Dimensionality reduction is often used to visualize complex expression profiling data. Here, we use the Uniform Manifold Approximation and Projection (UMAP) method on published transcript profiles of 1484 single gene deletions of Saccharomyces cerevisiae. Proximity in low-dimensional UMAP space identifies groups of genes that correspond to protein complexes and pathways, and finds novel protein interactions, even within well-characterized complexes. This approach…
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Brain circuits comprise vast numbers of interconnected neurons with diverse molecular, anatomical and physiological properties. To allow targeting of individual neurons for structural and functional studies, we created light-inducible site-specific DNA recombinases based on Cre, Dre and Flp (RecVs). RecVs can induce genomic modifications by one-photon or two-photon light induction in vivo. They can produce targeted, sparse and strong labeling…
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Diabetes is now a pandemic disease. Moreover, a large number of people with prediabetes are at risk for developing frank diabetes worldwide. Both type 1 and type 2 diabetes increase the risk of atherosclerotic cardiovascular disease (CVD). Even with statin treatment to lower LDL cholesterol, patients with diabetes have a high residual CVD risk. Factors mediating the residual risk are…
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How do tuft cells regulate type 2 immune responses? Initial work identified the cytokine IL-25 as a key effector molecule that tuft cells secrete to initiate type 2 immunity, but this is not the whole story. The authors found that tuft cells produce a second type of effector, called cysteinyl leukotrienes, that cooperate with IL-25 to amplify the type 2 response. Tuft cells release leukotrienes upon sensing helminths in the lumen of the small intestine, and that this is an important signal for rapidly initiating the anti-helminth immune response.
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The authors have developed a realistic 3D model which captures the mechanisms that allow a small number of T cells to eliminate rapidly spreading herpes simplex virus-2 in genital skin. The model generates videos which provide an approximation of what the disease looks like as it spread through tissue, but is ultimately contained. The work has broad applicability for multiple human viral infections. It suggests that antiviral cytokines are highly effective at diffusing within tissue and preventing viral spread, even there are only a small number of T cells in a defensive role.
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The expression of E-cadherin has been implicated in tumor metastasis, often as a tumor suppressor, but also as a promoter of growth and metastasis. We have shown that the functional activity of E-cadherin at the cell surface is often modified in response to environmental factors, and have developed monoclonal antibodies (mAbs) that activate E-cadherin adhesive function. These activating mAbs inhibit…
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Engineering Heart Morphogenesis

There is high potential for current technologies to be used to recapitulate heart development in vitro by focusing on its earliest stage of morphogenesis: the embryonic heart tube. Recent advances in stem cell biology have enabled the production of cardiac progenitor lineages for bioengineering approaches. Biofabrication techniques can create structures and features of the heart tube at the appropriate scale. Biochemical…
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Candidate Silencer Elements for the Human and Mouse Genomes

The study of gene regulation is dominated by a focus on the control of gene activation or increase in the level of expression. Just as critical is the process of gene repression or silencing. Chromatin signatures have identified enhancers, however, genome-wide identification of silencers by computational or experimental approaches are lacking. Here, we first define uncharacterized cis-regulatory elements likely containing silencers…
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Targeting metabolic aberrations has been a major focus in cancer research, and genome-scale metabolic network models have been used to guide the identification of selective targets. However, such models are often based on gene expression data of the whole tumor biopsy, which contains both malignant and non-malignant cells, and lacks specificity. The authors exploited the extensive spatial heterogeneity of metabolic activities in a tumor biopsy to pinpoint a few selective vulnerabilities of prostate cancer cells.
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Data from several randomized studies have shown that a CD33 antibody-drug conjugate reduces relapse risks and improves survival when added to intensive chemotherapy in some patients with AML. However, they do not work on all patients. To develop improved CD33-targeted drugs, the authors have generated and characterized two antibodies recognizing the extracellular domain that is preserved in a splice variant of CD33 that lacks exon 2. They have found that this variant is neither expressed on human AML cell lines nor on primary blast cells from a smaller cohort of AML patients.
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