Biology subjects

Buck, E.

Publications and source records attributed to Buck, E..

3 recordsLinked to original sources

bioRxiv2026

Mucosal vaccine-elicited IgA is protective against zoonotic Betacoronavirus challenge

Current vaccines for respiratory viruses are primarily administered intramuscularly. Messenger RNA-lipid nanoparticle (LNP)-based intramuscular vaccination for respiratory coronaviruses induces strong systemic IgG antibody responses; they do not consistently elicit IgA in the upper and lower respiratory tracts. Using a synthetic consensus spike protein aimed to broadening immunity against SARS-like viruses, SarbConS, coupled to ferritin nanoparticles co-delivered with mastoparan-7 and an FDA-approved CpG adjuvant, we intranasally boost SARS-CoV-2-immune animals. This intranasal boosting strategy elicits durable mucosal IgA responses in the respiratory tract, along with robust systemic IgG responses, and demonstrates durable protection against SARS-CoV-2 and zoonotic SARS-like viruses from bats and pangolins. Intranasal delivery of mastoparan-7 and CpG with MERS-CoV spike protein similarly elicits MERS-CoV-specific mucosal IgA and protects against MERS-CoV challenge in mice. Moreover, we observe durable protection against these genetically divergent zoonotic SARS-like viral challenges compared to intramuscular mRNA-LNP or unadjuvanted intranasal spike boosters. Intranasal SarbConS-ferritin nanoparticle intranasal vaccination similarly elicited durable mucosal IgA and antigen-specific memory B cell responses in the airways. The protective efficacy of M7-CpG adjuvanted SarbConS ferritin nanoparticle intranasal boosters was abolished in IgA knockout mice, suggesting a requirement for IgA in mediating respiratory mucosal vaccine-mediated protection against coronavirus infection. Altogether, our results demonstrate that respiratory mucosal vaccination can elicit durable and cross-protective mucosal IgA responses against genetically diverse zoonotic coronaviruses with implications for improved mucosal vaccines for highly transmissible respiratory viral pathogens.

immunology↗

bioRxiv2019

EGFR Oncogenes Expressed In Glioblastoma Are Activated As Covalent Dimers And Paradoxically Stimulated By Erlotinib

Mutation of both the intracellular catalytic domain and the extracellular domain of the receptor for epidermal growth factor (EGFR) can drive oncogenicity. Despite clinical success with targeting EGFR catalytic site mutations, no drugs have proven effective in patients expressing allosteric extracellular domain EGFR mutations, including glioblastomas (GBM) where these mutations are highly expressed. We define the molecular mechanism for oncogenic activation of families of extracellular EGFR mutations and reveal how this mechanism renders current generation small molecule ATP-site inhibitors ineffective. We demonstrate that a group of commonly expressed extracellular domain EGFR mutants expressed in GBM is activated by disulfide-bond mediated covalent dimerization, collectively referred to as locked dimerization (LoDi) EGFR oncogenes. Strikingly, small molecules binding to the active kinase conformation (Type I), but not those binding to the inactive kinase conformation (Type II), potently inhibit catalytic site mutants, but induce covalent dimerization and activate LoDi-EGFR oncogenes, manifesting in paradoxical acceleration of proliferation.\n\nSignificanceOur data demonstrate how the locked-dimer mechanism of EGFR oncogenesis has a profound impact on the activity of small molecule inhibitors. This provides a mechanistic understanding for the failure of current generation EGFR inhibitors to effectively treat LoDi-EGFR mutants in GBM, and sets guidelines for discovery of selective LoDi-EGFR inhibitors.

cancer biology↗

bioRxiv2019

Species and sex divergence in vocalizations between hybridizing role-reversed shorebirds, Northern Jacana (Jacana spinosa) and Wattled Jacana (Jacana jacana)

Species-specific vocalizations can act as a reproductive isolating mechanism between closely related populations. We analyzed vocal divergence between two hybridizing species of sex-role reversed polyandrous shorebirds, the Northern Jacana (Jacana spinosa) and Wattled Jacana (Jacana jacana). We found that J. spinosa calls have higher peak frequency and fundamental frequency than J. jacana calls. We also compared calls between males and females, as both jacana species are sex-role reversed and females compete for male mates. Males produce calls with a higher peak frequency, exhibit shorter note lengths and emit a greater number of notes within a calling bout than females, which could relate to mate attraction. These results suggest that vocal divergence could act as a behavioral barrier to limit hybridization between the species and vocalizations may function differently between male and female jacanas.

animal behavior and cognition↗