To develop an iterative concomitant field and motion corrected (iCoMoCo) reconstruction for isotropic high-resolution UTE pulmonary imaging at 0.55 T.
A free-breathing golden-angle stack-of-spirals ...UTE sequence was used to acquire data for 8 min with prototype and commercial 0.55 T MRI scanners. The data was binned into 12 respiratory phases based on superior-inferior navigator readouts. The previously published iterative motion corrected (iMoCo) reconstruction was extended to include concomitant field correction directly in the cost function. The reconstruction was implemented within the Gadgetron framework for inline reconstruction. Data were retrospectively reconstructed to simulate scan times of 2, 4, 6, and 8 min. Image quality was assessed using apparent SNR and image sharpness. The technique was evaluated in healthy volunteers and patients with known lung pathology including coronavirus disease 2019 infection, chronic granulomatous disease, lymphangioleiomyomatosis, and lung nodules.
The technique provided diagnostic-quality images, and image quality was maintained with a slight loss in SNR for simulated scan times down to 4 min. Parenchymal apparent SNR was 4.33 ± 0.57, 5.96 ± 0.65, 7.36 ± 0.64, and 7.87 ± 0.65 using iCoMoCo with scan times of 2, 4, 6, and 8 min, respectively. Image sharpness at the diaphragm was comparable between iCoMoCo and reference images. Concomitant field corrections visibly improved the sharpness of anatomical structures away from the isocenter. Inline image reconstruction and artifact correction were achieved in <5 min.
The proposed iCoMoCo pulmonary imaging technique can generate diagnostic quality images with 1.75 mm isotropic resolution in less than 5 min using a 6-min acquisition, on a 0.55 T scanner.
Phosphorylation of the microtubule-associated protein Tau influences the assembly and stabilization of microtubules and is deregulated in several neurodegenerative diseases. The high flexibility of ...Tau, however, has prevented an atomic-level description of its phosphorylation-induced structural changes. Employing an extensive set of distance and orientational restraints together with a novel ensemble calculation approach, we determined conformational ensembles of Tau fragments in the non-phosphorylated state and, when phosphorylated at T231/S235 or T231/S235/S237/S238, four important sites of phosphorylation in Alzheimer disease. Comparison of the molecular ensembles showed that phosphorylation of the regulatory T231 does not perturb the backbone conformation of the proximal microtubule-binding 225KVAVVR230 motif. Instead, phosphorylated T231 selectively engages in a salt bridge with R230 that can compete with the formation of intermolecular salt bridges to tubulin. Our study provides an ensemble description which will be useful for the analysis of conformational transitions in Tau and other intrinsically disordered proteins.
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•A novel ensemble calculation approach was developed•Molecular ensembles of phosphorylated Tau fragments were determined•Phosphorylated T231 selectively engages in a salt bridge with R230•Integration of NOE restraints with ensemble calculations are highly useful for IDPs
Alzheimer disease-related protein Tau is a phosphoprotein, and a number of different residues are subject to phosphorylation. Schwalbe et al. develop a molecular ensemble approach and use it to reveal an atomic-level description of the phosphorylation-induced structural changes in Tau phosphorylated at Thr231.
Intrinsically disordered proteins (IDPs) represent a significant fraction of the human proteome. The classical structure function paradigm that has successfully underpinned our understanding of ...molecular biology breaks down when considering proteins that have no stable tertiary structure in their functional form. One convenient approach is to describe the protein in terms of an equilibrium of rapidly inter-converting conformers. Currently, tools to generate such ensemble descriptions are extremely rare, and poorly adapted to the prediction of experimental data.
We present flexible-meccano-a highly efficient algorithm that generates ensembles of molecules, on the basis of amino acid-specific conformational potentials and volume exclusion. Conformational sampling depends uniquely on the primary sequence, with the possibility of introducing additional local or long-range conformational propensities at an amino acid-specific resolution. The algorithm can also be used to calculate expected values of experimental parameters measured at atomic or molecular resolution, such as nuclear magnetic resonance (NMR) and small angle scattering, respectively. We envisage that flexible-meccano will be useful for researchers who wish to compare experimental data with those expected from a fully disordered protein, researchers who see experimental evidence of deviation from 'random coil' behaviour in their protein, or researchers who are interested in working with a broad ensemble of conformers representing the flexibility of the IDP of interest.
A fully documented multi-platform executable is provided, with examples, at http://www.ibs.fr/science-213/scientific-output/software/flexible-meccano/
martin.blackledge@ibs.fr.
The development of molecular descriptions of intrinsically disordered proteins (IDPs) is essential for elucidating conformational transitions that characterize common neurodegenerative disorders. We ...use nuclear magnetic resonance, small angle scattering, and molecular ensemble approaches to characterize the IDPs Tau and α-synuclein. Ensemble descriptions of IDPs are highly underdetermined due to the inherently large number of degrees of conformational freedom compared with available experimental measurements. Using extensive cross-validation we show that five different types of independent experimental parameters are predicted more accurately by selected ensembles than by statistical coil descriptions. The improvement increases in regions whose local sampling deviates from statistical coil, validating the derived conformational description. Using these approaches we identify enhanced polyproline II sampling in aggregation-nucleation sites, supporting suggestions that this region of conformational space is important for aggregation.
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•Atomic resolution ensemble description of 441-residue natively disordered Tau protein•Quantitative prediction of different sets of independent data by ASTEROIDS ensembles•Tau and α-synuclein sample enhanced polyproline II in aggregation-nucleation sites•Combination of experimental data reporting on local and long-range dynamic structure
Schwalbe et al. use NMR, SAXS, and molecular ensemble descriptions to characterize the intrinsically disordered proteins (IDPs) Tau and α-synuclein. They identify enhanced polyproline II sampling in aggregation-nucleation sites and discuss enhanced performance of the method to obtain structural insights into IDPs.
