4,840 research outputs found
Safety and efficacy of gene therapy for Pompe disease
No full textLa malattia di Pompe è una malattia neuromuscolare grave causata da mutazioni nell’enzima lisosomiale -glucosidasi acida (GAA), le quali determinano l'accumulo patologico di glicogeno in tutti i tessuti. La terapia di sostituzione enzimatica (ERT) è disponibile per la suddetta malattia, ma essa ha solo una limitata efficacia, mentre mostra un’elevata immunogenicità, e non riesce a correggere gruppi di tessuti muscolari e nervosi più refrattari alla cross-csorrezione. Usando l'analisi bioinformatica e ingegnerizzando l’enzima, abbiamo sviluppato transgeni GAA secrenibili per una maggiore cross-correzione della malattia di Pompe tramite virus adeno associati (AAV) attraverso l’espressione epato-specifica della GAA. I topi Pompe sono stati trattati con vettori AAV ottimizzati per l'espressione dei transgeni secrenibili della GAA e fatto un follow-up di 10 mesi. Il trasferimento genico ha evidenziato una correzione dose e tempo dipendente di entrambi i difetti biochimici e funzionali nei muscoli, sistema nervoso centrale e del midollo spinale, con normalizzazione di ipertrofia cardiaca, muscolare e funzione respiratoria, e la sopravvivenza indistinguibile dai topi wild-type. In questi esperimenti, transgeni GAA secernibili hanno mostrato un’efficacia terapeutica superiore e decisamente una bassa immunogenicità rispetto alla loro controparte GAA non secreta. La dimostrazione di un grande potenziale terapeutico e’ evidenziata dal fatto che l’AAV iniettato in primati era in grado di eprimere e secernere discreti livelli di GAA in circolo, ed utilizzando nuovi serotipi di AAV potevamo esprimere la GAA anche in epatociti primari. Considerando che l'immunogenicità della -glucosidasi acida ricombinante (rhGAA) nella terapia enzimatica sostitutiva (ERT) è un problema cosi come l'efficacia nella gestione della malattia di Pompe nei pazienti adulti (LOPD), effetti a lungo termine del ERT sulle risposte umorali e cellulari alla GAA sono ancora poco compresi. Per capire meglio l'impatto dell’immunogenicità del rhGAA sull'efficacia della ERT, dati clinici e campioni di sangue di pazienti LOPD sottoposti a ERT per più di 4 anni o non trattati sono stati raccolti e analizzati. Nei pazienti trattati LOPD, anticorpi anti-GAA avevano un picco entro i primi 1000 giorni di ERT, mentre l'esposizione a lungo termine per rhGAA comportava una clearance degli anticorpi con una produzione residua di IgG non neutralizzanti. Analisi di risposte delle cellule T al rhGAA mostravano una rilevabile reattività delle cellule T solo dopo una ristimolazione in vitro. Incremento di diverse citochine e chemochine era rilevabile sia in soggetti LOPD trattati e non trattati, mentre la secrezione di IL-2 era rilevabile solo nei soggetti che avevano ricevuto ERT. Questi risultati indicano che l’ERT a lungo termine in pazienti LOPD comporta una diminuzione dei titoli anticorpali ed una produzione residua di IgG non inibitorie. Una risposta immunitaria alla GAA a lungo termine in soggetti sottoposti a ERT non sembra influenzare l'efficacia della terapia e sono coerenti con un effetto immunomodulante eventualmente mediata da cellule T regolatorie.Pompe disease is a severe neuromuscular disorder caused by mutations in the lysosomal enzyme acid -glucosidase (GAA), which result in the pathological accumulation of glycogen in all tissues. Enzyme replacement therapy (ERT) is available for Pompe disease, however it has only limited efficacy, high immunogenicity, and fails to correct nervous tissue and muscle groups more refractory to cross-correction. Using bioinformatics analysis and protein engineering, we developed secretable GAA transgenes for enhanced cross-correction of Pompe disease via adeno-associated virus (AAV) vector liver gene transfer. Pompe mice were treated with AAV vectors optimized for hepatic expression of secretable GAA transgenes and followed for up to 10 months post-gene transfer. Gene transfer resulted in dose- and time- dependent whole-body correction of both the biochemical and functional defects in muscle, central nervous system and spinal cord, with normalization of cardiac hypertrophy, muscle and respiratory function, and survival undistinguishable from wild-type littermates. In these experiments, secretable GAA transgenes showed superior therapeutic efficacy and markedly low immunogenicity compared with their native GAA counterpart. Scale up to non-human primates, and modeling of GAA expression in primary hepatocytes using novel AAV vector serotypes, demonstrate the therapeutic potential of AAV vector-mediated liver expression of secretable GAA transgenes, and support the feasibility of the approach in Pompe patients.
