RGS4 negatively modulates Nociceptin/Orphanin FQ opioid receptor signaling: implication for L-Dopa induced dyskinesia

Background and purpose Regulator of G-protein signal 4 (RGS4) is a signal transduction protein that accelerates intrinsic GTPase activity of Gαi/o and Gαq subunits, suppressing GPCR signaling. Here we investigate whether RGS4 modulates nociceptin/orphanin FQ (N/OFQ) opioid (NOP) receptor signaling and this modulation has relevance for L-Dopa-induced dyskinesia. Experimental approach HEK293T cells transfected with NOP, NOP/RGS4 or NOP/RGS19 were challenged with N/OFQ and the small molecule NOP agonist AT-403, using D1-stimulated cAMP levels as a readout. Primary rat striatal neurons and adult mouse striatal slices were challenged with N/OFQ or AT-403 in the presence of the experimental RGS4 chemical probe, CCG-203920, and D1-stimulated cAMP or phosphorylated extracellular signal regulated kinase 1/2 (pERK) responses were monitored. In vivo, CCG-203920 was co-administered with AT-403 and L-Dopa to 6-hydroxydopamine hemilesioned rats, and dyskinetic movements, striatal biochemical correlates of dyskinesia (pERK and pGluR1 levels) and striatal RGS4 levels were measured. Key results RGS4 expression reduced NOFQ and AT-403 potency and efficacy in HEK293T cells. CCG-203920 increased N/OFQ potency in primary rat striatal neurons, and potentiated AT-403 response in mouse striatal slices. CCG-203920 enhanced AT-403 mediated inhibition of dyskinesia and its biochemical correlates, without compromising its motor-improving effects. Unilateral dopamine depletion caused bilateral reduction of RGS4 levels, which was reversed by L-Dopa. L-Dopa acutely upregulated RGS4 in the lesioned striatum. Conclusions and Implications RGS4 physiologically inhibits NOP receptor signaling. CCG-203920 enhanced NOP responses and improved the antidyskinetic potential of NOP receptor agonists, mitigating the effects of striatal RGS4 upregulation occurring during dyskinesia expression

Molecular and imaging prodromal markers of dopamine neuron degeneration in animal models of Parkinson’s disease: pathophysiology and clinical perspectives

The target of the proposal is to identify pre-degenerative/premotor molecular and cellular alterations, that initiate and contribute to early structural synaptic and axonal dopaminergic damage in the Caudate-Putamen (CPu) of mice that model Parkinson’s disease (PD)-like pathology, in order to delineate new diagnostic and therapeutic strategies that can be translated to the clinic to healing dopaminergic neurodegeneration. To achieve this target, we will use classical neuropathological and functional investigations and advanced microscopy techniques to correlate molecular/structural imaging with data obtained from MRI and PET analysis. This strategy will help to clarify whether and how key events involved in PD pathogenesis, such as alpha-synuclein (AS) pathology, neuroinflammation and mitochondrial derangement, can trigger synaptic and axonal damage detectable by brain imaging to provide very early diagnostic markers of PD. The project will also evaluate the effects of novel neuroprotective compounds (some of them under patent), which may be used to counteract the neuronal demise underlying PD. The deliverables of this project own great potential of scientific and technological advancement in PD research, with significant social and economic impact

The ASEAN Commission on the Promotion and Protection of the Rights of Women and Children

The chapter explains the origins, nature, and tools of the Commission on the Promotion and Protection of the Rights of Women and Children (ACWC) created by the Association of South-East Asian Nations (ASEAN) in 2010. First, it reviews the long path to the creation of this ASEAN human rights mechanism, specifically underlining its source in the United Nations 1993 Vienna World Conference on Human Rights (VWC). In-depth analyses of the 1993 Bangkok Declaration and the Vienna Declaration and Programme of Action (VDPA) are presented with a focus on the normative recognition of women’s rights. Second, this chapter considers the overall transformation of ASEAN toward the realization of a “community of caring societies.” Specifically, the ASEAN Intergovernmental Commission on Human Rights (2009) is analyzed and the content of the ASEAN Human Rights Declaration (2012) and the terms of reference, tools, and functions of the ACWC are explained. The role of the ACWC in linking ASEAN states and the international human rights system is discussed. Finally, the main political goals of the ACWC are defined taking into account: two 5-year plans of action adopted by ACWC in 2012 and 2016, the 2013 Declaration on the Elimination of Violence against Women and Children, and the 2015 ASEAN Regional Plan of Action on the Elimination of Violence against Women

