Antiviral Activity of Catechin against Dengue Virus Infection.

Dengue virus (DENV) is the cause of dengue fever, infecting 390 million people worldwide per year. It is transmitted to humans through the bites of mosquitoes and could potentially develop severe symptoms. In spite of the rising social and economic impact inflicted by the disease on the global population, a conspicuous lack of efficacious therapeutics against DENV still persists. In this study, catechin, a natural polyphenol compound, was evaluated as a DENV infection inhibitor in vitro. Through time-course studies, catechin was shown to inhibit a post-entry stage of the DENV replication cycle. Further investigation revealed its role in affecting viral protein translation. Catechin inhibited the replication of all four DENV serotypes and chikungunya virus (CHIKV). Together, these results demonstrate the ability of catechin to inhibit DENV replication, hinting at its potential to be used as a starting scaffold for further development of antivirals against DENV infection.

A Neurocomputational Model for Intrinsic Reward.

Standard economic indicators provide an incomplete picture of what we value both as individuals and as a society. Furthermore, canonical macroeconomic measures, such as GDP, do not account for non-market activities (e.g., cooking, childcare) that nevertheless impact well-being. Here, we introduce a computational tool that measures the affective value of experiences (e.g., playing a musical instrument without errors). We go on to validate this tool with neural data, using fMRI to measure neural activity in male and female human subjects performing a reinforcement learning task that incorporated periodic ratings of subjective affective state. Learning performance determined level of payment (i.e., extrinsic reward). Crucially, the task also incorporated a skilled performance component (i.e., intrinsic reward) which did not influence payment. Both extrinsic and intrinsic rewards influenced affective dynamics, and their relative influence could be captured in our computational model. Individuals for whom intrinsic rewards had a greater influence on affective state than extrinsic rewards had greater ventromedial prefrontal cortex (vmPFC) activity for intrinsic than extrinsic rewards. Thus, we show that computational modeling of affective dynamics can index the subjective value of intrinsic relative to extrinsic rewards, a "computational hedonometer" that reflects both behavior and neural activity that quantifies the affective value of experience.SIGNIFICANCE STATEMENT Traditional economic indicators are increasingly recognized to provide an incomplete picture of what we value as a society. Standard economic approaches struggle to accurately assign values to non-market activities that nevertheless may be intrinsically rewarding, prompting a need for new tools to measure what really matters to individuals. Using a combination of neuroimaging and computational modeling, we show that despite their lack of instrumental value, intrinsic rewards influence subjective affective state and ventromedial prefrontal cortex (vmPFC) activity. The relative degree to which extrinsic and intrinsic rewards influence affective state is predictive of their relative impacts on neural activity, confirming the utility of our approach for measuring the affective value of experiences and other non-market activities in individuals.

Endogenous fluctuations in the dopaminergic midbrain drive behavioral choice variability.

Human behavior is surprisingly variable, even when facing the same problem under identical circumstances. A prominent example is risky decision making. Economic theories struggle to explain why humans are so inconsistent. Resting-state studies suggest that ongoing endogenous fluctuations in brain activity can influence low-level perceptual and motor processes, but it remains unknown whether endogenous fluctuations also influence high-level cognitive processes including decision making. Here, using real-time functional magnetic resonance imaging, we tested whether risky decision making is influenced by endogenous fluctuations in blood oxygenation level-dependent (BOLD) activity in the dopaminergic midbrain, encompassing ventral tegmental area and substantia nigra. We show that low prestimulus brain activity leads to increased risky choice in humans. Using computational modeling, we show that increased risk taking is explained by enhanced phasic responses to offers in a decision network. Our findings demonstrate that endogenous brain activity provides a physiological basis for variability in complex human behavior.

A Decision Analysis of Observation vs Immediate Reintervention for Asymptomatic Residual Fragments Less than 4 mm Following Ureteroscopic Lithotripsy.

