Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource for the adult brain across 1866 individuals. The PsychENCODE resource contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles for many cell types; expression quantitative-trait loci (QTLs); and further QTLs associated with chromatin, splicing, and cell-type proportions. Integration shows that varying cell-type proportions largely account for the cross-population variation in expression (with >88% reconstruction accuracy). It also allows building of a gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 for schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic risk scores and identifies key genes and pathways in psychiatric disorders.

The causative virus of the COVID-19 pandemic, SARS-CoV-2, uses its nonstructural protein 1 (Nsp1) to suppress cellular, but not viral, protein synthesis through yet unknown mechanisms. We show here that among all viral proteins, Nsp1 has the largest impact on host viability in the cells of human lung origin. Differential expression analysis of mRNA-seq data revealed that Nsp1 broadly alters the cellular transcriptome. Our cryo-EM structure of the Nsp1-40S ribosome complex shows that Nsp1 inhibits translation by plugging the mRNA entry channel of the 40S. We also determined the structure of the 48S preinitiation complex formed by Nsp1, 40S, and the cricket paralysis virus internal ribosome entry site (IRES) RNA, which shows that it is nonfunctional because of the incorrect position of the mRNA 3′ region. Our results elucidate the mechanism of host translation inhibition by SARS-CoV-2 and advance understanding of the impacts from a major pathogenicity factor of SARS-CoV-2.

Highlights d In vivo and in vitro genome-scale CD8 T cell CRISPR screen in immunotherapy contexts d Dhx37 knockout in CD8 T cells enhances adoptive transfer efficacy d Dhx37 modulates CD8 T cell activation, cytokine production, and cytotoxicity d DHX37 interacts with PDCD11 and influences NF-kB activity

Identification of T cell targets to improve immunotherapies is of prime interest. To facilitate largescale CRISPR screens directly in T cells in vivo, here, we developed a hybrid genetic screening system with adeno associated virus (AAV) and the Sleeping Beauty (SB) transposon, where the transposon is nested in the viral vector. The approach enables efficient gene editing in primary murine T cells and genomic integration of the sgRNA cassette for screen readout. We performed Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Highlights d exceRpt processes and analyzes exRNA profiling data d exceRpt generates quality control metrics, RNA abundance estimates, and reports d A user-friendly, browser-based graphical interface is available d exceRpt processes all RNA-seq datasets in the exRNA Atlas