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Despite advances in sampling and scoring strategies, Monte Carlo modeling methods still struggle to accurately predict de novo the structures of large proteins, membrane proteins, or proteins of complex topologies. Previous approaches have addressed these shortcomings by leveraging sparse distance data gathered using site-directed spin labeling and electron paramagnetic resonance spectroscopy to improve protein structure prediction and refinement outcomes. However, existing computational implementations entail compromises between coarse-grained models of the spin label that lower the resolution and explicit models that lead to resource-intense simulations. These methods are further limited by their reliance on distance distributions, which are calculated from a primary refocused echo decay signal and contain uncertainties that may require manual refinement. Here, we addressed these challenges by developing RosettaDEER, a scoring method within the Rosetta software suite capable of simulating double electron-electron resonance spectroscopy decay traces and distance distributions between spin labels fast enough to fold proteins de novo. We demonstrate that the accuracy of resulting distance distributions match or exceed those generated by more computationally intensive methods. Moreover, decay traces generated from these distributions recapitulate intermolecular background coupling parameters even when the time window of data collection is truncated. As a result, RosettaDEER can discriminate between poorly folded and native-like models by using decay traces that cannot be accurately converted into distance distributions using regularized fitting approaches. Finally, using two challenging test cases, we demonstrate that RosettaDEER leverages these experimental data for protein fold prediction more effectively than previous methods. These benchmarking results confirm that RosettaDEER can effectively leverage sparse experimental data for a wide array of modeling applications built into the Rosetta software suite.
Copyright © 2019 Biophysical Society. Published by Elsevier Inc. All rights reserved.
We have previously reported that the dispersion of spin-lattice relaxation rates in the rotating frame (R ) of tissue water protons at high field can be dominated by chemical exchange contributions. Ischemia in brain causes changes in tissue pH, which in turn may affect proton exchange rates. Amide proton transfer (APT, a form of chemical exchange saturation transfer) has been shown to be sensitive to chemical exchange rates and able to detect pH changes non-invasively following ischemic stroke. However, the specificity of APT to pH changes is decreased because of the influence of several other factors that affect magnetization transfer. R is less influenced by such confounding factors and thus may be more specific for detecting variations in pH. Here, we applied a spin-locking sequence to detect ischemic stroke in animal models. Although R images acquired with a single spin-locking amplitude (ω ) have previously been used to assess stroke, here we use ΔR , which is the difference in R values acquired with two different locking fields to emphasize selectively the contribution of chemical exchange effects. Numerical simulations with different exchange rates and measurements of tissue homogenates with different pH were performed to evaluate the specificity of ΔR to detect tissue acidosis. Spin-lock and APT data were acquired on five rat brains after ischemic strokes induced via middle cerebral artery occlusions. Correlations between these data were analyzed at different time points after the onset of stroke. The results show that ΔR (but not R acquired with a single ω ) was significantly correlated with APT metrics consistent with ΔR varying with pH.
Copyright © 2018 John Wiley & Sons, Ltd.
Elevated flow velocities in adults with sickle cell anemia (SCA) may cause rapid erythrocyte transit through capillaries. This phenomenon could present as dural venous sinus hyperintensity on arterial spin labeling (ASL)-MRI and could be indicative of capillary shunting. Here, the prevalence of ASL venous hyperintensities and association with relevant physiology in adults with SCA was investigated. SCA ( n = 46) and age-matched control ( n = 16) volunteers were recruited for 3.0 T MRI. Pseudo-continuous ASL-MRI was acquired for cerebral blood flow (CBF) calculation and venous hyperintensity determination; venous signal intensity and a categorical venous score (three raters; 0 = no hyperintensity, 1 = focal hyperintensity, and 2 = diffuse hyperintensity) were recorded. Flow velocity in cervical internal carotid artery segments was determined from phase contrast data (v = 40 cm/s) and whole-brain oxygen extraction fraction (OEF) was determined from T-relaxation-under-spin-tagging MRI. Cerebral metabolic rate of oxygen was calculated as the product of OEF, CBF, and blood oxygen content. ASL venous hyperintensities were significantly ( p < 0.001) more prevalent in SCA (65%) relative to control (6%) participants and were associated with elevated flow velocities ( p = 0.03). CBF ( p < 0.001), but not OEF, increased with increasing hyperintensity score. Prospective trials that evaluate this construct as a possible marker of impaired oxygen delivery and stroke risk may be warranted.
