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Single-nucleotide polymorphism was used in the construction of an expressed sequence tag map of Aegilops tauschii, the diploid source of the wheat D genome. Comparisons of the map with the rice and sorghum genome sequences revealed 50 inversions and translocations; 2, 8, and 40 were assigned respectively to the rice, sorghum, and Ae. tauschii lineages, showing greatly accelerated genome evolution in the large Triticeae genomes. The reduction of the basic chromosome number from 12 to 7 in the Triticeae has taken place by a process during which an entire chromosome is inserted by its telomeres into a break in the centromeric region of another chromosome. The original centromere-telomere polarity of the chromosome arms is maintained in the new chromosome. An intrachromosomal telomere-telomere fusion resulting in a pericentric translocation of a chromosome segment or an entire arm accompanied or preceded the chromosome insertion in some instances. Insertional dysploidy has been recorded in three grass subfamilies and appears to be the dominant mechanism of basic chromosome number reduction in grasses. A total of 64% and 66% of Ae. tauschii genes were syntenic with sorghum and rice genes, respectively. Synteny was reduced in the vicinity of the termini of modern Ae. tauschii chromosomes but not in the vicinity of the ancient termini embedded in the Ae. tauschii chromosomes, suggesting that the dependence of synteny erosion on gene location along the centromere-telomere axis either evolved recently in the Triticeae phylogenetic lineage or its evolution was recently accelerated.

Liquid organic light-emitting diodes (liquid OLEDs) are unique devices consisting only of liquid organic semiconductors in the active layer, and the device performances have been investigated recently. However, the device degradation, especially, the origin has been unknown. In this study, we show that material degradation occurs in liquid OLEDs, whose active layer is composed of carbazole with an ethylene glycol chain. Nuclear magnetic resonance (NMR) experiments clearly exhibit that the dimerization reaction of carbazole moiety occurs in the liquid OLEDs during driving the devices. In contrast, cleavages of the ethylene glycol chain are not detected within experimental error. The dimerization reaction is considered to be related to the device degradation.

Purpose: To develop and evaluate a physics-driven, saturation contrast-aware, deep-learning-based framework for motion artifact correction in CEST MRI., Methods: A neural network was designed to correct motion artifacts directly from a Z-spectrum frequency (Ω) domain rather than an image spatial domain. Motion artifacts were simulated by modeling 3D rigid-body motion and readout-related motion during k-space sampling. A saturation-contrast-specific loss function was added to preserve amide proton transfer (APT) contrast, as well as enforce image alignment between motion-corrected and ground-truth images. The proposed neural network was evaluated on simulation data and demonstrated in healthy volunteers and brain tumor patients., Results: The experimental results showed the effectiveness of motion artifact correction in the Z-spectrum frequency domain (MOCO Ω ) compared to in the image spatial domain. In addition, a temporal convolution applied to a dynamic saturation image series was able to leverage motion artifacts to improve reconstruction results as a denoising process. The MOCO Ω outperformed existing techniques for motion correction in terms of image quality and computational efficiency. At 3 T, human experiments showed that the root mean squared error (RMSE) of APT images decreased from 4.7% to 2.1% at 1 μT and from 6.2% to 3.5% at 1.5 μT in case of "moderate" motion and from 8.7% to 2.8% at 1 μT and from 12.7% to 4.5% at 1.5 μT in case of "severe" motion, after motion artifact correction., Conclusion: The MOCO Ω could effectively correct motion artifacts in CEST MRI without compromising saturation transfer contrast., (© 2025 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: To evaluate the influence of the confounding factors, direct water saturation (DWS), and magnetization transfer contrast (MTC) effects on measured Z-spectra and amide proton transfer (APT) contrast in brain tumors., Methods: High-grade glioma patients were scanned using an RF saturation-encoded 3D MR fingerprinting (MRF) sequence at 3 T. For MRF reconstruction, a recurrent neural network was designed to learn free water and semisolid macromolecule parameter mappings of the underlying multiple tissue properties from saturation-transfer MRF signals. The DWS spectra and MTC spectra were synthesized by solving Bloch-McConnell equations and evaluated in brain tumors., Results: The dominant contribution to the saturation effect at 3.5 ppm was from DWS and MTC effects, but 25%-33% of the saturated signal in the gadolinium-enhancing tumor (13%-20% for normal tissue) was due to the APT effect. The APT # signal of the gadolinium-enhancing tumor was significantly higher than that of the normal-appearing white matter (10.1% vs. 8.3% at 1 μT and 11.2% vs. 7.8% at 1.5 μT)., Conclusion: The RF saturation-encoded MRF allowed us to separate contributions to the saturation signal at 3.5 ppm in the Z-spectrum. Although free water and semisolid MTC are the main contributors, significant APT contrast between tumor and normal tissues was observed., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: To implement rosette readout trajectories with compressed sensing reconstruction for fast and motion-robust CEST and magnetization transfer contrast imaging with inherent correction of B 0 inhomogeneity., Methods: A pulse sequence was developed for fast saturation transfer imaging using a stack of rosette trajectories with a higher sampling density near the k-space center. Each rosette lobe was segmented into two halves to generate dual-echo images. B 0 inhomogeneities were estimated using the phase difference between the images and corrected subsequently. The rosette-based imaging was evaluated in comparison to a fully sampled Cartesian trajectory and demonstrated on CEST phantoms (creatine solutions and egg white) and healthy volunteers at 3 T., Results: Compared with the conventional Cartesian acquisition, compressed sensing reconstructed rosette images provided image quality with overall higher contrast-to-noise ratio and significantly faster readout time. Accurate B 0 map estimation was achieved from the rosette acquisition with a negligible bias of 0.01 Hz between the rosette and dual-echo Cartesian gradient echo B 0 maps, using the latter as ground truth. The water-saturation spectra (Z-spectra) and amide proton transfer weighted signals obtained from the rosette-based sequence were well preserved compared with the fully sampled data, both in the phantom and human studies., Conclusions: Fast, motion-robust, and inherent B 0 -corrected CEST and magnetization transfer contrast imaging using rosette trajectories could improve subject comfort and compliance, contrast-to-noise ratio, and provide inherent B 0 homogeneity information. This work is expected to significantly accelerate the translation of CEST-MRI into a robust, clinically viable approach., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: To develop a fast denoising framework for high-dimensional MRI data based on a self-supervised learning scheme, which does not require ground truth clean image., Theory and Methods: Quantitative MRI faces limitations in SNR, because the variation of signal amplitude in a large set of images is the key mechanism for quantification. In addition, the complex non-linear signal models make the fitting process vulnerable to noise. To address these issues, we propose a fast deep-learning framework for denoising, which efficiently exploits the redundancy in multidimensional MRI data. A self-supervised model was designed to use only noisy images for training, bypassing the challenge of clean data paucity in clinical practice. For validation, we used two different datasets of simulated magnetization transfer contrast MR fingerprinting (MTC-MRF) dataset and in vivo DWI image dataset to show the generalizability., Results: The proposed method drastically improved denoising performance in the presence of mild-to-severe noise regardless of noise distributions compared to previous methods of the BM3D, tMPPCA, and Patch2self. The improvements were even pronounced in the following quantification results from the denoised images., Conclusion: The proposed MD-S2S (Multidimensional-Self2Self) denoising technique could be further applied to various multi-dimensional MRI data and improve the quantification accuracy of tissue parameter maps., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: To develop a 3D, high-sensitivity CEST mapping technique based on the 3D stack-of-spirals (SOS) gradient echo readout, the proposed approach was compared with conventional acquisition techniques and evaluated for its efficacy in concurrently mapping of guanidino (Guan) and amide CEST in human brain at 3 T, leveraging the polynomial Lorentzian line-shape fitting (PLOF) method., Methods: Saturation time and recovery delay were optimized to achieve maximum CEST time efficiency. The 3DSOS method was compared with segmented 3D EPI (3DEPI), turbo spin echo, and gradient- and spin-echo techniques. Image quality, temporal SNR (tSNR), and test-retest reliability were assessed. Maps of Guan and amide CEST derived from 3DSOS were demonstrated on a low-grade glioma patient., Results: The optimized recovery delay/saturation time was determined to be 1.4/2 s for Guan and amide CEST. In addition to nearly doubling the slice number, the gradient echo techniques also outperformed spin echo sequences in tSNR: 3DEPI (193.8 ± 6.6), 3DSOS (173.9 ± 5.6), and GRASE (141.0 ± 2.7). 3DSOS, compared with 3DEPI, demonstrated comparable GuanCEST signal in gray matter (GM) (3DSOS: [2.14%-2.59%] vs. 3DEPI: [2.15%-2.61%]), and white matter (WM) (3DSOS: [1.49%-2.11%] vs. 3DEPI: [1.64%-2.09%]). 3DSOS also achieves significantly higher amideCEST in both GM (3DSOS: [2.29%-3.00%] vs. 3DEPI: [2.06%-2.92%]) and WM (3DSOS: [2.23%-2.66%] vs. 3DEPI: [1.95%-2.57%]). 3DSOS outperforms 3DEPI in terms of scan-rescan reliability (correlation coefficient: 3DSOS: 0.58-0.96 vs. 3DEPI: -0.02 to 0.75) and robustness to motion as well., Conclusion: The 3DSOS CEST technique shows promise for whole-cerebrum CEST imaging, offering uniform contrast and robustness against motion artifacts., (© 2024 International Society for Magnetic Resonance in Medicine.)

