As severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) evolves to escape natural antibodies, it also loses sensitivity to therapeutic antibody drugs. By contrast, evolution selects for binding to ACE2, the cell-surface receptor required for SARS-CoV-2 infection. Consistent with this, we find that an ACE2 decoy neutralizes antibody-resistant variants, including Omicron, with no loss in potency. To identify design features necessary for…
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The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci.…
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Age-Associated Remodeling of T Cell Immunity and Metabolism

Aging results in remodeling of T cell immunity and is associated with poor clinical outcomes in age-related diseases such as cancer. Among the hallmarks of aging, changes in host and cellular metabolism critically affect the development, maintenance, and function of T cells. Although metabolic perturbations impact anti-tumor T cell responses, the link between age-associated metabolic dysfunction and anti-tumor immunity remains unclear. In this…
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Programming T lymphocytes to distinguish self from non-self is a vital, multi-step process arising in the thymus1-4. Signalling through the pre-T cell receptor (preTCR), a CD3-associated heterodimer comprising an invariant pTα chain and a clone-specific β chain, constitutes a critical early checkpoint in thymocyte development within the αβ T-cell lineage5,6. PreTCRs arrayed on double negative (DN) thymocytes, like αβ TCRs…
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Immune cells are being engineered to recognize and respond to disease states, acting as a “living drug” when transferred into patients. Therapies based on engineered immune cells are now a clinical reality, with multiple engineered T cell therapies approved for treatment of hematologic malignancies. Ongoing preclinical and clinical studies are testing diverse strategies to modify the fate and function of…
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RBPs (RNA-binding proteins) perform indispensable functions in the post-transcriptional regulation of gene expression. Numerous RBPs have been implicated in cardiac development or physiology based on gene knockout studies and the identification of pathogenic RBP gene mutations in monogenic heart disorders. The discovery and characterization of additional RBPs performing indispensable functions in the heart will advance basic and translational cardiovascular research.
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Toxin B (TcdB) is a major exotoxin responsible for diseases associated with Clostridioides difficile infection. Its sequence variations among clinical isolates may contribute to the difficulty in developing effective therapeutics. Here, we investigate receptor-binding specificity of major TcdB subtypes (TcdB1 to TcdB12). We find that representative members of subtypes 2, 4, 7, 10, 11, and 12 do not recognize the established host…
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Bioelectric Regulation of Intestinal Stem Cells

Ion channels, pumps, and exchangers regulate the transport of ions, such as Na+, Cl–, K+, and Ca2+, in and out of cells, and gap junctions allow the movement of ions across cells. Ion imbalance is highly associated with intestinal disorders and even cancer; therefore, a genetic model capable of decoding in vivo how ion regulation affects intestinal stem cell proliferation could have…
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Dr. Heidi Greulich's group is interested in understanding the mechanism of action of velcrin compounds, which kill cancer cells expressing elevated levels of PDE3A and SLFN12 by inducing PDE3A-SLFN12 complex formation, which in turn upregulates the RNase activity of SLFN12.  They are also interested in leveraging the PDE3A-SLFN12 interaction to develop a cancer therapeutic.
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The Landscape of mRNA Nanomedicine

Messenger RNA (mRNA) is an emerging class of therapeutic agent for the prevention and treatment of a wide range of diseases. The recent success of the two highly efficacious mRNA vaccines produced by Moderna and Pfizer–BioNTech to protect against COVID-19 highlights the huge potential of mRNA technology for revolutionizing life science and medical research. Challenges related to mRNA stability and…
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