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Despite the success of the BNT162b2 mRNA vaccine, the immunological mechanisms that underlie its efficacy are poorly understood. Here we analyzed the innate and adaptive responses to BNT162b2 in mice, and show that immunization stimulated potent antibody and antigen-specific T cell responses, as well as strikingly enhanced innate responses after secondary immunization, which was concurrent with enhanced serum interferon (IFN)-γ levels 1 d following secondary immunization. Notably, we found that natural killer cells and CD8+ T cells in the draining lymph nodes are the major producers of this circulating IFN-γ. Analysis of knockout mice revealed that induction of antibody and T cell responses to BNT162b2 was not dependent on signaling via Toll-like receptors 2, 3, 4, 5 and 7 nor inflammasome activation, nor the necroptosis or pyroptosis cell death pathways. Rather, the CD8+ T cell response induced by BNT162b2 was dependent on type I interferon-dependent MDA5 signaling. These results provide insights into the molecular mechanisms by which the BNT162b2 vaccine stimulates immune responses.How mRNA-based coronavirus disease 2019 vaccines drive immune responses is not clear. Here the authors characterize immune responses to the BNT162b2 vaccine in mice, and show how it stimulates innate immunity, with antigen-specific CD8+ T cell responses dependent on the RNA sensor MDA5.

22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease. A human stem cell–derived model helps to uncover neuronal phenotypes associated with genetic forms of neuropsychiatric disease.

Owing to recent medical and technological advances in neonatal care, infants born extremely premature have increased survival rates1,2. After birth, these infants are at high risk of hypoxic episodes because of lung immaturity, hypotension and lack of cerebral-flow regulation, and can develop a severe condition called encephalopathy of prematurity3. Over 80% of infants born before post-conception week 25 have moderate-to-severe long-term neurodevelopmental impairments4. The susceptible cell types in the cerebral cortex and the molecular mechanisms underlying associated gray-matter defects in premature infants remain unknown. Here we used human three-dimensional brain-region-specific organoids to study the effect of oxygen deprivation on corticogenesis. We identified specific defects in intermediate progenitors, a cortical cell type associated with the expansion of the human cerebral cortex, and showed that these are related to the unfolded protein response and changes. Moreover, we verified these findings in human primary cortical tissue and demonstrated that a small-molecule modulator of the unfolded protein response pathway can prevent the reduction in intermediate progenitors following hypoxia. We anticipate that this human cellular platform will be valuable for studying the environmental and genetic factors underlying injury in the developing human brain.Brain organoids derived from human iPSCs are used to study the effects of hypoxia on early cortical neurodevelopment and identify defects in specific human progenitor populations that likely contribute to encephalopathy of prematurity.

Abstract Study Objectives While caregiver-reported sleep disturbances are common in children and adolescents with autism spectrum disorder ([‘), few studies have measured objective sleep in ASD compared to controls, and their findings are mixed. We investigated (1) differences in sleep architecture, specifically slow-wave sleep (SWS) and rapid eye movement (REM) sleep, between ASD and typically developing controls (TD); and (2) if any observed differences in sleep were associated with core ASD symptoms. Methods We used ambulatory polysomnography (PSG) in 53 participants with ASD (ages 4–18) and 66 age-matched TD in their home sleeping environment. The primary outcome measures were SWS and REM sleep. Core behavioral ASD symptoms were assessed using the Autism Diagnostic Interview-Revised (ADI-R). Spectral power bands during sleep, and additional behavioral measures, were examined in exploratory analyses. Results Compared to TD, participants with ASD exhibited a higher SWS ratio and lower REM sleep ratio. Within the ASD group, higher SWS was associated with more severe symptoms on the Restricted, Repetitive, and Stereotyped Behaviors subscale of the ADI-R. No association was observed between REM sleep ratio and any ASD symptom. Conclusions Increased SWS and reduced REM sleep ratio differentiated ASD from TD. However, only increased SWS was associated with more severe core ASD symptoms. Increased SWS may reflect neuronal immaturity specific to ASD in this age group. These findings may inform the underlying mechanisms of clinical symptoms observed in children and adolescents with ASD. Graphical Abstract Graphical Abstract

