Neural signatures of cognitive flexibility and reward sensitivity following nicotinic receptor stimulation in dependent smokers : a randomized trial

IMPORTANCE Withdrawal from nicotine is an important contributor to smoking relapse. Understanding how reward-based decision making is affected by abstinence and by pharmacotherapies such as nicotine replacement therapy and varenicline tartrate may aid cessation treatment. OBJECTIVE To independently assess the effects of nicotine dependence and stimulation of the nicotinic acetylcholine receptor on the ability to interpret valence information (reward sensitivity) and subsequently alter behavior as reward contingencies change (cognitive flexibility) in a probabilistic reversal learning task. DESIGN, SETTING, AND PARTICIPANTS Nicotine-dependent smokers and nonsmokers completed a probabilistic reversal learning task during acquisition of functional magnetic resonance imaging (fMRI) in a 2-drug, double-blind placebo-controlled crossover design conducted from January 21, 2009, to September 29, 2011. Smokers were abstinent from cigarette smoking for 12 hours for all sessions. In a fully Latin square fashion, participants in both groups underwent MRI twice while receiving varenicline and twice while receiving a placebo pill, wearing either a nicotine or a placebo patch. Imaging analysis was performed from June 15, 2015, to August 10, 2016. MAIN OUTCOME AND MEASURES A well-established computational model captured effects of smoking status and administration of nicotine and varenicline on probabilistic reversal learning choice behavior. Neural effects of smoking status, nicotine, and varenicline were tested for on MRI contrasts that captured reward sensitivity and cognitive flexibility. RESULTS The study included 24 nicotine-dependent smokers (12 women and 12 men; mean [SD] age, 35.8 [9.9] years) and 20 nonsmokers (10 women and 10 men; mean [SD] age, 30.4 [7.2] years). Computational modeling indicated that abstinent smokers were biased toward response shifting and that their decisions were less sensitive to the available evidence, suggesting increased impulsivity during withdrawal. These behavioral impairments were mitigated with nicotine and varenicline. Similarly, decreased mesocorticolimbic activity associated with cognitive flexibility in abstinent smokers was restored to the level of nonsmokers following stimulation of nicotinic acetylcholine receptors (familywise error-corrected P<.05). Conversely, neural signatures of decreased reward sensitivity in smokers (vs nonsmokers; familywise error-corrected P<.05) in the dorsal striatum and anterior cingulate cortex were not mitigated by nicotine or varenicline. CONCLUSIONS AND RELEVANCE There was a double dissociation between the effects of chronic nicotine dependence on neural representations of reward sensitivity and acute effects of stimulation of nicotinic acetylcholine receptors on behavioral and neural signatures of cognitive flexibility in smokers. These chronic and acute pharmacologic effects were observed in overlapping mesocorticolimbic regions, suggesting that available pharmacotherapies may alleviate deficits in the same circuitry for certain mental computations but not for others

Gallus GBrowse: a unified genomic database for the chicken

Gallus GBrowse (http://birdbase.net/cgi-bin/gbrowse/gallus/) provides online access to genomic and other information about the chicken, Gallus gallus. The information provided by this resource includes predicted genes and Gene Ontology (GO) terms, links to Gallus In Situ Hybridization Analysis (GEISHA), Unigene and Reactome, the genomic positions of chicken genetic markers, SNPs and microarray probes, and mappings from turkey, condor and zebra finch DNA and EST sequences to the chicken genome. We also provide a BLAT server (http://birdbase.net/cgi-bin/webBlat) for matching user-provided sequences to the chicken genome. These tools make the Gallus GBrowse server a valuable resource for researchers seeking genomic information regarding the chicken and other avian species

The receptor protein tyrosine phosphatase PTPRB negatively regulates FGF2-dependent branching morphogenesis