SIGNIFICANCE - Oxidative stress contributes to numerous pathophysiological conditions such as development of cancer, neurodegenerative, and cardiovascular diseases. A variety of measurements of oxidative stress markers in biological systems have been developed; however, many of these methods are not specific, can produce artifacts, and do not directly detect the free radicals and reactive oxygen species (ROS) that cause oxidative stress. Electron paramagnetic resonance (EPR) is a unique tool that allows direct measurements of free radical species. Cyclic hydroxylamines are useful and convenient molecular probes that readily react with ROS to produce stable nitroxide radicals, which can be quantitatively measured by EPR. In this work, we critically review recent applications of various cyclic hydroxylamine spin probes in biology to study oxidative stress, their advantages, and the shortcomings. Recent Advances: In the past decade, a number of new cyclic hydroxylamine spin probes have been developed and their successful application for ROS measurement using EPR has been published. These new state-of-the-art methods provide improved selectivity and sensitivity for in vitro and in vivo studies.
CRITICAL ISSUES - Although cyclic hydroxylamine spin probes EPR application has been previously described, there has been lack of translation of these new methods into biomedical research, limiting their widespread use. This work summarizes "best practice" in applications of cyclic hydroxylamine spin probes to assist with EPR studies of oxidative stress.
FUTURE DIRECTIONS - Additional studies to advance hydroxylamine spin probes from the "basic science" to biomedical applications are needed and could lead to better understanding of pathological conditions associated with oxidative stress. Antioxid. Redox Signal. 28, 1433-1443.
BACKGROUND - PD patients treated with dopamine therapy can develop maladaptive impulsive and compulsive behaviors, manifesting as repetitive participation in reward-driven activities. This behavioral phenotype implicates aberrant mesocorticolimbic network function, a concept supported by past literature. However, no study has investigated the acute hemodynamic response to dopamine agonists in this subpopulation.
OBJECTIVES - We tested the hypothesis that dopamine agonists differentially alter mesocortical and mesolimbic network activity in patients with impulsive-compulsive behaviors.
METHODS - Dopamine agonist effects on neuronal metabolism were quantified using arterial-spin-labeling MRI measures of cerebral blood flow in the on-dopamine agonist and off-dopamine states. The within-subject design included 34 PD patients, 17 with active impulsive compulsive behavior symptoms, matched for age, sex, disease duration, and PD severity.
RESULTS - Patients with impulsive-compulsive behaviors have a significant increase in ventral striatal cerebral blood flow in response to dopamine agonists. Across all patients, ventral striatal cerebral blood flow on-dopamine agonist is significantly correlated with impulsive-compulsive behavior severity (Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease- Rating Scale). Voxel-wise analysis of dopamine agonist-induced cerebral blood flow revealed group differences in mesocortical (ventromedial prefrontal cortex; insular cortex), mesolimbic (ventral striatum), and midbrain (SN; periaqueductal gray) regions.
CONCLUSIONS - These results indicate that dopamine agonist therapy can augment mesocorticolimbic and striato-nigro-striatal network activity in patients susceptible to impulsive-compulsive behaviors. Our findings reinforce a wider literature linking studies of maladaptive behaviors to mesocorticolimbic networks and extend our understanding of biological mechanisms of impulsive compulsive behaviors in PD. © 2017 International Parkinson and Movement Disorder Society.
© 2017 International Parkinson and Movement Disorder Society.
BACKGROUND - Vascular pathology is common in late-life depression (LLD) and may contribute to alterations in cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). In turn, such hemodynamic deficits may adversely affect brain function and clinical course. The goal of this study was to examine whether altered cerebral hemodynamics in depressed elders predicted antidepressant response.
METHODS - 21 depressed elders completed cranial 3T MRI, including a pseudo-continuous Arterial Spin Labeling (pcASL) acquisition on both room air and during a hypercapnia challenge. Participants then completed 12 weeks of open-label sertraline. Statistical analyses examined the relationship between regional normalized CBF and CVR values and change in Montgomery-Asberg Depression Rating Scale (MADRS) and tested for differences based on remission status.
RESULTS - 10 participants remitted and 11 did not. After controlling for age and baseline MADRS, greater change in MADRS with treatment was associated with lower pre-treatment normalized CBF in the caudal anterior cingulate cortex (cACC) and lateral orbitofrontal cortex (OFC), as well as lower CVR with hypercapnia in the caudal medial frontal gyrus (cMFG). After controlling for age and baseline MADRS score, remitters exhibited lower CBF in the cACC and lower CVR in the cMFG.
LIMITATIONS - Our sample was small, did not include a placebo arm, and we examined only specific regions of interest.
CONCLUSIONS - Our findings suggest that increased perfusion of the OFC and the ACC is associated with a poor antidepressant response. They do not support that vascular pathology as measured by CBF and CVR negatively affects acute treatment outcomes.
Published by Elsevier B.V.
