Policy Adjustment in a Dynamic Economic Game

Making sequential decisions to harvest rewards is a notoriously difficult problem. One difficulty is that the real world is not stationary and the reward expected from a contemplated action may depend in complex ways on the history of an animal's choices. Previous functional neuroimaging work combined with principled models has detected brain responses that correlate with computations thought to guide simple learning and action choice. Those works generally employed instrumental conditioning tasks with fixed action-reward contingencies. For real-world learning problems, the history of reward-harvesting choices can change the likelihood of rewards collected by the same choices in the near-term future. We used functional MRI to probe brain and behavioral responses in a continuous decision-making task where reward contingency is a function of both a subject's immediate choice and his choice history. In these more complex tasks, we demonstrated that a simple actor-critic model can account for both the subjects' behavioral and brain responses, and identified a reward prediction error signal in ventral striatal structures active during these non-stationary decision tasks. However, a sudden introduction of new reward structures engages more complex control circuitry in the prefrontal cortex (inferior frontal gyrus and anterior insula) and is not captured by a simple actor-critic model. Taken together, these results extend our knowledge of reward-learning signals into more complex, history-dependent choice tasks. They also highlight the important interplay between striatum and prefrontal cortex as decision-makers respond to the strategic demands imposed by non-stationary reward environments more reminiscent of real-world tasks

Improving Efficiency and Quality of the Children’s ASD Diagnostic Pathway: Lessons Learned from Practice

The ‘autism diagnosis crisis’ and long waiting times for assessment are as yet unresolved, leading to undue stress and limiting\ud access to effective support. There is therefore a significant need for evidence to support practitioners in the development of\ud efficient services, delivering acceptable waiting times and effectively meeting guideline standards. This study reports statistically\ud significant reductions in waiting times for autism diagnostic assessment following a children’s health service improvement\ud programme. The average wait between referral and first appointment reduced from 14.2 to 10.4 weeks (t(21) = 4.3,\ud p < 0.05) and between referral and diagnosis shared, reduced from 270 to 122.5 days, (t(20) = 5.5, p < 0.05). The proportion\ud of girls identified increased from 5.6 to 2.7:1. Methods reported include: local improvement action planning; evidence based\ud pathways; systematic clinical data gathering and a training plan. This is a highly significant finding for many health services\ud wrestling with the challenges of demand and capacity for autism diagnosis and assessment

Anti-HIV-1 activity of anionic polymers: a comparative study of candidate microbicides

BACKGROUND: Cellulose acetate phthalate (CAP) in soluble form blocks coreceptor binding sites on the virus envelope glycoprotein gp120 and elicits gp41 six-helix bundle formation, processes involved in virus inactivation. CAP is not soluble at pH < 5.5, normal for microbicide target sites. Therefore, the interaction between insoluble micronized CAP and HIV-1 was studied. Carbomer 974P/BufferGel; carrageenan; cellulose sulfate; dextran/dextrin sulfate, poly(napthalene sulfonate) and poly(styrene-4-sulfonate) are also being considered as anti-HIV-1 microbicides, and their antiviral properties were compared with those of CAP. METHODS: Enzyme linked immunosorbent assays (ELISA) were used to (1) study HIV-1 IIIB and BaL binding to micronized CAP; (2) detect virus disintegration; and (3) measure gp41 six-helix bundle formation. Cells containing integrated HIV-1 LTR linked to the β-gal gene and expressing CD4 and coreceptors CXCR4 or CCR5 were used to measure virus infectivity. RESULTS: 1) HIV-1 IIIB and BaL, respectively, effectively bound to micronized CAP. 2) The interaction between HIV-1 and micronized CAP led to: (a) gp41 six-helix bundle formation; (b) virus disintegration and shedding of envelope glycoproteins; and (c) rapid loss of infectivity. Polymers other than CAP, except Carbomer 974P, elicited gp41 six-helix bundle formation in HIV-1 IIIB but only poly(napthalene sulfonate), in addition to CAP, had this effect on HIV-1 BaL. These polymers differed with respect to their virucidal activities, the differences being more pronounced for HIV-1 BaL. CONCLUSIONS: Micronized CAP is the only candidate topical microbicide with the capacity to remove rapidly by adsorption from physiological fluids HIV-1 of both the X4 and R5 biotypes and is likely to prevent virus contact with target cells. The interaction between micronized CAP and HIV-1 leads to rapid virus inactivation. Among other anionic polymers, cellulose sulfate, BufferGel and aryl sulfonates appear most effective in this respect

