Published data support genetic variants, as well as certain infectious agents, as potential risk factors for schizophrenia. Less is known about interactions between the risk factors.To evaluate exposure to infectious agents and host genetic variation as joint risk factors.We investigated four infectious agents: cytomegalovirus (CMV), herpes simplex viruses 1 and 2 (HSV1, HSV2), and Toxoplasma gondii (TOX). We initially compared exposure using specific serum antibodies, among simplex and multiplex nuclear families (one or more than one affected offspring, respectively). If interactions between infectious agents and host genetic variation are important risk factors for schizophrenia, we reasoned that they would be more prominent among multiplex versus simplex families. We also evaluated the role of variation at chromosome 6p21-p23 in conjunction with exposure. We used 22 short tandem repeat polymorphisms (STRPs) dispersed across this region.Though exposure to all four agents was increased among multiplex families versus simplex families, the difference was consistently significant only for CMV (odds of exposure to CMV in multiplex families: 2.47, 95% CI: 1.48-5.33). Transmission disequilibrium tests and case-control comparisons using STRPs revealed significant linkage/association with D6S2672 among CMV+ schizophrenia patients.Polymorphisms near D6S2672 could confer risk for schizophrenia in conjunction with CMV exposure.
INTRODUCTION: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. The ability to model pathophysiological processes through 3D cultures systems may enable new treatments while eliminating the need for animal and human testing. Advances in 3D cell culture systems have resulted in the generation of human cerebral organoids, which to a great extent recapitulate key neural cytoarchitectural features. We currently have no in-vitro human TBI model. METHODS: We generated cerebral organoids from human embryonic stem cells. After maturation, the organoids were subjected to a custom-designed Mechanical Excitation Testbed (MET) that delivered compressed the organoid with controlled strain rates and strain for a given number of pulses. We investigated the repercussions of organoid compression by assessing the neuronal function, calcium signaling, and morphological changes, electrophysiology, real-time calcium imaging, and immunohistochemistry. Molecular and gene ontology analysis was also performed using RNA-seq and Ingenuity Pathway Analysis/Gene Set Enrichment. RESULTS: Our results demonstrated significant real-time calcium signaling upregulation and altered neuronal activity consistent with TBI severity. Moreover, RNA-seq data demonstrate unsupervised clustering of gene activity of moderate and severe TBI. Furthermore, gene enrichment analysis identified 3 key genes ENO1, CARD9, and FOXP3 which are associated with neuronal development, regulation of cellular apoptosis & IL-17 mediated inflammation pathway, and immunoregulation of T-cells respectively. Finally, TBI response pathways were identified involving stromal elasticity, and extracellular matrix, consistent with TBI. CONCLUSIONS: This in-vitro brain organoid TBI model shows strong phenotypic and genetic similarities with TBI patients. Furthermore, This novel TBI model could provide a basis for a high-throughput personalized patient-less model that could be used to study TBIs and test potential therapeutic modalities.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)