An order parameter without magic angle effect (OPTIMA) derived from R1ρ dispersion in ordered tissue

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153626/1/mrm28045.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153626/2/mrm28045_am.pd

A unique anisotropic R2 of collagen degeneration (ARCADE) mapping as an efficient alternative to composite relaxation metric (R2â R1Ï ) in human knee cartilage study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148373/1/mrm27621.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148373/2/mrm27621_am.pd

Long-Term Stability of Gradient Characteristics Warrants Model-Based Correction of Diffusion Weighting Bias

The study aims to test the long-term stability of gradient characteristics for model-based correction of diffusion weighting (DW) bias in an apparent diffusion coefficient (ADC) for multisite imaging trials. Single spin echo (SSE) DWI of a long-tube ice-water phantom was acquired quarterly on six MR scanners over two years for individual diffusion gradient channels, along with B0 mapping, as a function of right-left (RL) and superior-inferior (SI) offsets from the isocenter. Additional double spin-echo (DSE) DWI was performed on two systems. The offset dependences of derived ADC were fit to 4th-order polynomials. Chronic shim gradients were measured from spatial derivatives of B0 maps along the tube direction. Gradient nonlinearity (GNL) was modeled using vendor-provided gradient field descriptions. Deviations were quantified by root-mean-square differences (RMSD), normalized to reference ice-water ADC, between the model and reference (RMSDREF), measurement and model (RMSDEXP), and temporal measurement variations (RMSDTMP). Average RMSDREF was 4.9 ± 3.2 (%RL) and –14.8 ± 3.8 (%SI), and threefold larger than RMSDEXP. RMSDTMP was close to measurement errors (~3%). GNL-induced bias across gradient systems varied up to 20%, while deviation from the model accounted at most for 6.5%, and temporal variation for less than 3% of ADC reproducibility error. Higher SSE RMSDEXP = 7.5–11% was reduced to 2.5–4.8% by DSE, consistent with the eddy current origin. Measured chronic shim gradients below 0.1 mT/m had a minor contribution to ADC bias. The demonstrated long-term stability of spatial ADC profiles and consistency with system GNL models justifies retrospective and prospective DW bias correction based on system gradient design models. Residual errors due to eddy currents and shim gradients should be corrected independent of GNL

Characterization of anisotropic T2W signals from human knee femoral cartilage: The magic angle effect on a spherical surface

The aim of the current study was to propose a generalized magic angle effect (gMAE) function for characterizing anisotropic T2W signals of human knee femoral cartilage with a spherical surface in clinical studies. A gMAE model function f(α, ε) was formulated for an orientation‐dependent (ε) transverse T2 (i.e., 1/R2) relaxation in cartilage assuming an axially symmetric distribution (α) of collagen fibers. T2W sagittal images were acquired on an adult volunteer’s healthy knee at 3 T, and ROI‐based average signals S(ε) were extracted from angularly and radially segmented femoral cartilage. Compared with the standard MAE (sMAE) functions in the deep (DZ, α = 0°) and in the superficial (SZ, α = 90°) zones, a general form of R2 orientation‐dependent function f(α, ε) was fitted to S(ε), including an isotropic R2 contribution (internal reference [REF]). Goodness of fit was evaluated by root‐mean‐square deviations (RMSDs). An F‐test and a paired t‐test were respectively used to assess significant differences between the observed variances and means, with statistical significance set to p less than .05. As a symmetric orientation‐dependence function with a varying dynamic range, the proposed gMAE model outperformed the previous sMAE functions manifested by significantly reduced RMSDs in the DZ (0.239 ± 0.122 vs. 0.267 ± 0.097, p = .014) and in the SZ (0.183 ± 0.081 vs. 0.254 ± 0.085, p < .001). The fitted average angle α (38.5 ± 34.6° vs. 45.1 ± 30.1°, p < .43) and REF (5.092 ± 0.369 vs. 5.305 ± 0.440, p < .001) were smaller in the DZ than those in SZ, in good agreement with the reported collagen fibril microstructural configurations and the nonbound water contribution to R2 in articular cartilage. In conclusion, a general form of the magic angle effect function was proposed and demonstrated for better characterizing anisotropic T2W signals from human knee femoral cartilage at 3 T in clinical studies.A generalized magic angle effect (gMAE) function was formulated based on an axially symmetric collagen fibril distribution to better characterize anisotropic T2W signals of cartilage on a curved surface. Compared with the standard MAE models, the proposed function provided significantly improved fitting of segmented T2W signals from an adult healthy knee femoral cartilage at 3 T. The potential applications of the proposed model function could be extended to other highly organized biological tissues beyond human knee articular cartilage.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/168330/1/nbm4535.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168330/2/nbm4535_am.pd

