Virginia Tech Carilion (VTC)
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Browsing Virginia Tech Carilion (VTC) by Department "Biomedical Engineering and Sciences"
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- In Cocaine Dependence, Neural Prediction Errors During Loss Avoidance Are Increased With Cocaine Deprivation and Predict Drug UseWang, John M.; Zhu, Lusha; Brown, Vanessa M.; De La Garza, Richard II; Newton, Thomas F.; Casas, Brooks; Chiu, Pearl H. (Elsevier, 2018-08-03)Background: In substance-dependent individuals, drug deprivation and drug use trigger divergent behavioral responses to environmental cues. These divergent responses are consonant with data showing that short- and long-term adaptations in dopamine signaling are similarly sensitive to state of drug use. The literature suggests a drug state–dependent role of learning in maintaining substance use; evidence linking dopamine to both reinforcement learning and addiction provides a framework to test this possibility. Methods: In a randomized crossover design, 22 participants with current cocaine use disorder completed a probabilistic loss-learning task during functional magnetic resonance imaging while on and off cocaine (44 sessions). Another 54 participants without Axis I psychopathology served as a secondary reference group. Within-drug state and paired-subjects’ learning effects were assessed with computational model–derived individual learning parameters. Model-based neuroimaging analyses evaluated effects of drug use state on neural learning signals. Relationships among model-derived behavioral learning rates (α+, α−), neural prediction error signals (δ+, δ−), cocaine use, and desire to use were assessed. Results: During cocaine deprivation, cocaine-dependent individuals exhibited heightened positive learning rates (α+), heightened neural positive prediction error (δ+) responses, and heightened association of α+ with neural δ+ responses. The deprivation-enhanced neural learning signals were specific to successful loss avoidance, comparable to participants without psychiatric conditions, and mediated a relationship between chronicity of drug use and desire to use cocaine. Conclusions: Neurocomputational learning signals are sensitive to drug use status and suggest that heightened reinforcement by successful avoidance of negative outcomes may contribute to drug seeking during deprivation. More generally, attention to drug use state is important for delineating substrates of addiction.
- A microchip platform for structural oncology applicationsWinton, Carly E.; Gilmore, Brian L.; Demmert, Andrew C.; Karageorge, Vasilea; Sheng, Zhi; Kelly, Deborah F. (2016)Recent advances in the development of functional materials offer new tools to dissect human health and disease mechanisms. The use of tunable surfaces is especially appealing as substrates can be tailored to fit applications involving specific cell types or tissues. Here we use tunable materials to facilitate the three-dimensional (3D) analysis of BRCA1 gene regulatory complexes derived from human cancer cells. We employed a recently developed microchip platform to isolate BRCA1 protein assemblies natively formed in breast cancer cells with and without BRCA1 mutations. The captured assemblies proved amenable to cryo-electron microscopy (EM) imaging and downstream computational analysis. Resulting 3D structures reveal the manner in which wild-type BRCA1 engages the RNA polymerase II (RNAP II) core complex that contained K63-linked ubiquitin moieties-a putative signal for DNA repair. Importantly, we also determined that molecular assemblies harboring the BRCA1(5382insC) mutation exhibited altered protein interactions and ubiquitination patterns compared to wild-type complexes. Overall, our analyses proved optimal for developing new structural oncology applications involving patient-derived cancer cells, while expanding our knowledge of BRCA1's role in gene regulatory events.
- Molecular Analysis of BRCA1 in Human Breast Cancer Cells Under Oxidative StressGilmore, Brian L.; Liang, Yanping; Winton, Carly E.; Patel, Kaya; Karageorge, Vasilea; Varano, A. Cameron; Dearnaley, William J.; Sheng, Zhi; Kelly, Deborah F. (Nature Publishing Group, 2017-03-06)The precise manner in which physical changes to the breast cancer susceptibility protein (BRCA1) affect its role in DNA repair events remain unclear. Indeed, cancer cells harboring mutations in BRCA1 suffer from genomic instability and increased DNA lesions. Here, we used a combination of molecular imaging and biochemical tools to study the properties of the BRCA1 in human cancer cells. Our results reveal new information for the manner in which full-length BRCA1 engages its binding partner, the BRCA1-associated Ring Domain protein (BARD1) under oxidative stress conditions. We also show how physical differences between wild type and mutated BRCA15382insC impact the cell’s response to oxidative damage. Overall, we demonstrate how clinically relevant changes to BRCA1 affect its structure-function relationship in hereditary breast cancer.
- A Molecular Toolkit to Visualize Native Protein Assemblies in the Context of Human DiseaseGilmore, Brian L.; Winton, Carly E.; Demmert, Andrew C.; Tanner, Justin R.; Bowman, Sam; Karageorge, Vasilea; Patel, Kaya; Sheng, Zhi; Kelly, Deborah F. (Springer Nature, 2015-09-23)We present a new molecular toolkit to investigate protein assemblies natively formed in the context of human disease. The system employs tunable microchips that can be decorated with switchable adaptor molecules to select for target proteins of interest and analyze them using molecular microscopy. Implementing our new streamlined microchip approach, we could directly visualize BRCA1 gene regulatory complexes from patient-derived cancer cells for the first time.
