Tobacco addiction in individuals with schizophrenia: A study in rats

<p>Schizophrenia as with most mental disorders develops due to an interaction of multiple genetic and environmental factors. Prenatal exposure to a maternal immuneactivation (MIA) is an environmental risk factor that can predispose offspring to develop schizophrenia later in life. The neurodevelopmental theory suggests that an immunechallenge during gestation can lead to long-lasting impairments such as in learning, memory,attention, or language (Brown & Patterson, 2012). Based on findings in human studies,prenatal exposure to a MIA has been utilized in preclinical research. Thus, the first aim of this study was to establish an animal model that generates subjects with schizophrenia-like cognitive impairments. To this end, a bacterial endotoxin, lipopolysaccharide (LPS) was used, which like most infectious agents, cannot cross the blood-placenta-barrier, yet reliably mimics an infection and initiates a MIA. Pregnant rats were subcutaneously (sc) injected with LPS (0.5 mg/kg) at one of three important neurodevelopmental time periods, gestation days (GD) 10/11, 15/16 or 18/19 (Fortier, Luheshi, & Boksa, 2007; Graciarena, Depino, & Pitossi, 2010). As individuals with schizophrenia commonly show deficits in multiple domains, three assessment paradigms were used to examine sensory and cognitive abilities in early and late adulthood. Tasks included prepulse inhibition to assess sensorimotor gating, latent inhibition to measure selective attention, and delayed non-matching to sample to evaluate working memory (WM). Several theories have been suggested to explain high smoking incidence in schizophrenic patients (75-90%) compared to the general population (23%). The self-medication theory suggests high smoking rates amongst patients because nicotine, the primary addictive constituent in tobacco smoke, ameliorates some of the symptoms of the disorder such as cognitive deficits (D'Souza & Markou, 2012). Thus, the second aim of this study was to determine whether repeated experimenter and self-administered nicotine ameliorates or reduces schizophrenia-like cognitive deficits. Finally, the third aim was to investigate the common substrate theory, which suggests that shared underlying biological pathways may lead to increased susceptibility for an individual to develop both schizophrenia and tobacco addiction (Chambers, Krystal, & Self, 2001). In conclusion, the findings of this study were coherently consistent and revealed that firstly, prenatal exposure to MIA early during foetal development led to long-lasting deficits in cognitive domains such as selective attention and WM. Secondly, supporting the self-medication theory, nicotine reversed MIA-induced cognitive impairments independent of the administration paradigm. Thirdly, increased responding rates for nicotine during self-administration acquisition in animals prenatally exposed to MIA were observed, yet there was no effect of prenatal treatment in dose response or progressive ratio testing. Thus, these findings only offer weak support for the common substrate theory. Importantly, the findings of this study revealed that animals can be repeatedly assessed in these paradigms to examine the therapeutic efficacy of drugs and other treatments. This is of particular importance considering the lack of effective pharmacological treatments for cognitive deficits in schizophrenic patients.</p>

