Searched for: school:SOM
Department/Unit:Neuroscience Institute
Mutant eIF2B leads to impaired mitochondrial oxidative phosphorylation in vanishing white matter disease
Raini, Gali; Sharet, Reut; Herrero, Melisa; Atzmon, Andrea; Shenoy, Anjana; Geiger, Tamar; Elroy-Stein, Orna
Eukaryotic translation initiation factor 2B (eIF2B) is a master regulator of protein synthesis under normal and stress conditions. Mutations in any of the five genes encoding its subunits lead to vanishing white matter (VWM) disease, a recessive genetic deadly illness caused by progressive loss of white matter in the brain. In this study we used fibroblasts, which are not involved in the disease, to demonstrate the involvement of eIF2B in mitochondrial function and abundance. Mass spectrometry of total proteome of mouse embryonic fibroblasts (MEFs) isolated from Eif2b5R132H/R132H mice revealed unbalanced stoichiometry of proteins involved in oxidative phosphorylation and of mitochondrial translation machinery components, among others. Mutant MEFs exhibit 55% decrease in oxygen consumption rate per mtDNA content and 47% increase in mitochondrial abundance (p < 0.005), reflecting adaptation to energy requirements. A more robust eIF2B-associated oxidative respiration deficiency was found in mutant primary astrocytes, which exhibit > 3-fold lower ATP-linked respiration per cell despite a 2-fold increase in mtDNA content (p < 0.03). The 2-fold increase in basal and stimulated glycolysis in mutant astrocytes (p = 0.03), but not in MEFs, demonstrates their higher energetic needs and further explicates their involvement in the disease. The data demonstrate the critical role of eIF2B in tight coordination of expression from nuclear and mitochondrial genomes and illuminates the importance of mitochondrial function in VWM pathology. Further dissection of the signaling network associated with eIF2B function will help generating therapeutic strategies for VWM disease and possibly other neurodegenerative disorders.
PMID: 28306143
ISSN: 1471-4159
CID: 2532372
Recent Advances in Cardiovascular Magnetic Resonance: Techniques and Applications
Salerno, Michael; Sharif, Behzad; Arheden, Hakan; Kumar, Andreas; Axel, Leon; Li, Debiao; Neubauer, Stefan
Cardiovascular magnetic resonance imaging has become the gold standard for evaluating myocardial function, volumes, and scarring. Additionally, cardiovascular magnetic resonance imaging is unique in its comprehensive tissue characterization, including assessment of myocardial edema, myocardial siderosis, myocardial perfusion, and diffuse myocardial fibrosis. Cardiovascular magnetic resonance imaging has become an indispensable tool in the evaluation of congenital heart disease, heart failure, cardiac masses, pericardial disease, and coronary artery disease. This review will highlight some recent novel cardiovascular magnetic resonance imaging techniques, concepts, and applications.
PMCID:5777859
PMID: 28611116
ISSN: 1942-0080
CID: 2615892
3D Motion Modeling and Reconstruction of Left Ventricle Wall in Cardiac MRI
Yang, Dong; Wu, Pengxiang; Tan, Chaowei; Pohl, Kilian M; Axel, Leon; Metaxas, Dimitris
The analysis of left ventricle (LV) wall motion is a critical step for understanding cardiac functioning mechanisms and clinical diagnosis of ventricular diseases. We present a novel approach for 3D motion modeling and analysis of LV wall in cardiac magnetic resonance imaging (MRI). First, a fully convolutional network (FCN) is deployed to initialize myocardium contours in 2D MR slices. Then, we propose an image registration algorithm to align MR slices in space and minimize the undesirable motion artifacts from inconsistent respiration. Finally, a 3D deformable model is applied to recover the shape and motion of myocardium wall. Utilizing the proposed approach, we can visually analyze 3D LV wall motion, evaluate cardiac global function, and diagnose ventricular diseases.
PMCID:5484578
PMID: 28664198
ISSN: n/a
CID: 3074312
Multi-cycle Reconstruction of Cardiac MRI for the Analysis of Inter-ventricular Septum Motion During Free Breathing
Chitiboi, Teodora; Ramb, Rebecca; Feng, Li; Piekarski, Eve; Tautz, Lennart; Hennemuth, Anja; Axel, Leon
Small variations in left-ventricular preload due to respiration produce measurable changes in cardiac function in normal subjects. We show that this mechanism is altered in patients with reduced ejection fraction (EF), hypertrophy, or volume-loaded right ventricle (RV). We propose a multi-dimensional retrospective image reconstruction, based on an adaptive, soft classification of data into respiratory and cardiac phases, to study these effects.
