diagnosis.MethodsThis prospective observational study included 88 male inpatients diagnosed with schizophrenia and comorbid AUD and who were followed over a 6-month period. Quality of life was assessed using the World Health Organization Quality of Life–BREF (WHOQoL–BREF). The clinical variables included severity of psychotic symptoms (Positive and Negative Syndrome Scale), alcohol use severity (Michigan Alcohol Screening Test), and treatment characteristics. Social and personal factors, such as self-care capacity, social support, education, and legal problems, were also evaluated. Multivariable regression analyses were conducted to identify predictors of QoL at baseline and follow-up.ResultsAt baseline, higher QoL was significantly associated with greater self-care capacity, social support, and higher positive symptom scores, while the need for antipsychotic treatment was associated with lower QoL. At the 6-month follow-up, better QoL was predicted by greater self-care capacity, higher educational level, and receipt of anti-craving medication. By contrast, negative and general psychopathology, medico-legal problems, and the need for antidepressant treatment were associated with poorer QoL. Alcohol use severity, as measured by the MAST, was not independently associated with QoL at either timepoint.ConclusionsIn patients with schizophrenia and comorbid AUD, QoL is shaped by a complex interaction of clinical severity, functional capacity, and treatment-related factors. Beyond symptom control, interventions targeting self-care, social functioning, and integrated addiction treatment appear essential to improve long-term outcomes. These findings support the implementation of a multidimensional, recovery-oriented approach for the management of patients with the dual diagnosis.
Assessing directional connections between symptoms, cognition, insight, and real-life functioning in schizophrenia: a partial ancestor graphs analysis
IntroductionSchizophrenia is a severe chronic mental disorder causing significant global disability. Understanding the intricate relationships between symptoms, cognitive functions, and real-life outcomes is essential for developing effective interventions. Prior research, while informative, could not often determine the direction of the association between these illness-related factors. This study aimed to investigate the possible causal connections within the interrelationships of these variables. MethodsThis cross-sectional study included 215 clinically stable patients diagnosed with schizophrenia. Comprehensive assessments covered psychopathology, neurocognition, social cognition, metacognition, clinical insight, and real-life functioning. Causal relationships were explored using Partial Ancestral Graphs, a causal discovery framework that accounts for mediators and confounders. The Greedy Fast Causal Inference algorithm was employed with 1,000 bootstrap replications to assign edge orientations.ResultsA central neurocognitive–metacognitive–functional system of directed connection emerged: visual learning was linked to attention/vigilance and working memory. Working memory showed a direct relationship with metacognition, which, in turn, was connected to real-life functioning. Two partly independent contributions to real-life functioning were also identified: conceptual disorganization and experiential negative symptoms, which were directly related to expressive deficits. Positive symptoms, depressive symptoms, and social cognition occupied peripheral positions, showing no significant connection with other variables. Unawareness and misattribution of symptoms showed an indeterminate association disconnected from the main network.DiscussionThe findings show a set of directed associations that start with neurocognitive abilities, pass through working memory and metacognition, and terminate in real-life functioning. Independently, conceptual disorganization and expressive negative symptoms also exert direct influences. These directed systems of connections provide operational guidance for clinical practice, highlighting critical targets for interventions such as cognitive remediation focused on working memory, metacognitive therapies, and strategies addressing disorganization and avolition, all aimed at improving real-life outcomes in schizophrenia.
Internalizing and externalizing pathways to internet gaming disorder: the roles of anger and social anxiety
BackgroundInternet Gaming Disorder (IGD) represents a significant behavioral health concern, yet the roles of internalizing and externalizing psychological vulnerabilities in its development remain underexplored, particularly in Arabic-speaking populations.ObjectiveThis study examined anger and social anxiety as distinct externalizing and internalizing predictors of IGD severity in a Saudi Arabian community sample.MethodsA cross-sectional survey was administered to 303 participants (60.1% female; estimated mean age = 29.79 years, SD = 8.83) across five regions of Saudi Arabia. Participants completed the Internet Gaming Disorder Scale–Short Form (IGDS9-SF), a three-item Anger Screening Scale, and a two-item Social Anxiety screener. Hierarchical linear regression and structural equation modeling (SEM) were conducted to examine unique and incremental contributions of anger and social anxiety to IGD symptoms.ResultsAnger and social anxiety were strongly intercorrelated (r = .86, p <.001) but demonstrated divergent patterns in multivariate models. Hierarchical regression indicated that both predictors contributed unique variance when entered simultaneously, with anger positively and social anxiety negatively predicting IGD after controlling for shared variance. However, SEM clarified that only social anxiety significantly predicted latent IGD severity (β = .32, p = .027), whereas anger did not (β = .07, p = .68). The final model explained approximately 13% of variance in IGD symptoms.ConclusionsSocial anxiety was associated with IGD severity as a distinct internalizing correlate, consistent with avoidance-based coping and online social preference accounts. These preliminary, cross-sectional findings suggest that social anxiety warrants consideration in future IGD screening and research efforts in Arabic-speaking contexts.
