Herpes simplex virus 1 (HSV-1) and influenza A viruses (IAV) induce Z-form-nucleic-acid-binding protein 1 (ZBP1)-initiated cell death1-8. ZBP1 is activated by Z-RNA1,7,9, and the Z-RNAs that trigger ZBP1 during HSV-1 and IAV infections were assumed to be of viral origin1. Here, however, we show that host cell-encoded Z-RNAs are major and sufficient ZBP1-activating ligands after infection by these two human pathogens. The majority of cellular Z-RNAs mapped to intergenic endogenous retroelements embedded within abnormally long 3' extensions of host cell mRNAs. These aberrant host cell transcripts arose as a consequence of disruption of transcription termination (DoTT)-a virus-driven phenomenon that disables cleavage and polyadenylation specificity factor (CPSF)-mediated 3' processing of nascent pre-mRNAs10-15. Mutant viruses lacking ICP27 or NS1-the virus-encoded proteins responsible for inhibiting CPSF and triggering DoTT13,15-did not induce host cell Z-RNA accrual and were attenuated in their ability to stimulate ZBP1. Ectopic expression of HSV-1 ICP27 or IAV NS1 or pharmacological blockade of CPSF activity induced accumulation of host cell Z-RNAs and activated ZBP1. These results demonstrate that DoTT-generated cellular Z-RNAs are bona fide ZBP1 ligands, and position ZBP1-activated cell death as a host response to counter viral disruption of the cellular transcriptional machinery.

Major depression (MD) is a leading cause of global disease burden, and both experimental and population-based studies suggest that differences in DNA methylation may be associated with the condition. However, previous DNA methylation studies have, so far, not been widely replicated, suggesting a need for larger meta-analysis studies. Here we conducted a meta-analysis of methylome-wide association analysis for lifetime MD across 18 studies of 24,754 European-ancestry participants (5,443 MD cases) and an East Asian sample (243 cases, 1,846 controls). We identified 15 CpG sites associated with lifetime MD with methylome-wide significance. The methylation score created using the methylome-wide association analysis summary statistics was significantly associated with MD status in an out-of-sample classification analysis (area under the curve 0.53). Methylation score was also associated with five inflammatory markers, with the strongest association found with tumor necrosis factor beta. Mendelian randomization analysis revealed 23 CpG sites potentially causally linked to MD, with 7 replicated in an independent dataset. Our study provides evidence that variations in DNA methylation are associated with MD, and further evidence supporting involvement of the immune system.

Persisting symptoms after concussion (PSaC) represent a complex and poorly understood neuropsychiatric phenomenon with limited treatment options. Neural network dysfunction has been associated with PSaC, and neuromodulation, particularly repetitive transcranial magnetic stimulation, may be a promising intervention. However, neuroimaging findings have been inconsistent, limiting understanding of underlying network dysfunction. We aimed to identify a core neural network associated with PSaC and explore whether this network could yield candidate cortical targets for neuromodulation at the individual level. We hypothesized that differences in network disruption would be evident between individuals with high versus low symptom burden in PSaC. Here we show that a convergent multi-analytic approach combining symptom-activation maps generated from existing fMRI datasets, systematic review of resting-state fMRI studies of PSaC, and network-based meta-analysis of coordinates derived from these studies co-localize to the salience network in high symptom burden PSaC. Using Human Connectome Project data, we mapped this network to cortical regions that could serve as individualized targets for neuromodulation. This aligns with current clinical models of PSaC and may present a new direction for network-based therapy.