Acetyl-Click Screening Platform Identifies Small-Molecule Inhibitors of Histone Acetyltransferase 1 (HAT1)
Not provided.
Pharmacology & Pharmacy↗
Engineering topics
Snyder, Michael P.
Publications and source records attributed to Snyder, Michael P..
Endogenous Retroviral Elements Generate Pathologic Neutrophils in Pulmonary Arterial Hypertension
Rationale: The role of neutrophils and their extracellular vesicles (EVs) in the pathogenesis of pulmonary arterial hypertension is unclear. Objectives: To relate functional abnormalities in pulmonary arterial hypertension neutrophils and their EVs to mechanisms uncovered by proteomic and transcriptomic profiling. Methods: Production of elastase, release of extracellular traps, adhesion, and migration were assessed in neutrophils from patients with pulmonary arterial hypertension and control subjects. Proteomic analyses were applied to explain functional perturbations, and transcriptomic data were used to find underlying mechanisms. CD66b-specific neutrophil EVs were isolated from plasma of patients with pulmonary arterial hypertension, and we determined whether they produce pulmonary hypertension in mice. Measurements and Main Results: Neutrophils from patients with pulmonary arterial hypertension produce and release increased neutrophil elastase, associated with enhanced extracellular traps. They exhibit reduced migration and increased adhesion attributed to elevated β1-integrin and vinculin identified by proteomic analysis and previously linked to an antiviral response. This was substantiated by a transcriptomic IFN signature that we related to an increase in human endogenous retrovirus K envelope protein. Transfection of human endogenous retrovirus K envelope in a neutrophil cell line (HL-60) increases neutrophil elastase and IFN genes, whereas vinculin is increased by human endogenous retrovirus K deoxyuridine triphosphate diphosphatase that is elevated in patient plasma. Neutrophil EVs from patient plasma contain increased neutrophil elastase and human endogenous retrovirus K envelope and induce pulmonary hypertension in mice, mitigated by elafin, an elastase inhibitor. Conclusions: Elevated human endogenous retroviral elements and elastase link a neutrophil innate immune response to pulmonary arterial hypertension.
60 APPLIED LIFE SCIENCES↗
Altered Cardiac Energetics and Mitochondrial Dysfunction in Hypertrophic Cardiomyopathy
Background: Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure–function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. Here, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. Methods: We performed a comprehensive multiomics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). Results: Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and phosphocreatine) and a reduction in mitochondrial genes involved in creatine kinase and ATP synthesis. Accompanying these metabolic derangements, electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. Conclusions: Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.
60 APPLIED LIFE SCIENCES↗
3D Printing in Zero-G ISS Technology Demonstration
The National Aeronautics and Space Administration (NASA) has a long term strategy to fabricate components and equipment on-demand for manned missions to the Moon, Mars, and beyond. To support this strategy, NASA and Made in Space, Inc. are developing the 3D Printing In Zero-G payload as a Technology Demonstration for the International Space Station. The 3D Printing In Zero-G experiment will be the first machine to perform 3D printing in space. The greater the distance from Earth and the longer the mission duration, the more difficult resupply becomes; this requires a change from the current spares, maintenance, repair, and hardware design model that has been used on the International Space Station up until now. Given the extension of the ISS Program, which will inevitably result in replacement parts being required, the ISS is an ideal platform to begin changing the current model for resupply and repair to one that is more suitable for all exploration missions. 3D Printing, more formally known as Additive Manufacturing, is the method of building parts/ objects/tools layer-by-layer. The 3D Print experiment will use extrusion-based additive manufacturing, which involves building an object out of plastic deposited by a wire-feed via an extruder head. Parts can be printed from data files loaded on the device at launch, as well as additional files uplinked to the device while on-orbit. The plastic extrusion additive manufacturing process is a low-energy, low-mass solution to many common needs on board the ISS. The 3D Print payload will serve as the ideal first step to proving that process in space. It is unreasonable to expect NASA to launch large blocks of material from which parts or tools can be traditionally machined, and even more unreasonable to fly up specialized manufacturing hardware to perform the entire range of function traditionally machining requires. The technology to produce parts on demand, in space, offers unique design options that are not possible through traditional manufacturing methods while offering cost-effective, high-precision, low-unit on-demand manufacturing. Thus, Additive Manufacturing capabilities are the foundation of an advanced manufacturing in space roadmap.
Johnston, Mallory M.↗