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Bradley Doll

Sobhana Babu Boga, Abdul-Basit Alhassan, Alan B Cooper, Ronald Doll, Neng-Yang Shih, Gerald Shipps, Yongqi Deng, Hugh Zhu, Yang Nan, Robert Sun, Liang Zhu, Jagdish Desai, Mehul Patel, Kiran Muppalla, Xiaolei Gao, James Wang, Xin Yao, Joseph Kelly, Subrahmanyam Gudipati, Sunil Paliwal, Hon-Chung Tsui, Tong Wang, Bradley Sherborne, Li Xiao, Alan Hruza, Alexei Buevich, Li-Kang Zhang, David Hesk, Ahmed A Samatar, Donna Carr, Brian Long, Stuart Black, Priya Dayananth, William Windsor, Paul Kirschmeier, Robert Bishop
Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100 nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10 mpk = 0 μM h; F% = 0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10 mpk = 26 μM h; F% = 70)...
April 26, 2018: Bioorganic & Medicinal Chemistry Letters
Katherine Duncan, Bradley B Doll, Nathaniel D Daw, Daphna Shohamy
People often perceive configurations rather than the elements they comprise, a bias that may emerge because configurations often predict outcomes. But how does the brain learn to associate configurations with outcomes and how does this learning differ from learning about individual elements? We combined behavior, reinforcement learning models, and functional imaging to understand how people learn to associate configurations of cues with outcomes. We found that configural learning depended on the relative predictive strength of elements versus configurations and was related to both the strength of BOLD activity and patterns of BOLD activity in the hippocampus...
May 2, 2018: Neuron
Daniela C Gonçalves-Bradley, Steve Iliffe, Helen A Doll, Joanna Broad, John Gladman, Peter Langhorne, Suzanne H Richards, Sasha Shepperd
BACKGROUND: Early discharge hospital at home is a service that provides active treatment by healthcare professionals in the patient's home for a condition that otherwise would require acute hospital inpatient care. This is an update of a Cochrane review. OBJECTIVES: To determine the effectiveness and cost of managing patients with early discharge hospital at home compared with inpatient hospital care. SEARCH METHODS: We searched the following databases to 9 January 2017: the Cochrane Effective Practice and Organisation of Care Group (EPOC) register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, and EconLit...
June 26, 2017: Cochrane Database of Systematic Reviews
Sasha Shepperd, Steve Iliffe, Helen A Doll, Mike J Clarke, Lalit Kalra, Andrew D Wilson, Daniela C Gonçalves-Bradley
BACKGROUND: Admission avoidance hospital at home provides active treatment by healthcare professionals in the patient's home for a condition that otherwise would require acute hospital inpatient care, and always for a limited time period. This is the third update of the original review. OBJECTIVES: To determine the effectiveness and cost of managing patients with admission avoidance hospital at home compared with inpatient hospital care. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, two other databases, and two trials registers on 2 March 2016...
September 1, 2016: Cochrane Database of Systematic Reviews
Lauren Y Atlas, Bradley B Doll, Jian Li, Nathaniel D Daw, Elizabeth A Phelps
Socially-conveyed rules and instructions strongly shape expectations and emotions. Yet most neuroscientific studies of learning consider reinforcement history alone, irrespective of knowledge acquired through other means. We examined fear conditioning and reversal in humans to test whether instructed knowledge modulates the neural mechanisms of feedback-driven learning. One group was informed about contingencies and reversals. A second group learned only from reinforcement. We combined quantitative models with functional magnetic resonance imaging and found that instructions induced dissociations in the neural systems of aversive learning...
May 12, 2016: ELife
Bradley B Doll, Nathaniel D Daw
Evidence increasingly suggests that dopaminergic neurons play a more sophisticated role in predicting rewards than previously thought.
April 21, 2016: ELife
Karin Foerde, Bernd Figner, Bradley B Doll, Isabel C Woyke, Erin Kendall Braun, Elke U Weber, Daphna Shohamy
Choosing between smaller prompt rewards and larger later rewards is a common choice problem, and studies widely agree that frontostriatal circuits heavily innervated by dopamine are centrally involved. Understanding how dopamine modulates intertemporal choice has important implications for neurobiological models and for understanding the mechanisms underlying maladaptive decision-making. However, the specific role of dopamine in intertemporal decisions is not well understood. Dopamine may play a role in multiple aspects of intertemporal choices--the valuation of choice outcomes and sensitivity to reward delays...
