Faculty Bibliography

Post-transplant lymphoproliferative disorders of T-cell origin are quite uncommon, and the vast majority represent neoplasms of mature, post-thymic T- or natural killer cells. Here, we report a rare case of T-cell acute lymphoblastic leukaemia (T-ALL), which occurred in an 18-year-old man who had undergone three liver transplants, initially for biliary atresia and subsequently for graft failure due to chronic rejection. He had received immunosuppression with cyclosporine and tacrolimus, as well as short-term treatment with OKT3. The T-ALL occurred 16 years after the first liver transplant. This case highlights the challenge for classifying rare neoplasms occurring in recipients of solid organ transplants that are currently not recognized to lie within the spectrum of post-transplant lymphoproliferative disorders. Given the long interval between the liver transplants and the development of T-ALL, a coincidental occurrence of the leukaemia cannot be ruled out. However, the potential roles of immunosuppressive therapy and other co-morbid conditions of the individual as possible risk factors for the pathogenesis of T-ALL are discussed.

Calculation of the free energy of protein folding and delineation of its pre-organization are of foremost importance for understanding, predicting and designing biological macromolecules. Here, we introduce an energy smoothing variant of parallel tempering replica exchange Monte Carlo (REMS) that allows for efficient configurational sampling of flexible solutes under the conditions of molecular hydration. Its usage to calculate the thermal stability of a model globular protein, Trp cage TC5b, achieves excellent agreement with experimental measurements. We find that the stability of TC5b is attained through the coupled formation of local and non-local interactions. Remarkably, many of these structures persist at high temperature, concomitant with the origin of native-like configurations and mesostates in an otherwise macroscopically disordered unfolded state. Graph manifold learning reveals that the conversion of these mesostates to the native state is structurally heterogeneous, and that the cooperativity of their formation is encoded largely by the unfolded state ensemble. In all, these studies establish the extent of thermodynamic and structural pre-organization of folding of this model globular protein, and achieve the calculation of macromolecular stability ab initio, as required for ab initio structure prediction, genome annotation, and drug design.

Definition of the unfolded state of proteins is essential for understanding their stability and folding on biological timescales. Here, we find that under near physiological conditions the configurational ensemble of the unfolded state of the simplest protein structure, polyalanine alpha-helix, cannot be described by the commonly used Flory random coil model, in which configurational probabilities are derived from conformational preferences of individual residues. We utilize novel effectively ergodic sampling algorithms in the presence of explicit aqueous solvation, and observe water-mediated formation of polyproline II helical (P(II)) structure in the natively unfolded state of polyalanine, and its facilitation of alpha-helix formation in longer peptides. The segmented P(II) helical coil preorganizes the unfolded state ensemble for folding pathway entry by reducing the conformational space available to the diffusive search. Thus, as much as half of the folding search in polyalanine is accomplished by preorganization of the unfolded state.

PURPOSE/OBJECTIVE:To investigate sodium magnetic resonance (MR) imaging for monitoring tissue viability in stroke. MATERIALS AND METHODS/METHODS:A comprehensive MR imaging protocol used to measure apparent diffusion coefficient and perfusion parameters was extended to include sodium imaging. Tissue sodium concentration was estimated by using a two-compartment model. This protocol lasted less than 45 minutes. These parameters were followed over the first 6 hours in a nonhuman primate model (n = 2) of acute embolic stroke without or with thrombolytic therapy. This protocol was used in patients in whom acute (< 24 hours, n = 11) or nonacute (> or = 24 hours, n = 31) stroke was ultimately confirmed. RESULTS:The animal model showed abnormal diffusion and perfusion parameters in the lesion immediately after embolization, and these remained abnormal for over 6 hours. Tissue sodium concentration increased with time (5.7 mmol/L/h) unless halted with thrombolytic therapy. Regions with sodium concentrations over 70 mmol/L were histochemically verified as being infarcted. In patients in whom stroke older than 6 hours was clinically confirmed, sodium concentrations over 70 mmol/L were found in the appropriate brain regions. CONCLUSION/CONCLUSIONS:Tissue sodium concentration provides a sensitive measure of tissue viability that is complementary to the diagnostic role of diffusion and perfusion imaging for ischemic insult.