Alzheimer’s disease (AD) is a multifactorial and heterogeneous disorder, which makes early detection a challenge. Studies have attempted to combine biomarkers to improve AD detection and predict progression. However, most of the existing work reports results in parallel or compares normalized findings but does not analyze data simultaneously. We tested a multi-dimensional network framework, applied to 490 subjects (cognitively normal [CN] = 147; mild cognitive impairment [MCI] = 287; AD = 56) from ADNI, to create a single model capable of capturing the heterogeneity and progression of AD. First, we constructed subject similarity networks for structural magnetic resonance imaging, amyloid-β positron emission tomography, cerebrospinal fluid, cognition, and genetics data and then applied multilayer community detection to find groups with shared similarities across modalities. Individuals were also followed-up longitudinally, with AD subjects having, on average, 4.5 years of follow-up. Our findings show that multilayer community detection allows for accurate identification of present and future AD (≈90%) and is also able to identify cases that were misdiagnosed clinically. From all MCI participants who developed AD or reverted to CN, the multilayer model correctly identified 90.8% and 88.5% of cases respectively. We observed similar subtypes across the full sample and when examining multimodal data from subjects with no AD pathology (i.e., amyloid negative). Finally, these results were also validated using an independent testing set. In summary, the multilayer framework is successful in detecting AD and provides unique insight into the heterogeneity of the disease by identifying subtypes that share similar multidisciplinary profiles of neurological, cognitive, pathological, and genetics information.

[...]increased research on identifying the most effective social cognitive measures for better capturing bvFTD, and developing batteries that standardly include such measures in the clinical trenches, could also support earlier diagnosis and connection to support. [...]increased public awareness of bvFTD symptoms could also ease the social burden of embarrassment and isolation. [...]this in-depth review from Karnatz and colleagues reminds us how different the dementia caregiving experience can be, depending upon which type of dementia the patient is experiencing.

Importance Cognitive deficits in depression have been associated with poor functional capacity, frontal neural circuit dysfunction, and worse response to conventional antidepressants. However, it is not known whether these impairments combine together to identify a specific cognitive subgroup (or “biotype”) of individuals with major depressive disorder (MDD), and the extent to which these impairments mediate antidepressant outcomes. Objective To undertake a systematic test of the validity of a proposed cognitive biotype of MDD across neural circuit, symptom, social occupational function, and treatment outcome modalities. Design, Setting, and Participants This secondary analysis of a randomized clinical trial implemented data-driven clustering in findings from the International Study to Predict Optimized Treatment in Depression, a pragmatic biomarker trial in which patients with MDD were randomized in a 1:1:1 ratio to antidepressant treatment with escitalopram, sertraline, or venlafaxine extended-release and assessed at baseline and 8 weeks on multimodal outcomes between December 1, 2008, and September 30, 2013. Eligible patients were medication-free outpatients with nonpsychotic MDD in at least the moderate range, and were recruited from 17 clinical and academic practices; a subset of these patients underwent functional magnetic resonance imaging. This prespecified secondary analysis was performed between June 10, 2022, and April 21, 2023. Main Outcomes and Measures Pretreatment and posttreatment behavioral measures of cognitive performance across 9 domains, depression symptoms assessed using 2 standard depression scales, and psychosocial function assessed using the Social and Occupational Functioning Assessment Scale and World Health Organization Quality of Life scale were analyzed. Neural circuit function engaged during a cognitive control task was measured using functional magnetic resonance imaging. Results A total of 1008 patients (571 [56.6%] female; mean [SD] age, 37.8 [12.6] years) participated in the overall trial and 96 patients participated in the imaging substudy (45 [46.7%] female; mean [SD] age, 34.5 [13.5] years). Cluster analysis identified what may be referred to as a cognitive biotype of 27% of depressed patients with prominent behavioral impairment in executive function and response inhibition domains of cognitive control. This biotype was characterized by a specific profile of pretreatment depressive symptoms, worse psychosocial functioning (d = −0.25; 95% CI, −0.39 to −0.11;P < .001), and reduced activation of the cognitive control circuit (right dorsolateral prefrontal cortex:d = −0.78; 95% CI, −1.28 to −0.27;P = .003). Remission was comparatively lower in the cognitive biotype positive subgroup (73 of 188 [38.8%] vs 250 of 524 [47.7%];P = .04) and cognitive impairments persisted regardless of symptom change (executive function:ηp2 = 0.241;P < .001; response inhibition:ηp2 = 0.750;P < .001). The extent of symptom and functional change was specifically mediated by change in cognition but not the reverse. Conclusions and Relevance Our findings suggest the presence of a cognitive biotype of depression with distinct neural correlates, and a functional clinical profile that responds poorly to standard antidepressants and instead may benefit from therapies specifically targeting cognitive dysfunction. Trial Registration ClinicalTrials.gov Identifier:NCT00693849