Purpose: To investigate the effects of compartmental anisotropy on filtered exchange imaging (FEXI) in white matter (WM)., Theory and Methods: FEXI signals were measured using multiple combinations of diffusion filter and detection directions in five healthy volunteers. Additional filters, including a trace-weighted diffusion filter with trapezoidal gradients, a spherical b-tensor encoded diffusion filter, and a T2 filter, were tested with trace-weighted diffusion detection., Results: A large range of apparent exchange rates (AXR) and both positive and negative filter efficiencies (σ) were found depending on the mutual orientation of the filter and detection gradients relative to WM fiber orientation. The data demonstrated that the fast-diffusion compartment suppressed by diffusional filtering is not exclusively extra-cellular, but also intra-cellular. While not comprehensive, a simple two-compartment diffusion tensor model with water exchange was able to account qualitatively for the trends in positive and negative filtering efficiencies, while standard model imaging (SMI) without exchange could not. This two-compartment diffusion tensor model also demonstrated smaller AXR variances across subjects. When employing trace-weighted diffusion detection, AXR values were on the order of the R 1 (=1/T1) of water at 3T for crossing fibers, while being less than R 1 for parallel fibers., Conclusion: Orientation-dependent AXR and σ values were observed when using multi-orientation filter and detection gradients in FEXI, indicating that WM FEXI models need to account for compartmental anisotropy. When using trace-weighted detection, AXR values were on the order of or less than R 1 , complicating the interpretation of FEXI results in WM in terms of biological exchange properties. These findings may contribute toward better understanding of FEXI results in WM., (© 2024 International Society for Magnetic Resonance in Medicine.)

Infections caused by Staphylococcus aureus, notably methicillin-resistant S. aureus (MRSA), pose treatment challenges due to its ability to tolerate antibiotics and develop antibiotic resistance. The former, a mechanism independent of genetic changes, allows bacteria to withstand antibiotics by altering metabolic processes. Here, a potent methylazanediyl bisacetamide derivative, MB6, is described, which selectively targets MRSA membranes over mammalian membranes without observable resistance development. Although MB6 is effective against growing MRSA cells, its antimicrobial activity against MRSA persisters is limited. Nevertheless, MB6 significantly potentiates the bactericidal activity of gentamicin against MRSA persisters by facilitating gentamicin uptake. In addition, MB6 in combination with daptomycin exhibits enhanced anti-persister activity through mutual reinforcement of their membrane-disrupting activities. Crucially, the "triple" combination of MB6, gentamicin, and daptomycin exhibits a marked enhancement in the killing of MRSA persisters compared to individual components or any double combinations. These findings underscore the potential of MB6 to function as a potent and selective membrane-active antimicrobial adjuvant to enhance the efficacy of existing antibiotics against persister cells. The molecular mechanisms of MB6 elucidated in this study provide valuable insights for designing anti-persister adjuvants and for developing new antimicrobial combination strategies to overcome the current limitations of antibiotic treatments., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Purpose: To develop a novel MR physics-driven, deep-learning, extrapolated semisolid magnetization transfer reference (DeepEMR) framework to provide fast, reliable magnetization transfer contrast (MTC) and CEST signal estimations, and to determine the reproducibility and reliability of the estimates from the DeepEMR., Methods: A neural network was designed to predict a direct water saturation and MTC-dominated signal at a certain CEST frequency offset using a few high-frequency offset features in the Z-spectrum. The accuracy, scan-rescan reproducibility, and reliability of MTC, CEST, and relayed nuclear Overhauser enhancement (rNOE) signals estimated from the DeepEMR were evaluated on numerical phantoms and in heathy volunteers at 3 T. In addition, we applied the DeepEMR method to brain tumor patients and compared tissue contrast with other CEST calculation metrics., Results: The DeepEMR method demonstrated a high degree of accuracy in the estimation of reference MTC signals at ±3.5 ppm for APT and rNOE imaging, and computational efficiency (˜190-fold) compared with a conventional fitting approach. In addition, the DeepEMR method achieved high reproducibility and reliability (intraclass correlation coefficient = 0.97, intersubject coefficient of variation = 3.5%, and intrasubject coefficient of variation = 1.3%) of the estimation of MTC signals at ±3.5 ppm. In tumor patients, DeepEMR-based amide proton transfer images provided higher tumor contrast than a conventional MT ratio asymmetry image, particularly at higher B 1 strengths (>1.5 μT), with a distinct delineation of the tumor core from normal tissue or peritumoral edema., Conclusion: The DeepEMR approach is feasible for measuring clean APT and rNOE effects in longitudinal and cross-sectional studies with low scan-rescan variability., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Objective: For patients presenting with acute ischemic stroke (AIS) caused by large vessel occlusions (LVO), mechanical thrombectomy (MT) is the treatment standard of care in eligible patients. Modified Thrombolysis in Cerebral Infarction (mTICI) grades of 2b, 2c, and 3 are all considered successful reperfusion; however, recent studies have shown achieving mTICI 2c/3 leads to better outcomes than mTICI 2b. This study aims to investigate whether any baseline preprocedural or periprocedural parameters are predictive of achieving mTICI 2c/3 in successfully recanalized LVO patients., Methods: We conducted a retrospective multicenter cohort study of consecutive patients presenting with AIS caused by a LVO from 1 January 2017 to 1 January 2023. Baseline and procedural data were collected through chart review. Univariate and multivariate analysis were applied to determine significant predictors of mTICI 2c/3., Results: A total of 216 patients were included in the study, with 159 (73.6%) achieving mTICI 2c/3 recanalization and 57 (26.4%) achieving mTICI 2b recanalization. We found that a higher groin puncture to first pass time (OR = 0.976, 95%CI: 0.960-0.992, p = 0.004), a higher first pass to recanalization time (OR = 0.985, 95%CI: 0.972-0.998, p = 0.029), a higher admission NIHSS (OR = 0.949, 95%CI: 0.904-0.995, p = 0.031), and a lower age (OR = 1.032, 95%CI: 1.01-1.055, p = 0.005) were associated with a decreased probability of achieving mTICI 2c/3., Interpretation: A lower groin puncture to first pass time, a lower first pass to recanalization time, a lower admission NIHSS, and a higher age were independent predictors of mTICI 2c/3 recanalization., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Purpose: Quantitative CT perfusion (CTP) thresholds for assessing the extent of ischemia in patients with acute ischemic stroke (AIS) have been established; relative cerebral blood flow (rCBF) <30% is typically used for estimating estimated ischemic core volume and T max (time to maximum) >6 seconds for critical hypoperfused volume in AIS patients with large vessel occlusion (LVO). In this study, we aimed to identify the optimal threshold values for patients presenting with AIS secondary to distal medium vessel occlusions (DMVOs)., Methods: In this retrospective study, consecutive AIS patients with anterior circulation DMVO who underwent pretreatment CTP and follow-up MRI/CT were included. The CTP data were processed by RAPID (iSchemaView, Menlo Park, CA) to generate estimated ischemic core volumes using rCBF <20%, <30%, <34%, and <38% and critical hypoperfused volumes using T max (seconds) >4, >6, >8, and >10. Final infarct volumes (FIVs) were obtained from follow-up MRI/CT within 5 days of symptom onset. Diagnostic performance between CTP thresholds and FIV was assessed in the successfully and unsuccessfully recanalized groups., Results: Fifty-five patients met our inclusion criteria (32 female [58.2%], 68.0 ± 12.1 years old [mean ± SD]). Recanalization was attempted with intravenous tissue-type plasminogen activator and mechanical thrombectomy in 27.7% and 38.1% of patients, respectively. Twenty-five patients (45.4%) were successfully recanalized. In the successfully recanalized patients, no CTP threshold significantly outperformed what is used in LVO setting (rCBF < 30%). All rCBF CTP thresholds demonstrated fair diagnostic performances for predicting FIV. In unsuccessfully recanalized patients, all T max CTP thresholds strongly predicted FIV with relative superiority of T max >10 seconds (area under the receiver operating characteristic curve = .875, p = .001)., Conclusion: In AIS patients with DMVOs, longer T max delays than T max  > 6 seconds, most notably, T max  > 10 seconds, best predict FIV in unsuccessfully recanalized patients. No CTP threshold reliably predicts FIV in the successfully recanalized group nor significantly outperformed rCBF < 30%., (© 2023 American Society of Neuroimaging.)