Perception of social support and psychological well-being among mothers of individuals with intellectual disabilities: the mediating role of self-efficacy
BackgroundThe aim of this study is to examine the mediating role of self-efficacy in the relationship between social support perception and psychological well-being among mothers of individuals with intellectual disabilities.MethodsA correlational survey model was used in this study in line with the research objectives. The study group consisted of mothers of individuals with intellectual disabilities (n=80) in two central districts of Malatya province. Convenience sampling was employed in the study. The Psychological Well-being Scale was used to measure the psychological well-being of the participating mothers, the “Perceived Support Scale for Families of Children with Disabilities” was used to measure their perceived levels of social support, and the “Parental Self-Efficacy Scale” was used to measure their self-efficacy. In addition, a personal information form was used to introduce the socio-demographic characteristics of the participants. Descriptive statistics were calculated for the variables, and the normality assumption was examined using the Kolmogorov-Smirnov and Shapiro-Wilk tests. The relationships between the variables were evaluated using Pearson’s product-moment correlation analysis. Mediation analyses were performed using the PROCESS Macro (Model 4) developed by Hayes, and the significance of indirect effects was tested using the bootstrap method (5000 samples). The internal consistency reliability of the scales used in this study sample was assessed using Cronbach’s alpha coefficient.ResultsThere are positive and significant relationships between each of the perceived social support sub-dimensions of appreciation, informational, emotional, and companionship and self-efficacy (r = 0.28–0.36; p <0.05). A positive and significant relationship was also found between the total perceived social support score and self-efficacy (r = 0.37, p <0.01). In contrast, no direct significant relationships were found between perceived social support and its sub-dimensions and psychological well-being (p> 0.05). Psychological well-being showed only a moderate, positive and significant relationship with self-efficacy (r = 0.45, p <0.01).ConclusionsIn conclusion, it can be said that the relationship between perceived social support and psychological well-being is not direct, but indirect, mediated by self-efficacy.
From cats to cortex: T. gondii and psychosis, depression, and anxiety
This review examines whether cat ownership, via exposure to the neurotropic parasite T. gondii, contributes to vulnerability for psychotic, depressive, and anxiety symptoms. T. gondii establishes lifelong latent infection in the brain and muscle, where it can modulate dopaminergic signaling, neuroinflammation, and tryptophan–kynurenine metabolism, providing a biologically plausible pathway to altered cognition, mood, and behavior. Epidemiological and meta-analytic data indicate small-to-moderate associations between T. gondii seropositivity and schizophrenia, with more variable but suggestive links to depression and anxiety. Evidence for cat ownership as an independent risk factor is inconsistent: some cohorts and recent meta-analyses report elevated odds of schizophrenia-related outcomes in those exposed to cats, whereas rigorously controlled studies frequently find attenuated or null effects. Methodological limitations, alternative explanations, and cultural implications are discussed, and priorities for mechanism-informed, longitudinal and interventional research are outlined.
Immune-remodeling mRNAs expressing IRF8 or NIK generate durable antitumor immunity in multiple cancer models
Nature Biotechnology, Published online: 13 May 2026; doi:10.1038/s41587-026-03115-2
Immune-remodeling mRNAs delivered in lipid nanoparticles boost antitumor immunity.
Deep peptide recognition profiling decodes TCR specificity and enables disease-associated antigen discovery
Nature Biotechnology, Published online: 13 May 2026; doi:10.1038/s41587-026-03128-x
A deep-learning method predicts T cell receptor specificity and disease-associated antigens.
Fluctuating internal states mediate neural–behavioral covariations in V1
Nature Neuroscience, Published online: 13 May 2026; doi:10.1038/s41593-026-02296-y
The authors report surprising covariations between subthreshold activity of single V1 neurons and behavior, demonstrating that interactions between external sensory inputs and internal states are implemented by a nonlinear modulatory signal in V1.