Biology subjects

Carter, R. M.

Publications and source records attributed to Carter, R. M..

5 recordsLinked to original sources

bioRxiv2023

The Multidrug Resistance Transporter P-glycoprotein Confers Resistance to Ferroptosis Inducers

Ferroptosis is a form of cell death caused by direct or indirect inhibition of glutathione peroxidase 4 that leads to lethal lipid peroxidation. Several small molecule ferroptosis inducers (FINs) have been reported, yet little information is available regarding resistance mechanisms, particularly their interaction with the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp, ABCB1) and ABCG2. Given the role that ABC transporters play in absorption, distribution, and excretion of many drugs, characterizing these interactions could provide information regarding oral bioavailability and brain penetration and may predict drug-drug interactions. Using ferroptosis-sensitive A673 cells transfected to express P-gp or ABCG2, we found that P-gp overexpression was able to confer resistance to FIN56 and the erastin derivatives imidazole ketone erastin and piperazine erastin. Results were confirmed with OVCAR8-derived NCI/ADR-RES cells that overexpress P-gp, where the P-gp inhibitor valspodar completely inhibited resistance to the FINs. P-gp-mediated resistance to imidazole ketone erastin and piperazine erastin was also reversed in UO-31 renal cancer cells by CRISPR-mediated knockout of ABCB1. At a concentration of 10 M, the FINs ML-162, GPX inhibitor 26a, and PACMA31 were able to increase intracellular rhodamine 123 fluorescence over 10-fold in P-gp-expressing MDR-19 cells and GPX inhibitor 26a was able to increase intracellular purpurin-18 fluorescence over 4-fold in ABCG2-expressing R-5 cells. Expression of P-gp may reduce the efficacy of these FINs in cancers that express the transporter and may prevent access to sanctuary sites such as the brain. The ability of some FINs to inhibit P-gp and ABCG2 suggests potential drug-drug interactions. SIGNIFICANCE STATEMENTWhile several small-molecule ferroptosis inducers have been described, little work has addressed potential interactions with ABC transporters such as P-glycoprotein or ABCG2 that might limit bioavailability or brain penetration. We find that the ferroptosis inducers FIN56, imidazole ketone erastin, and piperazine erastin are substrates of P-glycoprotein. ML-162, GPX inhibitor 26a, and PACMA31 were found to inhibit P-glycoprotein, while GPX inhibitor 26a was additionally able to inhibit ABCG2, suggesting the potential for drug-drug interactions.

pharmacology and toxicology↗

bioRxiv2022

Efficiency of heterogenous functional connectomes explains variance in callous-unemotional traits after computational lesioning of cortical midline and salience regions

Callous-unemotional (CU) traits are a youth antisocial phenotype hypothesized to be a result of differences in the integration of multiple brain systems. However, mechanistic insights into these brain systems are a continued challenge. Where prior work describes activation and connectivity of the connectome in relation to these systems, new mechanistic insights can be derived by removing nodes and characterizing changes in network properties (hereafter referred to as computational lesioning) to characterize the resilience and vulnerability of the brains functional connectome. Here, we study the resilience of connectome integration in CU traits by estimating changes in efficiency after computationally lesioning individual-level connectomes. From resting-state data of 86 participants (48% female, age 14.52{+/-}1.31) drawn from the Nathan Kline institutes Rockland study, individual-level connectomes were estimated using graphical lasso. Computational lesioning was conducted both sequentially and by targeting global and local hubs. We calculated changes in network efficiency after each lesion. Then, elastic net regression was applied to determine how these changes explained variance in CU traits. Follow-up analyses characterized modeled node hubs, examined moderation, determined impact of targeting, and decoded the brain mask by comparing regions to meta-analytic maps. Elastic net regression revealed that computational lesioning of 23 nodes, network modularity, and Tanner stage explained variance in CU traits. Hub assignment of selected hubs differed at higher CU traits. No evidence for moderation between simulated lesioning and CU traits was found. Targeting global hubs increased efficiency and targeting local hubs had no effect at higher CU traits. Identified brain mask meta-analytically associated with more emotion and cognitive terms. Although reliable patterns were found across participants, adolescent brains were heterogeneous even for those with a similar CU traits score. Adolescent brain response to simulated lesioning revealed a pattern of connectome resiliency and vulnerability that explains variance in CU traits, which can aid prediction of youth at greater risk for higher CU traits.

neuroscience↗

bioRxiv2020

Distinct brain mechanisms linked to evidence accumulation and crime-type bias in juror decisions

