Design and characterization of a protein fold switching network.

To better understand how amino acid sequence encodes protein structure, we engineered mutational pathways that connect three common folds (3α, ß-grasp, and α/ß-plait). The structures of proteins at high sequence-identity intersections in the pathways (nodes) were determined using NMR spectroscopy and analyzed for stability and function. To generate nodes, the amino acid sequence encoding a smaller fold is embedded in the structure of an ~50% larger fold and a new sequence compatible with two sets of native interactions is designed. This generates protein pairs with a 3α or ß-grasp fold in the smaller form but an α/ß-plait fold in the larger form. Further, embedding smaller antagonistic folds creates critical states in the larger folds such that single amino acid substitutions can switch both their fold and function. The results help explain the underlying ambiguity in the protein folding code and show that new protein structures can evolve via abrupt fold switching.

Rapid and reversible recruitment of early visual cortex for touch.

BACKGROUND: The loss of vision has been associated with enhanced performance in non-visual tasks such as tactile discrimination and sound localization. Current evidence suggests that these functional gains are linked to the recruitment of the occipital visual cortex for non-visual processing, but the neurophysiological mechanisms underlying these crossmodal changes remain uncertain. One possible explanation is that visual deprivation is associated with an unmasking of non-visual input into visual cortex. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the effect of sudden, complete and prolonged visual deprivation (five days) in normally sighted adult individuals while they were immersed in an intensive tactile training program. Following the five-day period, blindfolded subjects performed better on a Braille character discrimination task. In the blindfold group, serial fMRI scans revealed an increase in BOLD signal within the occipital cortex in response to tactile stimulation after five days of complete visual deprivation. This increase in signal was no longer present 24 hours after blindfold removal. Finally, reversible disruption of occipital cortex function on the fifth day (by repetitive transcranial magnetic stimulation; rTMS) impaired Braille character recognition ability in the blindfold group but not in non-blindfolded controls. This disruptive effect was no longer evident once the blindfold had been removed for 24 hours. CONCLUSIONS/SIGNIFICANCE: Overall, our findings suggest that sudden and complete visual deprivation in normally sighted individuals can lead to profound, but rapidly reversible, neuroplastic changes by which the occipital cortex becomes engaged in processing of non-visual information. The speed and dynamic nature of the observed changes suggests that normally inhibited or masked functions in the sighted are revealed by visual loss. The unmasking of pre-existing connections and shifts in connectivity represent rapid, early plastic changes, which presumably can lead, if sustained and reinforced, to slower developing, but more permanent structural changes, such as the establishment of new neural connections in the blind.

Time-dependent changes in cortical excitability after prolonged visual deprivation.

Transcranial magnetic stimulation applied to the occipital cortex can elicit phosphenes. Changes in the phosphene threshold provide a measure of visual cortex excitability. Phosphene threshold was measured in participants blindfolded for five consecutive days to assess the effects of prolonged visual deprivation on visual cortical excitability. After 48 h of blindfolding, an acute decrease in phosphene threshold was observed, followed by a significant increase by day 5. Phosphene threshold returned to preblindfold levels within 2 h of light re-exposure. Thus, light deprivation is characterized by a transient increase in visual cortical excitability, followed by a sustained decrease in visual cortex excitability that quickly returns to baseline levels after re-exposure to light.

Braille character discrimination in blindfolded human subjects.

Visual deprivation may lead to enhanced performance in other sensory modalities. Whether this is the case in the tactile modality is controversial and may depend upon specific training and experience. We compared the performance of sighted subjects on a Braille character discrimination task to that of normal individuals blindfolded for a period of five days. Some participants in each group (blindfolded and sighted) received intensive Braille training to offset the effects of experience. Blindfolded subjects performed better than sighted subjects in the Braille discrimination task, irrespective of tactile training. For the left index finger, which had not been used in the formal Braille classes, blindfolding had no effect on performance while subjects who underwent tactile training outperformed non-stimulated participants. These results suggest that visual deprivation speeds up Braille learning and may be associated with behaviorally relevant neuroplastic changes.