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This article explores an experimental effort to develop a short-term informal learning experience to achieve awareness, confidence and knowledge in geography and geospatial technologies related to environmental and climate change for all participants but particularly for female secondary learners. The intervention incorporated various elements to promote gender-sensitive technical and cultural literacy through an international outreach and science diplomacy framework, justified by various kind of literature in STEM learning. We recount the experiences of three cohorts of students learning about impacts of climate change at sites in Bolivia, South Africa and Panama. The results of student surveys before, immediately after, and 9 months post-participation reveal the extent to which the design met objectives for learning, across genders. Our experimental conclusion reinforces the idea that even short-term, informal learning programs can elicit greater confidence, knowledge and abilities in all students, especially female students, when as many as possible of the elements known to improve gendered participation for STEM are taken into consideration into the very design of the experience. We coin the term "overdetermined design" to designate this kind of approach to take reinforcing, even redundant steps to increase the likelihood of obtaining desired results of improved confidence overall and reducing the gender gap, particularly through the use of geospatial technologies.

L-3,4-dihydroxyphenylalanine (L-DOPA) is the main treatment for Parkinson's disease (PD) but with long term administration, motor complications such as dyskinesia are induced. Glycine transporter 1 (GlyT1) inhibition was shown to produce an anti-dyskinetic effect in parkinsonian rats and primates, coupled with an improvement in the anti-parkinsonian action of L-DOPA. The expression of GlyT1 in the brain in the dyskinetic state remains to be investigated. Here, we quantified the levels of GlyT1 across different brain regions using [3H]-NFPS in the presence of Org-25,935. Brain sections were chosen from sham-lesioned rats, L-DOPA-naïve 6-hydroxydopamine (6-OHDA)-lesioned rats and 6-OHDA-lesioned rats exhibiting mild or severe abnormal involuntary movements (AIMs). [3H]-NFPS binding decreased in the ipsilateral and contralateral thalamus, by 28% and 41%, in 6-OHDA-lesioned rats with severe AIMs compared to sham-lesioned animals (P < 0.01 and 0.001). [3H]-NFPS binding increased by 21% in the ipsilateral substantia nigra of 6-OHDA-lesioned rats with severe AIMs compared to 6-OHDA-lesioned rats with mild AIMs (P < 0.05). [3H]-NFPS binding was lower by 19% in the contralateral primary motor cortex and by 20% in the contralateral subthalamic nucleus of 6-OHDA-lesioned rats with mild AIMs animals compared to rats with severe AIMs (both P < 0.05). The severity of AIMs scores positively correlated with [3H]-NFPS binding in the ipsilateral substantia nigra (P < 0.05), ipsilateral entopeduncular nucleus (P < 0.05) and contralateral primary motor cortex (P < 0.05). These data provide an anatomical basis to explain the efficacy of GlyT1 inhibitors in dyskinesia in PD. [ABSTRACT FROM AUTHOR]

