78 research outputs found

    Preclinical Evaluation of a Lentiviral Vector for Huntingtin Silencing.

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    Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder resulting from a polyglutamine expansion in the huntingtin (HTT) protein. There is currently no cure for this disease, but recent studies suggest that RNAi to downregulate the expression of both normal and mutant HTT is a promising therapeutic approach. We previously developed a small hairpin RNA (shRNA), vectorized in an HIV-1-derived lentiviral vector (LV), that reduced pathology in an HD rodent model. Here, we modified this vector for preclinical development by using a tat-independent third-generation LV (pCCL) backbone and removing the original reporter genes. We demonstrate that this novel vector efficiently downregulated HTT expression in vitro in striatal neurons derived from induced pluripotent stem cells (iPSCs) of HD patients. It reduced two major pathological HD hallmarks while triggering a minimal inflammatory response, up to 6 weeks after injection, when administered by stereotaxic surgery in the striatum of an in vivo rodent HD model. Further assessment of this shRNA vector in vitro showed proper processing by the endogenous silencing machinery, and we analyzed gene expression changes to identify potential off-targets. These preclinical data suggest that this new shRNA vector fulfills primary biosafety and efficiency requirements for further development in the clinic as a cure for HD

    Itinerant effects and enhanced magnetic interactions in Bi-based multilayer cuprates

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    The cuprate high temperature superconductors exhibit a pronounced trend in which the superconducting transition temperature Tc increases with the number of CuO2 planes n in the crystal structure. We compare the magnetic excitation spectrum of Bi2+xSr2−xCuO6+ή (Bi-2201) and Bi2Sr2Ca2Cu3O10+ή (Bi-2223), with n = 1 and 3, respectively, using Cu L3-edge resonant inelastic x-ray scattering. Near the antinodal zone boundary we find the paramagnon energy in Bi-2223 is substantially higher than that in Bi-2201, indicating that multilayer cuprates host stronger effective magnetic exchange interactions, providing a possible explanation for the Tc vs n scaling. In contrast, the nodal direction exhibits very strongly damped, almost nondispersive excitations. We argue that this implies that the magnetism in the doped cuprates is partially itinerant in nature

    Excitonic Instability in the Transition from the Black Phase to the Golden Phase of SmS under Pressure Investigated by Infrared Spectroscopy

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    We report the pressure-dependent optical reflectivity spectra of a strongly correlated insulator, samarium monosulfide (SmS), in the far- and middle-infrared regions to investigate the origin of the pressure-induced phase transition from the black phase to the golden phase. The energy gap becomes narrow with increasing pressure in the black phase. A valence transition from Sm2+ in the black phase to mainly Sm3+ in the golden phase accompanied by spectral change from insulator to metal were observed at the transition pressure of 0.65 GPa. The black-to-golden phase transition occurs when the energy gap size of black SmS becomes the same as the binding energy of the exciton at the indirect energy gap before the gap closes. This result indicates that the valence transition originates from an excitonic instability.Comment: 5 pages, 4 figures. To be published in J. Phys. Soc. Jpn. Vol. 77, No. 1

    Changing the prehistory of Sindh and Las Bela coast: twenty-five years of Italian contribution

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    The paper discusses the prehistory of Lowr Sindh and Las Bela Coast, and the role played by the Italian archaeologists since the 1980's. New date are presented regarding mainly the radiocarbon chronology the Indus Delta settlement on rocky outcrops and the shell middens of Las Bela

    Manquements au droit Ă  l’information du sujet ĂągĂ© cognitivement dĂ©pendant

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    International audienceRĂ©sumĂ© Les auteurs rappellent qu’un des droits fondamentaux du sujet ĂągĂ© cognitivement dĂ©pendant est celui d’ĂȘtre informĂ© clairement de ce qui le concerne (santĂ©, finances, entourage) mais ce droit peut ĂȘtre aisĂ©ment mĂ©connu. Ceci relĂšve sans doute d’intentions altruistes (Ă©viter des souffrances) mais ne prend guĂšre en compte les effets dĂ©lĂ©tĂšres occasionnĂ©s dĂšs lors que le sujet n’est plus considĂ©rĂ© comme acteur de sa propre vie. Ainsi nous pouvons considĂ©rer trois exemples de situations courantes de mĂ©sinformation du sujet ĂągĂ© cognitivementdĂ©pendant : l’annonce du diagnostic de maladie neurocognitive et notamment de maladie d’Alzheimer (annonce partielle ou au seul profit de l’entourage) ; l’absence d’annonce du dĂ©cĂšs d’un proche (enfant-conjoint) dĂšs lors que le sujet ĂągĂ© prĂ©sente une altĂ©ration cognitive patente ; le manque de clartĂ© dans l’annonce de l’institutionnalisation. Cet exposĂ© n’a pas vocation Ă  juger des comportements soignants, mĂ©dicaux ou d’aidants mais Ă  tĂ©moigner des limites d’un systĂšme de prise en soin, marquĂ© par le manque, sinon l’absence, de contrĂŽlesjuridiques concernant notamment l’institutionnalisation
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