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The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation.
Fischer K, Fenzl A, Liu D, Dyar KA, Kleinert M, Brielmeier M, Clemmensen C, Fedl A, Finan B, Gessner A, Jastroch M, Huang J, Keipert S, Klingenspor M, Brüning JC, Kneilling M, Maier FC, Othman AE, Pichler BJ, Pramme-Steinwachs I, Sachs S, Scheideler A, Thaiss WM, Uhlenhaut H, Ussar S, Woods SC, Zorn J, Stemmer K, Collins S, Diaz-Meco M, Moscat J, Tschöp MH, Müller TD
(2020) Nat Commun 11: 2306
MeSH Terms: Activating Transcription Factor 2, Adipogenesis, Adipose Tissue, Brown, Adipose Tissue, White, Animals, Cell Nucleus, Magnetic Resonance Imaging, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Positron Emission Tomography Computed Tomography, Protein Binding, Sequestosome-1 Protein, Uncoupling Protein 1, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added July 22, 2020
During β-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1α promoter. P62 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62 mice, global p62 and Ucp1-Cre p62 mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding.
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18 MeSH Terms
Using novel magnetic resonance imaging methods to predict stroke risk in individuals with sickle cell anemia.
Jordan LC, Kassim AA, Wilkerson KL, Lee CA, Waddle SL, Donahue MJ
(2020) Hematol Oncol Stem Cell Ther 13: 76-84
MeSH Terms: Adolescent, Anemia, Sickle Cell, Child, Child, Preschool, Female, Humans, Magnetic Resonance Imaging, Male, Risk, Stroke
Show Abstract · Added March 24, 2020
Sickle cell anemia (SCA) is a well-characterized monogenetic disorder with a high prevalence of cerebral vasculopathy, silent cerebral infarcts, and strokes. A significant mechanism for cerebral infarction in SCA is hemodynamic imbalance. To compensate for reduced oxygen-carrying capacity due to anemia, individuals with SCA have chronically elevated cerebral blood flow to maintain viable oxygen delivery to the brain tissue. Often the oxygen extraction fraction (ratio of oxygen consumed to oxygen delivered) is increased in more severely affected individuals. Subsequently, cerebrovascular reserve capacity, the ability of arterioles to dilate and further increase the cerebral blood volume and flow, will be reduced. These hemodynamic profiles have been associated with prior cerebral infarcts and increased evidence of disease severity. These cerebral hemodynamic parameters can be assessed noninvasively with noncontrast magnetic resonance imaging (MRI) of the brain utilizing specific MRI methods. This review focuses on using advanced neuroimaging methods to assess stroke risk in individuals with SCA, and such methods may be utilized before and after bone marrow or hematopoietic stem cell transplant to assess cerebral hemodynamic response. This manuscript is part of the Proceeding of The European Group for Blood and Marrow Transplantation (EBMT) Congress on Sickle Cell Disease, 16th-17 May 2019, Regensburg, Germany.
Copyright © 2020 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.
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10 MeSH Terms
Repeatability and Reproducibility of Pancreas Volume Measurements Using MRI.
Williams JM, Hilmes MA, Archer B, Dulaney A, Du L, Kang H, Russell WE, Powers AC, Moore DJ, Virostko J
(2020) Sci Rep 10: 4767
MeSH Terms: Adolescent, Adult, Child, Diabetes Mellitus, Type 1, Female, Humans, Magnetic Resonance Imaging, Male, Organ Size, Pancreas, Reproducibility of Results, Young Adult
Show Abstract · Added March 19, 2020
Reduced pancreas volume, as measured by non-contrast magnetic resonance imaging (MRI), is observed in individuals with newly-diagnosed type 1 diabetes (T1D) and declines over the first year after diagnosis. In this study, we determined the repeatability and inter-reader reproducibility of pancreas volume measurements by MRI. Test-retest scans in individuals with or without T1D (n = 16) had an intraclass correlation coefficient (ICC) of 0.985 (95% CI 0.961 to 0.995) for pancreas volume. Independent pancreas outlines by two board-certified radiologists (n = 30) yielded an ICC of 0.945 (95% CI 0.889 to 0.973). The mean Dice coefficient, a measurement of the degree of overlap between pancreas regions of interest between the two readers, was 0.77. Prandial state did not influence pancreatic measurements, as stomach volume did not correlate with pancreas volume. These data demonstrate that MRI measurements of pancreas volume between two readers are repeatable and reproducible with ICCs that correspond to excellent clinical significance (ICC > 0.9), are not related to changes in stomach volume, and could be a useful tool for clinical investigation of diabetes and other pancreas pathologies.