The realization that a protein can be fully functional even in the absence of a stable three-dimensional structure has motivated a large number of studies describing the conformational behaviour of ...these proteins at atomic resolution. Here, we review recent advances in the determination of local structural propensities of intrinsically disordered proteins (IDPs) from experimental NMR chemical shifts. A mapping of the local structure in IDPs is of paramount importance in order to understand the molecular details of complex formation, in particular, for IDPs that fold upon binding or undergo structural transitions to pathological forms of the same protein. We discuss experimental strategies for the spectral assignment of IDPs, chemical shift prediction algorithms and the generation of representative structural ensembles of IDPs on the basis of chemical shifts. Additionally, we highlight the inherent degeneracies associated with the determination of IDP sub-state populations from NMR chemical shifts alone.
Widening the availability of fetal MRI with fully automatic real-time planning of radiological brain planes on 0.55T MRI.
Deep learning-based detection of key brain landmarks on a whole-uterus echo ...planar imaging scan enables the subsequent fully automatic planning of the radiological single-shot Turbo Spin Echo acquisitions. The landmark detection pipeline was trained on over 120 datasets from varying field strength, echo times, and resolutions and quantitatively evaluated. The entire automatic planning solution was tested prospectively in nine fetal subjects between 20 and 37 weeks. A comprehensive evaluation of all steps, the distance between manual and automatic landmarks, the planning quality, and the resulting image quality was conducted.
Prospective automatic planning was performed in real-time without latency in all subjects. The landmark detection accuracy was 4.2
2.6 mm for the fetal eyes and 6.5
3.2 for the cerebellum, planning quality was 2.4/3 (compared to 2.6/3 for manual planning) and diagnostic image quality was 2.2 compared to 2.1 for manual planning.
Real-time automatic planning of all three key fetal brain planes was successfully achieved and will pave the way toward simplifying the acquisition of fetal MRI thereby widening the availability of this modality in nonspecialist centers.
Joint bright- and black-blood MRI techniques provide improved scar localization and contrast. Black-blood contrast is obtained after the visual selection of an optimal inversion time (TI) which often ...results in uncertainties, inter- and intra-observer variability and increased workload. In this work, we propose an artificial intelligence-based algorithm to enable fully automated TI selection and simplify myocardial scar imaging.
The proposed algorithm first localizes the left ventricle using a U-Net architecture. The localized left cavity centroid is extracted and a squared region of interest (“focus box”) is created around the resulting pixel. The focus box is then propagated on each image and the sum of the pixel intensity inside is computed. The smallest sum corresponds to the image with the lowest intensity signal within the blood pool and healthy myocardium, which will provide an ideal scar-to-blood contrast. The image's corresponding TI is considered optimal. The U-Net was trained to segment the epicardium in 177 patients with binary cross-entropy loss. The algorithm was validated retrospectively in 152 patients, and the agreement between the algorithm and two magnetic resonance (MR) operators' prediction of TI values was calculated using the Fleiss' kappa coefficient. Thirty focus box sizes, ranging from 2.3mm2 to 20.3cm2, were tested. Processing times were measured.
The U-Net's Dice score was 93.0 ± 0.1%. The proposed algorithm extracted TI values in 2.7 ± 0.1 s per patient (vs. 16.0 ± 8.5 s for the operator). An agreement between the algorithm's prediction and the MR operators' prediction was found in 137/152 patients (κ= 0.89), for an optimal focus box of size 2.3cm2.
The proposed fully-automated algorithm has potential of reducing uncertainties, variability, and workload inherent to manual approaches with promise for future clinical implementation for joint bright- and black-blood MRI.
Cardiac fiber direction is an important factor determining the propagation of electrical activity, as well as the development of mechanical force. In this article, we imaged the ventricles of several ...species with special attention to the intraventricular septum to determine the functional consequences of septal fiber organization. First, we identified a dual-layer organization of the fiber orientation in the intraventricular septum of ex vivo sheep hearts using diffusion tensor imaging at high field MRI. To expand the scope of the results, we investigated the presence of a similar fiber organization in five mammalian species (rat, canine, pig, sheep, and human) and highlighted the continuity of the layer with the moderator band in large mammalian species. We implemented the measured septal fiber fields in three-dimensional electromechanical computer models to assess the impact of the fiber orientation. The downward fibers produced a diamond activation pattern superficially in the right ventricle. Electromechanically, there was very little change in pressure volume loops although the stress distribution was altered. In conclusion, we clarified that the right ventricular septum has a downwardly directed superficial layer in larger mammalian species, which can have modest effects on stress distribution.
A dual-layer organization of the fiber orientation in the intraventricular septum was identified in ex vivo hearts of large mammals. The RV septum has a downwardly directed superficial layer that is continuous with the moderator band. Electrically, it produced a diamond activation pattern. Electromechanically, little change in pressure volume loops were noticed but stress distribution was altered. Fiber distribution derived from diffusion tensor imaging should be considered for an accurate strain and stress analysis.
Misfolding of the microtubule‐associated protein Tau is a hallmark of Alzheimer disease and several other neurodegenerative disorders. Because of the dynamic nature of the Tau protein, little is ...known about the changes in Tau structure that occur during misfolding. Here we studied the structural consequences upon binding of the repeat domain of Tau, which plays a key role in pathogenic aggregation, to an aggregation enhancer. By combining NMR experiments with molecular simulations we show that binding of the aggregation enhancer polyglutamic acid remodels the conformational ensemble of Tau. Our study thus provides insight into an early event during misfolding of Tau.
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