May 2016: Journal of Cognitive Neuroscience
Bradley B Doll, Kevin G Bath, Nathaniel D Daw, Michael J Frank
UNLABELLED: Considerable evidence suggests that multiple learning systems can drive behavior. Choice can proceed reflexively from previous actions and their associated outcomes, as captured by "model-free" learning algorithms, or flexibly from prospective consideration of outcomes that might occur, as captured by "model-based" learning algorithms. However, differential contributions of dopamine to these systems are poorly understood. Dopamine is widely thought to support model-free learning by modulating plasticity in striatum...
January 27, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Satoru Sagae, Bradley J Monk, Eric Pujade-Lauraine, David K Gaffney, Kailash Narayan, Sang Young Ryu, Mary McCormack, Marie Plante, Antonio Casado, Alexander Reuss, Adriana Chávez-Blanco, Henry Kitchener, Byung-Ho Nam, Anuja Jhingran, Sarah Temkin, Linda Mileshkin, Els Berns, Suzy Scholl, Corinne Doll, Nadeem R Abu-Rustum, Fabrice Lecuru, William Small
OBJECTIVE: Cervical cancer is responsible for more than a quarter of a million deaths globally each year, mostly in developing countries, making therapeutic advances in all health care settings a top priority. The Gynecologic Cancer InterGroup (GCIG) is a worldwide collaboration of leading national research groups that develops and promotes multinational trials in gynecologic cancer. In recognition of the pressing need for action, the GCIG convened an international meeting with expert representation from the GCIG groups and selected large sites in low- and middle-income countries...
January 2016: International Journal of Gynecological Cancer
Leor M Hackel, Bradley B Doll, David M Amodio
Humans learn about people and objects through positive and negative experiences, yet they can also look beyond the immediate reward of an interaction to encode trait-level attributes. We found that perceivers encoded both reward and trait-level information through feedback in an instrumental learning task, but relied more heavily on trait representations in cross-context decisions. Both learning types implicated ventral striatum, but trait learning also recruited a network associated with social impression formation...
September 2015: Nature Neuroscience
Bradley B Doll, Katherine D Duncan, Dylan A Simon, Daphna Shohamy, Nathaniel D Daw
Decisions may arise via 'model-free' repetition of previously reinforced actions or by 'model-based' evaluation, which is widely thought to follow from prospective anticipation of action consequences using a learned map or model. While choices and neural correlates of decision variables sometimes reflect knowledge of their consequences, it remains unclear whether this actually arises from prospective evaluation. Using functional magnetic resonance imaging and a sequential reward-learning task in which paths contained decodable object categories, we found that humans' model-based choices were associated with neural signatures of future paths observed at decision time, suggesting a prospective mechanism for choice...
May 2015: Nature Neuroscience
Johannes H Decker, Frederico S Lourenco, Bradley B Doll, Catherine A Hartley
Throughout our lives, we face the important task of distinguishing rewarding actions from those that are best avoided. Importantly, there are multiple means by which we acquire this information. Through trial and error, we use experiential feedback to evaluate our actions. We also learn which actions are advantageous through explicit instruction from others. Here, we examined whether the influence of these two forms of learning on choice changes across development by placing instruction and experience in competition in a probabilistic-learning task...
June 2015: Cognitive, Affective & Behavioral Neuroscience
Darrell A Worthy, A Ross Otto, Bradley B Doll, Kaileigh A Byrne, W Todd Maddox
Recent work suggests that older adults' decision-making behavior is highly affected by recent events. In the present work younger and older adults performed a two-choice task where one option provided a larger average reward, but there was a large amount of noise around the mean reward for each option which led to sharp improvements or declines in rewards over trials. Older adults showed greater responsiveness to recent events than younger adults as evidenced by fits of Reinforcement Learning (RL) models. Older adults were particularly sensitive to recent negative events, which was evidenced by a strong tendency for older adults to switch to the other option following steep declines in reward...