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12 MeSH Terms
Resting-state "physiological networks".
Chen JE, Lewis LD, Chang C, Tian Q, Fultz NE, Ohringer NA, Rosen BR, Polimeni JR
(2020) Neuroimage 213: 116707
MeSH Terms: Adult, Brain, Connectome, Female, Heart Rate, Humans, Magnetic Resonance Imaging, Male, Nerve Net, Respiration, Rest
Show Abstract · Added March 18, 2020
Slow changes in systemic brain physiology can elicit large fluctuations in fMRI time series, which manifest as structured spatial patterns of temporal correlations between distant brain regions. Here, we investigated whether such "physiological networks"-sets of segregated brain regions that exhibit similar responses following slow changes in systemic physiology-resemble patterns associated with large-scale networks typically attributed to remotely synchronized neuronal activity. By analyzing a large group of subjects from the 3T Human Connectome Project (HCP) database, we demonstrate brain-wide and noticeably heterogenous dynamics tightly coupled to either respiratory variation or heart rate changes. We show, using synthesized data generated from physiological recordings across subjects, that these physiologically-coupled fluctuations alone can produce networks that strongly resemble previously reported resting-state networks, suggesting that, in some cases, the "physiological networks" seem to mimic the neuronal networks. Further, we show that such physiologically-relevant connectivity estimates appear to dominate the overall connectivity observations in multiple HCP subjects, and that this apparent "physiological connectivity" cannot be removed by the use of a single nuisance regressor for the entire brain (such as global signal regression) due to the clear regional heterogeneity of the physiologically-coupled responses. Our results challenge previous notions that physiological confounds are either localized to large veins or globally coherent across the cortex, therefore emphasizing the necessity to consider potential physiological contributions in fMRI-based functional connectivity studies. The rich spatiotemporal patterns carried by such "physiological" dynamics also suggest great potential for clinical biomarkers that are complementary to large-scale neuronal networks.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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11 MeSH Terms
Spin-lock relaxation rate dispersion reveals spatiotemporal changes associated with tubulointerstitial fibrosis in murine kidney.
Wang F, Colvin DC, Wang S, Li H, Zu Z, Harris RC, Zhang MZ, Gore JC
(2020) Magn Reson Med 84: 2074-2087
MeSH Terms: Amides, Animals, Disease Models, Animal, Fibrosis, Kidney, Magnetic Resonance Imaging, Male, Mice
Show Abstract · Added March 9, 2020
PURPOSE - To develop and evaluate a reliable non-invasive means for assessing the severity and progression of fibrosis in kidneys. We used spin-lock MR imaging with different locking fields to detect and characterize progressive renal fibrosis in an hHB-EGF mouse model.
METHODS - Male hHB-EGF mice, a well-established model of progressive fibrosis, and age-matched normal wild type (WT) mice, were imaged at 7T at ages 5-7, 11-13, and 30-40 weeks. Spin-lock relaxation rates R were measured at different locking fields (frequencies) and the resultant dispersion curves were fit to a model of exchanging water pools. The obtained MRI parameters were evaluated as potential indicators of tubulointerstitial fibrosis in kidney. Histological examinations of renal fibrosis were also carried out post-mortem after MRI.
RESULTS - Histology detected extensive fibrosis in the hHB-EGF mice, in which collagen deposition and reductions in capillary density were observed in the fibrotic regions of kidneys. R and R values at different spin-lock powers clearly dropped in the fibrotic region as fibrosis progressed. There was less variation in the asymptotic locking field relaxation rate between the groups. The exchange parameter S and the inflection frequency ω changed by larger factors.
CONCLUSION - Both S and ω depend primarily on the average exchange rate between water and other chemically shifted resonances such as hydroxyls and amides. Spin-lock relaxation rate dispersion, rather than single measurements of relaxation rates, provides more comprehensive and specific information on spatiotemporal changes associated with tubulointerstitial fibrosis in murine kidney.
© 2020 International Society for Magnetic Resonance in Medicine.
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8 MeSH Terms
Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis.
