Transferrin receptor (TfR) binding entities can be used as vehicles for CNS drug delivery, however pose challenges for drug development due to huge increase in drug mass. The authors identified a series of TfR-binding cystine-dense peptides that can deliver the neuropeptide neurotensin (model drug), to a mouse's brain while only adding 6 kilodaltons to its mass.
Multidrug resistance (MDR) of pathogens is an ongoing public health crisis exacerbated by the horizontal transfer of antibiotic resistance genes via conjugative plasmids. Factors that stabilize these plasmids in bacterial communities contribute to an even higher incidence of MDR, given the increased likelihood that a host will already contain a plasmid when it acquires another through conjugation. Here, we show…
The opportunistic pathogen Pseudomonas aeruginosa is a leading cause of airway infection in cystic fibrosis (CF) patients. P. aeruginosa employs several hierarchically arranged and interconnected quorum sensing (QS) regulatory circuits to produce a battery of virulence factors such as elastase, phenazines, and rhamnolipids. The QS transcription factor LasR sits atop this hierarchy and activates the transcription of dozens of genes,…
The hippocampal dentate gyrus (DG) is a unique brain region maintaining neural stem cells (NCSs) and neurogenesis into adulthood. We used multiphoton imaging to visualize genetically defined progenitor subpopulations in live slices across key stages of mouse DG development, testing decades old static models of DG formation with molecular identification, genetic-lineage tracing, and mutant analyses. We found novel progenitor migrations,…
The authors describe several features of bacterial genes that impose stringent requirements on CRISPR-Cas tools to activate gene expression, and strategies for overcoming these requirements. Their most surprising finding was that there is a very narrow range of target sites that effectively activated bacterial gene expression. This and other behaviors suggest an explanation for why gene activation methods in bacteria have lagged far behind comparable tools in eukaryotic systems, where such strict target site requirements are absent.
Autism Spectrum Disorder (ASD) risk genes are often described as either developmental or synaptic. However, a growing body of evidence shows substantial overlaps and links between these categories, raising the question of how useful the distinction between the two is, in the context of ASD. Developmental processes, such as the radial migration of cortical excitatory neurons and apoptosis of inhibitory…
This manuscript provides validation of an approach to rapidly screen zebrafish using first-generation CRISPR-edited mutants for phenotypes related to human skeletal disease. Despite genetic mosaicism and variability in phenotypic penetrance between and within individual zebrafish, the demonstrate that phenomic analysis, paired with appropriate statistical analyses, can allow for the rapid detection of distributed and variable phenotypes in the zebrafish skeleton.
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…
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…
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…