Early adversity is a strong and enduring predictor of psychiatric disorders including mood disorders, anxiety disorders, substance abuse or dependence, and posttraumatic stress disorder. However, the mechanisms of this effect are not well understood. The purpose of this review is to summarize and integrate the current research knowledge pertaining to the long-term effects of early adversity on psychiatric disorders, particularly in late life. We explore definitional considerations including key dimensions of the experience such as type, severity, and timing of adversity relative to development. We then review the potential biological and environmental mediators and moderators of the relationships between early adversity and psychiatric disorders. We conclude with clinical implications, methodological challenges and suggestions for future research.

As of May 2021, more than 32 million cases of COVID-19 have been confirmed in the United States, resulting in more than 615 000 deaths. Anaphylactic reactions associated with the Food and Drug Administration (FDA)-authorized mRNA COVID-19 vaccines have been reported. To characterize the immunologic mechanisms underlying allergic reactions to these vaccines. This case series included 22 patients with suspected allergic reactions to mRNA COVID-19 vaccines between December 18, 2020, and January 27, 2021, at a large regional health care network. Participants were individuals who received at least 1 of the following International Statistical Classification of Diseases and Related Health Problems, Tenth Revision anaphylaxis codes: T78.2XXA, T80.52XA, T78.2XXD, or E949.9, with documentation of COVID-19 vaccination. Suspected allergy cases were identified and invited for follow-up allergy testing. FDA-authorized mRNA COVID-19 vaccines. Allergic reactions were graded using standard definitions, including Brighton criteria. Skin prick testing was conducted to polyethylene glycol (PEG) and polysorbate 80 (P80). Histamine (1 mg/mL) and filtered saline (negative control) were used for internal validation. Basophil activation testing after stimulation for 30 minutes at 37 °C was also conducted. Concentrations of immunoglobulin (Ig) G and IgE antibodies to PEG were obtained to determine possible mechanisms. Of 22 patients (20 [91%] women; mean [SD] age, 40.9 [10.3] years; 15 [68%] with clinical allergy history), 17 (77%) met Brighton anaphylaxis criteria. All reactions fully resolved. Of patients who underwent skin prick tests, 0 of 11 tested positive to PEG, 0 of 11 tested positive to P80, and 1 of 10 (10%) tested positive to the same brand of mRNA vaccine used to vaccinate that individual. Among these same participants, 10 of 11 (91%) had positive basophil activation test results to PEG and 11 of 11 (100%) had positive basophil activation test results to their administered mRNA vaccine. No PEG IgE was detected; instead, PEG IgG was found in tested individuals who had an allergy to the vaccine. Based on this case series, women and those with a history of allergic reactions appear at have an elevated risk of mRNA vaccine allergy. Immunological testing suggests non-IgE-mediated immune responses to PEG may be responsible in most individuals.