Zhang L, Awadalla M, Mahmood SS, Nohria A, Hassan MZO, Thuny F, Zlotoff DA, Murphy SP, Stone JR, Golden DLA, Alvi RM, Rokicki A, Jones-O'Connor M, Cohen JV, Heinzerling LM, Mulligan C, Armanious M, Barac A, Forrestal BJ, Sullivan RJ, Kwong RY, Yang EH, Damrongwatanasuk R, Chen CL, Gupta D, Kirchberger MC, Moslehi JJ, Coelho-Filho OR, Ganatra S, Rizvi MA, Sahni G, Tocchetti CG, Mercurio V, Mahmoudi M, Lawrence DP, Reynolds KL, Weinsaft JW, Baksi AJ, Ederhy S, Groarke JD, Lyon AR, Fradley MG, Thavendiranathan P, Neilan TG
(2020) Eur Heart J 41: 1733-1743
MeSH Terms: Contrast Media, Gadolinium, Humans, Immune Checkpoint Inhibitors, Magnetic Resonance Imaging, Cine, Magnetic Resonance Spectroscopy, Myocarditis, Predictive Value of Tests, Stroke Volume, Ventricular Function, Left
Show Abstract · Added May 29, 2020
AIMS - Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented.
METHODS AND RESULTS - From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE.
CONCLUSION - These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
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Optimization of a transmit/receive surface coil for squirrel monkey spinal cord imaging.
Lu M, Wang F, Chen LM, Gore JC, Yan X
(2020) Magn Reson Imaging 68: 197-202
MeSH Terms: Animals, Cervical Cord, Diagnostic Tests, Routine, Diffusion Tensor Imaging, Equipment Design, Magnets, Multiparametric Magnetic Resonance Imaging, Neck, Phantoms, Imaging, Saimiri, Signal-To-Noise Ratio, Spinal Cord
Show Abstract · Added March 3, 2020
MR Imaging the spinal cord of non-human primates (NHP), such as squirrel monkey, is important since the injuries in NHP resemble those that afflict human spinal cords. Our previous studies have reported a multi-parametric MRI protocol, including functional MRI, diffusion tensor imaging, quantitative magnetization transfer and chemical exchange saturation transfer, which allows non-invasive detection and monitoring of injury-associated structural, functional and molecular changes over time. High signal-to-noise ratio (SNR) is critical for obtaining high-resolution images and robust estimates of MRI parameters. In this work, we describe our construction and use of a single channel coil designed to maximize the SNR for imaging the squirrel monkey cervical spinal cord in a 21 cm bore magnet at 9.4 T. We first numerically optimized the coil dimension of a single loop coil and then evaluated the benefits of a quadrature design. We then built an optimized coil based on the simulation results and compared its SNR performance with a non-optimized single coil in both phantoms and in vivo.
Copyright © 2020 Elsevier Inc. All rights reserved.
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12 MeSH Terms
Does the magnetization transfer effect bias chemical exchange saturation transfer effects? Quantifying chemical exchange saturation transfer in the presence of magnetization transfer.
Smith AK, Ray KJ, Larkin JR, Craig M, Smith SA, Chappell MA
(2020) Magn Reson Med 84: 1359-1375
MeSH Terms: Bias, Humans, Magnetic Resonance Imaging, Phantoms, Imaging, Protons
Show Abstract · Added March 30, 2020
PURPOSE - Chemical exchange saturation transfer (CEST) is an MRI technique sensitive to the presence of low-concentration solute protons exchanging with water. However, magnetization transfer (MT) effects also arise when large semisolid molecules interact with water, which biases CEST parameter estimates if quantitative models do not account for macromolecular effects. This study establishes under what conditions this bias is significant and demonstrates how using an appropriate model provides more accurate quantitative CEST measurements.
METHODS - CEST and MT data were acquired in phantoms containing bovine serum albumin and agarose. Several quantitative CEST and MT models were used with the phantom data to demonstrate how underfitting can influence estimates of the CEST effect. CEST and MT data were acquired in healthy volunteers, and a two-pool model was fit in vivo and in vitro, whereas removing increasing amounts of CEST data to show biases in the CEST analysis also corrupts MT parameter estimates.
RESULTS - When all significant CEST/MT effects were included, the derived parameter estimates for each CEST/MT pool significantly correlated (P < .05) with bovine serum albumin/agarose concentration; minimal or negative correlations were found with underfitted data. Additionally, a bootstrap analysis demonstrated that significant biases occur in MT parameter estimates (P < .001) when unmodeled CEST data are included in the analysis.
CONCLUSIONS - These results indicate that current practices of simultaneously fitting both CEST and MT effects in model-based analyses can lead to significant bias in all parameter estimates unless a sufficiently detailed model is utilized. Therefore, care must be taken when quantifying CEST and MT effects in vivo by properly modeling data to minimize these biases.
© 2020 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.
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5 MeSH Terms
Tissue sodium content in patients with systemic lupus erythematosus: association with disease activity and markers of inflammation.