January 2015: Decisions
Elizabeth Doll, Jacob Wilkes, Lawrence J Cook, E Kent Korgenski, Roger G Faix, Bradley A Yoder, Rajendu Srivastava, Catherine M T Sherwin, Michael G Spigarelli, Erin A S Clark, Joshua L Bonkowsky
OBJECTIVE: Chronic neurological deficits are a significant complication of preterm birth. Magnesium supplementation has been suggested to have neuroprotective function in the developing brain. Our objective was to determine whether higher neonatal serum magnesium levels were associated with better long-term neurodevelopmental outcomes in very-low birth weight infants. STUDY DESIGN: A retrospective cohort of 75 preterm infants (<1500 g, gestational age <27 weeks) had follow-up for the outcomes of abnormal motor exam and for epilepsy...
2014: Frontiers in Pediatrics
Bradley B Doll, Daphna Shohamy, Nathaniel D Daw
It has recently become widely appreciated that value-based decision making is supported by multiple computational strategies. In particular, animal and human behavior in learning tasks appears to include habitual responses described by prominent model-free reinforcement learning (RL) theories, but also more deliberative or goal-directed actions that can be characterized by a different class of theories, model-based RL. The latter theories evaluate actions by using a representation of the contingencies of the task (as with a learned map of a spatial maze), called an "internal model...
January 2015: Neurobiology of Learning and Memory
Bradley B Doll, James A Waltz, Jeffrey Cockburn, Jaime K Brown, Michael J Frank, James M Gold
Patients with schizophrenia (SZ) show cognitive impairments on a wide range of tasks, with clear deficiencies in tasks reliant on prefrontal cortex function and less consistently observed impairments in tasks recruiting the striatum. This study leverages tasks hypothesized to differentially recruit these neural structures to assess relative deficiencies of each. Forty-eight patients and 38 controls completed two reinforcement learning tasks hypothesized to interrogate prefrontal and striatal functions and their interaction...
June 2014: Cognitive, Affective & Behavioral Neuroscience
Bradley B Doll, Dylan A Simon, Nathaniel D Daw
The reward prediction error (RPE) theory of dopamine (DA) function has enjoyed great success in the neuroscience of learning and decision-making. This theory is derived from model-free reinforcement learning (RL), in which choices are made simply on the basis of previously realized rewards. Recently, attention has turned to correlates of more flexible, albeit computationally complex, model-based methods in the brain. These methods are distinguished from model-free learning by their evaluation of candidate actions using expected future outcomes according to a world model...
December 2012: Current Opinion in Neurobiology
David Badre, Bradley B Doll, Nicole M Long, Michael J Frank
How do individuals decide to act based on a rewarding status quo versus an unexplored choice that might yield a better outcome? Recent evidence suggests that individuals may strategically explore as a function of the relative uncertainty about the expected value of options. However, the neural mechanisms supporting uncertainty-driven exploration remain underspecified. The present fMRI study scanned a reinforcement learning task in which participants stop a rotating clock hand in order to win points. Reward schedules were such that expected value could increase, decrease, or remain constant with respect to time...
February 9, 2012: Neuron
Bradley B Doll, Kent E Hutchison, Michael J Frank
The striatum is critical for the incremental learning of values associated with behavioral actions. The prefrontal cortex (PFC) represents abstract rules and explicit contingencies to support rapid behavioral adaptation in the absence of cumulative experience. Here we test two alternative models of the interaction between these systems, and individual differences thereof, when human subjects are instructed with prior information about reward contingencies that may or may not be accurate. Behaviorally, subjects are overly influenced by prior instructions, at the expense of learning true reinforcement statistics...
April 20, 2011: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Ami Tsuchida, Bradley B Doll, Lesley K Fellows
Damage to the orbitofrontal cortex (OFC) has been linked to impaired reinforcement processing and maladaptive behavior in changing environments across species. Flexible stimulus-outcome learning, canonically captured by reversal learning tasks, has been shown to rely critically on OFC in rats, monkeys, and humans. However, the precise role of OFC in this learning remains unclear. Furthermore, whether other frontal regions also contribute has not been definitively established, particularly in humans. In the present study, a reversal learning task with probabilistic feedback was administered to 39 patients with focal lesions affecting various sectors of the frontal lobes and to 51 healthy, demographically matched control subjects...
December 15, 2010: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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