PMCID:6258012
PMID: 30498813
ISSN: n/a
CID: 3520122
Risk factors for persistence of lower respiratory symptoms among community members exposed to the 2001 World Trade Center terrorist attacks
Jordan, Hannah T; Friedman, Stephen M; Reibman, Joan; Goldring, Roberta M; Miller Archie, Sara A; Ortega, Felix; Alper, Howard; Shao, Yongzhao; Maslow, Carey B; Cone, James E; Farfel, Mark R; Berger, Kenneth I
OBJECTIVES: We studied the course of lower respiratory symptoms (LRS; cough, wheeze or dyspnoea) among community members exposed to the 9/11/2001 World Trade Center (WTC) attacks during a period of 12-13 years following the attacks, and evaluated risk factors for LRS persistence, including peripheral airway dysfunction and post-traumatic stress disorder (PTSD). METHODS: Non-smoking adult participants in a case-control study of post-9/11-onset LRS (exam 1, 2008-2010) were recruited for follow-up (exam 2, 2013-2014). Peripheral airway function was assessed with impulse oscillometry measures of R5 and R5-20. Probable PTSD was a PTSD checklist score >/=44 on a 2006-2007 questionnaire. RESULTS: Of 785 exam 1 participants, 545 (69%) completed exam 2. Most (321, 59%) were asymptomatic at all assessments. Among 192 participants with initial LRS, symptoms resolved for 110 (57%) by exam 2, 55 (29%) had persistent LRS and 27 (14%) had other patterns. The proportion with normal spirometry increased from 65% at exam 1 to 85% at exam 2 in the persistent LRS group (p<0.01) and was stable among asymptomatic participants and those with resolved LRS. By exam 2, spirometry results did not differ across symptom groups; however, R5 and R5-20 abnormalities were more common among participants with persistent LRS (56% and 46%, respectively) than among participants with resolved LRS (30%, p<0.01; 27%, p=0.03) or asymptomatic participants (20%, p<0.001; 8.2%, p<0.001). PTSD, R5 at exam 1, and R5-20 at exam 1 were each independently associated with persistent LRS. CONCLUSIONS: Peripheral airway dysfunction and PTSD may contribute to LRS persistence. Assessment of peripheral airway function detected pulmonary damage not evident on spirometry. Mental and physical healthcare for survivors of complex environmental disasters should be coordinated carefully.
PMCID:5520238
PMID: 28341697
ISSN: 1470-7926
CID: 2508762
Opioid Overuse or NSAID Underuse? A Response to the Pain Guide [Letter]
Hiremath, Swapnil; Goldfarb, David S; Juurlink, David N
PMID: 28454686
ISSN: 1523-6838
CID: 2575412
Deciphering neuronal population codes for acute thermal pain
Chen, Zhe; Zhang, Qiaosheng; Tong, Ai Phuong Sieu; Manders, Toby R; Wang, Jing
OBJECTIVE: Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Current pain research mostly focuses on molecular and synaptic changes at the spinal and peripheral levels. However, a complete understanding of pain mechanisms requires the physiological study of the neocortex. Our goal is to apply a neural decoding approach to read out the onset of acute thermal pain signals, which can be used for brain-machine interface. APPROACH: We used micro wire arrays to record ensemble neuronal activities from the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC) in freely behaving rats. We further investigated neural codes for acute thermal pain at both single-cell and population levels. To detect the onset of acute thermal pain signals, we developed a novel latent state-space framework to decipher the sorted or unsorted S1 and ACC ensemble spike activities, which reveal information about the onset of pain signals. MAIN RESULTS: The state space analysis allows us to uncover a latent state process that drives the observed ensemble spike activity, and to further detect the 'neuronal threshold' for acute thermal pain on a single-trial basis. Our method achieved good detection performance in sensitivity and specificity. In addition, our results suggested that an optimal strategy for detecting the onset of acute thermal pain signals may be based on combined evidence from S1 and ACC population codes. SIGNIFICANCE: Our study is the first to detect the onset of acute pain signals based on neuronal ensemble spike activity. It is important from a mechanistic viewpoint as it relates to the significance of S1 and ACC activities in the regulation of the acute pain onset.
