Gene editing is often touted as a permanent method for correcting mutations, but its long-term benefits in Duchenne muscular dystrophy (DMD) may depend on sufficiently high editing efficiencies to halt muscle degeneration. Here we explored the persistence of dystrophin expression following rAAV6:CRISPR/Cas9-mediated multi-exon deletion/reframing in systemically injected 2- and 11-week old dystrophic mice, and show that induction of low dystrophin…
A safe, effective, and scalable vaccine is needed to halt the ongoing SARS-CoV-2 pandemic. We describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 SARS-CoV-2 spike receptor-binding domains (RBDs) in a highly immunogenic array and induce neutralizing antibody titers ten-fold higher than the prefusion-stabilized…
SARS-CoV-2 is a betacoronavirus virus responsible for the COVID-19 pandemic. Here, we determine the X-ray crystal structure of a potent neutralizing monoclonal antibody, CV30, isolated from a patient infected with SARS-CoV-2, in complex with the receptor binding domain. The structure reveals that CV30 binds to an epitope that overlaps with the human ACE2 receptor binding motif providing a structural basis…
An underlying motivation for the current development of vaccines against the coronavirus SARS-CoV-2 is the premise that neutralizing antibodies will provide lasting protection from infection, drawn in part from experiences with other anti-viral vaccines. This desire to elicit neutralizing antibodies via a vaccine stems from the idea that antibodies should prevent infection if they block entry of the virus into…
Impaired glucose metabolism in diabetes causes severe acute and long‐term complications, making real‐time detection of blood glucose indispensable for diabetic patients. Existing continuous glucose monitoring systems are unsuitable for long‐term clinical glycemic management due to poor long‐term stability. Polymer dot (Pdot) glucose transducers are implantable optical nanosensors that exhibit excellent brightness, sensitivity, selectivity, and biocompatibility. Here, it is shown that…
Head and neck squamous cell carcinoma (HNSCC) associated with high-risk human papilloma virus (HPV) infection is a growing clinical problem. The WEE1 kinase inhibitor AZD1775 (WEE1i) overrides cell cycle checkpoints and is being studied in HNSCC regimens. We show that the HPV16 E6/E7 oncoproteins sensitize HNSCC cells to single-agent WEE1i treatment through activation of a FOXM1-CDK1 circuit that drives mitotic…
In this study we identified a growth factor, epigen, that is highly upregulated in tumor cell clusters. When this growth factor is knocked down in tumor cell clusters, metastatic outgrowth in lungs was reduced by over 94%. These data show that epigen is a signal for metastatic outgrowth of tumor cell clusters, and suggest that it could be used as a therapeutic target against cluster-based metastasis.
Electron microscopy (EM) is widely used for studying cellular structure and network connectivity in the brain. We have built a parallel imaging pipeline using transmission electron microscopes that scales this technology, implements 24/7 continuous autonomous imaging, and enables the acquisition of petascale datasets. The suitability of this architecture for large-scale imaging was demonstrated by acquiring a volume of more than 1 mm3 of…
Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that either develops de novo or arises from prostate adenocarcinoma as a result of treatment resistance. Although the prostate basal cells have been shown to directly generate tumor cells with neuroendocrine features when transduced with oncogenic signaling, the identity of the cell-of-origin for de novo NEPC remains unclear. We…
Efficient therapeutic options are needed to control the spread of SARS-CoV-2 that has caused more than 922,000 fatalities as of September 13th, 2020. We report the isolation and characterization of two ultrapotent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that protect hamsters against SARS-CoV-2 challenge. Cryo-electron microscopy structures show that S2E12 and S2M11 competitively block ACE2 attachment and that S2M11…