Tobacco addiction in individuals with schizophrenia: A study in rats

<p>Schizophrenia as with most mental disorders develops due to an interaction of multiple genetic and environmental factors. Prenatal exposure to a maternal immuneactivation (MIA) is an environmental risk factor that can predispose offspring to develop schizophrenia later in life. The neurodevelopmental theory suggests that an immunechallenge during gestation can lead to long-lasting impairments such as in learning, memory,attention, or language (Brown & Patterson, 2012). Based on findings in human studies,prenatal exposure to a MIA has been utilized in preclinical research. Thus, the first aim of this study was to establish an animal model that generates subjects with schizophrenia-like cognitive impairments. To this end, a bacterial endotoxin, lipopolysaccharide (LPS) was used, which like most infectious agents, cannot cross the blood-placenta-barrier, yet reliably mimics an infection and initiates a MIA. Pregnant rats were subcutaneously (sc) injected with LPS (0.5 mg/kg) at one of three important neurodevelopmental time periods, gestation days (GD) 10/11, 15/16 or 18/19 (Fortier, Luheshi, & Boksa, 2007; Graciarena, Depino, & Pitossi, 2010). As individuals with schizophrenia commonly show deficits in multiple domains, three assessment paradigms were used to examine sensory and cognitive abilities in early and late adulthood. Tasks included prepulse inhibition to assess sensorimotor gating, latent inhibition to measure selective attention, and delayed non-matching to sample to evaluate working memory (WM). Several theories have been suggested to explain high smoking incidence in schizophrenic patients (75-90%) compared to the general population (23%). The self-medication theory suggests high smoking rates amongst patients because nicotine, the primary addictive constituent in tobacco smoke, ameliorates some of the symptoms of the disorder such as cognitive deficits (D'Souza & Markou, 2012). Thus, the second aim of this study was to determine whether repeated experimenter and self-administered nicotine ameliorates or reduces schizophrenia-like cognitive deficits. Finally, the third aim was to investigate the common substrate theory, which suggests that shared underlying biological pathways may lead to increased susceptibility for an individual to develop both schizophrenia and tobacco addiction (Chambers, Krystal, & Self, 2001). In conclusion, the findings of this study were coherently consistent and revealed that firstly, prenatal exposure to MIA early during foetal development led to long-lasting deficits in cognitive domains such as selective attention and WM. Secondly, supporting the self-medication theory, nicotine reversed MIA-induced cognitive impairments independent of the administration paradigm. Thirdly, increased responding rates for nicotine during self-administration acquisition in animals prenatally exposed to MIA were observed, yet there was no effect of prenatal treatment in dose response or progressive ratio testing. Thus, these findings only offer weak support for the common substrate theory. Importantly, the findings of this study revealed that animals can be repeatedly assessed in these paradigms to examine the therapeutic efficacy of drugs and other treatments. This is of particular importance considering the lack of effective pharmacological treatments for cognitive deficits in schizophrenic patients.</p>

Epoxidation and late-stage C-H functionalization by P450 TamI is mediated by variant heme-iron oxidizing species

P450-catalyzed hydroxylation reactions are well understood mechanistically including the identity of the active oxidizing species. However, the catalytically active heme-iron species in P450 iterative oxidation cascades that involve mechanistically divergent pathways and distinct carbon atoms within a common substrate remains unexplored. Recently, we reported the enzymatic synthesis of tri-functionalized tirandamycin O (9) and O’ (10) using a bacterial P450 TamI variant and developed mechanistic hypotheses to explore their formation. Here, we report the ability of bacterial P450 TamI L295A to shift between different oxidizing species as it catalyzes the sequential epoxidation, hydroxylation and radical-catalyzed epoxide-opening cascade to create new tirandamycin antibiotics. We also provide evidence that the TamI peroxo-iron species could be a viable catalyst to enable nucleophilic epoxide opening in the absence of iron-oxo Compound I. Using site-directed mutagenesis, kinetic solvent isotope effects, artificial oxygen surrogates, end-point assays, and density functional theory (DFT) calculations, we provide new insights into the active oxidant species that P450 TamI employs to introduce its unique pattern of oxidative decorations.

Genetic factors influencing a neurobiological substrate for psychiatric disorders

A retrospective meta-analysis of magnetic resonance imaging voxel-based morphometry studies proposed that reduced gray matter volumes in the dorsal anterior cingulate and the left and right anterior insular cortex—areas that constitute hub nodes of the salience network—represent a common substrate for major psychiatric disorders. Here, we investigated the hypothesis that the common substrate serves as an intermediate phenotype to detect genetic risk variants relevant for psychiatric disease. To this end, after a data reduction step, we conducted genome-wide association studies of a combined common substrate measure in four population-based cohorts (n = 2271), followed by meta-analysis and replication in a fifth cohort (n = 865). After correction for covariates, the heritability of the common substrate was estimated at 0.50 (standard error 0.18). The top single-nucleotide polymorphism (SNP) rs17076061 was associated with the common substrate at genome-wide significance and replicated, explaining 1.2% of the common substrate variance. This SNP mapped to a locus on chromosome 5q35.2 harboring genes involved in neuronal development and regeneration. In follow-up analyses, rs17076061 was not robustly associated with psychiatric disease, and no overlap was found between the broader genetic architecture of the common substrate and genetic risk for major depressive disorder, bipolar disorder, or schizophrenia. In conclusion, our study identified that common genetic variation indeed influences the common substrate, but that these variants do not directly translate to increased disease risk. Future studies should investigate gene-by-environment interactions and employ functional imaging to understand how salience network structure translates to psychiatric disorder risk.

Latin sāpō ‘hair-dye, soap’, the Germanic Words for Soap, and the Common Substrate of Celtic and Germanic

This article argues that the traditional etymology of Latin sāpō as a loanword from the Germanic words for ‘soap’ is phonologically not possible. Instead, it proposes a phonologically regular explanation: a loanword in both Germanic and Latin from the common Celtic-Germanic substrate (with Gaulish transmission in the case of Latin).

