Combinatorial Tau pseudophosphorylation: markedly different regulatory effects on microtubule assembly and dynamic instability than the sum of the individual parts.

Tau is a multiply phosphorylated protein that is essential for the development and maintenance of the nervous system. Errors in Tau action are associated with Alzheimer disease and related dementias. A huge literature has led to the widely held notion that aberrant Tau hyperphosphorylation is central to these disorders. Unfortunately, our mechanistic understanding of the functional effects of combinatorial Tau phosphorylation remains minimal. Here, we generated four singly pseudophosphorylated Tau proteins (at Thr(231), Ser(262), Ser(396), and Ser(404)) and four doubly pseudophosphorylated Tau proteins using the same sites. Each Tau preparation was assayed for its abilities to promote microtubule assembly and to regulate microtubule dynamic instability in vitro. All four singly pseudophosphorylated Tau proteins exhibited loss-of-function effects. In marked contrast to the expectation that doubly pseudophosphorylated Tau would be less functional than either of its corresponding singly pseudophosphorylated forms, all of the doubly pseudophosphorylated Tau proteins possessed enhanced microtubule assembly activity and were more potent at regulating dynamic instability than their compromised singly pseudophosphorylated counterparts. Thus, the effects of multiple pseudophosphorylations were not simply the sum of the effects of the constituent single pseudophosphorylations; rather, they were generally opposite to the effects of singly pseudophosphorylated Tau. Further, despite being pseudophosphorylated at different sites, the four singly pseduophosphorylated Tau proteins often functioned similarly, as did the four doubly pseudophosphorylated proteins. These data lead us to reassess the conventional view of combinatorial phosphorylation in normal and pathological Tau action. They may also be relevant to the issue of combinatorial phosphorylation as a general regulatory mechanism.

Analysis of head gesture and prosody patterns for prosody-driven head-gesture animation.

We propose a new two-stage framework for joint analysis of head gesture and speech prosody patterns of a speaker towards automatic realistic synthesis of head gestures from speech prosody. In the first stage analysis, we perform Hidden Markov Model (HMM) based unsupervised temporal segmentation of head gesture and speech prosody features separately to determine elementary head gesture and speech prosody patterns, respectively, for a particular speaker. In the second stage, joint analysis of correlations between these elementary head gesture and prosody patterns is performed using Multi-Stream HMMs to determine an audio-visual mapping model. The resulting audio-visual mapping model is then employed to synthesize natural head gestures from arbitrary input test speech given a head model for the speaker. In the synthesis stage, the audio-visual mapping model is used to predict a sequence of gesture patterns from the prosody pattern sequence computed for the input test speech. The Euler angles associated with each gesture pattern are then applied to animate the speaker head model. Objective and subjective evaluations indicate that the proposed synthesis by analysis scheme provides natural looking head gestures for the speaker with any input test speech, as well as in "prosody transplant" and gesture transplant" scenarios.