Bioorthogonal Chemical Reporters Reveal Fatty-Acylation of Histone H3 Variants and Cholesterol Modification of Proteins and Trafficking in Cells

Lipids are essential components to all known life. They serve many functions from basic building blocks to covalent protein modification and are particularly involved in signaling. Many rare and widespread human health concerns involve lipids but despite their importance, their analysis either free or protein-bound has remained difficult for decades. Here, using bioorthogonal chemistry, we have developed a robust system to identify the proteins modified by lipids and advanced the ability to image cholesterol in cells and tissues. The unbiased proteomic analysis of fatty-acylated proteins using chemical reporters undertaken here revealed a greater diversity of lipid-modified proteins in mammalian cells than had previously been appreciated. Proteins targeted by a series of fatty acid chemical reporters ranging from myristic to stearic acid showed their involvement in a vast range of cellular processes from all cellular compartments. Many nuclear proteins were found, in particular histone H3 variants. Histones H3.1, H3.2 and H3.3 were demonstrated to be modified with fatty acid chemical reporters on the conserved cysteine 110, a novel site of S-acylation on histone H3.2. This newly discovered modification of histone H3 variants could have implications for nuclear organization and chromatin regulation. Cholesterol is an abundant sterol in the membranes of higher eukaryotes that is important in mammalian physiology and disease. This ancient lipid serves multiple essential functions in membranes and signaling, but the precise mechanisms of its trafficking and function as a protein PTM remain to be fully elucidated. The multiple techniques developed to visualize cholesterol often give conflicting results and can inaccurately depict cholesterol distribution due to structural perturbations of analogs or staining specificities. Here, using click chemistry, we developed the fluorescent visualization of cholesterol protein modification and cholesterol trafficking in vivo with 25-azidonorcholesterol (az-chol). Az-chol exhibits minimal structural perturbation, is covalently attached to proteins, incorporates into membranes like cholesterol, faithfully detects alterations in lipid trafficking and reveals an asymmetrical cholesterol distribution in the brain of the developing mouse embryo. The bioorthogonal chemical reporter az-chol provides a new, sensitive and versatile tool to investigate cholesterol distribution from individual proteins to whole organisms

Management of Agitation During the COVID-19 Pandemic

The coronavirus disease 2019 (COVID-19) pandemic caused by the coronavirus SARS-CoV-2 has radically altered delivery of care in emergency settings. Unprecedented hardship due to ongoing fears of exposure and threats to personal safety, along with societal measures enacted to curb disease transmission, have had broad psychosocial impact on patients and healthcare workers alike. These changes can significantly affect diagnosing and managing behavioral emergencies such as agitation in the emergency department. On behalf of the American Association for Emergency Psychiatry, we highlight unique considerations for patients with severe behavioral symptoms and staff members managing symptoms of agitation during COVID-19. Early detection and treatment of agitation, precautions to minimize staff hazards, coordination with security personnel and psychiatric services, and avoidance of coercive strategies that cause respiratory depression will help mitigate heightened risks to safety caused by this outbreak

Advanced Cosmic Ray Composition Experiment for Space Station (ACCESS)

In 1994 the first high-energy particle physics experiment for the Space Station, the Alpha Magnetic Spectrometer (AMS), was selected by NASA's Administrator as a joint collaboration with the U.S. Department of Energy (DOE). The AMS program was chartered to place a magnetic spectrometer in Earth orbit and search for cosmic antimatter. A natural consequence of this decision was that NASA would begin to explore cost-effective ways through which the design and implementation of AMS might benefit other promising payload experiments which were evolving from the Office of Space Science. The first such experiment to come forward was ACCESS in 1996. It was proposed as a new mission concept in space physics to place a cosmic-ray experiment of weight, volume, and geometry similar to the AMS on the ISS, and replace the latter as its successor when the AMS is returned to Earth. This was to be an extension of NASA's sub-orbital balloon program, with balloon payloads serving as the precursor flights and heritage for ACCESS. The balloon programs have always been a cost-effective NASA resource since the particle physics instrumentation for balloon and space applications are directly related. The next step was to expand the process, pooling together expertise from various NASA centers and universities while opening up definition of the ACCESS science goals to the international community through the standard practice of peer-review. This process is still on-going and the Accommodation Study presented here will discuss the baseline definition of ACCESS as we understand it today. Further detail on the history, scope, and background of the study is provided in Appendix A