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Unbound chemicals to plasma proteins are more efficiently available to diffusion across cell membrane

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This distinction leaves a gap what about someone who smokes less than 5 per day but has done for the past year, or someone who stopped smoking after many years, but only 6 months ago how did the authors decide which group these examples would fall into

Another ligand for RAGE is the nuclear protein high-mobility group box-1 (HMGB1), which is normally buried deep within the nucleus and can be released into the extracellular space by passive diffusion from necrotic cells or by active secretion from activated macrophages/monocytes