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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
Invited Commentary on "Optimizing Diffusion-Tensor Imaging Acquisition for Spinal Cord Assessment," with Response from Dr Martín Noguerol et al.
Smith SA
(2020) Radiographics 40: 428-431
MeSH Terms: Diffusion Tensor Imaging, Physical Examination, Spinal Cord
Added March 30, 2020
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3 MeSH Terms
Initial Experience with Using a Structured Light 3D Scanner and Image Registration to Plan Bedside Subdural Evacuating Port System Placement.
Bow H, Yang X, Chotai S, Feldman M, Yu H, Englot DJ, Miga MI, Pruthi S, Dawant BM, Parker SL
(2020) World Neurosurg 137: 350-356
MeSH Terms: Craniotomy, Hematoma, Subdural, Chronic, Humans, Imaging, Three-Dimensional, Models, Anatomic, Neuronavigation, Neurosurgical Procedures, Printing, Three-Dimensional, Tomography, X-Ray Computed
Show Abstract · Added March 30, 2020
BACKGROUND - Chronic subdural hematoma evacuation can be achieved in select patients through bedside placement of the Subdural Evacuation Port System (SEPS; Medtronic, Inc., Dublin, Ireland). This procedure involves drilling a burr hole at the thickest part of the hematoma. Identifying this location is often difficult, given the variable tilt of available imaging and distant anatomic landmarks. This paper evaluates the feasibility and accuracy of a bedside navigation system that relies on visible light-based 3-dimensional (3D) scanning and image registration to a pre-procedure computed tomography scan. The information provided by this system may increase accuracy of the burr hole location.
METHODS - In Part 1, the accuracy of this system was evaluated using a rigid 3D printed phantom head with implanted fiducials. In Part 2, the navigation system was tested on 3 patients who underwent SEPS placement.
RESULTS - The error in registration of this system was less than 2.5 mm when tested on a rigid 3D printed phantom head. Fiducials located in the posterior aspect of the head were difficult to reliably capture. For the 3 patients who underwent 5 SEPS placements, the distance between anticipated SEPS burr hole location based on registration and actual burr hole location was less than 1cm.
CONCLUSIONS - A bedside cranial navigation system based on 3D scanning and image registration has been introduced. Such a system may increase the success rate of bedside procedures, such as SEPS placement. However, technical challenges such as the ability to scan hair and practical challenges such as minimization of patient movement during scans must be overcome.
Copyright © 2020 Elsevier Inc. All rights reserved.
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9 MeSH Terms
Impaired vigilance networks in temporal lobe epilepsy: Mechanisms and clinical implications.
Englot DJ, Morgan VL, Chang C
(2020) Epilepsia 61: 189-202
MeSH Terms: Arousal, Brain Mapping, Epilepsy, Temporal Lobe, Humans, Nerve Net, Neuroimaging
Show Abstract · Added March 18, 2020
Mesial temporal lobe epilepsy (mTLE) is a neurological disorder in which patients suffer from frequent consciousness-impairing seizures, broad neurocognitive deficits, and diminished quality of life. Although seizures in mTLE originate focally in the hippocampus or amygdala, mTLE patients demonstrate cognitive deficits that extend beyond temporal lobe function-such as decline in executive function, cognitive processing speed, and attention-as well as diffuse decreases in neocortical metabolism and functional connectivity. Given prior observations that mTLE patients exhibit impairments in vigilance, and that seizures may disrupt the activity and long-range connectivity of subcortical brain structures involved in vigilance regulation, we propose that subcortical activating networks underlying vigilance play a critical role in mediating the widespread neural and cognitive effects of focal mTLE. Here, we review evidence for impaired vigilance in mTLE, examine clinical implications and potential network underpinnings, and suggest neuroimaging strategies for determining the relationship between vigilance, brain connectivity, and neurocognition in patients and healthy controls.
Wiley Periodicals, Inc. © 2020 International League Against Epilepsy.
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6 MeSH Terms
Cerebral blood flow in 5- to 8-month-olds: Regional tissue maturity is associated with infant affect.