Purpose: Water saturation shift referencing (WASSR) Z-spectra are used commonly for field referencing in chemical exchange saturation transfer (CEST) MRI. However, their analysis using least-squares (LS) Lorentzian fitting is time-consuming and prone to errors because of the unavoidable noise in vivo. A deep learning-based single Lorentzian Fitting Network (sLoFNet) is proposed to overcome these shortcomings., Methods: A neural network architecture was constructed and its hyperparameters optimized. Training was conducted on a simulated and in vivo-paired data sets of discrete signal values and their corresponding Lorentzian shape parameters. The sLoFNet performance was compared with LS on several WASSR data sets (both simulated and in vivo 3T brain scans). Prediction errors, robustness against noise, effects of sampling density, and time consumption were compared., Results: LS and sLoFNet performed comparably in terms of RMS error and mean absolute error on all in vivo data with no statistically significant difference. Although the LS method fitted well on samples with low noise, its error increased rapidly when increasing sample noise up to 4.5%, whereas the error of sLoFNet increased only marginally. With the reduction of Z-spectral sampling density, prediction errors increased for both methods, but the increase occurred earlier (at 25 vs. 15 frequency points) and was more pronounced for LS. Furthermore, sLoFNet performed, on average, 70 times faster than the LS-method., Conclusion: Comparisons between LS and sLoFNet on simulated and in vivo WASSR MRI Z-spectra in terms of robustness against noise and decreased sample resolution, as well as time consumption, showed significant advantages for sLoFNet., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

New or enlarged lesions in malignant gliomas after surgery and chemoradiation can be associated with tumor recurrence or treatment effect. Due to similar radiographic characteristics, conventional-and even some advanced MRI techniques-are limited in distinguishing these two pathologies. Amide proton transfer-weighted (APTw) MRI, a protein-based molecular imaging technique that does not require the administration of any exogenous contrast agent, was recently introduced into the clinical setting. In this study, we evaluated and compared the diagnostic performances of APTw MRI with several non-contrast-enhanced MRI sequences, such as diffusion-weighted imaging, susceptibility-weighted imaging, and pseudo-continuous arterial spin labeling. Thirty-nine scans from 28 glioma patients were obtained on a 3 T MRI scanner. A histogram analysis approach was employed to extract parameters from each tumor area. Statistically significant parameters (P < 0.05) were selected to train multivariate logistic regression models to evaluate the performance of MRI sequences. Multiple histogram parameters, particularly from APTw and pseudo-continuous arterial spin labeling images, demonstrated significant differences between treatment effect and recurrent tumor. The regression model trained on the combination of all significant histogram parameters achieved the best result (area under the curve = 0.89). We found that APTw images added value to other advanced MR images for the differentiation of treatment effect and tumor recurrence., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: To develop a unified deep-learning framework by combining an ultrafast Bloch simulator and a semisolid macromolecular magnetization transfer contrast (MTC) MR fingerprinting (MRF) reconstruction for estimation of MTC effects., Methods: The Bloch simulator and MRF reconstruction architectures were designed with recurrent neural networks and convolutional neural networks, evaluated with numerical phantoms with known ground truths and cross-linked bovine serum albumin phantoms, and demonstrated in the brain of healthy volunteers at 3 T. In addition, the inherent magnetization-transfer ratio asymmetry effect was evaluated in MTC-MRF, CEST, and relayed nuclear Overhauser enhancement imaging. A test-retest study was performed to evaluate the repeatability of MTC parameters, CEST, and relayed nuclear Overhauser enhancement signals estimated by the unified deep-learning framework., Results: Compared with a conventional Bloch simulation, the deep Bloch simulator for generation of the MTC-MRF dictionary or a training data set reduced the computation time by 181-fold, without compromising MRF profile accuracy. The recurrent neural network-based MRF reconstruction outperformed existing methods in terms of reconstruction accuracy and noise robustness. Using the proposed MTC-MRF framework for tissue-parameter quantification, the test-retest study showed a high degree of repeatability in which the coefficients of variance were less than 7% for all tissue parameters., Conclusion: Bloch simulator-driven, deep-learning MTC-MRF can provide robust and repeatable multiple-tissue parameter quantification in a clinically feasible scan time on a 3T scanner., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: To develop a fast, deep-learning approach for quantitative magnetization-transfer contrast (MTC)-MR fingerprinting (MRF) that simultaneously estimates multiple tissue parameters and corrects the effects of B 0 and B 1 variations., Methods: An only-train-once recurrent neural network was designed to perform the fast tissue-parameter quantification for a large range of different MRF acquisition schedules. It enabled a dynamic scan-wise linear calibration of the scan parameters using the measured B 0 and B 1 maps, which allowed accurate, multiple-tissue parameter mapping. MRF images were acquired from 8 healthy volunteers at 3 T. Estimated parameter maps from the MRF images were used to synthesize the MTC reference signal (Z ref ) through Bloch equations at multiple saturation power levels., Results: The B 0 and B 1 errors in MR fingerprints, if not corrected, would impair the tissue quantification and subsequently corrupt the synthesized MTC reference images. Bloch equation-based numerical phantom studies and synthetic MRI analysis demonstrated that the proposed approach could correctly estimate water and semisolid macromolecule parameters, even with severe B 0 and B 1 inhomogeneities., Conclusion: The only-train-once deep-learning framework can improve the reconstruction accuracy of brain-tissue parameter maps and be further combined with any conventional MRF or CEST-MRF method., (© 2023 International Society for Magnetic Resonance in Medicine.)

