Engineered receptors for soluble cellular communication and disease sensing.

Despite recent advances in mammalian synthetic biology, there remains a lack of modular synthetic receptors that can robustly respond to soluble ligands and in turn activate bespoke cellular functions. Such receptors would have extensive clinical potential to regulate the activity of engineered therapeutic cells, but to date only receptors against cell surface targets have approached clinical translation. To address this gap, we developed a receptor architecture called synthetic intramembrane proteolysis receptor (SNIPR), that has the added ability to be activated by soluble ligands, both natural and synthetic, with remarkably low baseline activity and high fold activation, through an endocytic, pH-dependent cleavage mechanism.

SARS-CoV-2 Omicron subvariant genomic variation associations with immune evasion in Northern California: A retrospective cohort study.

Background: The possibility of association between SARS-CoV-2 genomic variation and immune evasion is not known among persons with Omicron variant SARS-CoV-2 infection.

Methods: In a retrospective cohort, using Poisson regression adjusting for sociodemographic variables and month of infection, we examined associations between individual non-lineage defining mutations and SARS-CoV-2 immunity status, defined as a) no prior recorded infection, b) not vaccinated but with at least one prior recorded infection, c) complete primary series vaccination, and/or d) primary series vaccination and ≥ 1 booster. We identified all non-synonymous single nucleotide polymorphisms (SNPs), insertions and deletions in SARS-CoV-2 genomes with ≥5% allelic frequency and population frequency of ≥5% and ≤95%.

Mitigation of Fetal Radiation Injury from Mid-Gestation Total-body Irradiation by Maternal Administration of Mitochondrial-Targeted GS-Nitroxide JP4-039.

Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal radiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal radiation injury by maternal administration of the mitochondrial-targeted gramicidin S (GS)-nitroxide radiation mitigator JP4-039.

Peptide-enabled ribonucleoprotein delivery for CRISPR engineering (PERC) in primary human immune cells and hematopoietic stem cells.

Peptide-enabled ribonucleoprotein delivery for CRISPR engineering (PERC) is a new approach for ex vivo genome editing of primary human cells. PERC uses a single amphiphilic peptide reagent to mediate intracellular delivery of the same pre-formed CRISPR ribonucleoprotein enzymes that are broadly used in research and therapeutics, resulting in high-efficiency editing of stimulated immune cells and cultured hematopoietic stem and progenitor cells (HSPCs). PERC facilitates nuclease-mediated gene knockout, precise transgene knock-in, and base editing.

Mitigation of Fetal Irradiation Injury from Mid-Gestation Total Body Radiation with Mitochondrial-Targeted GS-Nitroxide JP4-039.

Unlabelled: Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal irradiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal irradiation injury by maternal administration of the mitochondrial-targeted gramicidin S (GS)- nitroxide radiation mitigator, JP4-039.