The availability of agonists and antagonists to modulate the activity of the 5- hydroxytryptamine (5-HT) type 3 ([5-HT.sub.3]) receptor has renewed interest in its role as a therapeutic target. Ondansetron is a highly selective [5-HT.sub.3] receptor antagonist that is well tolerated as an anti-emetic for patients undergoing chemotherapy. Preclinical studies in rat have shown the effects of small doses of ondansetron on cognition, behavioural sensitisation, and epilepsy. However, the pharmacokinetic (PK) profile of ondansetron in rat has not been described, which limits the translational relevance of these findings. Here, we aim to determine, in the rat, the PK profile of ondansetron in the plasma and to determine associated brain levels. The plasma PK profile was determined following acute subcutaneous administration of ondansetron (0.1,1, and 10 [micro]g/kg). Brain levels were measured following subcutaneous administration of ondansetron at 1 [micro]g/kg. Plasma and brain levels of ondansetron were determined using high-performance liquid chromatography --tandem mass spectrometry. Following administration of all three doses, measured ondansetron plasma levels ([approximately equal to] 30-3000 pg/mL) were below levels achieved with doses usually administered in the clinic, with a rapid absorption phase and a short half-life ([approximately equal to] 30-40 min). We also found that brain levels of ondansetron at 1 [micro]g/kg were significantly lower than plasma levels, with brain to plasma ratios of 0.45 and 0.46 in the motor and prefrontal cortices. We discuss our findings in the context of a minireview of the literature. We hope that our study will be helpful to the design of preclinical studies with therapeutic end-points. Key words: rat, ondansetron, pharmacokinetics, [5-HT.sub.3] receptor antagonist, HPLC-MS/MS. La disponibilite d'agonistes et d'antagonistes permettant de moduler l'activite des recepteurs de la 5-hydroxytryptamine (5-HT) de type 3 ([5-HT.sub.3]) a renouvele l'interet dans son role comme cible therapeutique. L'ondansetron est un antagoniste tres selectif des recepteurs [5-HT.sub.3] avec une bonne tolerabilite en tant qu'antiemetique chez les patients sous chimiotherapie. Des etudes precliniques chez le rat ont montre les effets de l'ondansetron a faibles doses sur l'etat cognitif, la sensibilisation comportementale et l'epilepsie. Cependant, le profil pharmacocinetique (PK) de l'ondansetron n'a pas ete decrit chez le rat, ce qui limite la pertinence translationnelle de ces resultats. Ici, nous cherchons a etablir le profil PK de l'ondansetron dans le plasma chez le rat et a etablir les niveaux cerebraux associes. Le profil PK plasmatique a ete etabli apres l'administration d'ondansetron (a 0,1,1 et 10 [micro]g/kg) par voie sous-cutanee. Nous avons mesure les niveaux cerebraux a la suite de l'administration sous-cutanee d'ondansetron a 1 [micro]g/kg. Nous avons etabli les niveaux plasmatiques et cerebraux d'ondansetron a l'aide de la chromatographie liquide a haute performance couple a la spectrometrie de masse en tandem. Apres l'administration de chacune des trois doses, nous avons mesure des niveaux plasmatiques d'ondansetron inferieurs a ceux obtenus avec des doses habituellement utilisees en clinique ([approximately equal to] 30-3000 pg/ mL), avec une phase d'absorption rapide et une courte demi-vie ([approximately equal to] 30-40 min). Nous avons aussi observe que les niveaux cerebraux d'ondansetron administre a 1 [micro]g/kg etaient nettement moins eleves que dans le plasma, avec des ratios cerveau a plasma de 0,45 et de 0,46 dans les cortex moteur et prefrontal, respectivement. Nous discutons de nos observations dans le contexte d'une courte synthese de la litterature. Nous esperons que notre etude sera utile pour la conception d'etudes precliniques avec des parametres d'evaluation therapeutiques. Mots-des: rat, ondansetron, pharmacocinetique, antagoniste des recepteurs [5- HT.sub.3], chromatographie liquide a haute performance en tandem avec la spectrometrie de masse., Introduction Initially described as the 'M receptor' in the guinea pig ileum, the 5-hydroxytryptamine (5-HT) type 3 ([5-HT.sub.3]) receptor is uniquely positioned in the 5-HT receptor family as the only [...]

Nelotanserin is a serotonin 2A and 2C (5‐HT2A/2C) inverse agonist that was previously tested in the clinic for rapid‐eye movement sleep behaviour disorder and psychosis in patients with Parkinson's disease (PD) dementia. Its effect on L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced dyskinesia has however not been investigated. As 5‐HT2A antagonism/inverse agonism is a validated approach to alleviate dyskinesia, we undertook the current study to evaluate the anti‐dyskinetic potential of nelotanserin in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned marmoset. Parkinsonism was induced in six common marmosets (Callithrix jacchus, three females and three males) that were then chronically treated with L‐DOPA to induce dyskinesia. On experimental days, they were administered L‐DOPA in combination with vehicle or nelotanserin (0.1, 0.3 and 1 mg/kg) subcutaneously, in a randomised fashion. Dyskinesia and parkinsonism were rated post hoc by a blinded observer. In comparison to vehicle, the addition of nelotanserin 0.3 and 1 mg/kg to L‐DOPA diminished peak dose dyskinesia by 47% (P < 0.05) and 69% (P < 0.001). Nelotanserin 0.3 and 1 mg/kg also reduced the severity of global dyskinesia, by 40% (P < 0.01) and 55% (P < 0.001), when compared to vehicle. Nelotanserin 0.1 mg/kg did not alleviate peak dose or global dyskinesia severity. Nelotanserin had no impact on the anti‐parkinsonian action of L‐DOPA. Our results highlight that nelotanserin may represent an efficacious anti‐dyskinetic drug and provide incremental evidence of the potential benefit of 5‐HT2A/2C antagonism/inverse agonism for drug‐induced dyskinesia in PD. [ABSTRACT FROM AUTHOR]

