3,272 research outputs found
[Luigi de Micheli (c. 1918), funerary sculpture]
No full textFrom Berresford: Luigi de Micheli (c. 1918), Enrico Butti, Cimitero Monumentale, Milan.Woman, lion.Title from Berresford
Orthosteric and allosteric ligands selectively acting at cholinergic receptor subtypes
No full textThe presentation will focus on the results recently achieved by our research group in the design, synthesis and pharmacological evaluation of selective ligands which target cholinergic receptor subtypes, belonging to both the nicotinic (nAChR) and the muscarinic (mAChR) acetylcholine receptor families. A set of spirocyclic derivatives will be illustrated, in which the simultaneous presence of the quinuclidinyl and Delta2-isoxazolinyl moieties, coupled with suitable stereoelectronic features of the substituent at position 3 of the spirocyclic ring, engendered a selective agonist profile at the homomeric neuronal alpha7 nAChRs [1]. The most promising compound in the series has been further investigated in preclinical studies and in in vivo models of CNS disorders and neuropathic pain. A group of novel hybrid peptides structurally related to natural alpha-conotoxins MII and PIA will be also presented, which behave as competitive antagonists able to discriminate alpha6beta2* and alpha3beta2* nAChR subtypes [2]. The five mAChR subtypes bind their physiological transmitter in the highly conserved orthosteric site within the transmembrane domains of the receptors. Orthosteric muscarinic agonists have negligible binding selectivity and poor signaling specificity. A less conserved allosteric site has been also characterized at the extracellular entrance of the binding pocket of mAChRs. To gain subtypeselective M2 receptor activation, we designed a group of putative bitopic compounds, i. e. hybrid derivatives fusing highly potent, unselective oxotremorinelike orthosteric activators with M2-selective bis(ammonio)alkane-type allosteric fragments. The new ligands interacted simultaneously with both recognition areas of the receptor protein, thus allowing the exploitation of favorable features of the orthosteric and the allosteric site by a single ligand molecule. The orthosteric interaction provided high affinity binding and activation of M2 mAChRs. The allosteric interaction yielded receptor subtype-selectivity and, in addition, could modulate efficacy and activate pathway-specific intracellular signaling [3]. [1] C.Dallanoce, P.Magrone, C.Matera, F.Frigerio, G.Grazioso, M.De Amici, S.Fucile, V.Piccari, K.Frydenvang, L.Pucci, C.Gotti, F.Clementi, C.De Micheli, ChemMedChem, 6, 2011, 889-903. [2] M.De Amici, G.Grazioso, C.Dallanoce, C.De Micheli et al., submitted. [3] K.Mohr, C.Tränkle, E.Kostenis, E.Barocelli, M.De Amici, U.Holzgrabe, Br.J.Pharmacol., 159, 2010, 997-1008
Design, synthesis and biological characterization of PfGAPDH inhibitors
No full textMalaria has a tremendous health, social and economic impact on people living in tropical and subtropical regions of the world. WHO estimated 214 million cases and 438 000 deaths in 2015 and 3.2 billion people are globally at risk of infection1. Available treatments are becoming progressively less effective, mainly because parasites are constantly acquiring resistance toward the drug in use. Therefore, there is an urgent need of developing therapeutic agents acting on new targets.
Plasmodium parasites (P. falciparum is the most lethal), in their amastigote phase, produce energy only through glycolysis. In this pathway, GAPDH catalyses the first energy productive step and thus represent a valuable target for drug discovery. Known GAPDH inhibitors that bind to the active site are small nonselective molecules (iodoacetamide, 3-bromopyruvate), which irreversibly react with cysteine residues of the enzyme, including the catalytic one. We designed and synthesized the first series of inhibitors characterized by a 3-bromoisoxazoline warhead2, inspired by 3-bromoacivicin, a known inhibitor of reactive cysteine containing enzymes3. The compounds were assayed for the inhibitory activity on the P. falciparum isolated enzyme showing a biphasic irreversible inactivation. MS/MS studies of the digested protein demonstrated the mild reactivity of the exploited warhead, which only reacts with catalytic Cys (activated by a His residues). The human ortholog of GAPDH is only partially inhibited (up to 25%). We explained this through a negative cooperativity that prevents the alkylation of all the four monomers of hGAPDH, resulting in selectivity among the two isoforms of GAPDH4. Compounds were also assayed on cultures of the bloodstream form of P. falciparum and human cell lines in order to determine their in vitro antiparasitic activity and toxicity.