Amide proton transfer (APT) imaging, a variant of chemical exchange saturation transfer MRI, has shown promise in detecting ischemic tissue acidosis following impaired aerobic metabolism in animal models and in human stroke patients due to the sensitivity of the amide proton exchange rate to changes in pH within the physiological range. Recent studies have demonstrated the possibility of using APT-MRI to detect acidosis of the ischemic penumbra, enabling the assessment of stroke severity and risk of progression, monitoring of treatment progress, and prognostication of clinical outcome. This paper reviews current APT imaging methods actively used in ischemic stroke research and explores the clinical aspects of ischemic stroke and future applications for these methods., (© 2022 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Chemical exchange saturation transfer (CEST) MRI has positioned itself as a promising contrast mechanism, capable of providing molecular information at sufficient resolution and amplified sensitivity. However, it has not yet become a routinely employed clinical technique, due to a variety of confounding factors affecting its contrast-weighted image interpretation and the inherently long scan time. CEST MR fingerprinting (MRF) is a novel approach for addressing these challenges, allowing simultaneous quantitation of several proton exchange parameters using rapid acquisition schemes. Recently, a number of deep-learning algorithms have been developed to further boost the performance and speed of CEST and semi-solid macromolecule magnetization transfer (MT) MRF. This review article describes the fundamental theory behind semisolid MT/CEST-MRF and its main applications. It then details supervised and unsupervised learning approaches for MRF image reconstruction and describes artificial intelligence (AI)-based pipelines for protocol optimization. Finally, practical considerations are discussed, and future perspectives are given, accompanied by basic demonstration code and data., (© 2022 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Background: Magnetic Resonance Imaging (MRI) is an indispensable tool for the diagnosis of temporal lobe epilepsy (TLE). However, about 30% of TLE patients show no lesion on structural MRI (sMRI-negative), posing a significant challenge for presurgical evaluation. This study aimed to investigate whether chemical exchange saturation transfer (CEST) MRI at 3 Tesla can lateralize the epileptic focus of TLE and study the metabolic contributors to the CEST signal measured., Methods: Forty TLE subjects (16 males and 24 females) were included in this study. An automated data analysis pipeline was established, including segmentation of the hippocampus and amygdala (HA), calculation of four CEST metrics and quantitative relaxation times (T 1 and T 2 ), and construction of prediction models by logistic regression. Furthermore, a modified two-stage Bloch-McConnell fitting method was developed to investigate the molecular imaging mechanism of 3 T CEST in identifying epileptic foci of TLE., Findings: The mean CEST ratio (CESTR) metric within 2.25-3.25 ppm in the HA was the most powerful index in predicting seizure laterality, with an area under the receiver-operating characteristic curve (AUC) of 0.84. And, the combination of T 2 and CESTR further increased the AUC to 0.92. Amine and guanidinium moieties were the two leading contributors to the CEST contrast between the epileptogenic HA and the normal HA., Interpretation: CEST at 3 Tesla is a powerful modality that can predict seizure laterality with high accuracy. This study can potentially facilitate the clinical translation of CEST MRI in identifying the epileptic foci of TLE or other localization-related epilepsies., Funding: National Natural Science Foundation of China, Science Technology Department of Zhejiang Province, and Zhejiang University., Competing Interests: Declaration of interests Yi-Cheng Hsu and Yi Sun are employed by Siemens Healthcare Ltd., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The purpose of this study was to evaluate the value of amide proton transfer-weighted (APTw) MRI radiomic features for the differentiation of tumor recurrence from treatment effect in malignant gliomas. Eighty-six patients who had suspected tumor recurrence after completion of chemoradiation or radiotherapy, and who had APTw-MRI data acquired at 3 T, were retrospectively analyzed. Using a fluid-attenuated inversion recovery (FLAIR) image-based mask, radiomics analysis was applied to the processed APTw and structural MR images. A chi-square automatic interaction detector decision tree was used for classification analysis. Models with and without APTw features were built using the same strategy. Tenfold cross-validation was applied to obtain the overall classification performance of each model. Sixty patients were confirmed as having tumor recurrence, and the remainder were confirmed as having treatment effect, at median time points of 190 and 171 days after therapy, respectively. There were 525 radiomic features extracted from each of the processed APTw and structural MR images. Based on these, the APTw-based model yielded the highest accuracy (86.0%) for the differentiation of tumor recurrence from treatment effect, compared with 74.4%, 76.7%, 83.7%, and 76.7% for T 1 w, T 2 w, FLAIR, and Gd-T 1 w, respectively. Model classification accuracy was 82.6% when using the combined structural MR images (T 1 w, T 2 w, FLAIR, Gd-T 1 w), and increased to 89.5% when using these structural plus APTw images. The corresponding sensitivity and specificity were 85.0% and 76.9% for the combination of structural MR images, and 85.0% and 100% after adding APTw image features. Adding APTw-based radiomic features increased MRI accuracy in the assessment of the treatment response in post-treatment malignant gliomas., (© 2022 John Wiley & Sons Ltd.)

Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Bacteria can evade antibiotics by acquiring resistance genes, as well as switching to a non-growing dormant state without accompanying genetic modification. Bacteria in this quiescent state are called persisters, and this non-inheritable ability to withstand multiple antibiotics is referred to as antibiotic tolerance. Although all bacteria are considered to be able to form antibiotic-tolerant persisters, the antibiotic tolerance of extremophilic bacteria is poorly understood. Previously, we identified the psychrotolerant bacterium Pseudomonas sp. B14-6 from the glacier foreland of Midtre Lovénbreen in High Arctic Svalbard. Herein, we investigated the resistance and tolerance of Pseudomonas sp. B14-6 against aminoglycosides at various temperatures. This bacterium was resistant to streptomycin and susceptible to apramycin, gentamicin, kanamycin, and tobramycin. The two putative aminoglycoside phosphotransferase genes aph1 and aph2 were the most likely contributors to streptomycin resistance. Notably, unlike the mesophilic Pseudomonas aeruginosa PA14, this cold-adapted bacterium demonstrated reduced susceptibility to all tested aminoglycosides in a temperature-dependent manner. Pseudomonas sp. B14-6 at a lower temperature formed the persister cells that shows tolerance to the 100-fold minimum inhibitory concentration (MIC) of gentamicin, as well as the partially tolerant cells that withstand 25-fold MIC gentamicin. The temperature-dependent gentamicin tolerance appears to result from reduced metabolic activity. Lastly, the partially tolerant Pseudomonas sp. B14-6 cells could slowly proliferate under the bactericidal concentrations of aminoglycosides. Our results demonstrate that Pseudomonas sp. B14-6 has a characteristic ability to form cells with a range of tolerance, which appears to be inversely proportional to its growth rate.

The opportunistic human pathogen Staphylococcus aureus can evade antibiotics by acquiring antibiotic resistance genes or by entering into a non-growing dormant state. Moreover, the particular circumstances of a specific infection site, such as acidity or anaerobicity, often weaken antibiotic potency. Decreased bacterial susceptibility combined with diminished antibiotic potency is responsible for high failure rates when treating S. aureus infections. Here, we report that the membrane-active antimicrobial agent nTZDpa does not only exhibit enhanced antibiotic activity against multidrug-resistant Gram-positive pathogens in acidic pH, but also retains antimicrobial potency under anaerobic conditions. This agent completely eradicated highly antibiotic-tolerant cells and biofilms formed by methicillin-resistant S. aureus at pH 5.5 at concentrations at which it was not potent at pH 7.4. Furthermore, nTZDpa was more potent at synergistically potentiating gentamicin killing against antibiotic-tolerant MRSA cells at low pH than at high pH. All-atom molecular dynamics simulations combined with membrane-permeabilization assays revealed that the neutral form of nTZDpa, which contains carboxylic acid, is more effective than the deprotonated form at penetrating the bacterial membrane and plays an essential role in membrane activity. An acidic pH increases the proportion of the neutrally charged nTZDpa, which results in antimicrobial enhancement. Our results provide key insights into rational design of pH-sensitive membrane-active antimicrobials and antibiotic adjuvants that are effective in an infection environment. These findings demonstrate that nTZDpa is a promising lead compound for developing new therapeutics against hard-to-cure infections caused by drug-resistant and -tolerant S. aureus., (Copyright © 2022. Published by Elsevier Masson SAS.)

Magnetization transfer contrast MR fingerprinting (MTC-MRF) is a novel quantitative imaging method that simultaneously quantifies free bulk water and semisolid macromolecule parameters using pseudo-randomized scan parameters. To improve acquisition efficiency and reconstruction accuracy, the optimization of MRF sequence design has been of recent interest in the MRF field, but has been challenging due to the large number of degrees of freedom to be optimized in the sequence. Herein, we propose a framework for learning-based optimization of the acquisition schedule (LOAS), which optimizes RF saturation-encoded MRF acquisitions with a minimal number of scan parameters for tissue parameter determination. In a supervised learning framework, scan parameters were subsequently updated to minimize a predefined loss function that can directly represent tissue quantification errors. We evaluated the performance of the proposed approach with a numerical phantom and in in vivo experiments. For validation, MRF images were synthesized using the tissue parameters estimated from a fully connected neural network framework and compared with references. Our results showed that LOAS outperformed existing indirect optimization methods with regard to quantification accuracy and acquisition efficiency. The proposed LOAS method could be a powerful optimization tool in the design of MRF pulse sequences., (© 2021 John Wiley & Sons, Ltd.)