Carranza-León DA, Oeser A, Marton A, Wang P, Gore JC, Titze J, Stein CM, Chung CP, Ormseth MJ
(2020) Lupus 29: 455-462
MeSH Terms: Adult, Biomarkers, Blood Pressure, Case-Control Studies, Cross-Sectional Studies, Female, Humans, Inflammation, Interleukin-10, Linear Models, Lupus Erythematosus, Systemic, Magnetic Resonance Imaging, Male, Middle Aged, Muscles, Skin, Sodium, Sodium Isotopes
Show Abstract · Added March 18, 2020
OBJECTIVES - Sodium (Na) is stored in the skin and muscle and plays an important role in immune regulation. In animal models, increased tissue Na is associated with activation of the immune system, and high salt intake exacerbates autoimmune disease and worsens hypertension. However, there is no information about tissue Na and human autoimmune disease. We hypothesized that muscle and skin Na content is (a) higher in patients with systemic lupus erythematosus (SLE) than in control subjects, and (b) associated with blood pressure, disease activity, and inflammation markers (interleukin (IL)-6, IL-10 and IL-17 A) in SLE.
METHODS - Lower-leg skin and muscle Na content was measured in 23 patients with SLE and in 28 control subjects using Na magnetic resonance imaging. Demographic and clinical information was collected from interviews and chart review, and blood pressure was measured. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI). Plasma inflammation markers were measured by multiplex immunoassay.
RESULTS - Muscle Na content was higher in patients with SLE (18.8 (16.7-18.3) mmol/L) than in control subjects (15.8 (14.7-18.3) mmol/L;  < 0.001). Skin Na content was also higher in SLE patients than in controls, but this difference was not statistically significant. Among patients with SLE, muscle Na was associated with SLEDAI and higher concentrations of IL-10 after adjusting for age, race, and sex. Skin Na was significantly associated with systolic blood pressure, but this was attenuated after covariate adjustment.
CONCLUSION - Patients with SLE had higher muscle Na content than control subjects. In patients with SLE, higher muscle Na content was associated with higher disease activity and IL-10 concentrations.
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18 MeSH Terms
Rapid whole-brain quantitative magnetization transfer imaging using 3D selective inversion recovery sequences.
Cronin MJ, Xu J, Bagnato F, Gochberg DF, Gore JC, Dortch RD
(2020) Magn Reson Imaging 68: 66-74
MeSH Terms: Adult, Algorithms, Brain, Brain Mapping, Computer Simulation, Echo-Planar Imaging, Female, Healthy Volunteers, Humans, Image Processing, Computer-Assisted, Imaging, Three-Dimensional, Magnetic Resonance Imaging, Male, Models, Theoretical, Myelin Sheath, Reproducibility of Results, White Matter
Show Abstract · Added March 18, 2020
Selective inversion recovery (SIR) is a quantitative magnetization transfer (qMT) method that provides estimates of parameters related to myelin content in white matter, namely the macromolecular pool-size-ratio (PSR) and the spin-lattice relaxation rate of the free pool (R), without the need for independent estimates of ∆B, B, and T. Although the feasibility of performing SIR in the human brain has been demonstrated, the scan times reported previously were too long for whole-brain applications. In this work, we combined optimized, short-TR acquisitions, SENSE/partial-Fourier accelerations, and efficient 3D readouts (turbo spin-echo, SIR-TSE; echo-planar imaging, SIR-EPI; and turbo field echo, SIR-TFE) to obtain whole-brain data in 18, 10, and 7 min for SIR-TSE, SIR-EPI, SIR-TFE, respectively. Based on numerical simulations, all schemes provided accurate parameter estimates in large, homogenous regions; however, the shorter SIR-TFE scans underestimated focal changes in smaller lesions due to blurring. Experimental studies in healthy subjects (n = 8) yielded parameters that were consistent with literature values and repeatable across scans (coefficient of variation: PSR = 2.2-6.4%, R = 0.6-1.4%) for all readouts. Overall, SIR-TFE parameters exhibited the lowest variability, while SIR-EPI parameters were adversely affected by susceptibility-related image distortions. In patients with relapsing remitting multiple sclerosis (n = 2), focal changes in SIR parameters were observed in lesions using all three readouts; however, contrast was reduced in smaller lesions for SIR-TFE, which was consistent with the numerical simulations. Together, these findings demonstrate that efficient, accurate, and repeatable whole-brain SIR can be performed using 3D TFE, EPI, or TSE readouts; however, the appropriate readout should be tailored to the application.
Copyright © 2020 Elsevier Inc. All rights reserved.
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17 MeSH Terms