Catalina Camacho M, King LS, Ojha A, Garcia CM, Sisk LM, Cichocki AC, Humphreys KL, Gotlib IH
(2020) Dev Sci 23: e12928
MeSH Terms: Brain, Cerebrovascular Circulation, Emotions, Female, Humans, Infant, Magnetic Resonance Imaging, Male, Mothers, Prefrontal Cortex, Stress, Psychological, Temperament
Show Abstract · Added March 3, 2020
Infancy is marked by rapid neural and emotional development. The relation between brain function and emotion in infancy, however, is not well understood. Methods for measuring brain function predominantly rely on the BOLD signal; however, interpretation of the BOLD signal in infancy is challenging because the neuronal-hemodynamic relation is immature. Regional cerebral blood flow (rCBF) provides a context for the infant BOLD signal and can yield insight into the developmental maturity of brain regions that may support affective behaviors. This study aims to elucidate the relations among rCBF, age, and emotion in infancy. One hundred and seven mothers reported their infants' (infant age M ± SD = 6.14 ± 0.51 months) temperament. A subsample of infants completed MRI scans, 38 of whom produced usable perfusion MRI during natural sleep to quantify rCBF. Mother-infant dyads completed the repeated Still-Face Paradigm, from which infant affect reactivity and recovery to stress were quantified. We tested associations of infant age at scan, temperament factor scores, and observed affect reactivity and recovery with voxel-wise rCBF. Infant age was positively associated with CBF in nearly all voxels, with peaks located in sensory cortices and the ventral prefrontal cortex, supporting the formulation that rCBF is an indicator of tissue maturity. Temperamental Negative Affect and recovery of positive affect following a stressor were positively associated with rCBF in several cortical and subcortical limbic regions, including the orbitofrontal cortex and inferior frontal gyrus. This finding yields insight into the nature of affective neurodevelopment during infancy. Specifically, infants with relatively increased prefrontal cortex maturity may evidence a disposition toward greater negative affect and negative reactivity in their daily lives yet show better recovery of positive affect following a social stressor.
© 2019 John Wiley & Sons Ltd.
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12 MeSH Terms
APOE ε4-specific associations of VEGF gene family expression with cognitive aging and Alzheimer's disease.
Moore AM, Mahoney E, Dumitrescu L, De Jager PL, Koran MEI, Petyuk VA, Robinson RA, Ruderfer DM, Cox NJ, Schneider JA, Bennett DA, Jefferson AL, Hohman TJ
(2020) Neurobiol Aging 87: 18-25
MeSH Terms: Aged, Aged, 80 and over, Aging, Apolipoprotein E4, Cognitive Aging, Cognitive Dysfunction, Female, Gene Expression, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Male, Neovascularization, Physiologic, Neuropilin-1, Vascular Endothelial Growth Factor A
Show Abstract · Added March 30, 2020
Literature suggests vascular endothelial growth factor A (VEGFA) is protective among those at highest risk for Alzheimer's disease (AD). Apolipoprotein E (APOE) ε4 allele carriers represent a highly susceptible population for cognitive decline, and VEGF may confer distinct protection among APOE-ε4 carriers. We evaluated interactions between cortical expression of 10 VEGF gene family members and APOE-ε4 genotype to clarify which VEGF genes modify the association between APOE-ε4 and cognitive decline. Data were obtained from the Religious Orders Study and Rush Memory and Aging Project (N = 531). Linear regression assessed interactions on global cognition. VEGF genes NRP1 and VEGFA interacted with APOE-ε4 on cognitive performance (p.fdr < 0.05). Higher NRP1 expression correlated with worse outcomes among ε4 carriers but better outcomes among ε4 noncarriers, suggesting NRP1 modifies the risk for poor cognitive scores based on APOE-ε4 status. NRP1 regulates angiogenesis, and literature suggests vessels in APOE-ε4 brains are more prone to leaking, perhaps placing young vessels at risk for ischemia. Results suggest that future therapeutics targeting brain angiogenesis should also consider ε4 allele status.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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16 MeSH Terms
Hyperactivity and Reduced Activation of Anterior Hippocampus in Early Psychosis.
McHugo M, Talati P, Armstrong K, Vandekar SN, Blackford JU, Woodward ND, Heckers S
(2019) Am J Psychiatry 176: 1030-1038
MeSH Terms: Case-Control Studies, Female, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Photic Stimulation, Schizophrenia, Time Factors, Young Adult
Show Abstract · Added January 31, 2020
OBJECTIVE - In schizophrenia, the anterior hippocampus is hyperactive and shows reduced task-related recruitment, but the relationship between these two findings is unclear. The authors tested the hypothesis that hyperactivity impairs recruitment of the anterior hippocampus during scene processing.