The purpose of this study was to develop and verify a convolutional neural network (CNN)-based deep-learning algorithm to identify tumor progression versus response by adding amide proton transfer-weighted (APTw) MRI data to structural MR images as the proposed model input. 145 scans with 2175 MR instances from 98 patients with malignant glioma (acquired between April 2010 and February 2018) were re-analyzed. An end-to-end classification framework based on a ResNet backbone was developed. The architecture includes a learnable subtraction layer and a hierarchical classification paradigm, and synthesizes information over multiple MR slices using a long short-term memory. Areas under the receiver-operating-characteristic curves (AUCs) were used to assess the impact of adding APTw MRI to structural MRI (T 1 w, T 2 w, FLAIR, and GdT 1 w) on classification of tumor response vs. progression, both on the slice- and scan-level. With both APTw and structural MRI data, adding a learnable subtraction layer and a hierarchical classification paradigm to the backbone ResNet model improved the slice-level classification performance from an AUC of 0.85 to 0.90. Adding APTw data to structural MR images as input to our proposed CNN classification framework led to an increase in AUCs from 0.88 to 0.90 for the slice-level classification (P < 0.001), and from 0.85 to 0.90 for the scan-level classification (P < 0.05). Generated saliency maps highlighted the vast majority of lesions. Complementing structural MRI sequences with protein-based APTw MRI enhanced CNN-based classification of recurrent glioma at the slice and scan levels. Addition of APTw MRI to structural MRI sequences enhanced CNN-based classification of recurrent glioma at the slice and scan levels., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Hyperpigmentation is induced by the overactivation of tyrosinase, which is a rate-limiting enzyme in melanogenesis. The defatted extract of hemp ( Cannabis sativa L.) seed is known to have inhibitory effects on melanogenesis; however, effective compounds in the extract have not been identified yet. In this study, three phenethyl cinnamamides present in hemp seed extract were prepared by purification and chemical synthesis and were assessed for their inhibitory effect on melanogenesis in B16F10 melanoma cells. A comparison of the anti-melanogenesis and anti-tyrosinase activity of hemp seed solvent fractions revealed that the ethyl acetate fraction possessed the greatest potential for suppressing melanogenesis in melanoma cells by decreasing tyrosinase activity. We tentatively identified 26 compounds in the ethyl acetate fraction by comparing spectroscopic data with the literature. Three phenethyl cinnamamides such as N - trans -caffeoyltyramine, N - trans -coumaroyltyramine, and N - trans -feruloyltyramine present abundantly in the ethyl acetate fraction were prepared and their anti-melanogenesis and anti-tyrosinase activities in melanoma cells were evaluated. We found that N - trans -caffeoyltyramine and N - trans -feruloyltyramine inhibited alpha melanocyte stimulating hormone (α-MSH)-induced melanogenesis without cytotoxicity, while N - trans -coumaroyltyramine inhibited melanogenesis with cytotoxicity. IC 50 values of N - trans -caffeoyltyramine, N - trans -feruloyltyramine, and N - trans -coumaroyltyramine for inhibition of α-MSH-mediated tyrosinase activation were 0.8, 20.2, and 6.3 μM, respectively. Overall, N - trans -caffeoyltyramine possessed the strongest anti-melanogenesis activity among the three phenethyl cinnamamides evaluated. The inhibitory effect of N - trans -caffeoyltyramine was verified by determining the melanin content and tyrosinase activity in melanoma after treating the cells with synthetic compounds. Thus, N - trans -caffeoyltyramine isolated from hemp seed extract could be useful in cosmetics as a skin-whitening agent., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Velutin, one of the flavones contained in natural plants, has various beneficial activities, such as skin whitening, as well as anti-inflammatory, anti-allergic, antioxidant, and antimicrobial activities. However, the relationship between the structure of velutin and its anti-melanogenesis activity is not yet investigated. In this study, we obtained 12 velutin derivatives substituted at C5, C7, C3', and C4' of the flavone backbone with hydrogen, hydroxyl, and methoxy functionalities by chemical synthesis, to perform SAR analysis of velutin structural analogues. The SAR study revealed that the substitution of functional groups at C5, C7, C3', and C4' of the flavone backbone affects biological activities related to melanin synthesis. The coexistence of hydroxyl and methoxy at the C5 and C7 position is essential for inhibiting tyrosinase activity. However, 1,2-diol compounds substituted at C3' and C4' of flavone backbone induce apoptosis of melanoma cells. Further, substitution at C3' and C4' with methoxy or hydrogen is essential for inhibiting melanogenesis. Thus, this study would be helpful for the development of natural-derived functional materials to regulate melanin synthesis.

Purpose: To develop a fast, quantitative 3D magnetization transfer contrast (MTC) framework based on an unsupervised learning scheme, which will provide baseline reference signals for CEST and nuclear Overhauser enhancement imaging., Methods: Pseudo-randomized RF saturation parameters and relaxation delay times were applied in an MR fingerprinting framework to generate transient-state signal evolutions for different MTC parameters. Prospectively compressed sensing-accelerated (four-fold) MR fingerprinting images were acquired from 6 healthy volunteers at 3 T. A convolutional neural network framework in an unsupervised fashion was designed to solve an inverse problem of a two-pool MTC Bloch equation, and was compared with a conventional Bloch equation-based fitting approach. The MTC images synthesized by the convolutional neural network architecture were used for amide proton transfer and nuclear Overhauser enhancement imaging as a reference baseline image., Results: The fully unsupervised learning scheme incorporated with the two-pool exchange model learned a set of unique features that can describe the MTC-MR fingerprinting input, and allowed only small amounts of unlabeled data for training. The MTC parameter values estimated by the unsupervised learning method were in excellent agreement with values estimated by the conventional Bloch fitting approach, but dramatically reduced computation time by ~1000-fold., Conclusion: Given the considerable time efficiency compared to conventional Bloch fitting, unsupervised learning-based MTC-MR fingerprinting could be a powerful tool for quantitative MTC and CEST/nuclear Overhauser enhancement imaging., (© 2020 International Society for Magnetic Resonance in Medicine.)

Key Message: Investigation of resource availability on allele effects for four yield component quantitative trait loci provides guidance for the improvement of grain yield in high and low yielding environments. A greater understanding of grain yield (GY) and yield component traits in spring wheat may increase selection efficiency for improved GY in high and low yielding environments. The objective of this study was to determine allelic response of four yield component quantitative trait loci (QTL) to variable resource levels which were manipulated by varying intraspecific plant competition and seeding density. The four QTL investigated in this study had been previously identified as impacting specific yield components. They included QTn.mst-6B for productive tiller number (PTN), WAPO-A1 for spikelet number per spike (SNS), and QGw.mst-3B and TaGW2-A1 for kernel weight (KWT). Near-isogenic lines for each of the four QTL were grown in multiple locations with three competition (border, no-border and space-planted) and two seeding densities (normal 216 seeds m -2 and low 76 seeds m -2 ). Allele response at QTn.mst-6B was driven by changes in resource availability, whereas allele response at WAPO-A1 and TaGW2-A1 was relatively unaffected by resource availability. The QTn.mst-6B.1 allele at QTn.mst-6B conferred PTN plasticity resulting in significant GY increases in high resource environments. The gw2-A1 allele at TaGW2-A1 significantly increased KWT, SNS and GPC offering a source of GY improvement without negatively impacting end-use quality. QGw.mst-3B allelic variation did not significantly impact KWT but did significantly impact SPS. Treatment effects in both experiments often resulted in significant positive impacts on GY and yield component traits when resource availability was increased. Results provide guidance for leveraging yield component QTL to improve GY performance in high- and low-yield environments.

