Selectively charged and zwitterionic analogues of the smallest immunogenic structure of Streptococcus pneumoniae type 14

Zwitterionic polysaccharides (ZPs) have been shown in recent years to display peculiar immunological properties, thus attracting the interest of the carbohydrate research community. To fully elucidate the mechanisms underlying these properties and exploit the potential of this kind of structures, in depth studies are still required. In this context, the preparation of two cationic, an anionic, as well as two zwitterionic tetrasaccharide analogues of the smallest immunogenic structure of Streptococcus pneumoniae type 14 (SP14) capsular polysaccharide are presented. By exploiting a block strategy, the negative charge has been installed on the non-reducing end of the lactose unit of the tetrasaccharide and the positive charge either on the non-reducing end of the lactosamine moiety or on an external linker. These structures have then been tested by competitive ELISA, showing that the structural variations we made do not modify the affinity of the neutral compound to binding to a specific antibody. However, lower efficacies than the natural SP14 compound were observed. The results obtained, although promising, point to the need to further elongate the polysaccharide structure, which is likely too short to cover the entire epitopes

Activation of carbonic anhydrases from human brain by amino alcohol oxime ethers: towards human carbonic anhydrase VII selective activators

The synthesis and carbonic anhydrase (CA; EC 4.2.1.1) activating effects of a series of oxime ether-based amino alcohols towards four human (h) CA isoforms expressed in human brain, hCA I, II, IV and VII, are described. Most investigated amino alcohol derivatives induced a consistent activation of the tested CAs, with KAs spanning from a low micromolar to a medium nanomolar range. Specifically, hCA II and VII, putative main CA targets when central nervous system (CNS) diseases are concerned, were most efficiently activated by these oxime ether derivatives. Furthermore, a multitude of selective hCA VII activators were identified. As hCA VII is one of the key isoforms involved in brain metabolism and other brain functions, the identified potent and selective hCA VII activators may be considered of interest for investigations of various therapeutic applications or as lead compounds in search of even more potent and selective CA activators

Confirmation of antiphospholipid antibody positivity: a year's results in a cohort of 113 patients

Objective: To evaluate the confirmation rate of antiphospholipid antibodies (aPL), to analyze their behaviour at confirmation time, and to study the clinical value of their confirmation. Methods: Blood samples from 380 subjects, enrolled in this study from June 1, 2007 to May 31, 2008, were tested for anti-cardiolipin (aCL) and anti-beta2glycoprotein (aβ2GPI) antibodies using an ELISA method and for Lupus anticoagulant (LA) using a series of clotting tests. The samples of the 113 subjects resulting positive at the first testing time were assayed again to confirm antiphospholipid positivity. Results: aPL positivity was confirmed in 67 out of the 113 subjects (59.3%). Medium-high antibody levels of all, except IgM aCL, aPL/ELISA had a significantly higher confirmation rate with respect to that in subjects with low levels. The confirmation rate in the category I antibody patients (multiple positivity) was higher than that in the category II antibody subjects (single positivity). LA positivity was confirmed only when it was associated to other aPL. The cut-off of 40 GPL produced a confirmation rate equal to that resulting from a 99th percentile cut-off. Confirmation of aPL positivity made it possible for us to confirm the diagnosis of antiphospholipid syndrome (APS) in 8 out of the 113 subjects originally resulting positive (7,1%). APS clinical features were vascular thrombosis in 4 of these and pregnancy morbidity in the other 4. Conclusions: Our data emphasize aPL positivity confirmation selectivity, and medium-high antibody levels and category I antibodies (multiple positivity) had the best confirmation rates

The westward lithospheric drift, its role on the subduction and transform zones surrounding Americas. Andean to cordilleran orogenic types cyclicity

