The dopamine D3-preferring D2/D3 dopamine receptor partial agonist, cariprazine, reverses behavioral changes in a rat neurodevelopmental model for schizophrenia

Current antipsychotic medication is largely ineffective against the negative and cognitive symptoms of schizophrenia. One promising therapeutic development is to design new molecules that balance actions on dopamine D2 and D3 receptors to maximise benefits and limit adverse effects. This study used two rodent paradigms to investigate the action of the dopamine D3-preferring D3/D2 receptor partial agonist cariprazine. In adult male rats, cariprazine (0.03-0.3mg/kg i.p.), and the atypical antipsychotic aripiprazole (1-3mg/kg i.p.) caused dose-dependent reversal of a delay-induced impairment in novel object recognition (NOR). Treating neonatal rat pups with phencyclidine (PCP) and subsequent social isolation produced a syndrome of behavioral alterations in adulthood including hyperactivity in a novel arena, deficits in NOR and fear motivated learning and memory, and a reduction and change in pattern of social interaction accompanied by increased ultrasonic vocalisations (USVs). Acute administration of cariprazine (0.1 and 0.3mg/kg) and aripiprazole (3mg/kg) to resultant adult rats reduced neonatal PCP-social isolation induced locomotor hyperactivity and reversed NOR deficits. Cariprazine (0.3mg/kg) caused a limited reversal of the social interaction deficit but neither drug affected the change in USVs or the deficit in fear motivated learning and memory. Results suggest that in the behavioral tests investigated cariprazine is at least as effective as aripiprazole and in some paradigms it showed additional beneficial features further supporting the advantage of combined dopamine D3/D2 receptor targeting. These findings support recent clinical studies demonstrating the efficacy of cariprazine in treatment of negative symptoms and functional impairment in schizophrenia patients

Methylmercury exposure and developmental neurotoxicity.

Comment on: Global methylmercury exposure from seafood consumption and risk of developmental neurotoxicity: a systematic review. [Bull World Health Organ. 2014]]]> Humans; Methylmercury Compounds; Neurotoxicity Syndromes eng https://serval.unil.ch/resource/serval:BIB_B254C52AD78C.P001/REF.pdf http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_B254C52AD78C2 info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_B254C52AD78C2 info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/openAccess Copying allowed only for non-profit organizations https://serval.unil.ch/disclaimer application/pdf oai:serval.unil.ch:BIB_B254CA78ED67 2022-05-07T01:25:17Z openaire documents urnserval <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_B254CA78ED67 Application of a computationally efficient method to approximate gap model results with a probabilistic approach info:doi:10.5194/gmd-7-1543-2014 info:eu-repo/semantics/altIdentifier/doi/10.5194/gmd-7-1543-2014 Scherstjanoi, M. Kaplan, J. O. Lischke, H. info:eu-repo/semantics/article article 2014 Geoscientific Model Development, vol. 7, no. 4, pp. 1543-1571 urn:issn:1991-959x eng https://serval.unil.ch/resource/serval:BIB_B254CA78ED67.P001/REF.pdf http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_B254CA78ED677 info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_B254CA78ED677 info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/openAccess Copying allowed only for non-profit organizations https://serval.unil.ch/disclaimer application/pdf oai:serval.unil.ch:BIB_B254D0E85D5E 2022-05-07T01:25:17Z <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_B254D0E85D5E Meningite purulente aigue a Listeria seeligeri chez un adulte immunocompetent. [Acute purulent Listeria seelingeri meningitis in an immunocompetent adult] info:eu-repo/semantics/altIdentifier/pmid/3082004 Rocourt, J. Hof, H. Schrettenbrunner, A. Malinverni, R. Bille, J. info:eu-repo/semantics/article article 1986-02 Schweizerische Medizinische Wochenschrift, vol. 116, no. 8, pp. 248-51 info:eu-repo/semantics/altIdentifier/pissn/0036-7672 <![CDATA[Within the genus Listeria, the species L. monocytogenes most frequently causes disease in animals and humans. L. Seeligeri, a species recently described, has been considered experimentally nonpathogenic so far. The authors report the first case of human infection in a previously healthy adult presenting with acute purulent meningitis due to L. seeligeri. The patient recovered promptly after a course of ampicillin and gentamicin, but developed severe neurological sequelae (epilepsy, hydrocephalus) one year after the acute episode. The pathogenic properties of this isolate were investigated in two experimental animal models and the results were as follows. The clinical isolate of L. seeligeri was able to colonize the spleens of adult mice without bacterial multiplication, in contrast to the type strain of L. seeligeri (no colonization) and to a L. monocytogenes strain (colonization and multiplication). Previous infection of adult mice with the clinical L. seeligeri isolate protected moderately against spleen colonization and bacterial multiplication after challenge with L. monocytogenes. No lethal effect was observed after inoculation of suckling mice with the clinical L. seeligeri isolate, in contrast to L. monocytogenes strains. Thus, L. seeligeri, previously described as experimentally nonpathogenic for mice, may in fact be a heterogeneous species regarding its pathogenicity, and include strains that may cause life-threatening diseases in humans