METHODS - Functional MRI data from 45 early-psychosis patients and 35 demographically matched healthy control subjects were analyzed using a block-design 1-back scene-processing task. Hippocampal activation in response to scenes and faces compared with scrambled images was measured. In a subset of 20 early-psychosis patients and 31 healthy control subjects, baseline hippocampal activity using cerebral blood volume (CBV) mapping was measured. Correlation analyses were used to examine the association between baseline hippocampal activity and task-related hippocampal activation.
RESULTS - Activation of the anterior hippocampus was significantly reduced and CBV in the anterior hippocampus was significantly increased in the early stages of psychosis. Increased CBV in early-psychosis patients was inversely correlated with task-related activation during scene processing in the anterior hippocampus.
CONCLUSIONS - Anterior hippocampal hyperactivity in early-psychosis patients appears to limit effective recruitment of this region during task performance. These findings provide novel support for the anterior hippocampus as a therapeutic target in the treatment of cognitive deficits in psychosis.
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2 Members
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10 MeSH Terms
Hydroxycarbamide and white matter integrity in pediatric sickle cell disease: Commentary to accompany: Hydroxycarbamide treatment in children with sickle cell anaemia is associated with more intact white matter integrity: a quantitative MRI study.
Lance EI, Jordan LC
(2019) Br J Haematol 187: 141-143
MeSH Terms: Anemia, Sickle Cell, Antisickling Agents, Child, Humans, Hydroxyurea, Magnetic Resonance Imaging, White Matter
Added March 24, 2020
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1 Members
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7 MeSH Terms
The human body at cellular resolution: the NIH Human Biomolecular Atlas Program.
HuBMAP Consortium
(2019) Nature 574: 187-192
MeSH Terms: Aging, Atlases as Topic, Biomedical Research, Female, Health, Humans, International Cooperation, Male, Models, Anatomic, Molecular Biology, National Institutes of Health (U.S.), Organ Specificity, Single-Cell Analysis, United States
Show Abstract · Added January 22, 2020
Transformative technologies are enabling the construction of three-dimensional maps of tissues with unprecedented spatial and molecular resolution. Over the next seven years, the NIH Common Fund Human Biomolecular Atlas Program (HuBMAP) intends to develop a widely accessible framework for comprehensively mapping the human body at single-cell resolution by supporting technology development, data acquisition, and detailed spatial mapping. HuBMAP will integrate its efforts with other funding agencies, programs, consortia, and the biomedical research community at large towards the shared vision of a comprehensive, accessible three-dimensional molecular and cellular atlas of the human body, in health and under various disease conditions.
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MeSH Terms
7T quantitative magnetization transfer (qMT) of cortical gray matter in multiple sclerosis correlates with cognitive impairment.
McKeithan LJ, Lyttle BD, Box BA, O'Grady KP, Dortch RD, Conrad BN, Thompson LM, Rogers BP, Newhouse P, Pawate S, Bagnato F, Smith SA
(2019) Neuroimage 203: 116190
MeSH Terms: Adult, Cerebral Cortex, Cognitive Dysfunction, Female, Gray Matter, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, Young Adult
Show Abstract · Added March 3, 2020
Cognitive impairment (CI) is a major manifestation of multiple sclerosis (MS) and is responsible for extensively hindering patient quality of life. Cortical gray matter (cGM) damage is a significant contributor to CI, but is poorly characterized by conventional MRI let alone with quantitative MRI, such as quantitative magnetization transfer (qMT). Here we employed high-resolution qMT at 7T via the selective inversion recovery (SIR) method, which provides tissue-specific indices of tissue macromolecular content, such as the pool size ratio (PSR) and the rate of MT exchange (kmf). These indices could represent expected demyelination that occurs in the presence of gray matter damage. We utilized selective inversion recovery (SIR) qMT which provides a low SAR estimate of macromolecular-bulk water interactions using a tailored, B1 and B0 robust inversion recovery (IR) sequence acquired at multiple inversion times (TI) at 7T and fit to a two-pool model of magnetization exchange. Using this sequence, we evaluated qMT indices across relapsing-remitting multiple sclerosis patients (N = 19) and healthy volunteers (N = 37) and derived related associations with neuropsychological measures of cognitive impairment. We found a significant reduction in k in cGM of MS patients (15.5%, p = 0.002), unique association with EDSS (ρ = -0.922, p = 0.0001), and strong correlation with cognitive performance (ρ = -0.602, p = 0.0082). Together these findings indicate that the rate of MT exchange (k) may be a significant biomarker of cGM damage relating to CI in MS.
Copyright © 2019 Elsevier Inc. All rights reserved.
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3 Members
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12 MeSH Terms