We investigate the effect of the westerly rotation of the lithosphere on the active margins that surround the Americas and find good correlations between the inferred easterly-directed mantle counterflow and the main structural grain and kinematics of the Andes and Sandwich arc slabs. In the Andes, the subduction zone is shallow and with low dip, because the mantle flow sustains the slab; the subduction hinge converges relative to the upper plate and generates an uplifting doubly verging orogen. The Sandwich Arc is generated by a westerly-directed SAM (South American) plate subduction where the eastward mantle flow is steepening and retreating the subduction zone. In this context, the slab hinge is retreating relative to the upper plate, generating the backarc basin and a low bathymetry single-verging accretionary prism. In Central America, the Caribbean plate presents a more complex scenario: a) To the East, the Antilles Arc is generated by westerly directed subduction of the SAM plate, where the eastward mantle flow is steepening and retreating the subduction zone. b) To the West, the Middle America Trench and Arc are generated by the easterly-directed subduction of the Cocos plate, where the shallow subduction caused by eastward mantle flow in its northern segment gradually steepens to the southern segment as it is infered by the preexisting westerly-directed subduction of the Caribbean Plateau. In the frame of the westerly lithospheric flow, the subduction of a divergent active ridge plays the role of introducing a change in the oceanic/continental plate's convergence angle, such as in NAM (North American) plate with the collision with the Pacific/Farallon active ridge in the Neogene (Cordilleran orogenic type scenario). The easterly mantle drift sustains strong plate coupling along NAM, showing at Juan de Fuca easterly subducting microplate that the subduction hinge advances relative to the upper plate. This lower/upper plate convergence coupling also applies along strike to the neighbor continental strike slip fault systems where subduction was terminated (San Andreas and Queen Charlotte). The lower/upper plate convergence coupling enables the capture of the continental plate ribbons of Baja California and Yakutat terrane by the Pacific oceanic plate, transporting them along the strike slip fault systems as para-autochthonous terranes. This Cordilleran orogenic type scenario, is also recorded in SAM following the collision with the Aluk/Farallon active ridge in the Paleogene, segmenting SAM margin into the eastwardly subducting Tupac Amaru microplate intercalated between the proto-Liquiñe-Ofqui and Atacama strike slip fault systems, where subduction was terminated and para-autochthonous terranes transported. In the Neogene, the convergence of Nazca plate with respect to SAM reinstalls subduction and the present Andean orogenic type scenario

Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide

ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Dysregulated aggrecanase activity of ADAMTS-5 has been directly linked to the etiology of osteoarthritis (OA). For this reason, ADAMTS-5 is a pharmaceutical target for the treatment of OA. ADAMTS-5 shares high structural and functional similarities with ADAMTS-4, which makes the design of selective inhibitors particularly challenging. Here we exploited the ADAMTS-5 binding capacity of β-N-acetyl-d-glucosamine to design a new class of sugar-based arylsulfonamides. Our most promising compound, 4b, is a non-zinc binding ADAMTS-5 inhibitor which showed high selectivity over ADAMTS-4. Docking calculations combined with molecular dynamics simulations demonstrated that 4b is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Furthermore, the interaction between 4b and the ADAMTS-5 Dis domain is mediated by hydrogen bonds between the sugar moiety and two lysine residues (K532 and K533). Targeted mutagenesis of these two residues confirmed their importance both for versicanase activity and inhibitor binding. This positively-charged cluster of ADAMTS-5 represents a previously unknown substrate-binding site (exosite) which is critical for substrate recognition and can therefore be targeted for the development of selective ADAMTS-5 inhibitors

Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide

ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Dysregulated aggrecanase activity of ADAMTS-5 has been directly linked to the etiology of osteoarthritis (OA). For this reason, ADAMTS-5 is a pharmaceutical target for the treatment of OA. ADAMTS-5 shares high structural and functional similarities with ADAMTS-4, which makes the design of selective inhibitors particularly challenging. Here we exploited the ADAMTS-5 binding capacity of β-N-acetyl-d-glucosamine to design a new class of sugar-based arylsulfonamides. Our most promising compound, 4b, is a non-zinc binding ADAMTS-5 inhibitor which showed high selectivity over ADAMTS-4. Docking calculations combined with molecular dynamics simulations demonstrated that 4b is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Furthermore, the interaction between 4b and the ADAMTS-5 Dis domain is mediated by hydrogen bonds between the sugar moiety and two lysine residues (K532 and K533). Targeted mutagenesis of these two residues confirmed their importance both for versicanase activity and inhibitor binding. This positively-charged cluster of ADAMTS-5 represents a previously unknown substrate-binding site (exosite) which is critical for substrate recognition and can therefore be targeted for the development of selective ADAMTS-5 inhibitors

Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines

Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeutic agents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)aminoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 by fluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular docking. The most promising hit was the quinoline derivative VS13, a nanomolar inhibitor of HDAC6, which exhibited a good antiproliferative effect on UM cell lines at micromolar concentration and a capability to modify the mRNA levels of HDAC target genes similar to that of SAHA

Sialendoscopy for salivary stones: principles, technical skills and therapeutic experience

