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In some embodiments, nucleic acid molecules encompassed by the invention can be optimized, e.g., to increase expression, improve the effectiveness of gene silencing for silencing a target gene, and the like

Because many tissues may have abundant D3 levels while the pituitary is uniquely void of D3, the inhibitory effects on the peripheral tissues causing hypothyroidism are not reflected by TSH testing (see Figures 2 and 3)