Comparative Pro-cognitive and Neurochemical Profiles of Glycine Modulatory Site Agonists and Glycine Reuptake Inhibitors in the Rat: Potential Relevance to Cognitive Dysfunction and Its Management

© 2020, The Author(s). Frontocortical NMDA receptors are pivotal in regulating cognition and mood, are hypofunctional in schizophrenia, and may contribute to autistic spectrum disorders. Despite extensive interest in agents potentiating activity at the co-agonist glycine modulatory site, few comparative functional studies exist. This study systematically compared the actions of the glycine reuptake inhibitors, sarcosine (40–200mg/kg) and ORG24598 (0.63–5mg/kg), the agonists, glycine (40–800mg/kg), and D-serine (10–160mg/kg) and the partial agonists, S18841 (2.5mg/kg s.c.) and D-cycloserine (2.5–40mg/kg) that all dose-dependently prevented scopolamine disruption of social recognition in adult rats. Over similar dose ranges, they also prevented a delay-induced impairment of novel object recognition (NOR). Glycine reuptake inhibitors specifically elevated glycine but not D-serine levels in rat prefrontal cortical (PFC) microdialysates, while glycine and D-serine markedly increased levels of glycine and D-serine, respectively. D-Cycloserine slightly elevated D-serine levels. Conversely, S18841 exerted no influence on glycine, D-serine, other amino acids, monamines, or acetylcholine. Reversal of NOR deficits by systemic S18841 was prevented by the NMDA receptor antagonist, CPP (20mg/kg), and the glycine modulatory site antagonist, L701,324 (10mg/kg). S18841 blocked deficits in NOR following microinjection into the PFC (2.5–10μg/side) but not the striatum. Finally, in rats socially isolated from weaning (a neurodevelopmental model of schizophrenia), S18841 (2.5 and 10mg/kgs.c.) reversed impairment of NOR and contextual fear-motivated learning without altering isolation-induced hyperactivity. In conclusion, despite contrasting neurochemical profiles, partial glycine site agonists and glycine reuptake inhibitors exhibit comparable pro-cognitive effects in rats of potential relevance to treatment of schizophrenia and other brain disorders where cognitive performance is impaired

Pinch Technique and the Batalin-Vilkovisky formalism

In this paper we take the first step towards a non-diagrammatic formulation of the Pinch Technique. In particular we proceed into a systematic identification of the parts of the one-loop and two-loop Feynman diagrams that are exchanged during the pinching process in terms of unphysical ghost Green's functions; the latter appear in the standard Slavnov-Taylor identity satisfied by the tree-level and one-loop three-gluon vertex. This identification allows for the consistent generalization of the intrinsic pinch technique to two loops, through the collective treatment of entire sets of diagrams, instead of the laborious algebraic manipulation of individual graphs, and sets up the stage for the generalization of the method to all orders. We show that the task of comparing the effective Green's functions obtained by the Pinch Technique with those computed in the background field method Feynman gauge is significantly facilitated when employing the powerful quantization framework of Batalin and Vilkovisky. This formalism allows for the derivation of a set of useful non-linear identities, which express the Background Field Method Green's functions in terms of the conventional (quantum) ones and auxiliary Green's functions involving the background source and the gluonic anti-field; these latter Green's functions are subsequently related by means of a Schwinger-Dyson type of equation to the ghost Green's functions appearing in the aforementioned Slavnov-Taylor identity.Comment: 45 pages, uses axodraw; typos corrected, one figure changed, final version to appear in Phys.Rev.