PMCID:5679238
PMID: 28384122
ISSN: 1741-2552
CID: 2521592
Thalamic control of functional cortical connectivity
Nakajima, Miho; Halassa, Michael M
The thalamus is an evolutionarily conserved structure with extensive reciprocal connections to cortical regions. While its role in transmitting sensory signals is well-studied, its broader engagement in cognition is unclear. In this review, we discuss evidence that the thalamus regulates functional connectivity within and between cortical regions, determining how a cognitive process is implemented across distributed cortical microcircuits. Within this framework, thalamic circuits do not necessarily determine the categorical content of a cognitive process (e.g., sensory details in feature-based attention), but rather provide a route by which task-relevant cortical representations are sustained and coordinated. Additionally, thalamic control of cortical connectivity bridges general arousal to the specific processing of categorical content, providing an intermediate level of cognitive and circuit description that will facilitate mapping neural computations onto thought and behavior.
PMCID:5604244
PMID: 28486176
ISSN: 1873-6882
CID: 2548952
Sharp wave ripples during learning stabilize the hippocampal spatial map
Roux, Lisa; Hu, Bo; Eichler, Ronny; Stark, Eran; Buzsaki, Gyorgy
Cognitive representation of the environment requires a stable hippocampal map, but the mechanisms maintaining a given map are unknown. Because sharp wave-ripples (SPW-R) orchestrate both retrospective and prospective spatial information, we hypothesized that disrupting neuronal activity during SPW-Rs affects spatial representation. Mice learned new sets of three goal locations daily in a multiwell maze. We used closed-loop SPW-R detection at goal locations to trigger optogenetic silencing of a subset of CA1 pyramidal neurons. Control place cells (nonsilenced or silenced outside SPW-Rs) largely maintained the location of their place fields after learning and showed increased spatial information content. In contrast, the place fields of SPW-R-silenced place cells remapped, and their spatial information remained unaltered. SPW-R silencing did not impact the firing rates or proportions of place cells. These results suggest that interference with SPW-R-associated activity during learning prevents stabilization and refinement of hippocampal maps.
PMCID:5446786
PMID: 28394323
ISSN: 1546-1726
CID: 2531272
Role of High-Resolution Dynamic Contrast-Enhanced MRI with Golden-Angle Radial Sparse Parallel Reconstruction to Identify the Normal Pituitary Gland in Patients with Macroadenomas
Sen, R; Sen, C; Pack, J; Block, K T; Golfinos, J G; Prabhu, V; Boada, F; Gonen, O; Kondziolka, D; Fatterpekar, G
BACKGROUND AND PURPOSE: Preoperative localization of the pituitary gland with imaging in patients with macroadenomas has been inadequately explored. The pituitary gland enhancing more avidly than a macroadenoma has been described in the literature. Taking advantage of this differential enhancement pattern, our aim was to evaluate the role of high-resolution dynamic MR imaging with golden-angle radial sparse parallel reconstruction in localizing the pituitary gland in patients undergoing trans-sphenoidal resection of a macroadenoma. MATERIALS AND METHODS: A retrospective study was performed in 17 patients who underwent trans-sphenoidal surgery for pituitary macroadenoma. Radial volumetric interpolated brain examination sequences with golden-angle radial sparse parallel technique were obtained. Using an ROI-based method to obtain signal-time curves and permeability measures, 3 separate readers identified the normal pituitary gland distinct from the macroadenoma. The readers' localizations were then compared with the intraoperative location of the gland. Statistical analyses were performed to assess the interobserver agreement and correlation with operative findings. RESULTS: The normal pituitary gland was found to have steeper enhancement-time curves as well as higher peak enhancement values compared with the macroadenoma (P < .001). Interobserver agreement was almost perfect in all 3 planes (kappa = 0.89). In the 14 cases in which the gland was clearly identified intraoperatively, the correlation between the readers' localization and the true location derived from surgery was also nearly perfect (kappa = 0.95). CONCLUSIONS: This study confirms our ability to consistently and accurately identify the normal pituitary gland in patients with macroadenomas with the golden-angle radial sparse parallel technique with quantitative permeability measurements and enhancement-time curves.
PMCID:6080601
PMID: 28495945
ISSN: 1936-959x
CID: 2548692