- Neural computations underlying social risk sensitivityLauharatanahirun, Nina; Christopoulos, George I.; Casas, Brooks (Frontiers, 2012-08-02)Under standard models of expected utility, preferences over stochastic events are assumed to be independent of the source of uncertainty. Thus, in decision-making, an agent should exhibit consistent preferences, regardless of whether the uncertainty derives from the unpredictability of a random process or the unpredictability of a social partner. However, when a social partner is the source of uncertainty, social preferences can influence decisions over and above pure risk attitudes (RA). Here, we compared risk-related hemodynamic activity and individual preferences for two sets of options that differ only in the social or non-social nature of the risk. Risk preferences in social and non-social contexts were systematically related to neural activity during decision and outcome phases of each choice. Individuals who were more risk averse in the social context exhibited decreased risk-related activity in the amygdala during non-social decisions, while individuals who were more risk averse in the non-social context exhibited the opposite pattern. Differential risk preferences were similarly associated with hemodynamic activity in ventral striatum at the outcome of these decisions. These findings suggest that social preferences, including aversion to betrayal or exploitation by social partners, may be associated with variability in the response of these subcortical regions to social risk.
- Opponent Effects of Hyperarousal and Re-experiencing on Affective Habituation in Posttraumatic Stress DisorderMcCurry, Katherine L.; Frueh, B. Christopher; Chiu, Pearl H.; Casas, Brooks (2020-02)BACKGROUND: Aberrant emotion processing is a hallmark of posttraumatic stress disorder (PTSD), with neurobiological models suggesting both heightened neural reactivity and diminished habituation to aversive stimuli. However, empirical work suggests that these response patterns may be specific to subsets of those with PTSD. This study investigates the unique contributions of PTSD symptom clusters (re-experiencing, avoidance and numbing, and hyperarousal) to neural reactivity and habituation to negative stimuli in combat-exposed veterans. METHODS: Ninety-five combat-exposed veterans (46 with PTSD) and 53 community volunteers underwent functional magnetic resonance imaging while viewing emotional images. This study examined the relationship between symptom cluster severity and hemodynamic responses to negative compared with neutral images (NEG>NEU). RESULTS: Veterans exhibited comparable mean and habituation-related responses for NEG>NEU, relative to civilians. However, among veterans, habituation, but not mean response, was differentially related to PTSD symptom severity. Hyperarousal symptoms were related to decreased habituation for NEG>NEU in a network of regions, including superior and inferior frontal gyri, ventromedial prefrontal cortex, superior and middle temporal gyri, and anterior insula. In contrast, re-experiencing symptoms were associated with increased habituation in a similar network. Furthermore, re-experiencing severity was positively related to amygdalar functional connectivity with the left inferior frontal gyrus and dorsal anterior cingulate cortex for NEG>NEU. CONCLUSIONS: These results indicate that hyperarousal symptoms in combat-related PTSD are associated with decreased neural habituation to aversive stimuli. These impairments are partially mitigated in the presence of re-experiencing symptoms, such that during exposure to negative stimuli, re-experiencing symptoms are positively associated with amygdalar connectivity to prefrontal regions implicated in affective suppression.
- Structural analysis of BRCA1 reveals modification hotspotLiang, Yanping; Dearnaley, William J.; Varano, A. Cameron; Winton, Carly E.; Gilmore, Brian L.; Alden, Nick A.; Sheng, Zhi; Kelly, Deborah F. (American Association for the Advancement of Science, 2017-09-01)
- TNF alpha Modulates Cardiac Conduction by Altering Electrical Coupling between MyocytesGeorge, Sharon A.; Calhoun, Patrick J.; Gourdie, Robert G.; Smyth, James W.; Poelzing, Steven (Frontiers, 2017-05-23)Background: Tumor Necrosis Factor alpha (TNF alpha) upregulation during acute inflammatory response has been associated with numerous cardiac effects including modulating Connexin43 and vascular permeability. This may in turn alter cardiac gap junctional (GJ) coupling and extracellular volume (ephaptic coupling) respectively. We hypothesized that acute exposure to pathophysiological TNF alpha levels can modulate conduction velocity (CV) in the heart by altering electrical coupling: GJ and ephaptic. Methods and Results: Hearts were optically mapped to determine CV from control, TNF alpha and TNF alpha + high calcium(2.5 vs. 1.25 mM) treated guinea pig hearts over 90 mins. Transmission electron microscopy was performed to measure changes in intercellular separation in the gap junction-adjacent extracellular nanodomain-perinexus (W-P). Cx43 expression and phosphorylation were determined by Western blotting and Cx43 distribution by confocal immunofluorescence. At 90 mins, longitudinal and transverse CV (CVL and CVT, respectively) increased with control Tyrode perfusion but TNF alpha slowed CVT alone relative to control and anisotropy of conduction increased, but not significantly. TNF alpha increased W-P relative to control at 90 mins, without significantly changing GJ coupling. Increasing extracellular calcium after 30 mins of just TNF alpha exposure increased CVT within 15 mins. TNF alpha + high calcium also restored CVT at 90 mins and reduced W-P to control values. Interestingly, TNF alpha + high calcium also improved GJ coupling at 90 mins, which along with reduced W-P may have contributed to increasing CV. Conclusions: Elevating extracellular calcium during acute TNF alpha exposure reduces perinexal expansion, increases ephaptic, and GJ coupling, improves CV and may be a novel method for preventing inflammation induced CV slowing.