Semisolid magnetization transfer contrast (MTC) and chemical exchange saturation transfer (CEST) MRI based on MT phenomenon have shown potential to evaluate brain development, neurological, psychiatric, and neurodegenerative diseases. However, a qualitative MT ratio (MTR) metric commonly used in conventional MTC imaging is limited in the assessment of quantitative semisolid macromolecular proton exchange rates and concentrations. In addition, CEST signals measured by MTR asymmetry analysis are unavoidably contaminated by upfield nuclear Overhauser enhancement (NOE) signals of mobile and semisolid macromolecules. To address these issues, we developed an MTC-MR fingerprinting (MTC-MRF) technique to quantify tissue parameters, which further allows an estimation of accurate MTC signals at a certain CEST frequency offset. A pseudorandomized RF saturation scheme was used to generate unique MTC signal evolutions for different tissues and a supervised deep neural network was designed to extract tissue properties from measured MTC-MRF signals. Through detailed Bloch equation-based digital phantom and in vivo studies, we demonstrated that the MTC-MRF can quantify MTC characteristics with high accuracy and computational efficiency, compared to a conventional Bloch equation fitting approach, and provide baseline reference signals for CEST and NOE imaging. For validation, MTC-MRF images were synthesized using the tissue parameters estimated from the deep-learning method and compared with experimentally acquired MTC-MRF images as the reference standard. The proposed MTC-MRF framework can provide quantitative 3D MTC, CEST, and NOE imaging of the human brain within a clinically acceptable scan time., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background Amide proton transfer (APT) MRI has the potential to demonstrate antitumor effects by reflecting biologically active tumor portion, providing different information from diffusion-weighted imaging (DWI) or dynamic susceptibility contrast (DSC) imaging. Purpose To evaluate whether a change in APT signal intensity after antiangiogenic treatment is predictive of early treatment response in recurrent glioblastoma. Materials and Methods In this retrospective study, APT MRI, DWI, and DSC imaging were performed in patients with recurrent glioblastoma from July 2015 to April 2019, both before treatment and 4-6 weeks after initiation of bevacizumab (follow-up). Progression was based on pathologic confirmation or clinical-radiologic assessment, and progression patterns were defined as local enhancing or diffuse nonenhancing. Changes in mean and histogram parameters (fifth and 95th percentiles) of APT signal intensity, apparent diffusion coefficient, and normalized cerebral blood volume (CBV) between imaging time points were calculated. Predictors of 12-month progression and progression-free survival (PFS) were determined by using logistic regression and Cox proportional hazard modeling and according to progression type. Results A total of 54 patients were included (median age, 56 years [interquartile range, 49-64 years]; 24 men). Mean APT signal intensity change after bevacizumab treatment indicated a low 12-month progression rate (odds ratio [OR], 0.36; 95% confidence interval [CI]: 0.13, 0.90; P = .04) and longer PFS (hazard ratio: 0.38; 95% CI: 0.20, 0.74; P = .004). High mean normalized CBV at follow-up was associated with a high 12-month progression rate (OR, 20; 95% CI: 2.7, 32; P = .04) and shorter PFS (hazard ratio, 9.4; 95% CI: 2.3, 38; P = .002). Mean APT signal intensity change was a significant predictor of diffuse nonenhancing progression (OR, 0.27; 95% CI: 0.06, 0.85; P = .047), whereas follow-up 95th percentile of the normalized CBV was a predictor of local enhancing progression (OR, 7.1; 95% CI: 2.4, 15; P = .04). Conclusion Early reduction in mean amide proton transfer signal intensity at 4-6 weeks after initiation of antiangiogenic treatment was predictive of a better response at 12 months and longer progression-free survival in patients with recurrent glioblastoma, especially in those with diffuse nonenhancing progression. © RSNA, 2020 Online supplemental material is available for this article.

Purpose: To extend the variably-accelerated sensitivity encoding (vSENSE) method from 2D to 3D for fast chemical exchange saturation transfer (CEST) imaging, and prospectively implement it for clinical MRI., Methods: The CEST scans were acquired from 7 normal volunteers and 15 brain tumor patients using a 3T clinical scanner. The 2D and 3D "artifact suppression" (AS) vSENSE algorithms were applied to generate sensitivity maps from a first scan acquired with conventional SENSE-accelerated 2D and 3D CEST data. The AS sensitivity maps were then applied to reconstruct the other CEST frames at higher acceleration factors. Both retrospective and prospective acceleration in phase-encoding and slice-encoding dimensions were implemented., Results: Applying the 2D AS vSENSE algorithm to a 2-fold undersampled 3.5-ppm CEST frame halved the scan time of conventional SENSE, while generating essentially identical reconstruction errors (p ≈ 1.0). The 3D AS vSENSE algorithm permitted prospective acceleration by up to 8-fold, in total, from phase-encoding and slice-encoding directions for individual source CEST images, and an overall speed-up in scan time of 5-fold. The resulting vSENSE-accelerated amide proton transfer-weighted images agreed with conventional 2-fold-accelerated SENSE CEST results in brain tumor patients and healthy volunteers. Importantly, the vSENSE method eliminated unfolding artifacts in the slice-encoding direction that compromised conventional SENSE CEST scans., Conclusion: The vSENSE method can be extended to 3D CEST imaging to provide higher acceleration factors than conventional SENSE without compromising accuracy., (© 2019 International Society for Magnetic Resonance in Medicine.)

Purpose: To develop prospectively accelerated 3D CEST imaging using compressed sensing (CS), combined with a saturation scheme based on time-interleaved parallel transmission., Methods: A variable density pseudo-random sampling pattern with a centric elliptical k-space ordering was used for CS acceleration in 3D. Retrospective CS studies were performed with CEST phantoms to test the reconstruction scheme. Prospectively CS-accelerated 3D-CEST images were acquired in 10 healthy volunteers and 6 brain tumor patients with an acceleration factor (R CS ) of 4 and compared with conventional SENSE reconstructed images. Amide proton transfer weighted (APTw) signals under varied RF saturation powers were compared with varied acceleration factors., Results: The APTw signals obtained from the CS with acceleration factor of 4 were well-preserved as compared with the reference image (SENSE R = 2) both in retrospective phantom and prospective healthy volunteer studies. In the patient study, the APTw signals were significantly higher in the tumor region (gadolinium [Gd]-enhancing tumor core) than in the normal tissue (p < .001). There was no significant APTw difference between the CS-accelerated images and the reference image. The scan time of CS-accelerated 3D APTw imaging was dramatically reduced to 2:10 minutes (in-plane spatial resolution of 1.8 × 1.8 mm 2 ; 15 slices with 4-mm slice thickness) as compared with SENSE (4:07 minutes)., Conclusion: Compressed sensing acceleration was successfully extended to 3D-CEST imaging without compromising CEST image quality and quantification. The CS-based CEST imaging can easily be integrated into clinical protocols and would be beneficial for a wide range of applications., (© 2019 International Society for Magnetic Resonance in Medicine.)

Wheat landrace accessions were chosen from areas of the world with historical European wheat stem sawfly (Cephus pygmaeus L.) selection pressure to develop six recombinant inbred line (RIL) populations. Molecular maps were constructed, and resistance due to antibiosis and antixenosis was assessed at sites in Montana naturally infested by Cephus cinctus Norton, the wheat stem sawfly (WSS). Novel QTLs were identified along with QTL previously identified in elite germplasm. A newly identified QTL on chromosome 1B provided a new source for pith-filled solid stems. An allele for resistance on chromosome 4A unrelated to solid stems was identified in four of the six RIL populations. A landrace from Turkey, PI 166471, contained alleles at three QTLs causing high levels of larval mortality. None of the QTLs were related to stem solidness, but their combined effect provided resistance similar to that observed in a solid-stemmed check cultivar. These results show the utility of genetic populations derived from geographically targeted landrace accessions to identify new alleles for insect resistance. New PCR-based molecular markers were developed for introgression of novel alleles for WSS resistance into elite lines. Comparison of results with previous analysis of elite cultivars addresses changes in allele frequencies during the wheat breeding process.