Effects of Transcriptional Pausing on Gene Expression Dynamics

Stochasticity in gene expression affects many cellular processes and is a source of phenotypic diversity between genetically identical individuals. Events in elongation, particularly RNA polymerase pausing, are a source of this noise. Since the rate and duration of pausing are sequence-dependent, this regulatory mechanism of transcriptional dynamics is evolvable. The dependency of pause propensity on regulatory molecules makes pausing a response mechanism to external stress. Using a delayed stochastic model of bacterial transcription at the single nucleotide level that includes the promoter open complex formation, pausing, arrest, misincorporation and editing, pyrophosphorolysis, and premature termination, we investigate how RNA polymerase pausing affects a gene's transcriptional dynamics and gene networks. We show that pauses' duration and rate of occurrence affect the bursting in RNA production, transcriptional and translational noise, and the transient to reach mean RNA and protein levels. In a genetic repressilator, increasing the pausing rate and the duration of pausing events increases the period length but does not affect the robustness of the periodicity. We conclude that RNA polymerase pausing might be an important evolvable feature of genetic networks

Behaviourally Mediated Phenotypic Selection in a Disturbed Coral Reef Environment

Natural and anthropogenic disturbances are leading to changes in the nature of many habitats globally, and the magnitude and frequency of these perturbations are predicted to increase under climate change. Globally coral reefs are one of the most vulnerable ecosystems to climate change. Fishes often show relatively rapid declines in abundance when corals become stressed and die, but the processes responsible are largely unknown. This study explored the mechanism by which coral bleaching may influence the levels and selective nature of mortality on a juvenile damselfish, Pomacentrus amboinensis, which associates with hard coral. Recently settled fish had a low propensity to migrate small distances (40 cm) between habitat patches, even when densities were elevated to their natural maximum. Intraspecific interactions and space use differ among three habitats: live hard coral, bleached coral and dead algal-covered coral. Large fish pushed smaller fish further from the shelter of bleached and dead coral thereby exposing smaller fish to higher mortality than experienced on healthy coral. Small recruits suffered higher mortality than large recruits on bleached and dead coral. Mortality was not size selective on live coral. Survival was 3 times as high on live coral as on either bleached or dead coral. Subtle behavioural interactions between fish and their habitats influence the fundamental link between life history stages, the distribution of phenotypic traits in the local population and potentially the evolution of life history strategies

Speed/Accuracy Trade-Off between the Habitual and the Goal-Directed Processes

Instrumental responses are hypothesized to be of two kinds: habitual and goal-directed, mediated by the sensorimotor and the associative cortico-basal ganglia circuits, respectively. The existence of the two heterogeneous associative learning mechanisms can be hypothesized to arise from the comparative advantages that they have at different stages of learning. In this paper, we assume that the goal-directed system is behaviourally flexible, but slow in choice selection. The habitual system, in contrast, is fast in responding, but inflexible in adapting its behavioural strategy to new conditions. Based on these assumptions and using the computational theory of reinforcement learning, we propose a normative model for arbitration between the two processes that makes an approximately optimal balance between search-time and accuracy in decision making. Behaviourally, the model can explain experimental evidence on behavioural sensitivity to outcome at the early stages of learning, but insensitivity at the later stages. It also explains that when two choices with equal incentive values are available concurrently, the behaviour remains outcome-sensitive, even after extensive training. Moreover, the model can explain choice reaction time variations during the course of learning, as well as the experimental observation that as the number of choices increases, the reaction time also increases. Neurobiologically, by assuming that phasic and tonic activities of midbrain dopamine neurons carry the reward prediction error and the average reward signals used by the model, respectively, the model predicts that whereas phasic dopamine indirectly affects behaviour through reinforcing stimulus-response associations, tonic dopamine can directly affect behaviour through manipulating the competition between the habitual and the goal-directed systems and thus, affect reaction time

Setting the stage: host invasion by HIV.