PTPRB is a transmembrane protein tyrosine phosphatase known to regulate blood vessel remodelling and angiogenesis. Here we demonstrate that PTPRB negatively regulates branching morphogenesis in the mammary epithelium. We show that Ptprb is highly expressed in adult mammary stem cells and also, although at lower levels, in estrogen receptor positive luminal cells. During mammary development Ptprb expression is down-regulated during puberty, a period of extensive of ductal outgrowth and branching. In vivo shRNA knockdown of Ptprb in the cleared mammary fat pad transplant assay resulted in smaller epithelial outgrowths with an increased branching density and also increased branching in an in vitro organoid assay. Organoid branching was dependent on stimulation by FGF2, and Ptprb knockdown in mammary epithelial cells resulted in a higher level of FGFR activation and ERK1/2 phosphorylation, both at baseline and following FGF2 stimulation. Therefore, PTPRB regulates branching morphogenesis in the mammary epithelium by modulating the response of the FGFR signalling pathway to FGF stimulation. Considering the importance of branching morphogenesis in multiple taxa, our findings have general importance outside mammary developmental biology

Testing for Evidence of Maternal Effects among Individuals and Populations of White Crappie

For an increasing number of species, maternal characteristics have been correlated with the characteristics of their eggs or larvae at the individual level. Documenting these maternal effects at the population level, however, is uncommon. For white crappies Pomoxis annularis, we evaluated whether individual maternal effects on eggs existed and then explored whether incorporating maternal effects explained additional variation in recruitment, a population-level response. Individual egg quality (measured as ovary energy density) increased with maternal length among individuals from seven Ohio reservoirs in 1999 and three in 2000. Among these same individuals, egg quality increased with maternal condition factor (measured as residual wet mass for a given length) in 1999 but not in 2000. In 2000 we estimated somatic energy density, an improved measure of condition; egg quality increased with somatic energy density, but somatic energy density was also strongly correlated with maternal length. Hence, we could not determine whether maternal length or condition was the primary factor influencing white crappie egg quality. Across seven populations, the relative population fecundity (i.e., stock size) of the 1999 year-class was unable to explain the variation in recruitment to age 2 (Ricker model r^2 = 0.04 and Beverton and Holt model r^2 = 0.02). Mean ovary energy density (i.e., egg quality), however, was unable to explain additional recruitment variability in either model. Hence, we documented evidence of maternal effects on individual ovaries but not on population-level recruitment. Nonetheless, we recommend that future studies seeking to understand white crappie recruitment continue to consider maternal effects as a potential factor, especially those studies that may have greater sample sizes at the population level and, in turn, a greater probability of documenting a population-level effect.This research was funded by Federal Aid in Sport Fish Restoration Project F-69-P, administered jointly by U.S. Fish and Wildlife Service and Ohio Department of Natural Resources, Division of Wildlife and the Department of Evolution, Ecology, and Organismal Biology at Ohio State University

Substructure in the Coma Cluster: Giants vs Dwarfs

The processes that form and shape galaxy clusters, such as infall, mergers and dynamical relaxation, tend to generate distinguishable differences between the distributions of a cluster's giant and dwarf galaxies. Thus the dynamics of dwarf galaxies in a cluster can provide valuable insights into its dynamical history. With this in mind, we look for differences between the spatial and velocity distributions of giant (b18) galaxies in the Coma cluster. Our redshift sample contains new measurements from the 2dF and WYFFOS spectrographs, making it more complete at faint magnitudes than any previously studied sample of Coma galaxies. It includes 745 cluster members - 452 giants and 293 dwarfs. We find that the line-of-sight velocity distribution of the giants is significantly non-Gaussian, but not that for the dwarfs. A battery of statistical tests of both the spatial and localised velocity distributions of the galaxies in our sample finds no strong evidence for differences between the giant and dwarf populations. These results rule out the cluster as a whole having moved significantly towards equipartition, and they are consistent with the cluster having formed via mergers between dynamically-relaxed subclusters.Comment: 23 pages, 6 figures, to appear in Ap

\u3cem\u3eShewanella oneidensis\u3c/em\u3e Cytochrome c Nitrite Reductase (ccNiR) Does Not Disproportionate Hydroxylamine to Ammonia and Nitrite, Despite a Strongly Favorable Driving Force