Considering that immunogenicity of recombinant human acid-alpha glucosidase (rhGAA) in enzyme replacement therapy (ERT) is a safety and efficacy concern in the management of late-onset Pompe disease (LOPD), long-term effects of ERT on humoral and cellular responses to GAA are still poorly understood. To better understand the impact of immunogenicity of rhGAA on the efficacy of ERT, clinical data and blood samples from LOPD patients undergoing ERT for more than 4 years or untreated were collected and analyzed. In treated LOPD patients, anti-GAA antibodies peaked within the first 1000 days of ERT, while long-term exposure to rhGAA resulted in clearance of antibodies with residual production of non-neutralizing IgG. Analysis of T cell responses to rhGAA showed detectable T cell reactivity only after in vitro restimulation. Upregulation of several cytokines and chemokines was detectable both treated and untreated LOPD subjects, while IL2 secretion was detectable only in subjects who received ERT. These results indicate that long-term ERT in LOPD patients results in a decrease in antibody titers and residual production of non-inhibitory IgGs. Immune responses to GAA following long-term ERT do not seem to affect efficacy of ERT and are consistent with an immunomodulatory effect possibly mediated by regulatory T cells
SO2 resistant soot oxidation catalysts based on orthovanadates
No full textMetal orthovanadates based on Fe, Al and Ce were prepared by co-precipitation and their structural,
morphological and reduction properties were characterized by means of XRD, BET and temperature
programmed reduction (H2-TPR). Catalytic soot oxidation was carried out with thermogravimetric analysis
(TGA) and temperature programmed oxidation (TPO), respectively, to study the influence of the soot-catalyst
contact (tight or loose) as well as the influence of SO2 contamination on the catalyst's activity. The catalysts were
compared with CeO2 as reference material. Under tight contact mode, metal orthovanadates were able to oxidize
soot at 466–483 °C while in loose contact mode their activity was close to that of CeO2. However, the former did
not suffer an activity loss due to SO2 poisoning, which is attributed to less adsorptive interactions between SO2
and the vanadates as could be proven by FT-IR and Raman spectroscopy
The carboxyl-terminal region is NOT essential for secreted and functional levels of coagulation factor X
No full textBackground: The homologous coagulation factor X (FX), VII (FVII), IX (FIX) and protein C (PC) display striking differences in the carboxyl-terminus, with that of FX being the most extended. This region is essential for FVII, FIX and PC secretion. Objectives: To provide experimental evidence for the role of the FX carboxyl-terminus. Methods: Recombinant FX (rFX) variants were expressed in multiple eukaryotic cell systems. Protein and activity levels were evaluated by ELISA, coagulant and amidolytic assays. Results and discussion: Expression of a panel of progressively truncated rFX variants in HEK293 cells revealed that the deletion of up to 21 residues in the carboxyl-terminus did not significantly affect secreted protein levels, as confirmed in HepG2 and BHK21 cells. In contrast, chimeric rFX-FVII variants with swapped terminal residues showed severely reduced levels. The truncated rFX variants revealed normal amidolytic activity, suggesting an intact active site. Intriguingly, these variants, which included that resembling the activated FXβ form once cleaved, also displayed remarkable or normal pro-coagulant capacity in PT- and aPTT-based assays. This supports the hypothesis that subjects with nonsense mutations in the FX carboxyl-terminus, so far never identified, would be asymptomatic. Conclusions: For the first time we demonstrate that the FX carboxyl-terminal region downstream of residue K467 is not essential for secretion and provides a modest contribution to pro-coagulant properties. These findings, which might suggest an involvement of the carboxyl-terminal region in the divergence of the homologous FX, FVII, FIX and PC, help to interpret the mutational pattern of FX deficiency
Improved process for the transformation of primary aliphatic alcohols into higher aliphatic alcohols
No full textA process for obtaining higher aliphatic alcohols starting from aliphatic primary alcohols by condensation reactions is disclosed. Specifically, the process comprises a step in which an aliphatic primary alcohol is contacted in a 5 homogeneous phase with a catalyst mixture comprising a transition metal, a base and an additive; specifically, this additive can be selected from the classes of compounds of the isoquinolines N-oxide, quinolines N-oxide, pyridines N-oxide, benzoquinones, naphthoquinones, or TEMPO. In particular, the process can be carried out by contacting said aliphatic primary alcohol with a catalyst of a 10 recycled transition metal, with a freshly added base and with a recycled additive of the aforementioned type
Francesco Scorza Barcellona o della passione agiografica
