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Costimulation serves as a mechanism to modulate the strength of the TCR signal and promote higher gene expression of immunomodulatory cytokines like interleukin-2, as well as other factors that facilitate T cell proliferation and differentiation ( A key mediator of T cell signaling is the divalent cation calcium (Ca 2+ )

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The reduction in AUC after oral administration can result from numerous mechanisms including: pH or bacterial-mediated metabolism of the drug within the GI tract, incomplete drug absorption from the GI tract, metabolism within the GI epithelium (which contains CYP3A4), excretion back into the GI tract by P-glycoprotein in the GI epithelium, hepatic metabolism, or biliary excretion into the GI tract

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Various systematic reviews and meta-analyses [57,58] reported that cortisol levels appear to be higher in the follicular versus luteal phase, whereas another systematic review and meta-analysis conducted by Klusmann et al