Beyond Nudging: Generalisable and transferable learning in human decision-making

Canonical work on human decision-making demonstrates consistent, stereotyped and sub-optimal risk-reward trade-offs. However, recent work on experienced-based-, perceptual- and sensori-motor choice appear to severely restrict the scope of the canonical work, demonstrating trade-offs that are either differently sub-optimal, or much closer to optimal. Such dissociations may reflect highly specific mechanisms, or other confounds between domains; impossible to tease apart with current observational methods. We develop a method for strong causal inference based on experimentally manipulating risk preferences. Using a double-blind randomized control design, we trained people in a single domain, evaluate the extent to which training generalizes beyond the training-set, and more importantly the extent to which training transfers to risk domains in which participants were not trained. Participants were trained to maximize their expected earnings (i.e., to be risk-neutral). In total, we tested for transfer to four different risk domains, all of which are known to dissociate. We find that training is necessary and sufficient to cause reliable changes in decision-making. Importantly, training transfers, with participants becoming more risk-neutral also in domains for which they had had no training, showing that risk-reward trade-offs in different domains and tasks share common substrate. Shared mechanisms open up the opportunity to for practical general-purpose training programmes to improve human decision-making.

Effects of Vermicompost, Compost and Digestate as Commercial Alternative Peat-Based Substrates on Qualitative Parameters of Salvia officinalis

Peat is a common substrate used for the cultivation of potted plants. However, the use of peat in horticulture has recently been questioned from an environmental standpoint, since it is a non-renewable resource and plays a major role in atmospheric CO2 sequestration. The aim of this work was to assess the potentialities of substrates obtained from vermicompost, compost and anaerobic digestion processes to partially substitute peat for sage (Salvia officinalis L.) cultivation. Therefore, we planned an experiment to assess the effect of these substrates on essential oil (EO) yield and composition, as well as on leaf nutrients concentration of sage plants. The three substrates were mixed with commercial peat (Radicom) at a ratio of 40% of alternative substrates and 40% of commercial peat. The chemical properties of the alternative substrates did not affect the leaf content of macro and micronutrients, as well as of heavy metals. Moreover, the EO yield and quality was not affected by the substrates and did not differ among them. Results provided evidence that the three alternative substrates can be used to partially substitute peat in soilless cultivation of sage plants. However, due to the higher values of the electrical conductivity of the substrates obtained from composting and anaerobic digestion processes, such substrates must be used with caution.

ASNS disruption shortens CTPS cytoophidia in Saccharomyces cerevisiae

Asparagine synthetase (ASNS) and CTP synthase (CTPS) are two metabolic enzymes that catalyze the biosynthesis of asparagine and CTP, respectively. Both CTPS and ASNS have been identified to form cytoophidia in Saccharomyces cerevisiae. Glutamine is a common substrate for both these enzymes, and they play an important role in glutamine homeostasis. Here, we find that the ASNS cytoophidia are shorter than the CTPS cytoophidia, and that disruption of ASNS shortens the length of CTPS cytoophidia. However, the deletion of CTPS has no effect on the formation and length of ASNS cytoophidia, or on the ASNS protein level. We also find that Asn1 overexpression induces the formation of a multi-dot structure in diauxic phase which suggests that the increased protein level may trigger cytoophidia formation. Collectively, our results reveal a connection between ASNS cytoophidia and CTPS cytoophidia.

Combining computational controls with natural text reveals new aspects of meaning composition

To study a core component of human intelligence—our ability to combine the meaning of words—neuroscientists look for neural correlates of meaning composition, such as brain activity proportional to the difficulty of understanding a sentence. However, little is known about the product of meaning composition—the combined meaning of words beyond their individual meaning. We term this product “supra-word meaning” and devise a computational representation for it by using recent neural network algorithms and a new technique to disentangle composed-from individual-word meaning. Using functional magnetic resonance imaging, we reveal that hubs that are thought to process lexical-level meaning also maintain supra-word meaning, suggesting a common substrate for lexical and combinatorial semantics. Surprisingly, we cannot detect supra-word meaning in magnetoencephalography, which suggests that composed meaning is maintained through a different neural mechanism than synchronized firing. This sensitivity difference has implications for past neuroimaging results and future wearable neurotechnology.