No full textL'autrice traccia, sul filo dei ricordi, il profilo scientifico ed umano di Francesco Scorza Barcellona ed introduce gli studi raccolti nel volume.The author traces, on the thread of memories, the scientific and human profile of Francesco Scorza Barcelona and introduces the studies collected in the book
Delle lodi di don Francesco Medici de' principi di Toscana : orazione /
No full textEngraved t.p. vignette of Medici arms. On recto of 2nd leaf is Callot's full-page engraved port. of Francesco de' Medici, son of Grand Duke Ferdinand I. It is in Lieure's 1st state. The port. also appeared the same year in Alessandro Adimari's Esequie dell' ill.mo & ecc.mo principe don Francesco Medici (Florence : Gio. Donato & Bernardino Giunti); see Lieure. Large woodcut Giunti device on p. [31].Lieure, J. Jacques Callot,Mode of access: Internet.At head of front pastedown is bookplate of Francesco Riccardi de Vernaccia (Florence, ca. 1780; see Gelli, p. 387). Below it is the label of Horatius (Orazio) Landau, with stamped shelfmark 53021. At foot is the bookplate of U. Manganelli, signed with the initials SER. A dedicatory inscription at foot of t.p. has been scratched out.Binding: modern marbled paper, backed in green vellum. Date, author & title writte on spine.Port. trimmed into the image at right margin and foot
Frankenstein
No full text@inproceedings{orsini2015graph,
title={Graph invariant kernels},
author={Orsini, Francesco and Frasconi, Paolo and De Raedt, Luc},
booktitle={IJCAI Proceedings-International Joint Conference on Artificial Intelligence. IJCAI},
year={2015}
Stacking the Nanochemistry Deck: Structural and Compositional Diversity in One-Dimensional Photonic Crystals
No full textOne-dimensional photonic structures, known as Bragg stacks reflectors or Bragg mirrors, represent a well-developed subject in the field of optical science. However, because of a lack of dynamic tunablity and their dependence on complex top-down techniques for their fabrication, they have received little attention from the materials science community present recent and ongoing developments on the way to fun dimensional photonic structures obtained from simple botton-up techniques. We focus on the versatility of this new approach, which allows the incorporation of a wide range of materials into photonic structures
Didattica e ricerca. L’esperienza del Laboratorio aragonese e sforzesco
No full textIn the workshop on Diplomatic correspondences in the Italian Renaissance, directed in January-May 2018 by Francesco Storti and Francesco Senatore in the Istituto italiano per gli studi filosofici of Naples, 12 undergraduate and graduate students learned to read and trascribe italian diplomatic dispatches of the 15th cent., producing a specimen of scientific edition. In the opinion of the author, such activities and similar ones are very useful for future school teachers and scholars and they could be introduced in the university and pHD courses of history. Students of humanistic sciences should have concrete contacts with the historical research on primary sources. On the other hand, editing of historical sources could become a marginal activity because it is not enough appreciated in the current research evaluation processes.
Keywords: Didattica, edizione documentaria, diplomazia rinascimentale; education, documentary edition, renaissance diplomac
LA MADONNA ESTERHAZY DI RAFFAELLO
No full textLA MADONNA ESTERHÁZY DI RAFFAELLO A PALAZZO MARINO, di Francesco Murano,
Fotografie di Sergio Oriani
Il curatore della mostra, Stefano Zuffi, ha voluto inquadrare criticamente l’opera di Raffaello
proveniente dal Museo di Budapest, ponendola tra la Vergine delle Rocce di Francesco Melzi,
proveniente dall’Istituto delle Suore Orsoline di Milano e la Madonna della Rosa di Giovanni
Antonio Boltraffio, proveniente dal Museo Poldi Pezzoli della stessa città. L’architetto Corrado
Anselmi ha progettato un affascinante allestimento, concependolo come un percorso che si
sviluppa attraverso tre soste utili all’ammirazione delle opere. L’autore Francesco Murano,
spiega con ricchezza di particolari i vincoli del progetto illuminotecnico e le scelte luministiche.Once again, for the Christmas season, the Municipally of Milan decided to display an important work in the frame of the Palazzo Marino’s Alessi Hall. For this year 2014, the choice has been to propose the Estheràzy Madonna by Raphael, from the Museum of Budapest.
The exhibition curator, Stefano Zuffi, wanted to critically frame to work of Raphael by placing it between the Vegine delle Rocce (Virgin of the Rocks) by Francesco Melzi, coming from the Milan’s Istituto delle Suore Orsoline, and the Madonna della Rosa by Giovanni Boltraffio, from the Milanese Museo Poldi Pezzoli.
The Architect Corrado Anselmi designed a fascinating display, convinced as a path that develops through three stops that are useful for the enjoyment of the works.
The author Francesco Murano, explains with many details the lighting design project
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