Concorso ProgettABILE

Nel novembre 2009 sono stata chiamata a far parte di una Commissione per un Concorso di idee bandito dalla Società Italiana di Medicina Fisica e Riabilitativa (SIMFER) per individuare una struttura aperta al pubblico con soluzioni innovative relativamente alla partecipazione ad attività svolte da persone con disabilità. La Commissione, era composta dal Presidente e vice Presidente della SIMFER, due medici, “digiuni” di teorie architettoniche, ma esperti di patologie che rendono disabili e, quindi, di problemi connessi alla disabilità, da me e dall’arch. Carlo Pisanò, per la SIMFER, e da tecnici referenti di associazioni di utenti. 13 i progetti presentati. I 3 gruppi di progettisti vincitori e un quarto gruppo che ha ricevuto la menzione speciale sono stati premiati il 25 maggio 2010 a Venezia in occasione del 38° Congresso Nazionale SIMFER e del 17° Congresso Europeo dell’ESPRM, in cui sono stata chiamata ad allestire la mostra dei 13 progetti, a presentare il Concorso ProgettABILE in una sessione dedicata alla premiazione dei progetti. I progetti premiati sono stati segnalati ai Sindaci dei Comuni interessati, alcuni presenti a Venezia, con l’intento di spingere alla realizzazione di questi interventi che si sono incentrati su aree di proprietà pubblica, particolarmente significative e strategiche ai fini del completamento e della riqualificazione e valorizzazione di uno spazio urbano accessibile a tutti

Safinamide Modulates Striatal Glutamatergic Signaling in a Rat Model of Levodopa-Induced Dyskinesia

Safinamide (Xadago) is a novel dual-mechanism drug that has been approved in the European Union and United States as add-on treatment to levodopa in Parkinson's disease therapy. In addition to its selective and reversible monoamine oxidase B inhibition, safinamide through use-dependent sodium channel blockade reduces overactive glutamatergic transmission in basal ganglia, which is believed to contribute to motor symptoms and complications including levodopa-induced dyskinesia (LID). The present study investigated the effects of safinamide on the development of LID in 6-hydroxydopamine (6-OHDA)-lesioned rats, evaluating behavioral, molecular, and neurochemical parameters associated with LID appearance. 6-OHDA-lesioned rats were treated with saline, levodopa (6 mg/kg), or levodopa plus safinamide (15 mg/kg) for 21 days. Abnormal involuntary movements, motor performance, molecular composition of the striatal glutamatergic synapse, glutamate, and GABA release were analyzed. In the striatum, safinamide prevented the rearrangement of the subunit composition of N-methyl-d-aspartate receptors and the levodopa-induced increase of glutamate release associated with dyskinesia without affecting the levodopa-stimulated motor performance and dyskinesia. Overall, these findings suggest that the striatal glutamate-modulating component of safinamide's activity may contribute to its clinical effects, where its long-term use as levodopa add-on therapy significantly improves motor function and "on" time without troublesome dyskinesia

A modified CPT based installation torque prediction for large screw piles in sand

Screw piles have been suggested as an alternative foundation solution to straight-shafted piles for jacket supported offshore wind turbines in deep water. The significant environmental loads in the marine environment will require substantially larger screw piles than those currently employed in onshore applications. This raises questions over the suitability of current design methods for capacity and installation torque. This paper aims to address this issue by presenting a screw pile installation torque prediction method based on cone resistance values from Cone Penetration Test (CPT) data. The proposed method, developed using centrifuge modelling techniques in dry sand, provides accurate predictions of installation torque for both centrifuge and field scale screw piles. Furthermore, unlike existing CPT-torque correlations, the proposed method is shown to be applicable to multi-helix screw piles