The goal of this project is to obtain compounds with improved potency and pharmacokinetic properties, suitable for in vivo studies on animal model of P. falciparum infections.
1. http://www.who.int/mediacentre/factsheets/fs094/en/
2. Bruno, S.; Pinto, A.; Paredi, G.; Tamborini, L.; De Micheli, C.; La Petra, V.; Marinelli, L.; Novellino, E.; Conti, P.; Mozzarelli, A. J. Med. Chem. 2014, 57(17), 7465-7471.
3. a) Conti, P.; Pinto, A.; Wong, P.E.; Major, L.L.; Tamborini, L.; Iannuzzi M.C.; De Micheli, C.; Barrett, M.P.; Smith, T.K. ChemMedChem 2011, 6(2), 329-333. b) Tamborini, L.; Pinto, A.; Smith, T.K.; Major, L.L.; Iannuzzi, M.C.; Cosconati, S.; Marinelli, L.; Novellino, E.; Lo Presti, L.; Wong, P.E.; Barrett, M.P.; De Micheli, C.; Conti, P. ChemMedChem 2012, 7(9), 1623-1634.
4. Bruno, S.; Margiotta, M.; Pinto, A.; Cullia, G.; Conti, P.; De Micheli, C.; Mozzarelli, A. Bioorg. Med. Chem. 2016, 24(12), 2654-2659
La grande rilevanza dei piccoli parlamenti
No full textThis paper investigates the role played by parliamentary committees in the process of democratic consolidation and institutionalization of Parliament during the First Republic, with special reference to the years between 1968 and 1994. It is a stage in a research project pursuing a deeper understanding of the parliamentary dynamics at a crucial moment after their first inception, when the parliamentary regime underwent gradual stabilisation, which was, however, marked by recurring political crises.Questo contributo si propone di analizzare il ruolo del sistema delle commissioni parlamentari nel processo di consolidamento democratico e, in particolare, nell’istituzionalizzazione dell’assemblea rappresentativa durante la Prima Repubblica, nel periodo compreso tra il 1968 e il 1994. L’elaborato rappresenta una tappa di un percorso di ricerca volto a fornire una comprensione approfondita delle dinamiche parlamentari di una fase cruciale del consolidamento del regime parlamentare, successiva alle legislature instaurative, caratterizzata da una progressiva stabilizzazione istituzionale attraversata, però, da crisi politiche ricorrenti
Neurobiología de los movimientos oculares
No full text4 p.Para que la visión sea posible deben intervenir varios sistemas, que dependen de circuitos neuronales que conectan múltiples áreas del cerebro involucradas en funciones visuales (Duchowski, 2017; Micheli et al., 2003). A continuación se mencionarán las principales regiones del cerebro relacionadas con los movimientos oculares.Para que la visión sea posible deben intervenir varios sistemas, que dependen de circuitos neuronales que conectan múltiples áreas del cerebro involucradas en funciones visuales (Duchowski, 2017; Micheli et al., 2003). A continuación se mencionarán las principales regiones del cerebro relacionadas con los movimientos oculares
Le vite degli uomini illustri di Plutarco volgarizzate da Girolamo Pompei con varie note trascelte dal commento di Dacier edizione stereotipa ... volume 1. (-12.) - vol. 4
No full textCremona : dalla stamperia e fonderia stereotipa di Luigi De-Micheli e Bernardo Bellini, 1824
Incisioni in ovale di G. Maina
Segn.: [1]-15/8.
Mutilo di 1 c. di tav. Legatura in cartone rigido
Fondo Catellani
https://galileodiscovery.unipd.it/discovery/fulldisplay?context=L&vid=39UPD_INST:VU1&search_scope=MyInst_and_CI&tab=Everything&docid=alma99002563265020604
Le vite degli uomini illustri di Plutarco volgarizzate da Girolamo Pompei con varie note trascelte dal commento di Dacier edizione stereotipa ... volume 1. (-12.) - vol. 10
No full textCremona : dalla stamperia e fonderia stereotipa di Luigi De-Micheli e Bernardo Bellini, 1824
Segn.: [1]-22/8
Mutilo di 2 c. di tav. Legatura in cartone rigido
Fondo Catellani
https://galileodiscovery.unipd.it/discovery/fulldisplay?context=L&vid=39UPD_INST:VU1&search_scope=MyInst_and_CI&tab=Everything&docid=alma99002563284020604
More Security or More Freedom? A Comparative Analysis of the Equilibrium in European Democratic Regimes
No full textValutare la relazione sicurezza-libertà nelle democrazie contemporanee. Lineamenti teorici e metodologici
No full text- …