NMR relaxation measurements and molecular dynamics simulation of ribonuclease binase: Experimental and theoretical studies of protein dynamics.

The characterization of dynamics has for a long time been considered an effective way to correlate protein structure with biological function. However, due to limitations in existing methods to measure dynamics, and in the number of systems investigated, not many of such correlations have been established to date. In this dissertation, I extended nuclear magnetic resonance relaxation methods to fully characterize the dynamic properties of the enzyme Binase, a microbial guanyl-specific ribonuclease. The results of the experimental methods were compared with theoretical predictions (molecular dynamics simulations). Together, these methods disclosed functionally important motions in this enzyme. Motions on the picosecond to nanosecond timescale were observed for the loop regions of this protein at backbone 13CO and 15 N sites, both with experimental and theoretical methods. The active site around the two catalytic residues E72 and H101 was found to be relatively rigid at this time scale. Using a combination of 13CO longitudinal relaxation and cross-relaxation measurements, a correlated dynamical mode was identified for the first alpha helix in Binase. This motion is likely to be of importance to the folding of the protein. Anisotropic local motions of peptide planes, so called crankshaft motions, were predicted by molecular dynamics simulation. These motions were demonstrated experimentally from novel 13CO cross-correlated relaxation studies as well. Newly developed nuclear magnetic resonance experiments also allowed up to three 13CO cross-correlated relaxation rates to be measured, which permitted, for the first time, 13CO chemical shift anisotropy tensors to be determined in solution. Using an original approach in 15N spin-spin relaxation measurements, residues involved in conformational exchange (mus-ms) were readily identified. The substrate recognition loop of Binase was shown to be undergoing conformational exchange at a timescale of the maximum enzymatic turnover rate. The active site loop containing the catalytic residue H101 was found to be dynamic at this time scale as well. Thus, a significant correlation between specific motions and enzymatic activity was established in this dissertation.Ph.D.Biological SciencesBiophysicsMolecular biologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/123758/2/3001023.pd

SKN-1 Is a Negative Regulator of DAF-16 and Somatic Stress Resistance in Caenorhabditis elegans

The transcription factor SKN-1, the C. elegans ortholog of mammalian Nrf protein, is a well-known longevity factor, and its activation is observed in several long-lived models. SKN-1 also plays essential roles in xenobiotic and oxidative stress responses. Here, we report deleterious functions of SKN-1 in somatic stress resistance that may impair lifespan. Constitutive SKN-1 activation impairs animal resistance to several stresses, including heat, ER stress and mitochondrial stress, which result from the suppression of DAF-16, another master regulator of longevity. SKN-1 activation abrogates DAF-16 nuclear import and downregulates DAF-16 target genes under stress conditions, while SKN-1 inhibition promotes the expression of DAF-16 targets, even in long-lived mutants. Further, SKN-1 activation induces the expression of vitellogenin proteins, which are required for SKN-1-mediated suppression of DAF-16 and stress resistance. Together, these findings identify detrimental roles for SKN-1 activation in animal health, and more importantly, inspire the rethinking of the complex roles for SKN-1 in aging regulation

An efficient R1Ï dispersion imaging method for human knee cartilage using constant magnetization prepared turbo- FLASH

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167754/1/nbm4500.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167754/2/nbm4500_am.pd