Efforts to explain complex human decisions have focused on competing theories emphasizing utility and narrative mechanisms. These are difficult to distinguish using behavior alone. Both narrative and utility theories have been proposed to explain juror decisions, which are among the most consequential complex decisions made in a modern society. Here, we asked jury-eligible male and female subjects to rate the strength of a series of criminal cases while recording the resulting patterns of brain activation. We compared patterns of brain activation associated with evidence accumulation to patterns of brain activation derived from a large neuroimaging database to look for signatures of the cognitive processes associated with different models of juror decision making. Evidence accumulation correlated with multiple narrative processes, including reading and recall. Of the cognitive processes traditionally viewed as components of utility, activation patterns associated with uncertainty, but not value, were more active with stronger evidence. Independent of utility and narrative, activations linked to reasoning and relational logic also correlated with increasing evidence. Hierarchical modeling of cognitive processes associated with evidence accumulation supported a more prominent role for narrative in weighing evidence in complex decisions. However, utility processes were also associated with evidence accumulation. These complementary findings support an emerging view that integrates utility and narrative processes in complex decisions. Significance StatementThe last decade has seen a sharply increased interest in narrative as a central cognitive process in human decision making and as an important factor in the evolution of human societies. However, the roles of narrative versus utility models of decision making remain hotly debated. While available models frequently produce similar behavioral predictions, they rely on different cognitive processes and so their roles can be separated using the right neural tests. Here, we use brain imaging during mock juror decisions to show that cognitive processes associated with narrative, and to a lesser extent utility, were engaged while subjects evaluated evidence. These results are consistent with interactions between narrative and utility processes during complex decision making.

neuroscience↗

bioRxiv2019

Identifying Brain Network Topology Changes in Task Processes and Psychiatric Disorders

ABSTRACTA central goal in neuroscience is to understand how dynamic networks of neural activity produce effective representations of the world. Advances in the theory of graph measures raise the possibility of elucidating network topologies central to the construction of these representations. We leverage a result from the description of lollipop graphs to identify an iconic network topology in functional magnetic resonance imaging data and characterize changes to those networks during task performance and in populations diagnosed with psychiatric disorders. During task performance, we find that task-relevant subnetworks change topology, becoming more integrated by increasing connectivity throughout cortex. Analysis of resting-state connectivity in clinical populations shows a similar pattern of subnetwork topology changes; resting-scans becoming less default-like with more integrated sensory paths. The study of brain network topologies and their relationship to cognitive models of information processing raises new opportunities for understanding brain function and its disorders. AUTHOR SUMMARYOur mental lives are made up of a series of predictions about the world calculated by our brains. The calculations that produce these predictions are a result of how areas in our brain interact. Measures based on graph representations can make it clear what information can be combined and therefore help us better understand the computations the brain is performing. We make use of cutting-edge techniques that overcome a number of previous limitations to identify specific shapes in the functional brain network. These shapes are similar to hierarchical processing streams which play a fundamental role in cognitive neuroscience. The importance of these structures and the technique is highlighted by how they change under different task constraints and in individuals diagnosed with psychiatric disorders.

neuroscience↗

bioRxiv2017

Reason’s Enemy Is Not Emotion: Engagement of Cognitive Control Networks Explains Biases in Gain/Loss Framing

In the classic gain/loss framing effect, describing a gamble as a potential gain or loss biases people to make risk-averse or risk-seeking decisions, respectively. The canonical explanation for this effect is that frames differentially modulate emotional processes - which in turn leads to irrational choice behavior. Here, we evaluate the source of framing biases by integrating functional magnetic resonance imaging (fMRI) data from 143 human participants performing a gain/loss framing task with meta-analytic data from over 8000 neuroimaging studies. We found that activation during choices consistent with the framing effect were most correlated with activation associated with the resting or default brain, while activation during choices inconsistent with the framing effect most correlated with the task-engaged brain. Our findings argue against the common interpretation of gain/loss framing as a competition between emotion and control. Instead, our study indicates that this effect results from differential cognitive engagement across decision frames.\n\nSignificance StatementThe biases frequently exhibited by human decision-makers have often been attributed to the presence of emotion. Using a large fMRI sample and analysis of whole-brain networks defined with the meta-analytic tool Neurosynth, we find that neural activity during frame-biased decisions are more significantly associated with default behaviors (and the absence of executive control) than with emotion. These findings point to a role for neuroscience in shaping longstanding psychological theories in decision science.

neuroscience↗