Bimodal Presentation Speeds up Auditory Processing and Slows Down Visual Processing.

Many situations require the simultaneous processing of auditory and visual information, however, stimuli presented to one sensory modality can sometimes interfere with processing in a second sensory modality (i.e., modality dominance). The current study further investigated modality dominance by examining how task demands and bimodal presentation affect speeded auditory and visual discriminations. Participants in the current study had to quickly determine if two words, two pictures, or two word-picture pairings were the same or different, and we manipulated task demands across three different conditions. In an immediate recognition task, there was only one second between the two stimuli/stimulus pairs and auditory dominance was found. Compared to the respective unimodal baselines, pairing pictures and words together slowed down visual responses and sped up auditory responses. Increasing the interstimulus interval to four seconds and blocking verbal rehearsal weakened auditory dominance effects, however, conflicting and redundant visual cues sped up auditory discriminations. Thus, simultaneously presenting pictures and words had different effects on auditory and visual processing, with bimodal presentation slowing down visual processing and speeding up auditory processing. These findings are consistent with a proposed mechanism underlying auditory dominance, which posits that auditory stimuli automatically grab attention and attenuate/delay visual processing.

SIRT1 represses estrogen-signaling, ligand-independent ERα-mediated transcription, and cell proliferation in estrogen-responsive breast cells.

In prostate and breast cancer, the androgen receptor and estrogen receptor (ER) mediate induction of androgen- and estrogen-responsive genes respectively and stimulate cell proliferation in response to the binding of their cognate steroid hormones. Sirtuin 1 (SIRT1) is a NAD+-dependent class III histone deacetylase that has been linked to gene silencing, control of the cell cycle, apoptosis, and energy homeostasis. In prostate cancer, SIRT1 is required for androgen antagonist-mediated transcriptional repression and growth suppression of prostate cancer cells. Whether SIRT1 plays a similar role in the actions of estrogen or antagonists had not been determined. We report here that SIRT1 represses the transcriptional and proliferative response of breast cancer cells to estrogens, and this repression is ERα dependent. Inhibition of SIRT1 activity results in the phosphorylation of ERα in an AKT-dependent manner, and this activation requires phosphoinositide 3-kinase activity. Phosphorylated ERα subsequently accumulates in the nucleus, where ERα binds DNA ER-responsive elements and activates transcription of estrogen-responsive genes. This ER-dependent transcriptional activation augments estrogen-induced signaling, but also activates ER signaling in the absence of estrogen, thus defining a novel and unexpected mechanism of ligand-independent ERα-mediated activation and target gene transcription. Like ligand-dependent activation of ERα, SIRT1 inhibition-mediated ERα activation in the absence of estrogen also results in breast cancer cell proliferation. Together, these data demonstrate that SIRT1 regulates the most important cell signaling pathway for the growth of breast cancer cells, both in the presence and the absence of estrogen.

Stimulation of KatG catalase activity by peroxidatic electron donors.

Catalase-peroxidases (KatGs) use a peroxidase scaffold to support robust catalase activity, an ability no other member of its superfamily possesses. Because catalase turnover requires H(2)O(2) oxidation, whereas peroxidase turnover requires oxidation of an exogenous electron donor, it has been anticipated that the latter should inhibit catalase activity. To the contrary, we report peroxidatic electron donors stimulated catalase activity up to 14-fold, particularly under conditions favorable to peroxidase activity (i.e., acidic pH and low H(2)O(2) concentrations). We observed a "low-" and "high-K(M)" component for catalase activity at pH 5.0. Electron donors increased the apparent k(cat) for the "low-K(M)" component. During stimulated catalase activity, less than 0.008 equivalents of oxidized donor accumulated for every H(2)O(2) consumed. Several classical peroxidatic electron donors were effective stimulators of catalase activity, but pyrogallol and ascorbate showed little effect. Stopped-flow evaluation showed that a Fe(III)-O(2)(·-)-like intermediate dominated during donor-stimulated catalatic turnover, and this intermediate converted directly to the ferric state upon depletion of H(2)O(2). In this respect, the Fe(III)-O(2)(·-) -like species was more prominent and persistent than in the absence of the donor. These results point toward a much more central role for peroxidase substrates in the unusual catalase mechanism of KatG.

Substitution of strictly conserved Y111 in catalase-peroxidases: Impact of remote interdomain contacts on active site structure and catalytic performance.

Catalase-peroxidase function is strictly dependent on a gene-duplicated C-terminal domain. This domain no longer has a functioning active site, but from 25 to 30A away it is essential for preventing the coordination of an active site base (His106) to the heme. The mechanisms by which this distant structure supports active site function have not yet been elucidated. Tyr111 is a strictly conserved member of an interdomain H-bonding network that supports the loop connecting the N-terminal B (bearing His106) and C helices. Spectroscopic evaluation of the Tyr111Ala variant of KatG showed a substantial increase in hexa-coordinate low-spin heme, giving it the appearance of a transition between the wild type (primarily high-spin) and the N-terminal domain alone (pure low-spin). Concomitant with the spectral changes was decreased activity compared to the wild type enzyme, suggesting that Tyr111 does have a role in preventing His106 coordination. Substitution of Tyr111 diminishes catalase activity more substantially than peroxidase activity. Such an effect cannot be explained by His106 coordination alone, suggesting that these interdomain interactions may help tune the catalase-peroxidase active site for bifunctionality.

The kinetic properties producing the perfunctory pH profiles of catalase-peroxidases.

Many structure-function relationship studies performed on the catalase-peroxidase enzymes are based on limited kinetic data. To provide a more substantive understanding of catalase-peroxidase function, we undertook a more exhaustive evaluation of catalase-peroxidase catalysis as a function of pH. Kinetic parameters across a broad pH range for the catalase and peroxidase activities of E. coli catalase peroxidase (KatG) were obtained, including the separate analysis of the oxidizing and reducing substrates of the peroxidase catalytic cycle. This investigation identified ABTS-dependent inhibition of peroxidase activity, particularly at low pH, unveiling that previously reported pH optima are clearly skewed. We show that turnover and efficiency of peroxidase activity increases with decreasing pH until the protein unfolds. The data also suggest that the catalase pH optimum is more complex than it is often assumed to be. The apparent optimum is in fact the intersection of the optimum for binding (7.00) and the optimum for activity (5.75). We also report the apparent pK(a)s for binding and catalysis of catalase activity as well as approximate values for certain peroxidatic and catalatic steps.