The Importance of Time Congruity in the Organisation.

In 1991 Kaufman, Lane, and Lindquist proposed that time congruity in terms of an individual's time preferences and the time use methods of an organisation would lead to satisfactory performance and enhancement of quality of work and general life. The research reported here presents a study which uses commensurate person and job measures of time personality in an organisational setting to assess the effects of time congruity on one aspect of work life, job-related affective well-being. Results show that time personality and time congruity were found to have direct effects on well-being and the influence of time congruity was found to be mediated through time personality, thus contributing to the person–job (P–J) fit literature which suggests that direct effects are often more important than indirect effects. The study also provides some practical examples of ways to address some of the previously cited methodological issues in P–J fit research

Untargeted Metabolomics Profiling of an 80.5 km Simulated Treadmill Ultramarathon

Metabolomic profiling of nine trained ultramarathon runners completing an 80.5 km self-paced treadmill-based time trial was carried out. Plasma samples were obtained from venous whole blood, collected at rest and on completion of the distance (post-80.5 km). The samples were analyzed by using high-resolution mass spectrometry in combination with both hydrophilic interaction (HILIC) and reversed phase (RP) chromatography. The extracted putatively identified features were modeled using Simca P 14.1 software (Umetrics, Umea, Sweden). A large number of amino acids decreased post-80.5 km and fatty acid metabolism was affected with an increase in the formation of medium-chain unsaturated and partially oxidized fatty acids and conjugates of fatty acids with carnitines. A possible explanation for the complex pattern of medium-chain and oxidized fatty acids formed is that the prolonged exercise provoked the proliferation of peroxisomes. The peroxisomes may provide a readily utilizable form of energy through formation of acetyl carnitine and other acyl carnitines for export to mitochondria in the muscles; and secondly may serve to regulate the levels of oxidized metabolites of long-chain fatty acids. This is the first study to provide evidence of the metabolic profile in response to prolonged ultramarathon running using an untargeted approach. The findings provide an insight to the effects of ultramarathon running on the metabolic specificities and alterations that may demonstrate cardio-protective effects

Exploring morphological correlations among H2CO, 12CO, MSX and continuum mappings

There are relatively few H2CO mappings of large-area giant molecular cloud (GMCs). H2CO absorption lines are good tracers for low-temperature molecular clouds towards star formation regions. Thus, the aim of the study was to identify H2CO distributions in ambient molecular clouds. We investigated morphologic relations among 6-cm continuum brightness temperature (CBT) data and H2CO (111-110; Nanshan 25-m radio telescope), 12CO (1--0; 1.2-m CfA telescope) and midcourse space experiment (MSX) data, and considered the impact of background components on foreground clouds. We report simultaneous 6-cm H2CO absorption lines and H110\alpha radio recombination line observations and give several large-area mappings at 4.8 GHz toward W49 (50'\times50'), W3 (70'\times90'), DR21/W75 (60'\times90') and NGC2024/NGC2023 (50'\times100') GMCs. By superimposing H2CO and 12CO contours onto the MSX color map, we can compare correlations. The resolution for H2CO, 12CO and MSX data was about 10', 8' and 18.3", respectively. Comparison of H2CO and 12CO contours, 8.28-\mu m MSX colorscale and CBT data revealed great morphological correlation in the large area, although there are some discrepancies between 12CO and H2CO peaks in small areas. The NGC2024/NGC2023 GMC is a large area of HII regions with a high CBT, but a H2CO cloud to the north is possible against the cosmic microwave background. A statistical diagram shows that 85.21% of H2CO absorption lines are distributed in the intensity range from -1.0 to 0 Jy and the \Delta V range from 1.206 to 5 km/s.Comment: 18 pages, 22 figures, 5 tables. Accepted to be published in Astrophysics and Space Scienc