INTRODUCTION: We performed a decision analysis model of the cost-effectiveness of observation vs intervention for asymptomatic residual fragments less than 4 mm in diameter following ureteroscopic holmium laser lithotripsy. METHODS: Outcomes data from a retrospective analysis evaluating the natural history, complications and reintervention rates of asymptomatic residual stone fragments performed by the EDGE (Endourology Disease Group for Excellence) Research Consortium were used. A decision analysis model was constructed to compare the cost-effectiveness of initial observation of residual fragments to immediate intervention. Cost of observation included emergency room visits, hospitalizations and reinterventions. The cost analysis model extended to 3 years to account for delayed reintervention rates for fragments less than 4 mm. Costs of emergency department visits, readmissions and reinterventions were calculated based on published figures from the literature. RESULTS: Decision analysis modeling demonstrated that when comparing initial observation to immediate reintervention, the cost was $2,183 vs $4,424. The difference in cost was largely driven by the fact that over 3 years, approximately 55% of all patients remained asymptomatic and did not incur additional costs. This represents an approximate annual per patient savings of $747, and $2,241 over 3 years when observation is selected over immediate reintervention. CONCLUSIONS: Our decision analysis model demonstrates superior cost-effectiveness for observation over immediate reintervention for asymptomatic residual stones less than 4 mm following ureteroscopic lithotripsy. Based on these findings careful stratification and selection of patients may enable surgeons to improve cost-effectiveness of managing small, asymptomatic residual fragments following ureteroscopic lithotripsy.

Learning Contextual Reward Expectations for Value Adaptation.

Substantial evidence indicates that subjective value is adapted to the statistics of reward expected within a given temporal context. However, how these contextual expectations are learned is poorly understood. To examine such learning, we exploited a recent observation that participants performing a gambling task adjust their preferences as a function of context. We show that, in the absence of contextual cues providing reward information, an average reward expectation was learned from recent past experience. Learning dependent on contextual cues emerged when two contexts alternated at a fast rate, whereas both cue-independent and cue-dependent forms of learning were apparent when two contexts alternated at a slower rate. Motivated by these behavioral findings, we reanalyzed a previous fMRI data set to probe the neural substrates of learning contextual reward expectations. We observed a form of reward prediction error related to average reward such that, at option presentation, activity in ventral tegmental area/substantia nigra and ventral striatum correlated positively and negatively, respectively, with the actual and predicted value of options. Moreover, an inverse correlation between activity in ventral tegmental area/substantia nigra (but not striatum) and predicted option value was greater in participants showing enhanced choice adaptation to context. The findings help understanding the mechanisms underlying learning of contextual reward expectation.

Neuropilin 2 Signaling Is Involved in Cell Positioning of Adult-born Neurons through Glycogen Synthase Kinase-3ß (GSK3ß).

Proper positioning of neurons is fundamental for brain functions. However, little is known on how adult-born neurons generated in the hilar side of hippocampal dentate gyrus migrate into the granular cell layer. Because class 3 Semaphorins (Sema3) are involved in dendritic growth of these newborn neurons, we examined whether they are essential for cell positioning. We disrupted Sema3 signaling by silencing neuropilin 1 (NRP1) or 2 (NRP2), the main receptors for Sema3A and Sema3F, in neural progenitors of adult mouse dentate gyrus. Silencing of NRP2, but not NRP1, affected cell positioning of adult newborn neurons. Glycogen synthase kinase-3ß (GSK3ß) knockdown phenocopied this NRP2 silencing-mediated cell positioning defect, but did not affect dendritic growth. Furthermore, GSK3ß is activated upon stimulation with Sema3F, and GSK3ß overexpression rescued the cell positioning phenotypes seen in NRP2-deficient neurons. These results point to a new role for NRP2 in the positioning of neurons during adult hippocampal neurogenesis, acting via the GSK3ß signaling pathway.

Multiple value signals in dopaminergic midbrain and their role in avoidance contexts.