La scialoadenite cronica ostruttiva rappresenta una delle più frequenti patologie non-neoplastiche delle ghiandole salivari e la scialoendoscopia è sempre più utilizzata nella sua diagnosi e nel suo trattamento, associata o meno con la litotripsia laser. La scialoendoscopia può essere inoltre associata ad approcci esterni mini-invasivi nelle litiasi troppo voluminose per essere rimosse con un approccio unicamente endoscopico. Il presente articolo riporta lesperienza delle Cliniche Otorinolaringoiatriche dellOspedale SantOrsola-Malpighi di Bologna e dellAzienda Ospedaliero Universitaria di Cagliari, Italia. È stata eseguita unanalisi retrospettiva su 48 pazienti (26 femmine, 22 maschi; età media di 45,3 anni; range 8-83 anni) trattati per patologia cronica ostruttiva delle ghiandole salivari maggiori mediante procedure chirurgiche endoscopiche o combinate da novembre 2010 ad aprile 2016 presso lAzienda-Ospedaliero-Universitaria di Cagliari. I risultati dellOspedale SantOrsola-Malpighi di Bologna erano stati precedentemente pubblicati. Gli aspetti tecnici della scialoendoscopia sono stati accuratamente descritti. I pazienti trattati presso lAzienda Ospedaliero Universitaria di Cagliari presentavano una patologia unilaterale in 40 casi e bilaterale in 8 casi; sono state trattate 56 ghiandole salivari maggiori (22 sottomandibolari e 34 parotidi). 5 pazienti sono stati sottoposti a scialoendoscopia bilaterale per parotite ricorrente giovanile, 10 per patologia ostruttiva non litiasica e 33 (68,75%) presentavano calcoli salivari (1 paziente presentava una litiasi parotidea bilaterale). Solo 8 pazienti sono stati sottoposti a scialectomia radicale per via esterna (5 scialectomie sottomandibolare e 3 parotidectomie). La chirurgia conservativa nei pazienti con scialoadenite cronica ostruttiva appare efficace e può essere realizzata mediante un approccio puramente endoscopico o combinato, con unalta percentuale di successo. La procedura richiede una strumentazione adeguata e deve essere eseguita da un chirurgo esperto, che abbia svolto un training specifico scialoendoscopico, in modo da evitare le possibili complicanze maggiori e minori. La scialectomia tradizionale rappresenta la extrema ratio, limitata nei casi in cui un approccio conservativo sia risultato inefficace o controindicato

The Bortoluzzi Mud Volcano (Ionian Sea, Italy) and its potential for tracking the seismic cycle of active faults

The Ionian Sea in southern Italy is at the center of active interaction and convergence between the Eurasian and African-Adriatic plates in the Mediterranean. This area is seismically active with instrumentally and/or historically recorded Mw > 7:0 earthquakes, and it is affected by recently discovered long strike-slip faults across the active Calabrian accretionary wedge. Many mud volcanoes occur on top of the wedge. A recently discovered one (called the Bortoluzzi Mud Volcano or BMV) was surveyed during the Seismofaults 2017 cruise (May 2017). High-resolution bathymetric backscatter surveys, seismic reflection profiles, geochemical and earthquake data, and a gravity core are used here to geologically, geochemically, and geophysically characterize this structure. The BMV is a circular feature ' 22 m high and ' 1100 m in diameter with steep slopes (up to a dip of 22). It sits atop the Calabrian accretionary wedge and a system of flower-like oblique-slip faults that are probably seismically active as demonstrated by earthquake hypocentral and focal data. Geochemistry of water samples from the seawater column on top of the BMV shows a significant contamination of the bottom waters from saline (evaporite-type) CH4-dominated crustal-derived fluids similar to the fluids collected from a mud volcano located on the Calabria mainland over the same accretionary wedge. These results attest to the occurrence of open crustal pathways for fluids through the BMV down to at least the Messinian evaporites at about-3000 m. This evidence is also substantiated by helium isotope ratios and by comparison and contrast with different geochemical data from three seawater columns located over other active faults in the Ionian Sea area. One conclusion is that the BMV may be useful for tracking the seismic cycle of active faults through geochemical monitoring. Due to the widespread diffusion of mud volcanoes in seismically active settings, this study contributes to indicating a future path for the use of mud volcanoes in the monitoring and mitigation of natural hazards

RAPPORTO SULLE INDAGINI DI SISMICA A RIFLESSIONE, GRAVIMETRICHE, MAGNETOMETRICHE, MORFOBATIMETRICHE E CAMPIONAMENTO FONDO MARE NELL’ ARCO CALABRO (MAR IONIO) CAMPAGNA CALAMARE08

The study of the Calabrian Arc in the Ionian Sea is key to understanding of the geological processes in the Mediterranean Sea. We present the technical details and results of cruise CALAMARE08 with N/O Urania during spring 2008. We acquired a large set of geological and geophysical data, among them Multichannels Seismic and SBP, magnetometry, gravimetry, swath bathymetry and coring of sea bottom