Dopamine D1 receptor stimulation modulates the formation and retrieval of novel object recognition memory: role of the prelimbic cortex

Previous studies have shown that dopamine D1 receptor antagonists impair novel object recognition memory but the effects of dopamine D1 receptor stimulation remain to be determined. This study investigated the effects of the selective dopamine D1 receptor agonist SKF81297 on acquisition and retrieval in the novel object recognition task in male Wistar rats. SKF81297 (0.4 and 0.8mg/kg s.c.) given 15 min before the sampling phase impaired novel object recognition evaluated 10 min or 24h later. The same treatments also reduced novel object recognition memory tested 24h after the sampling phase and when given 15min before the choice session. These data indicate that D1 receptor stimulation modulates both the encoding and retrieval of object recognition memory. Microinfusion of SKF81297 (0.025 or 0.05 μg/side) into the prelimbic sub-region of the medial prefrontal cortex (mPFC) in this case 10 min before the sampling phase also impaired novel object recognition memory, suggesting that the mPFC is one important site mediating the effects of D1 receptor stimulation on visual recognition memory

Dual-acting agents for improving cognition and real-world function in Alzheimer's disease: Focus on 5-HT6 and D3 receptors as hubs

© 2020 Elsevier Ltd To date, there are no interventions that impede the inexorable progression of Alzheimer's disease (AD), and currently-available drugs cholinesterase (AChE) inhibitors and the N-Methyl-D-Aspartate receptor antagonist, memantine, offer only modest symptomatic benefit. Moreover, a range of mechanistically-diverse agents (glutamatergic, histaminergic, monoaminergic, cholinergic) have disappointed in clinical trials, alone and/or in association with AChE inhibitors. This includes serotonin (5-HT) receptor-6 antagonists, despite compelling preclinical observations in rodents and primates suggesting a positive influence on cognition. The emphasis has so far been on high selectivity. However, for a multi-factorial disorder like idiopathic AD, 5-HT6 antagonists possessing additional pharmacological actions might be more effective, by analogy to “multi-target” antipsychotics. Based on this notion, drug discovery programmes have coupled 5-HT6 blockade to 5-HT4 agonism and inhibition of AchE. Further, combined 5-HT6/dopamine D3 receptor (D3) antagonists are of especial interest since D3 blockade mirrors 5-HT6 antagonism in exerting broad-based pro-cognitive properties in animals. Moreover, 5-HT6 and dopamine D3 antagonists promote neurocognition and social cognition via both distinctive and convergent actions expressed mainly in frontal cortex, including suppression of mTOR over-activation and reinforcement of cholinergic and glutamatergic transmission. In addition, 5-HT6 blockade affords potential anti-anxiety, anti-depressive and anti-epileptic properties, and antagonising 5-HT6 receptors may be associated with neuroprotective (“disease-modifying”) properties. Finally D3 antagonism may counter psychotic episodes and D3 receptors themselves offer a promising hub for multi-target agents. The present article reviews the status of “R and D” into multi-target 5-HT6 and D3 ligands for improved treatment of AD and other neurodegenerative disorders of aging. This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’

Modeling DNA Structure, Elasticity and Deformations at the Base-pair Level

We present a generic model for DNA at the base-pair level. We use a variant of the Gay-Berne potential to represent the stacking energy between neighboring base-pairs. The sugar-phosphate backbones are taken into account by semi-rigid harmonic springs with a non-zero spring length. The competition of these two interactions and the introduction of a simple geometrical constraint leads to a stacked right-handed B-DNA-like conformation. The mapping of the presented model to the Marko-Siggia and the Stack-of-Plates model enables us to optimize the free model parameters so as to reproduce the experimentally known observables such as persistence lengths, mean and mean squared base-pair step parameters. For the optimized model parameters we measured the critical force where the transition from B- to S-DNA occurs to be approximately $140{pN}$. We observe an overstretched S-DNA conformation with highly inclined bases that partially preserves the stacking of successive base-pairs.Comment: 15 pages, 25 figures. submitted to PR