For more than two decades, HIV has infected millions of people worldwide each year through mucosal transmission. Our knowledge of how HIV secures a foothold at both the molecular and cellular levels has been expanded by recent investigations that have applied new technologies and used improved techniques to isolate ex vivo human tissue and generate in vitro cellular models, as well as more relevant in vivo animal challenge systems. Here, we review the current concepts of the immediate events that follow viral exposure at genital mucosal sites where most documented transmissions occur. Furthermore, we discuss the gaps in our knowledge that are relevant to future studies, which will shape strategies for effective HIV prevention

Tm1: A Mutator/Foldback Transposable Element Family in Root-Knot Nematodes

Three closely related parthenogenetic species of root-knot nematodes, collectively termed the Meloidogyne incognita-group, are economically significant pathogens of diverse crop species. Remarkably, these asexual root-knot nematodes are capable of acquiring heritable changes in virulence even though they lack sexual reproduction and meiotic recombination. Characterization of a near isogenic pair of M. javanica strains differing in response to tomato with the nematode resistance gene Mi-1 showed that the virulent strain carried a deletion spanning a gene called Cg-1. Herein, we present evidence that the Cg-1 gene lies within a member of a novel transposable element family (Tm1; Transposon in Meloidogyne-1). This element family is defined by composite terminal inverted repeats of variable lengths similar to those of Foldback (FB) transposable elements and by 9 bp target site duplications. In M. incognita, Tm1 elements can be classified into three general groups: 1) histone-hairpin motif elements; 2) MITE-like elements; 3) elements encoding a putative transposase. The predicted transposase shows highest similarity to gene products encoded by aphids and mosquitoes and resembles those of the Phantom subclass of the Mutator transposon superfamily. Interestingly, the meiotic, sexually-reproducing root-knot nematode species M. hapla has Tm1 elements with similar inverted repeat termini, but lacks elements with histone hairpin motifs and contains no elements encoding an intact transposase. These Tm1 elements may have impacts on root-knot nematode genomes and contribute to genetic diversity of the asexual species

Season of Birth and Dopamine Receptor Gene Associations with Impulsivity, Sensation Seeking and Reproductive Behaviors

Season of birth (SOB) has been associated with many physiological and psychological traits including novelty seeking and sensation seeking. Similar traits have been associated with genetic polymorphisms in the dopamine system. SOB and dopamine receptor genetic polymorphisms may independently and interactively influence similar behaviors through their common effects on the dopaminergic system.Based on a sample of 195 subjects, we examined whether SOB was associated with impulsivity, sensation seeking and reproductive behaviors. Additionally we examined potential interactions of dopamine receptor genes with SOB for the same set of traits. Phenotypes were evaluated using the Sociosexual Orientation Inventory, the Barratt Impulsivity Scale, the Eysenck Impulsivity Questionnaire, the Sensation Seeking Scale, and the Delay Discounting Task. Subjects were also asked about their age at first sex as well as their desired age at the birth of their first child. The dopamine gene polymorphisms examined were Dopamine Receptor D2 (DRD2) TaqI A and D4 (DRD4) 48 bp VNTR. Primary analyses included factorial genderxSOB ANOVAs or binary logistic regression models for each dependent trait. Secondary analysis extended the factorial models by also including DRD2 and DRD4 genotypes as independent variables. Winter-born males were more sensation seeking than non-winter born males. In factorial models including both genotype and season of birth as variables, two previously unobserved effects were discovered: (1) a SOBxDRD4 interaction effect on venturesomeness and (2) a DRD2xDRD4 interaction effect on sensation seeking.These results are consistent with past findings that SOB is related to sensation seeking. Additionally, these results provide tentative support for the hypothesis that SOB modifies the behavioral expression of dopaminergic genetic polymorphism. These findings suggest that SOB should be included in future studies of risky behaviors and behavioral genetic studies of the dopamine system

Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases

Age-associated neurodegenerative disorders such as Alzheimer’s disease are a major public health challenge, due to the demographic increase in the proportion of older individuals in society. However, the relatively few currently approved drugs for these conditions provide only symptomatic relief. A major goal of neurodegeneration research is therefore to identify potential new therapeutic compounds that can slow or even reverse disease progression, either by impacting directly on the neurodegenerative process or by activating endogenous physiological neuroprotective mechanisms that decline with ageing. This requires model systems that can recapitulate key features of human neurodegenerative diseases that are also amenable to compound screening approaches. Mammalian models are very powerful, but are prohibitively expensive for high-throughput drug screens. Given the highly conserved neurological pathways between mammals and invertebrates, Caenorhabditis elegans has emerged as a powerful tool for neuroprotective compound screening. Here we describe how C. elegans has been used to model various human ageing-associated neurodegenerative diseases and provide an extensive list of compounds that have therapeutic activity in these worm models and so may have translational potential