Amide proton transfer-weighted (APTw) imaging is a molecular MRI technique that generates image contrast based predominantly on the amide protons in mobile cellular proteins and peptides that are endogenous in tissue. This technique, the most studied type of chemical exchange saturation transfer imaging, has been used successfully for imaging of protein content and pH, the latter being possible due to the strong dependence of the amide proton exchange rate on pH. In this article we briefly review the basic principles and recent technical advances of APTw imaging, which is showing promise clinically, especially for characterizing brain tumors and distinguishing recurrent tumor from treatment effects. Early applications of this approach to stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and traumatic brain injury are also illustrated. Finally, we outline the technical challenges for clinical APT-based imaging and discuss several controversies regarding the origin of APTw imaging signals in vivo. Level of Evidence: 3 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2019;50:347-364., (© 2019 International Society for Magnetic Resonance in Medicine.)

Current chemical exchange saturation transfer (CEST) neuroimaging protocols typically acquire CEST-weighted images, and, as such, do not essentially provide quantitative proton-specific exchange rates (or brain pH) and concentrations. We developed a dictionary-free MR fingerprinting (MRF) technique to allow CEST parameter quantification with a reduced data set. This was accomplished by subgrouping proton exchange models (SPEM), taking amide proton transfer (APT) as an example, into two-pool (water and semisolid macromolecules) and three-pool (water, semisolid macromolecules, and amide protons) models. A variable radiofrequency saturation scheme was used to generate unique signal evolutions for different tissues, reflecting their CEST parameters. The proposed MRF-SPEM method was validated using Bloch-McConnell equation-based digital phantoms with known ground-truth, which showed that MRF-SPEM can achieve a high degree of accuracy and precision for absolute CEST parameter quantification and CEST phantoms. For in-vivo studies at 3 T, using the same model as in the simulations, synthetic Z-spectra were generated using rates and concentrations estimated from the MRF-SPEM reconstruction and compared with experimentally measured Z-spectra as the standard for optimization. The MRF-SPEM technique can provide rapid and quantitative human brain CEST mapping., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To quantify the accuracy of amide proton transfer-weighted (APTw) MRI for identifying active glioma after treatment via radiographically guided stereotactic tissue validation. Experimental Design: Twenty-one patients who were referred for surgery for MRI features concerning for tumor progression versus treatment effect underwent preoperative APTw imaging. Stereotactic biopsy samples were taken from regions of interest with varying APTw signal intensities. The relationship between final clinical pathology and the histopathology of each of the 64 specimens was analyzed relative to APTw results. Analysis of confirmed recurrent tumor or treatment effect tissue was used to perform ROC analysis., Results: Eighteen of 21 patients had recurrent tumor, and 3 had treatment effect on clinical pathology. In 12 patients, there were multiple histopathologic assignments confirmed within the same tumor. Of the 64 total specimens, 20 specimens were active glioma, 27 mixed active and quiescent glioma, and 17 quiescent/no identifiable tumor. APTw signal intensity and histopathologic assignment, cellularity, and proliferation index had significant positive correlations ( R = 0.651, 0.580, and 0.458, respectively; all P < 0.001). ROC analysis with a 1.79% APTw intensity cutoff differentiated active from nonactive tumor (AUC of 0.881) with 85.1% sensitivity and 94.1% specificity. Analysis of clinical pathology showed the mean APTw intensity for each patient had 94.4% sensitivity and 100% positive predictive value for identifying recurrent glioma at this cutoff., Conclusions: APTw imaging hyperintensity may be a marker of active malignant glioma. It is able to distinguish between regions of heterogeneous abnormality on anatomic brain MRI with high sensitivity and specificity., (©2018 American Association for Cancer Research.)

Objective: Stent-assisted coil embolization of intracranial wide-necked aneurysm requires long-term postoperative antiplatelet therapy to prevent in-stent thrombosis. This study aimed to demonstrate results of temporary stent placement for coiling wide necked small intracranial aneurysms, which eliminated need for antiplatelet agents, and to discuss its feasibility and safety., Methods: Data of 156 patients who underwent stent-assisted coil embolization between 2011 and 2014 were retrospectively analyzed. Thirteen cases of temporary stent-assisted coil embolization were included, and their clinical and radiological results were evaluated., Results: The aneurysms treated were all unruptured except one case. All of them had wide neck with mean dome-to-neck ratio of 0.96 and were small-sized aneurysms with mean maximal diameter of 4.2 mm. There was no technical failure in retrieval of stent after completion of embolization of the target aneurysm. Immediate angiography revealed 11 complete and two partial embolization (one residual neck and one residual aneurysm). Two cases encountered thrombosis complication, and they were managed without neurological sequelae. The mean follow-up period was 43 months, angiographic follow-up revealed two cases with minor recurrence, and clinical outcome was good with modified Rankin scale score of 0., Conclusion: Temporary stent-assisted coil embolization of small wide-necked intracranial aneurysm using fully retrievable stent appears safe and effective. Further application and evaluation of this technique in more cases with larger size aneurysm is warranted.

Purpose: To investigate the dependence of magnetization transfer ratio asymmetry at 3.5 ppm (MTR asym (3.5 ppm)), quantitative amide proton transfer (APT # ), and nuclear Overhauser enhancement (NOE # ) signals or contrasts on experimental imaging parameters., Methods: Modified Bloch equation-based simulations using 2-pool and 5-pool exchange models and in vivo rat brain tumor experiments at 4.7T were performed with varied RF saturation power levels, saturation lengths, and relaxation delays. The MTR asym (3.5 ppm), APT # , and NOE # contrasts between tumor and normal tissues were compared among different experimental parameters., Results: The MTR asym (3.5 ppm) image contrasts between tumor and normal tissues initially increased with the RF saturation length, and the maxima occurred at 1.6-2 s under relatively high RF saturation powers (>2.1 μT) and at a longer saturation length under relatively low RF saturation powers (<1.3 μT). The APT # contrasts also increased with the RF saturation length but peaked at longer RF saturation lengths relative to MTR asym (3.5 ppm). The NOE # contrasts were either positive or negative, depending on the experimental parameters applied., Conclusion: Tumor MTR asym (3.5 ppm), APT # , and NOE # contrasts can be maximized at different saturation parameters. The maximum MTR asym (3.5 ppm) contrast can be obtained with a relatively longer RF saturation length (several seconds) at a relatively lower RF saturation power., (© 2018 International Society for Magnetic Resonance in Medicine.)

Objectives: To explore the feasibility of using amide proton transfer-weighted (APTw) MRI metrics as surrogate biomarkers to identify the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in glioblastoma (GBM)., Methods: Eighteen newly diagnosed GBM patients, who were previously scanned at 3T and had a confirmed MGMT methylation status, were retrospectively analysed. For each case, a histogram analysis in the tumour mass was performed to evaluate several quantitative APTw MRI metrics. The Mann-Whitney test was used to evaluate the difference in APTw parameters between MGMT methylated and unmethylated GBMs, and the receiver-operator-characteristic analysis was further used to assess diagnostic performance., Results: Ten GBMs were found to harbour a methylated MGMT promoter, and eight GBMs were unmethylated. The mean, variance, 50th percentile, 90th percentile and Width 10-90 APTw values were significantly higher in the MGMT unmethylated GBMs than in the MGMT methylated GBMs, with areas under the receiver-operator-characteristic curves of 0.825, 0.837, 0.850, 0856 and 0.763, respectively, for the discrimination of MGMT promoter methylation status., Conclusions: APTw signal metrics have the potential to serve as valuable imaging biomarkers for identifying MGMT methylation status in the GBM population., Key Points: • APTw-MRI is applied to predict MGMT promoter methylation status in GBMs. • GBMs with unmethylated MGMT promoter present higher APTw-MRI than methylated GBMs. • Multiple APTw histogram metrics can identify MGMT methylation status. • Mean APTw values showed the highest diagnostic accuracy (AUC = 0.825).

The purpose of this study was to explore the capability and uniqueness of amide proton transfer-weighted (APTw) imaging in the detection of primary and secondary injury after controlled cortical impact (CCI)-induced traumatic brain injury (TBI) in rats. Eleven adult rats had craniotomy plus CCI surgery under isoflurane anesthesia. Multi-parameter MRI data were acquired at 4.7 T, at eight time points (1, 6 h, and 1, 2, 3, 7, 14, and 28 days after TBI). At one and six hours post-injury, average APTw signal intensities decreased significantly in the impacted and peri-lesional areas due to tissue acidosis. A slightly high APTw signal was seen in the core lesion area with respect to the peri-lesional area, which was due to hemorrhage, as shown by T 2 *w. After the initial drop, the APTw signals dramatically increased in some peri-lesional areas at two and three days post-injury, likely due to the secondary inflammatory response. The use of APTw MRI has the potential to introduce a novel molecular neuroimaging approach for the simultaneous detection of ischemia, hemorrhage, and neuroinflammation in TBI.

