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"Roth, Jonathan"
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This planet rocks!
Two mismatched rovers alone on a distant planet - what could possibly go wrong? When Rover crash-lands on a rocky planet and finds Speck stranded and in need of a battery charge, the two hardly seem destined to be teammates. Rover: organized, careful and on a mission to explore the galaxy. Speck: impulsive, excitable and not sure what his mission is. Their differences are forgotten, however, when they make their first discovery: they're not alone! And suddenly their only mission is to escape from the rock creatures that are chasing them!
Book
Increased hepatoprotective effects of the novel farnesoid X receptor agonist INT-787 versus obeticholic acid in a mouse model of nonalcoholic steatohepatitis
The nuclear farnesoid X receptor (FXR), a master regulator of bile acid and metabolic homeostasis, is a key target for treatment of nonalcoholic steatohepatitis (NASH). This study compared efficacy of FXR agonists obeticholic acid (OCA) and INT-787 by liver histopathology, plasma biomarkers of liver damage, and hepatic gene expression profiles in the Amylin liver NASH (AMLN) diet–induced and biopsy-confirmed Lep ob/ob mouse model of NASH. Lep ob/ob mice were fed the AMLN diet for 12 weeks before liver biopsy and subsequent treatment with vehicle, OCA, or INT-787 for 8 weeks. Hepatic steatosis, inflammation, and fibrosis (liver lipids, galectin-3, and collagen 1a1 [Col1a1], respectively), as well as plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, were assessed. Hepatic gene expression was assessed in Lep ob/ob mice that were fed the AMLN diet for 14 weeks then treated with vehicle, OCA, or INT-787 for 2 weeks. INT-787, which is equipotent to OCA but more hydrophilic, significantly reduced liver lipids, galectin-3, and Col1a1 compared with vehicle, and to a greater extent than OCA. INT-787 significantly reduced plasma ALT and AST levels, whereas OCA did not. INT-787 modulated a substantially greater number of genes associated with FXR signaling, lipid metabolism, and stellate cell activation relative to OCA in hepatic tissue. These findings demonstrate greater efficacy of INT-787 treatment compared with OCA in improving liver histopathology, decreasing liver enzyme levels, and enhancing gene regulation, suggesting superior clinical potential of INT-787 for the treatment of NASH and other chronic liver diseases.
Journal Article
Double trouble
While working on his duplication ray, Bob accidentally makes clones of himself and his alien friend Beep, and soon finds out that their doubles are evil and plan to rule the Earth.
Book
Precision mutational scanning: your multipass to the future of genetics
Massively parallel base and prime editing screens provide unparalleled interrogation of genetic variants with single-nucleotide resolution.
Journal Article
Party crashers
Beep and his best friend, Bob, are accused of stealing guests' jewelry during Lani's birthday voyage on luxurious Starship Titanic, but things go downhill when Titanic plummets toward Neptune. Includes facts about Neptune.
Book
Design of synthetic collagens that assemble into supramolecular banded fibers as a functional biomaterial testbed
Collagens are the most abundant proteins of the extracellular matrix, and the hierarchical folding and supramolecular assembly of collagens into banded fibers is essential for mediating cell-matrix interactions and tissue mechanics. Collagen extracted from animal tissues is a valuable commodity, but suffers from safety and purity issues, limiting its biomaterials applications. Synthetic collagen biomaterials could address these issues, but their construction requires molecular-level control of folding and supramolecular assembly into ordered banded fibers, comparable to those of natural collagens. Here, we show an innovative class of banded fiber-forming synthetic collagens that recapitulate the morphology and some biological properties of natural collagens. The synthetic collagens comprise a functional-driver module that is flanked by adhesive modules that effectively promote their supramolecular assembly. Multiscale simulations support a plausible molecular-level mechanism of supramolecular assembly, allowing precise design of banded fiber morphology. We also experimentally demonstrate that synthetic fibers stimulate osteoblast differentiation at levels comparable to natural collagen. This work thus deepens understanding of collagen biology and disease by providing a ready source of safe, functional biomaterials that bridge the current gap between the simplicity of peptide biophysical models and the complexity of in vivo animal systems.
Journal Article
Too much space!
After being humiliated while on a field trip to Pluto, Bob, with the help of his alien friend Beep, tries to change his personality and overcome his fears (heights, darkness, space, and spiders) before the next field trip to a black hole. Includes facts about Pluto.
Book
Pooled‐matrix protein interaction screens using Barcode Fusion Genetics
High‐throughput binary protein interaction mapping is continuing to extend our understanding of cellular function and disease mechanisms. However, we remain one or two orders of magnitude away from a complete interaction map for humans and other major model organisms. Completion will require screening at substantially larger scales with many complementary assays, requiring further efficiency gains in proteome‐scale interaction mapping. Here, we report Barcode Fusion Genetics‐Yeast Two‐Hybrid (BFG‐Y2H), by which a full matrix of protein pairs can be screened in a single multiplexed strain pool. BFG‐Y2H uses Cre recombination to fuse DNA barcodes from distinct plasmids, generating chimeric protein‐pair barcodes that can be quantified via next‐generation sequencing. We applied BFG‐Y2H to four different matrices ranging in scale from ~25 K to 2.5 M protein pairs. The results show that BFG‐Y2H increases the efficiency of protein matrix screening, with quality that is on par with state‐of‐the‐art Y2H methods.
Synopsis
Barcode Fusion Genetics‐Yeast Two‐Hybrid, a new technology allowing many‐by‐many screening of protein interactions in a single pooled assay, is presented. High‐quality interactions are identified in search matrices up to ~2.5 million protein pairs in scale.
Barcode Fusion Genetics (BFG) enables phenotypic analysis of millions of strains, each carrying two engineered loci.
BFG is applied to perform highly multiplexed yeast two‐hybrid protein interaction assays (BFG‐Y2H).
Protein interactions for ˜2.5 million protein pairs are tested in a single BFG‐Y2H run.
The quality of BFG‐Y2H results is on par with current state‐of‐the‐art Y2H methods.
Graphical Abstract
Barcode Fusion Genetics‐Yeast Two‐Hybrid, a new technology allowing many‐by‐many screening of protein interactions in a single pooled assay, is presented. High‐quality interactions are identified in search matrices up to ~2.5 million protein pairs in scale.
Journal Article
Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies
Body weight is regulated by complex neurohormonal interactions between endocrine signals of long-term adiposity (e.g., leptin, a hypothalamic signal) and short-term satiety (e.g., amylin, a hindbrain signal). We report that concurrent peripheral administration of amylin and leptin elicits synergistic, fat-specific weight loss in leptin-resistant, diet-induced obese rats. Weight loss synergy was specific to amylin treatment, compared with other anorexigenic peptides, and dissociable from amylin's effect on food intake. The addition of leptin after amylin pretreatment elicited further weight loss, compared with either monotherapy condition. In a 24-week randomized, double-blind, clinical proof-of-concept study in overweight/obese subjects, coadministration of recombinant human leptin and the amylin analog pramlintide elicited 12.7% mean weight loss, significantly more than was observed with either treatment alone (P < 0.01). In obese rats, amylin pretreatment partially restored hypothalamic leptin signaling (pSTAT3 immunoreactivity) within the ventromedial, but not the arcuate nucleus and up-regulated basal and leptin-stimulated signaling in the hindbrain area postrema. These findings provide both nonclinical and clinical evidence that amylin agonism restored leptin responsiveness in diet-induced obesity, suggesting that integrated neurohormonal approaches to obesity pharmacotherapy may facilitate greater weight loss by harnessing naturally occurring synergies.
Journal Article