Cytochrome c nitrite reductase (ccNiR) from Shewanella oneidensis, which catalyzes the six-electron reduction of nitrite to ammonia in vivo, was shown to oxidize hydroxylamine in the presence of large quantities of this substrate, yielding nitrite as the sole free nitrogenous product. UV–visible stopped-flow and rapid-freeze-quench electron paramagnetic resonance data, along with product analysis, showed that the equilibrium between hydroxylamine and nitrite is fairly rapidly established in the presence of high initial concentrations of hydroxylamine, despite said equilibrium lying far to the left. By contrast, reduction of hydroxylamine to ammonia did not occur, even though disproportionation of hydroxylamine to yield both nitrite and ammonia is strongly thermodynamically favored. This suggests a kinetic barrier to the ccNiR-catalyzed reduction of hydroxylamine to ammonia. A mechanism for hydroxylamine reduction is proposed in which the hydroxide group is first protonated and released as water, leaving what is formally an NH2+ moiety bound at the heme active site. This species could be a metastable intermediate or a transition state but in either case would exist only if it were stabilized by the donation of electrons from the ccNiR heme pool into the empty nitrogen p orbital. In this scenario, ccNiR does not catalyze disproportionation because the electron-donating hydroxylamine does not poise the enzyme at a sufficiently low potential to stabilize the putative dehydrated hydroxylamine; presumably, a stronger reductant is required for this

Delusional beliefs and reason giving

Delusions are often regarded as irrational beliefs, but their irrationality is not sufficient to explain what is pathological about them. In this paper we ask whether deluded subjects have the capacity to support the content of their delusions with reasons, that is, whether they can author their delusional states. The hypothesis that delusions are characterised by a failure of authorship, which is a dimension of self knowledge, deserves to be empirically tested because (a) it has the potential to account for the distinction between endorsing a delusion and endorsing a framework belief; (b) it contributes to a philosophical analysis of the relationship between rationality and self knowledge; and (c) it informs diagnosis and therapy in clinical psychiatry. However, authorship cannot provide a demarcation criterion between delusions and other irrational belief states

Chronic cigarette smoking is linked with structural alterations in brain regions showing acute nicotinic drug-induced functional modulations

Background Whereas acute nicotine administration alters brain function which may, in turn, contribute to enhanced attention and performance, chronic cigarette smoking is linked with regional brain atrophy and poorer cognition. However, results from structural magnetic resonance imaging (MRI) studies comparing smokers versus nonsmokers have been inconsistent and measures of gray matter possess limited ability to inform functional relations or behavioral implications. The purpose of this study was to address these interpretational challenges through meta-analytic techniques in the service of clarifying the impact of chronic smoking on gray matter integrity and more fully contextualizing such structural alterations. Methods We first conducted a coordinate-based meta-analysis of structural MRI studies to identify consistent structural alterations associated with chronic smoking. Subsequently, we conducted two additional meta-analytic assessments to enhance insight into potential functional and behavioral relations. Specifically, we performed a multimodal meta-analytic assessment to test the structural?functional hypothesis that smoking-related structural alterations overlapped those same regions showing acute nicotinic drug-induced functional modulations. Finally, we employed database driven tools to identify pairs of structurally impacted regions that were also functionally related via meta-analytic connectivity modeling, and then delineated behavioral phenomena associated with such functional interactions via behavioral decoding. Results Across studies, smoking was associated with convergent structural decreases in the left insula, right cerebellum, parahippocampus, multiple prefrontal cortex (PFC) regions, and the thalamus. Indicating a structural?functional relation, we observed that smoking-related gray matter decreases overlapped with the acute functional effects of nicotinic agonist administration in the left insula, ventromedial PFC, and mediodorsal thalamus. Suggesting structural-behavioral implications, we observed that the left insula?s task-based, functional interactions with multiple other structurally impacted regions were linked with pain perception, the right cerebellum?s interactions with other regions were associated with overt body movements, interactions between the parahippocampus and thalamus were linked with memory processes, and interactions between medial PFC regions were associated with face processing. Conclusions Collectively, these findings emphasize brain regions (e.g., ventromedial PFC, insula, thalamus) critically linked with cigarette smoking, suggest neuroimaging paradigms warranting additional consideration among smokers (e.g., pain processing), and highlight regions in need of further elucidation in addiction (e.g., cerebellum). Electronic supplementary material The online version of this article (doi:10.1186/s12993-016-0100-5) contains supplementary material, which is available to authorized users