Linker histones (H1s) are a major component of metazoan chromatin. The H1 C-terminal domain (CTD) is an intrinsically disordered domain that adopts a condensed structure upon binding to nucleosomes, with at least a portion of the CTD directly contacting linker DNA. H1 stabilizes self-association of nucleosome arrays into higher order chromatin structures and causes >100-fold reduction in accessibility to nucleosome linker DNA. However we find that the nucleosome-binding high mobility group proteins 1 and 2 (HMGN1 and 2) counteract the H1-dependent stabilization of higher-order chromatin structure, but do not displace H1s from nucleosomes; rather these proteins bind nucleosomes simultaneously with H1s without disturbing specific contacts between the H1 globular domain and nucleosomal DNA. We find that the HMGNs alter the nucleosome-dependent condensation of the linker histone C-terminal domain, and reorganize interactions of the core histone tail domains with nucleosomal DNA, redirecting the tails to more interior positions within the nucleosome. Our results suggest that HMGN1 and 2, at least in part, open chromatin by remodeling core and linker histone tail domain interactions critical for formation of higher order structures.

Constraint-induced movement therapy (CI therapy) is a well-researched intervention for treatment of upper limb function. Our lab is specifically interested in two modalities of CI therapy: Traditional CI therapy and a new modality developed in our lab, Gaming CI therapy. Overall, traditional CI therapy has been shown to yield clinically meaningful improvements in speed of task completion and greatly increases use of one's affected arm during daily activities. However, individual improvements vary widely, meaning that not everyone will benefit from this therapy. Therefore, we hypothesized that 1) some baseline, pre-therapy characteristics can be used to predict the extent of motor after CI therapy, 2) some of these characteristics, such as pre-therapy motor ability or somatosensation, are more predictive of recovery than others and 3) that some characteristics are robust predictors regardless of CI therapy modality. We tested this hypothesis by developing an enhanced probabilistic neural network (EPNN) prognostic computational model to identify which baseline characteristics predict extent of motor recovery, as measured by the Wolf Motor Function Test (WMFT), brief kinesthesia test, and touch test monofilimants. Results show that highly accurate predictive classification can be achieved (>90%) based on only a small subset of the available characteristics. This is important because high accuracy allows for personalized therapy planning whereby therapists can determine, beforehand, if their patient will respond well to therapy. This, then, can lead to greatly increased efficiency and cost-effectiveness of care.

Using innovative experimental and analytical approaches, we show that exchange of clathrin coat components take place predominantly at the edges of clathrin plaques. These findings provide important insights into the mechanisms of plaque-associated endocytosis.