Our mutagenesis study suggested residues in the core region of the TLX LBD involved in TLX modulation by xanthines. In essence, we found Phe226 and Ile230 located in helix 5 playing a role in mediating the effects of the xanthines. Moreover, consistent with previous studies knockdown has been reported to upregulate expression of both genes, too . Upregulation of SIRT1, in contrast, according to current understanding indicates TLX activation by xanthines.