In the neocortex, subcerebral axonal projections originate largely from layer 5 (L5) extratelencephalic-projecting (ET) neurons. The unique morpho-electric properties of these neurons have been mainly described in rodents, where retrograde tracers or transgenic lines can label them. Similar labeling strategies are infeasible in the human neocortex, rendering the translational relevance of findings in rodents unclear. We leveraged the recent discovery…
The authors used a combination of computational and experimental techniques to study the variation of DNA replication fidelity among different strains of the yeast Saccharomyces cerevisiae. Their computational analysis suggested that a certain type of beer-brewing yeast accumulates mutations from C to A more quickly than other yeast, and we were able to go one step further using laboratory experiments that aren't possible in humans.
Some people have a harder time losing weight than others. The current study, along with a growing body of evidence from other research groups, suggests that one of the major factors that modulate our ability to lose weight is our gut microbes. We've identified specific genetic signatures in the gut microbiome that were predictive of weight loss responses in a small cohort of patients following a healthy lifestyle intervention.
Links between T cell clonotypes, as defined by T cell receptor (TCR) sequences, and phenotype, as reflected in gene expression (GEX) profiles, surface protein expression and peptide:major histocompatibility complex binding, can reveal functional relationships beyond the features shared by clonally related cells. Here we present clonotype neighbor graph analysis (CoNGA), a graph theoretic approach that identifies correlations between GEX profile…
A better understanding of the metabolic alterations in immune cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may elucidate the wide diversity of clinical symptoms experienced by individuals with coronavirus disease 2019 (COVID-19). Here, we report the metabolic changes associated with the peripheral immune response of 198 individuals with COVID-19 through an integrated analysis of plasma metabolite and…
For the past decade, scientists have performed genome-wide screens to identify important cancer genes – first with shRNA and in the past few years with CRISPR. However, we and others noticed that paralogs – duplicated genes – were underrepresented as hits in these screens. We wondered if this absence was due to redundancy between the two genes – if so, knocking out duplicated genes in tandem should produce an effect and reveal the function of the genes.
Immunologic mechanisms influence how a cancer patient responds to therapy. Monoclonal antibodies (mAbs) to the epidermal growth factor receptor are clinically approved, and a lung cancer vaccine inducing antibodies to epidermal growth factor (EGF) has some beneficial clinical effects. We tested the hypothesis that mAbs to epidermal growth factor receptor, EGF, and tumor growth factor alpha (TGF-α), in addition to…
A significant barrier to effective immunotherapy in AML is the shared immunophenotype between AML and normal hematopoietic cells. We show that MSLN protein is expressed on the cell surface of AML blasts and leukemic stem cells (LSCs) but entirely silent on normal hematopoietic stem and progenitor cells (HSPCs). We developed CAR T cells targeting MSLN and show that the MSLN-directed CAR T cells effectively eliminate both AML blasts and LSCs while sparing normal HPSCs.
My lab is working in two major directions – molecular evolution of human pathogens and structure-functional analysis of microbial cell attachment proteins. On the evolutionary side, we are specializing in determining how the smallest genetic changes – point mutations – can increase microbial virulence or drug resistance. Here, our primary model organism is E. coli causing urinary tract and bloodstream infections. However, we apply our molecular evolutionary tools to many other human pathogens, including viruses.
Chimeric antigen receptor (CAR)–modified T cell therapy is effective in treating lymphomas, leukemias, and multiple myeloma in which the tumor cells express high amounts of target antigen. However, achieving durable remission for these hematological malignancies and extending CAR T cell therapy to patients with solid tumors will require receptors that can recognize and eliminate tumor cells with a low density…