The role of dopaminergic brain regions in avoidance behaviour is unclear. Active avoidance requires motivation, and the latter is linked to increased activity in dopaminergic regions. However, avoidance is also often tethered to the prospect of punishment, a state typically characterized by below baseline levels of dopaminergic function. Avoidance has been considered from the perspective of two-factor theories where the prospect of safety is considered to act as a surrogate for reward, leading to dopamine release and enhanced motivational drive. Using fMRI we investigated predictions from two-factor theory by separating the neural representation of a conventional net expected value, which is negative in the case of avoidance, from an adjusted expected value which factors in a possibility of punishment and is larger for both big rewards and big (predictably avoidable) punishments. We show that neural responses in ventral striatum and ventral tegmental area/substantial nigra (VTA/SN) covaried with net expected value. Activity in VTA/SN also covaried with an adjusted expected value, as did activity in anterior insula. Consistent with two-factor theory models, the findings indicate that VTA/SN and insula process an adjusted expected value during avoidance behaviour.

Dopamine Increases a Value-Independent Gambling Propensity.

Although the impact of dopamine on reward learning is well documented, its influence on other aspects of behavior remains the subject of much ongoing work. Dopaminergic drugs are known to increase risk-taking behavior, but the underlying mechanisms for this effect are not clear. We probed dopamine's role by examining the effect of its precursor L-DOPA on the choices of healthy human participants in an experimental paradigm that allowed particular components of risk to be distinguished. We show that choice behavior depended on a baseline (ie, value-independent) gambling propensity, a gambling preference scaling with the amount/variance, and a value normalization factor. Boosting dopamine levels specifically increased just the value-independent baseline gambling propensity, leaving the other components unaffected. Our results indicate that the influence of dopamine on choice behavior involves a specific modulation of the attractiveness of risky options-a finding with implications for understanding a range of reward-related psychopathologies including addiction.

The Dopaminergic Midbrain Mediates an Effect of Average Reward on Pavlovian Vigor.

Dopamine plays a key role in motivation. Phasic dopamine response reflects a reinforcement prediction error (RPE), whereas tonic dopamine activity is postulated to represent an average reward that mediates motivational vigor. However, it has been hard to find evidence concerning the neural encoding of average reward that is uncorrupted by influences of RPEs. We circumvented this difficulty in a novel visual search task where we measured participants' button pressing vigor in a context where information (underlying an RPE) about future average reward was provided well before the average reward itself. Despite no instrumental consequence, participants' pressing force increased for greater current average reward, consistent with a form of Pavlovian effect on motivational vigor. We recorded participants' brain activity during task performance with fMRI. Greater average reward was associated with enhanced activity in dopaminergic midbrain to a degree that correlated with the relationship between average reward and pressing vigor. Interestingly, an opposite pattern was observed in subgenual cingulate cortex, a region implicated in negative mood and motivational inhibition. These findings highlight a crucial role for dopaminergic midbrain in representing aspects of average reward and motivational vigor.

Lentiviral silencing of GSK-3ß in adult dentate gyrus impairs contextual fear memory and synaptic plasticity.

Attempts have been made to use glycogen synthase kinase-3 beta (GSK3ß) inhibitors for prophylactic treatment of neurocognitive conditions. However the use of lithium, a non-specific inhibitor of GSK3ß results in mild cognitive impairment in humans. The effects of global GSK3ß inhibition or knockout on learning and memory in healthy adult mice are also inconclusive. Our study aims to better understand the role of GSK3ß in learning and memory through a more regionally, targeted approach, specifically performing lentiviral-mediated knockdown of GSK3ß within the dentate gyrus (DG). DG-GSK3ß-silenced mice showed impaired contextual fear memory retrieval. However, cue fear memory, spatial memory, locomotor activity and anxiety levels were similar to control. These GSK3ß-silenced mice also showed increased induction and maintenance of DG long-term potentiation (DG-LTP) compared to control animals. Thus, this region-specific, targeted knockdown of GSK3ß in the DG provides better understanding on the role of GSK3ß in learning and memory.