Which is also supported by the agreement between our mathematical model fits and the experimental data, which indicates that force enhances the transition rates. Without force, the up position of the a7-helix in the aA domain is the favored conformation, where the MIDAS ion tends to stay at the outward position, and the ligand binding affinity is low. When force is applied, the equilibrium of the a7-helix position is shifted to middle and down; as a result, the MIDAS metal ion tends to stay at the inward position, and the ligand binding affinity is high. In summary, this study defines the structural basis for mechanical regulation of the kinetics of LFA-1 aA domain conformational changes and relates these simulation results to experimental data of force-induced dissociation of single LFA-1/ICAM-1 bonds by a new mathematical model. Future studies may include simulations to compare aA domains of other integrins and model refinements to add reverse transitions among the three conformational states. One promising disease-modifying strategy for Parkinson’s Disease is the provision of neurotrophic factors for protection and restoration of the damaged dopaminergic innervation of the basal ganglia. The most clinically advanced family of factors is defined by the prototype, glial cell line-derived neurotrophic factor. Based upon strong preclinical data of its protective effects on DA neurons, several clinical trials were undertaken in which recombinant GDNF was infused either into cerebral ventricles or into the putamen through an indwelling catheter. The significance of these clinical studies remains controversial, although apparent efficacy was reported in one trial. One issue identified in these studies was whether the infused GDNF was adequately localized to the target region. The fact that some trial participants developed anti-GDNF antibodies and that a few treated non-human primates showed cerebellar pathology, suggests that GDNF protein delivery was sub-optimal. Nevertheless, parenchymal GDNF infusion has the BAY-60-7550 inhibitor significant advantage that treatment can be terminated if necessary, a feature unavailable to clinical gene transfer at present. GDNF gene therapy, however, is attractive because it provides an effectively localized expression of GDNF at levels many orders of magnitude lower than protein infusions with impressive efficacy in Parkinsonian nonhuman primates in both neuroprotective and neurorestorative paradigms. The possibility, therefore, of developing a regulated gene therapy vector is highly attractive since it promises to combine localized GDNF delivery with the capacity to adjust steady state levels through exogenous administration of a brainpenetrant small molecule regulator. Regulated gene expression can be achieved via a chimeric gene construction linking a regulatory cis element upstream of the gene to be transcribed. One such strategy is to use a drug that can cross the blood-brain barrier to act on drug-dependent promoters that directly activate or repress target gene transcription.