The epistatic interaction between the dopamine D3 receptor and dysbindin-1 modulates higher-order cognitive functions in mice and humans

The dopamine D2 and D3 receptors are implicated in schizophrenia and its pharmacological treatments. These receptors undergo intracellular trafficking processes that are modulated by dysbindin-1 (Dys). Indeed, Dys variants alter cognitive responses to antipsychotic drugs through D2-mediated mechanisms. However, the mechanism by which Dys might selectively interfere with the D3 receptor subtype is unknown. Here, we revealed an interaction between functional genetic variants altering Dys and D3. Specifically, both in patients with schizophrenia and in genetically modified mice, concomitant reduction in D3 and Dys functionality was associated with improved executive and working memory abilities. This D3/Dys interaction produced a D2/D3 imbalance favoring increased D2 signaling in the prefrontal cortex (PFC) but not in the striatum. No epistatic effects on the clinical positive and negative syndrome scale (PANSS) scores were evident, while only marginal effects on sensorimotor gating, locomotor functions, and social behavior were observed in mice. This genetic interaction between D3 and Dys suggests the D2/D3 imbalance in the PFC as a target for patient stratification and procognitive treatments in schizophrenia

A feasible path-based approach for Dividing Wall Column design procedure

Process integration has become the best practice over the last years in separation units design. In particular, distillation trains can be reduced in a single column shell by means of internal separating wall under the name of Dividing Wall Column. This configuration allows on average for a 30% total costs reduction and is more and more popular for multicomponent mixtures purification. However, the DWC design optimization results much more complex than the one related to a series of standard distillation columns due to the higher number of column sections and side cuts. Moreover, in case of process simulation assisted design, the model convergence is very sensitive with respect to the initial guess, resulting in discontinuities in the sequence of optimization steps. In this paper an innovative design procedure based on feasible paths is presented for an ABEW mixture separation case study. Starting from a converged design based on shortcut methods, the number of trays can be increased and or removed from the proper column section selected with the help of composition profiles analysis. This procedure results to be particularly effective for non-ideal mixtures separations, such as the ABEW one, likely to undergo simulation convergence failures. This design algorithm provides an optimized solution really close to the optimal one in a relatively short time and without the need to solve the related MINLP problem

Flexibility and environmental assessment of process-intensified design solutions: A DWC case study

During the last decades, energy and process integration have become the most spread practices to optimize chemical processes both from economic and environmental perspectives. While the design of the integrated and conventional configurations are usually compared by referring to nominal operating conditions, assessing the implications of process integration on system flexibility could be of critical importance, especially when considering the uncertain nature of renewables. This paper aims then at the comparison of different integrated and conventional unit design performances under uncertain conditions by means of a biorefinery Acetone-Butanol-Ethanol separation case study. An indirect distillation train and different configurations of Dividing Wall Column have been designed and compared to assess the environmental and economic advantages for different flexibility ranges. The proposed methodology allows to select the most suitable configuration for the required performance and to have more conscious expectations about investment costs and emissions when flexibility is taken into account

Activation of 5-HT7 serotonin receptors reverses metabotropic glutamate receptor-mediated synaptic plasticity in wild-type and Fmr1 knockout mice, a model of Fragile X Syndrome

Background: Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism. Fmr1 knockout (Fmr1KO) mice, an animal model of FXS, exhibit spatial memory impairment and synapse malfunctioning in the hippocampus, with abnormal enhancement of long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). The neurotransmitter serotonin (5-HT) modulates hippocampal-dependent cognitive functions through 5-HT1A and 5-HT7 receptors, respectively impairing and improving learning; the underlying mechanisms are unknown. Methods: we used electrophysiology to test the effects of 5-HT on mGluR-LTD in wild-type and Fmr1KO mice, and immunocytochemistry and biotinylation assay to study related changes of GluR2 AMPA receptor subunit surface expression. Results: application of 5-HT or 8-OH-DPAT (a mixed 5-HT1A/5-HT7 agonist) reversed mGluR-LTD induced by DHPG, a group-I mGluR agonist, on CA1 pyramidal neurons in hippocampal slices. Reversal of mGluR-LTD by 8-OH-DPAT persisted in the presence of the 5-HT1A receptor antagonist WAY- 100635, was abolished by SB-269970 (5-HT7 receptor antagonist) and was mimicked by LP-211, a novel selective 5-HT7 receptor agonist. Consistently, 8-OH-DPAT decreased DHPG-mediated reduction of GluR2 surface expression in hippocampal slices and in cultured hippocampal neurons, an effect mimicked by LP-211 and blocked by SB-269970. In Fmr1KO mice, mGluR-LTD was abnormally enhanced; similarly to wild-type, 8-OH-DPAT reversed mGluR-LTD and decreased DHPG-induced reduction of surface AMPA receptors, an effect antagonized by SB-269970. Conclusions: 5-HT7 receptor activation reverses mGluR-induced AMPA receptor internalization and LTD both in wild-type and in Fmr1KO mice, correcting excessive mGluR-LTD. Therefore, selective activation of 5-HT7 receptors may represent a novel strategy in the therapy of FXS