1,720,973 research outputs found
Design, synthesis and pharmacology of novel ligands targeting neuronal nicotinic acetylcholine receptor subtypes
No full textNeuronal nicotinic acetylcholine receptors (nAChRs) make up a family of pentameric ligand-gated ion channels which are formed by combinations of alpha and beta subunits or exist as homopentamers, in the cases of α-7, α-8, and α-9 receptors, which are inhibited by α-bungarotoxin. To date, nine α (α-2-α-10) and three β(β2-β4) isoforms have been characterized, though only a relatively small subset of combinations generates functionally and physiologically relevant channels. Nicotinic receptors are widely distributed in the brain, where they primarily modulate the release of other neurotransmitters and, to a lesser extent, mediate synaptic transmission. Neuronal nAChRs are involved in various processes such as cognition, learning and memory, cerebral blood flow and metabolism, as well as an array of pathological conditions such as Alzheimer’s and Parkinson’s diseases, mild cognitive impairment (MCI), schizophrenia, epilepsy, Tourette’s syndrome, anxiety, depression, attention-deficit hyperactivity disorder (ADHD), and nicotine addiction. The heteromeric α4β2 and the homomeric α7 nAChR subtypes represent the most relevant biological targets in view of potential therapeutic applications for the above cited pathologies.
In this study, the group of novel stereoisomeric Δ2-isoxazolines 1a-1f and 2a-f, structurally related to the α4β2 selective nicotinic agonist ABT-418, has been prepared and tested at neuronal α4β2 and α7 nAChR subtypes. Moreover, (-)-Cytisine 3, a natural selective α4β2 ligand, was taken as model compound to synthesize the group of 4-substituted derivatives 4-8.The two series of derivates were synthesized by taking advantage of a 1,3-dipolar or a 1,6-intramolecular cycloaddition processes.On the other hand, as an extension of a previous research project, we prepared a group of novel derivatives characterized by a spirocylic junction between the quinuclidine ring and the Δ2-isoxazoline (8a-g and 9a-g) or the isoxazolidin-3-one (10a-b) moieties. Some of the compounds under study behaved as potent and selective α7 nAChR agonists/partial agonists and were further investigated in in vitro and in vivo tests
A stability result for Mountain Pass type solutions of semilinear elliptic variational inequalities
No full textThe aim of the present paper is to establish a stability result for the so called Mountain Pass type solutions of a class of
semilinear elliptic variational inequalities with superlinear and subcritical nonlinearities
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Agonisti nicotinici selettivi nel trattamento di patologie del Sistema Nervoso Centrale
No full textI recettori nicotinici neuronali costituiscono una famiglia di recettori canale a struttura pentamerica attivati da un ligando e costituiti sia da svariate combinazioni eteromeriche di subunità alfa e beta sia da assemblaggi omomerici delle subunità alpha7, alpha8 e alpha9.[1,2] I due sottotipi maggiormente espressi nel sistema nervoso centrale (SNC) sono la combinazione eteromerica alpha4beta2 e quella omomerica alpha7.[3] Studi di tipo neuroanatomico ed elettrofisiologico, convalidati da test comportamentali, hanno evidenziato l'importanza di questi due sottotipi recettoriali nei processi di apprendimento e di memoria.[4] Da queste premesse, i due recettori nicotinici sopra menzionati sono stati individuati come bersagli di farmaci utilizzabili in importanti patologie del SNC quali il morbo di Alzheimer, il morbo di Parkinson, la sindrome di Tourette, l'ansia, stati depressivi, l'epilessia, il dolore neuropatico, la schizofrenia e la dipendenza da nicotina.[1] La progettazione di ligandi selettivi per un solo sottotipo recettoriale è essenziale per valutarne il coinvolgimento in stati patologici e successivamente per sviluppare farmaci caratterizzati da limitati effetti collaterali. Pertanto molte delle ricerche attuali in questo settore sono rivolte alla progettazione di agonisti alpha4beta2 selettivi da impiegare nel trattamento del dolore neuropatico, nel trattamento sintomatico di patologie neurodegenerative del SNC e nei programmi di disuassefazione da nicotina. Per quest'ultima indicazione terapeutica, nel 2006 la FDA ha approvato la Vareniclina. Intensi studi sono anche rivolti alla progettazione di agonisti alpha 7 selettivi avendo come obiettivo lo sviluppo di farmaci in grado di trattare affezioni neurologiche e psichiatriche, quali il morbo di Alzheimer e la schizofrenia, e processi infiammatori.[5,6] In questa relazione verranno illustrate le strategie utilizzate per progettare, da un lato, agonisti selettivi per il sottotipo recettoriale alpha4beta2 e, dall'altro, di generare ligandi capaci di interagire selettivamente con il sottotipo alpha7. Questi studi sono stati effettuati utilizzando modelli recettoriali sviluppati utilizzando le più moderne tecniche computazionali e validati con dati di letteratura. Bibliografia [1] A. A. Jensen et al., J. Med. Chem. 2005, 48, 4705-4745. [2] P. Séguél et al., J. Neurosci. 1993, 13, 596-604. [3] S. Weiland et al.., Behav. Brain Res. 2000, 113, 43-56. [4] E. D. Levin, B. B. Simon Psycopharmacology 1998, 138, 217-230. [5] L. Ulloa. Nature Reviews - Drug Discovery 2005, 673-68
Exploiting enzymatic regioselectivity : a facile methodology for the synthesis of polyhydroxylated hybrid compounds
No full textPolyhydroxylated hybrid molecules have been synthesized using a protocol based on the regioselective acylation of the target compounds with activated dicarboxylic acids catalyzed by Novozym-435. The procedure implies that the mixed ester derivatives prepared and isolated from the first esterification step act as acylating agents in the second esterification step
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