Sickle cell anemia (SCA) is a genetic disorder resulting in reduced oxygen carrying capacity and elevated stroke risk. Pseudo-continuous arterial spin labeling (pCASL) measures of cerebral blood flow (CBF) may have relevance for stroke risk assessment; however, the effects of elevated flow velocity and reduced bolus arrival time (BAT) on CBF quantification in SCA patients have not been thoroughly characterized, and pCASL model parameters used in healthy adults are often applied to patients with SCA. Here, cervical arterial flow velocities and pCASL labeling efficiencies were computed in adults with SCA (n = 19) and age- and race-matched controls without sickle trait (n = 7) using pCASL in sequence with phase contrast MR angiography (MRA). Controls (n = 7) and a subgroup of patients (n = 8) also underwent multi-post-labeling-delay pCASL for BAT assessment. Mean flow velocities were elevated in SCA adults (velocity = 28.3 ± 4.1 cm/s) compared with controls (velocity = 24.5 ± 3.8 cm/s), and mean pCASL labeling efficiency (α) was reduced in SCA adults (α = 0.72) relative to controls (α = 0.91). In patients, mean whole-brain CBF from phase contrast MRA was 91.8 ± 18.1 ml/100 g/min, while mean pCASL CBF when assuming a constant labeling efficiency of 0.86 was 75.2 ± 17.3 ml/100 g/min (p < 0.01), resulting in a mean absolute quantification error of 23% when a labeling efficiency appropriate for controls was assumed. This difference cannot be accounted for by BAT (whole-brain BAT: control, 1.13 ± 0.06 s; SCA, 1.02 ± 0.09 s) or tissue T variation. In conclusion, BAT variation influences pCASL quantification less than elevated cervical arterial velocity and labeling efficiency variation in SCA adults; thus, a lower labeling efficiency (α = 0.72) or subject-specific labeling efficiency should be incorporated for SCA patients.
Copyright © 2017 John Wiley & Sons, Ltd.
Sickle cell anaemia is a monogenetic disorder with a high incidence of stroke. While stroke screening procedures exist for children with sickle cell anaemia, no accepted screening procedures exist for assessing stroke risk in adults. The purpose of this study is to use novel magnetic resonance imaging methods to evaluate physiological relationships between oxygen extraction fraction, cerebral blood flow, and clinical markers of cerebrovascular impairment in adults with sickle cell anaemia. The specific goal is to determine to what extent elevated oxygen extraction fraction may be uniquely present in patients with higher levels of clinical impairment and therefore may represent a candidate biomarker of stroke risk. Neurological evaluation, structural imaging, and the non-invasive T2-relaxation-under-spin-tagging magnetic resonance imaging method were applied in sickle cell anaemia (n = 34) and healthy race-matched control (n = 11) volunteers without sickle cell trait to assess whole-brain oxygen extraction fraction, cerebral blood flow, degree of vasculopathy, severity of anaemia, and presence of prior infarct; findings were interpreted in the context of physiological models. Cerebral blood flow and oxygen extraction fraction were elevated (P < 0.05) in participants with sickle cell anaemia (n = 27) not receiving monthly blood transfusions (interquartile range cerebral blood flow = 46.2-56.8 ml/100 g/min; oxygen extraction fraction = 0.39-0.50) relative to controls (interquartile range cerebral blood flow = 40.8-46.3 ml/100 g/min; oxygen extraction fraction = 0.33-0.38). Oxygen extraction fraction (P < 0.0001) but not cerebral blood flow was increased in participants with higher levels of clinical impairment. These data provide support for T2-relaxation-under-spin-tagging being able to quickly and non-invasively detect elevated oxygen extraction fraction in individuals with sickle cell anaemia with higher levels of clinical impairment. Our results support the premise that magnetic resonance imaging-based assessment of elevated oxygen extraction fraction might be a viable screening tool for evaluating stroke risk in adults with sickle cell anaemia.
© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
Multiple nonmorphologic magnetic resonance sequences are available in musculoskeletal imaging that can provide additional information to better characterize and diagnose musculoskeletal disorders and diseases. These sequences include blood-oxygen-level-dependent (BOLD), arterial spin labeling (ASL), diffusion-weighted imaging (DWI), and diffusion-tensor imaging (DTI). BOLD and ASL provide different methods to evaluate skeletal muscle microperfusion. The BOLD signal reflects the ratio between oxyhemoglobin and deoxyhemoglobin. ASL uses selective tagging of inflowing blood spins in a specific region for calculating local perfusion. DWI and DTI provide information about the structural integrity of soft tissue including muscles and fibers as well as pathologies.
Copyright © 2015 Elsevier Inc. All rights reserved.