Rationale: Positive allosteric modulation of metabotropic glutamate type 4 (mGlu4) receptors is a promising strategy to alleviate parkinsonian disability and L-3,4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia. ADX-88178 is a highly selective mGlu4 positive allosteric modulator (PAM) that previously enhanced the anti-parkinsonian action of L-DOPA in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease (PD). Objectives: We sought to explore the effects of ADX-88178 on psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. We also aimed to determine the effect of ADX-88178 on parkinsonism and dyskinesia. Methods: Six MPTP-lesioned marmosets were administered L-DOPA chronically to induce stable PLBs and dyskinesias. They were then administered ADX-88178 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA/benserazide (15/3.75 mg/kg), both sub-cutaneously, in a randomised fashion. PLBs, parkinsonism and dyskinesia were then measured. Results: ADX-88178 mildly worsened global PLBs at the dose of 1 mg/kg (by 13%, P = 0.020). L-DOPA alone conferred 158 min of on-time, while the duration of on-time was 212 min (34% increase, P = 0.011), after adding ADX-88178 1 mg/kg to L-DOPA. Accordingly, ADX-88178 1 mg/kg reduced global parkinsonian disability, by 38% (P = 0.0096). ADX-88178 1 mg/kg diminished peak dose dyskinesia by 34% (P = 0.015). Minimal effects were provided by lower doses. Conclusions: Whereas these results provide additional evidence of the anti-parkinsonian and anti-dyskinetic effects of mGlu4 positive allosteric modulation as an adjunct to L-DOPA, they also suggest that ADX-88178 may exacerbate dopaminergic psychosis. Further studies are needed to evaluate this possible adverse effect of mGlu4 PAMs on PD psychosis. [ABSTRACT FROM AUTHOR]

LY-404,039 is an orthosteric agonist of metabotropic glutamate 2 and 3 receptors (mGluR2/3) that may harbour additional agonist effect at dopamine D2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously entered clinical trials as treatment options for schizophrenia. They could therefore be repurposed, if proven efficacious, for other conditions, notably Parkinson's disease (PD). We have previously shown that the mGluR2/3 orthosteric agonist LY-354,740 alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Unlike LY-404,039, LY-354,740 does not stimulate dopamine D2 receptors, suggesting that LY-404,039 may elicit broader therapeutic effects in PD. Here, we sought to investigate the effect of this possible additional dopamine D2-agonist action of LY-404,039 by assessing its efficacy on dyskinesia, PLBs and parkinsonism in the MPTP-lesioned marmoset. We first determined the pharmacokinetic profile of LY-404,039 in the marmoset, in order to select doses resulting in plasma concentrations known to be well tolerated in the clinic. Marmosets were then injected L-DOPA with either vehicle or LY-404,039 (0.1, 0.3, 1 and 10 mg/kg). The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of global dyskinesia (by 55%, P < 0.01) and PLBs (by 50%, P < 0.05), as well as reduction of global parkinsonism (by 47%, P < 0.05). Our results provide additional support of the efficacy of mGluR2/3 orthosteric stimulation at alleviating dyskinesia, PLBs and parkinsonism. Because LY-404,039 has already been tested in clinical trials, it could be repurposed for indications related to PD. [ABSTRACT FROM AUTHOR]