Purpose: To assess the amide proton transfer-weighted (APTw) MRI features of isocitrate dehydrogenase (IDH)-wildtype and IDH-mutant grade II gliomas and to test the hypothesis that the APTw signal is a surrogate imaging marker for identifying IDH mutation status preoperatively., Methods: Twenty-seven patients with pathologically confirmed low-grade glioma, who were previously scanned at 3T, were retrospectively analyzed. The Mann-Whitney test was used to evaluate relationships between APTw intensities for IDH-mutant and IDH-wildtype groups, and receiver operator characteristic (ROC) analysis was used to assess the diagnostic performance of APTw., Results: Based on histopathology and molecular analysis, seven cases were diagnosed as IDH-wildtype grade II gliomas and 20 cases as IDH-mutant grade II gliomas. The maximum and minimum APTw values, based on multiple regions of interest, as well as the whole-tumor histogram-based mean and 50th percentile APTw values, were significantly higher in the IDH-wildtype gliomas than in the IDH-mutant groups. This corresponded to the areas under the ROC curves of 0.89, 0.76, 0.75, and 0.75, respectively, for the prediction of the IDH mutation status., Conclusion: IDH-wildtype lesions typically were associated with relatively high APTw signal intensities as compared with IDH-mutant lesions. The APTw signal could be a valuable imaging biomarker by which to identify IDH1 mutation status in grade II gliomas. Magn Reson Med 78:1100-1109, 2017. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

Purpose: Pathological assessment using World Health Organization (WHO) criteria is the gold standard for diagnosis of gliomas. However, the accuracy of diagnosis is limited by tissue sampling, particularly for infiltrating, heterogeneous tumours. We assessed the accuracy of amide proton transfer-weighted (APTw) magnetic resonance imaging (MRI)-guided tissue sampling to identify regions of high-grade glioma via radiographic-histopathologic correlation in patients with newly suspected glioma., Patients and Methods: Twenty-four patients with previously undiagnosed gliomas underwent a volumetric APTw MRI prior to their first neurosurgical procedure. A total of 70 specimens were collected via APTw image-directed stereotactic biopsy. Cellularity, necrosis, proliferation and glioma WHO grade were analysed for all specimens and correlated with corresponding APTw signal intensities., Results: Thirty-three specimens displayed grade-II pathology, 14 grade-III, 15 grade-IV, and eight specimens revealed only peritumoural oedema. Multiple glioma grades were found within a single lesion in six patients. APTw signal intensities of the biopsied sites and the maximum APTw values across all biopsied sites in each patient were significantly higher for high-grade versus low-grade specimens. APTw signal intensities were significantly positively correlated with cellularity (R = 0.757) and proliferation (R = 0.538). Multiple linear regression analysis showed that tumour cellularity and proliferation index were the best predictors of APTw signal intensities., Conclusion: APTw imaging identified tumour areas of higher cellularity and proliferation, allowing identification of high-grade regions within heterogeneous gliomas. APTw imaging can be readily translated for more widespread use and can assist diagnostic neurosurgical procedures by increasing the accuracy of tumour sampling in patients with infiltrating gliomas., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: To quantify amide protein transfer (APT) effects in acidic ischemic lesions and assess the spatial-temporal relationship among diffusion, perfusion, and pH deficits in acute stroke patients., Methods: Thirty acute stroke patients were scanned at 3 T. Quantitative APT (APT # ) effects in acidic ischemic lesions were measured using an extrapolated semisolid magnetization transfer reference signal technique and compared with commonly used MTR asym (3.5ppm) or APT-weighted parameters., Results: The APT # images showed clear pH deficits in the ischemic lesion, whereas the MTR asym (3.5ppm) signals were slightly hypointense. The APT # contrast between acidic ischemic lesions and normal tissue in acute stroke patients was more than three times larger than MTR asym (3.5ppm) contrast (-1.45 ± 0.40% for APT # versus -0.39 ± 0.52% for MTR asym (3.5ppm), P < 4.6 × 10 -4 ). Hypoperfused and acidic areas without an apparent diffusion coefficient abnormality were observed and assigned to an ischemic acidosis penumbra. Hypoperfused areas at normal pH were also observed and assigned to benign oligemia. Hyperintense APT signals were observed in a hemorrhage area in one case., Conclusions: The quantitative APT study using the extrapolated semisolid magnetization transfer reference signal approach enhances APT MRI sensitivity to pH compared with conventional APT-weighted MRI, allowing more reliable delineation of an ischemic acidosis in the penumbra. Magn Reson Med 78:871-880, 2017. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

Purpose: The widespread clinical use of chemical exchange saturation transfer (CEST) imaging is hampered by relatively long scan times due to its requirement that multiple saturation-offset image frames be acquired. Here, a novel variably-accelerated sensitivity encoding (vSENSE) method is proposed that provides faster CEST acquisition than conventional SENSE., Theory and Methods: The vSENSE method fully samples one CEST saturation frame, then undersamples the other frames variably. The fully-sampled frame, in conjunction with newly proposed incoherence absorption and artifact suppression strategies, improves the accuracy of sensitivity maps and permits higher acceleration factors for the other undersampled frames than regular SENSE. vSENSE is validated in a phantom, a normal volunteer and eight brain tumor patients at 3 Tesla., Results: vSENSE with an acceleration factor of four generated a 3-6 times smaller error on average than conventional SENSE (P ≤ 0.02), with acceleration factors of 2-4, as compared with full k-space reconstruction. vSENSE permitted four-fold acceleration for amide proton transfer-weighted images, while regular SENSE could only provide a factor of two. When conventional SENSE is used with vSENSE's variable undersampling pattern, erroneous (∼9%) z-spectra result., Conclusion: The vSENSE method enabled twice the acceleration and generated more accurate images than conventional SENSE. Magn Reson Med 77:2225-2238, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Purpose: To evaluate the reliability of four CEST imaging metrics for brain tumors, at varied saturation power levels and magnetic field strengths (3-9.4 Tesla (T))., Methods: A five-pool proton exchange model (free water, semisolid, amide, amine, and NOE-related protons) was used for the simulations. For the in vivo study, eight glioma-bearing rats were scanned at 4.7 T. The CEST ratio (CESTR), CESTR normalized with the reference value (CESTR nr ), inverse Z-spectrum-based (MTR Rex ), and apparent exchange-related relaxation (AREX) were compared., Results: The simulated CEST signal intensities using MTR Rex and AREX were substantially increased at relatively high radiofrequency (RF) saturation powers at 3 T and 4.7 T, whereas CESTR and CESTR nr metrics remained relatively stable. There were tremendously high MTR Rex and AREX signals around the water frequency at all field strengths because of the small denominators. In the rat tumor study at 4.7 T, both CESTR and CESTR nr showed clear contrasts in the tumor with respect to the normal tissue across all saturation power levels (0.5-3 μT), whereas the AREX showed negligible to negative insignificant contrasts., Conclusions: CEST metrics must be carefully selected based on the different experimental settings. CESTR and CESTR nr are more reliable at 3 T (a clinical field strength) and 4.7 T. Magn Reson Med 77:1853-1865, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

The clinical use of amide proton transfer (APT) imaging is hindered by long scan times. Accuracy generally limits the use of conventional sensitivity encoding (SENSE) methods in APT, to an acceleration factor of 2. A novel variably-accelerated sensitivity encoding (vSENSE) method can provide more accurate results and therefore substantially higher overall acceleration factors than conventional SENSE. Here, vSENSE is further developed to eliminate the requirement that one fully-sampled APT frame be acquired, and extended to three dimensions (3D). Furthermore, we combine vSENSE with parallel transmit saturation, and apply it proactively to three normal volunteers and eleven patients with brain tumors.