Modelling schizophrenia using human induced pluripotent stem cells.

Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80-85%. Although post-mortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (Supplementary Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cyclic AMP and WNT signalling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder.

Transcatheter Aortic Valve Replacement for Severe Aortic Valve Stenosis: Do Patients Experience Better Quality of Life Regardless of Gradient?

BACKGROUND: Aortic valve replacement improves survival for patients with low-gradient aortic valve stenosis, but there is a paucity of data on postoperative quality of life for this population. METHODS: In a single-center retrospective analysis of 304 patients with severe aortic valve stenosis who underwent transcatheter aortic valve replacement, patients were divided into 4 groups based on mean pressure gradient, left ventricular ejection fraction, and stroke volume index. Using the Kansas City Cardiomyopathy Questionnaire-12, quality of life was assessed immediately before and 1 month after transcatheter aortic valve replacement. RESULTS: Most patients in the low-flow, low-gradient group were men; this group had higher relative rates of cardiovascular disease and type 2 diabetes than the paradoxical low-flow, low-gradient group; the normal-flow, low-gradient group; and the high-gradient group. All-cause mortality did not differ significantly among the groups at 1 month after surgery, and all groups experienced a significant improvement in quality-of-life scores after surgery. The mean improvement was 27 points in the low-flow, low-gradient group, 25 points in the paradoxical low-flow, low-gradient group, 30 points in the normal-flow, low-gradient group, and 30 points in the high-gradient group (all P < .001). CONCLUSION: Quality of life improves significantly across all subgroups of aortic valve stenosis after trans-catheter aortic valve replacement, regardless of flow characteristics or aortic valve gradients.

Acute myocarditis following a third dose of COVID-19 mRNA vaccination in adults.

INTRODUCTION: Myocarditis has been reported following the second dose of COVID-19 mRNA vaccination. Whether administration of additional doses of COVID-19 vaccines further increases the risk of myocarditis is unknown. METHODS: We included individuals who received one to three doses of BNT162b2 or mRNA-1273 mRNA vaccine between 12/14/2020 and 2/18/2022. Myocarditis within 21 days of vaccine administration was identified using electronic medical records. Incidence rate ratios were calculated by comparing the observed incidence with the expected incidence from the same population during a 365-day baseline period. RESULTS: Of 3,076,660 KPSC members who received at least one dose of COVID-19 mRNA vaccines, 2,916,739 (94.5%) received at least two doses, and 1,146,254 (47.0%) received three doses. The incidence rate ratio for myocarditis was 0.86 (95% CI 0.31-1.93) for the first dose, 4.22 (95% CI 2.63-6.53) for the second dose, and 2.61 (1.13-5.29) for the third dose. Most myocarditis cases following the second and third dose occurred within seven days of vaccination. CONCLUSION: Myocarditis was a rare event observed after the second or third dose of vaccination. Most cases presented within seven days of vaccination. The incidence of myocarditis following the third dose was not significantly higher than that observed after the second dose.

Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells.

Converging evidence indicates that microRNAs (miRNAs) may contribute to disease risk for schizophrenia (SZ). We show that microRNA-9 (miR-9) is abundantly expressed in control neural progenitor cells (NPCs) but also significantly downregulated in a subset of SZ NPCs. We observed a strong correlation between miR-9 expression and miR-9 regulatory activity in NPCs as well as between miR-9 levels/activity, neural migration, and diagnosis. Overexpression of miR-9 was sufficient to ameliorate a previously reported neural migration deficit in SZ NPCs, whereas knockdown partially phenocopied aberrant migration in control NPCs. Unexpectedly, proteomic- and RNA sequencing (RNA-seq)-based analysis revealed that these effects were mediated primarily by small changes in expression of indirect miR-9 targets rather than large changes in direct miR-9 targets; these indirect targets are enriched for migration-associated genes. Together, these data indicate that aberrant levels and activity of miR-9 may be one of the many factors that contribute to SZ risk, at least in a subset of patients.

Spatial parkin translocation and degradation of damaged mitochondria via mitophagy in live cortical neurons.

Mitochondria are essential for neuronal survival and function. Proper degradation of aged and damaged mitochondria through mitophagy is a key cellular pathway for mitochondrial quality control. Recent studies have indicated that PINK1/Parkin-mediated pathways ensure mitochondrial integrity and function. Translocation of Parkin to damaged mitochondria induces mitophagy in many nonneuronal cell types. However, evidence showing Parkin translocation in primary neurons is controversial, leaving unanswered questions as to how and where Parkin-mediated mitophagy occurs in neurons. Here, we report the unique process of dissipating mitochondrial Δψ(m)-induced and Parkin-mediated mitophagy in mature cortical neurons. Compared with nonneuronal cells, neuronal mitophagy is a much slower and compartmentally restricted process, coupled with reduced anterograde mitochondrial transport. Parkin-targeted mitochondria are accumulated in the somatodendritic regions where mature lysosomes are predominantly located. Time-lapse imaging shows dynamic formation and elimination of Parkin- and LC3-ring-like structures surrounding depolarized mitochondria through the autophagy-lysosomal pathway in the soma. Knocking down Parkin in neurons impairs the elimination of dysfunctional mitochondria. Thus, our study provides neuronal evidence for dynamic and spatial Parkin-mediated mitophagy, which will help us understand whether altered mitophagy contributes to pathogenesis of several major neurodegenerative diseases characterized by mitochondrial dysfunction and impaired transport.

Markers of basal ganglia dysfunction and conversion to psychosis: neurocognitive deficits and dyskinesias in the prodromal period.

BACKGROUND: Movement abnormalities and cognitive deficits may represent external markers of an underlying neural process linked with the early etiology of psychosis. As basal ganglia function plays a governing role in both movement and cognitive processes, an understanding of the relationship between these phenomena stands to inform etiologic conceptualizations of vulnerability and psychotic disorders. METHODS: In this investigation, trained raters coded movement abnormalities in videotapes from structured interviews of adolescents and young adults with a prodromal risk syndrome (n = 90). The participants were administered a neuropsychological battery including measures of verbal comprehension, perceptual organization, immediate/delayed auditory memory, and an estimate of full-scale intelligence quotient. Diagnostic status was followed for a 2-year period utilizing structured clinical interviews, during which time 24 high-risk participants (26.66%) converted to an Axis I psychotic disorder. RESULTS: Elevated dyskinetic movements in the upper-body region were correlated with deficits in domains of verbal comprehension, perceptual organization, and both immediate and delayed auditory memory. Further, discriminant function analyses indicated that baseline movement abnormalities and neurocognitive deficits significantly classified those high-risk participants who would eventually convert to a psychotic disorder (72.3%). CONCLUSIONS: Results support a common cortico-striato-pallido-thalamic circuit irregularity, underlying both movement abnormalities and cognitive deficits in individuals at high risk for psychosis. Models incorporating external markers of progressive basal ganglia dysfunction may enhance detection and preventive intervention for those high-risk individuals most in need of treatment.