A method for the analysis of the oligomerization profile of the Huntington’s disease-associated, aggregation-prone mutant huntingtin protein by isopycnic ultracentrifugation

Conformational diseases, such as Alzheimer’s, Parkinson’s and Huntington’s diseases as well as ataxias and fronto-temporal disorders, are part of common class of neurological disorders characterised by the aggregation and progressive accumulation of mutant proteins which display aberrant conformation. In particular, Huntington’s disease (HD) is caused by mutations leading to an abnormal expansion in the polyglutamine (poly-Q) tract of the huntingtin protein (HTT), leading to the formation of inclusion bodies in neurons of affected patients. Furthermore, recent experimental evidence is challenging the conventional view of the disease by revealing the ability of mutant HTT to be transferred between cells by means of extracellular vesicles (EVs), allowing the mutant protein to seed oligomers involving both the mutant and wild type forms of the protein. There is still no successful strategy to treat HD. In addition, the current understanding of the biological processes leading to the oligomerization and aggregation of proteins bearing the poly-Q tract has been derived from studies conducted on isolated poly-Q monomers and oligomers, whose structural properties are still unclear and often inconsistent. Here we describe a standardised biochemical approach to analyse by isopycnic ultracentrifugation the oligomerization of the N-terminal fragment of mutant HTT. The dynamic range of our method allows one to detect large and heterogeneous HTT complexes. Hence, it could be harnessed for the identification of novel molecular determinants responsible for the aggregation and the prion-like spreading properties of HTT in the context of HD. Equally, it provides a tool to test novel small molecules or bioactive compounds designed to inhibit the aggregation of mutant HTT

Petrology, geochemistry and U-Pb zircon geochronology of lower crust pyroxenites from northen Apennine (Italy): insights into the post-collisional Variscan evolution

Spinel pyroxenites occur locally as clasts in polygenic breccias from the Late Cretaceous sedimentary melanges of the Northern Apennine (Italy). They are of cumulus origin and formed in the deep crust by early precipitation of clinopyroxene and minor olivine and late crystallisation of orthopyroxene, spinel, Ti-pargasite and sulphides. Pyroxenites underwent high-temperature (ca. 850 °C) subsolidus re-equilibration and ductile deformation with development of mylonitic bands made of clinopyroxene, orthopyroxene, Ti-pargasite and spinel. U-Pb geochronology on zircons revealed the occurrence of inherited grains of Early Proterozoic to Late Devonian age. The inherited zircons are locally rimmed by recrystallised zircon domains. The oldest rims yield a mean concordia U-Pb age at 306 ± 8 Ma, which is considered to date the emplacement of the pyroxenites, in the framework of the post-Variscan lithospheric extension. The incompatible element compositions of calculated melts in equilibrium with clinopyroxenes from the pyroxenites are characterised by Ba, Nb, LREE and Sr enrichment relative to N-MORB. The depleted Nd isotopic signature of the pyroxenites (initial εNd values of +5.3 to +6.1) may be thus linked to primary magmas produced by low degrees of melting of asthenospheric mantle. In addition, the pyroxenites locally record the infiltration of plagioclase-saturated hydrous melts, most likely evolved through fractional crystallisation and enriched in highly incompatible elements, within the clinopyroxene-dominated crystal mush. A thermal event in Late Permian-Middle Triassic caused the partial resetting of zircon U-Pb system

Infrastrutture dei trasporti e città

In questo volume sono raccolti gli esiti del 6° Seminario Internazionale di Progettazione "Napoli, architettura e città". Eduard Bru, David Chipperfield, Max Dudler, Adolf Krischanitz, Christoph makler, Walter Arno Noebel hanno guidato i giovani architetti partecipanti nel progetto sulle aree degli svincoli del Vomero e dei Camaldoli della Tangenziale di Napoli. Il volume si conclude con i contributi di Kenneth Frampton e Robert Maxwell

La città di fondazione. Il quartiere di Monteruscello

I Seminari Internazionali di Progettazione "Napoli Architettura e Città" sono divenuti nel tempo una realtà importante nel panorama dei laboratori internazionali di progettazione. Questo volume documenta l'esperienza progettuale sul quartiere di Monteruscello -vera e propria città di fondazione- svolta da oltre cento giovani architetti guidati da Goncalo Byrne, Alberto Campo Baeza, David Chipperfield, Max Dudler, Luis Mateo e Jaques Sbriglio

Origin and timing of the post-Variscan gabbro-granite complex of Porto (Western Corsica)

The post-Variscan complex of Porto consists of metaluminous to slightly peraluminous A-type biotite granites mingled with gabbro-dioritic rocks, and late dykes with basaltic to trachyandesitic composition. U-Pb zircon dating by LA-ICP-MS on two mafic intrusive samples constrains the time of the gabbro-granite crystallisation at 281 ± 3 Ma and 283 ± 2 Ma. Hornblende 40Ar-39Ar ages from a late trachyandesite dyke date the dyking event at 280 ± 2 Ma, which is within error the U-Pb zircon ages of the intrusives. Biotite granites show variable major and trace element compositions and similar initial εNd (-0.3 to +0.9). Whole rock chemistry variations and trace element compositions of plagioclase and allanite indicate that the granites are genetically linked, essentially through fractional crystallisation of feldspars and minor allanite. On the basis of whole-rock chemistry (e.g. initial εNd +4.9 to +1.7) and trace element clinopyroxene compositions, we have ascertained that the mafic intrusives and basic dykes formed from isotopically depleted mantle source-derived melts with similar trace element signature. These basic melts experienced slightly different evolutionary histories, controlled by fractional crystallisation and crustal contamination, mainly by the acid magma that gave rise to the associated biotite granites, but also by the enclosing older Variscan granitoids. U-Pb zircon data suggest that the Porto complex was affected by hydrothermal fluid circulation at 259 ± 9 Ma

Interaction between basic and acid magmas during the latest stages of the post-collisional Variscan evolution: Clues from the gabbro-granite association of Ota (Corsica-Sardinia batholith)

The intrusive association of Ota (post-Variscan Corsica-Sardinia batholith) consists of mafic rocks and granites displaying mingling relations. The mafic rocks are olivine gabbros to quartz-diorites, and the granites are subsolvus and characterised by biotite as the only mafic phase. Minor amounts of amphibole-bearing granodiorites to granites develop along the contacts between mafic rocks and granites. The rather high initial εNd (+4.5) of the most primitive mafic sample indicates that parental basic melts had an extensive contribution from a depleted mantle source. In the mafic rocks, the decrease of initial εNd (to +2.1) is associated with an increase of Th and U concentrations in clinopyroxene, thus indicating that the Ota basic melts underwent a process of crustal contamination. Associated biotite granites have low initial εNd (+0.4) and high Th and U concentrations. The chemical evolution of Ota basic melts most likely occurred through fractional crystallisation and concomitant contamination with the acid magma that gave rise to associated biotite granites. The incompatible element signature of late-stage anhedral amphibole from variably evolved mafic rocks is similar, thus suggesting that the whole Ota mafic sequence recorded the contamination process, possibly by percolation within the gabbroic crystal mush of a melt contaminated by the acid magma. Hybridisation between basic and acid magmas is also documented by contact amphibole-bearing granitoids. In particular, major and trace element zoning of amphibole from granodiorites reveals that such a hybridisation was associated with reactions between crystals from the basic magma (amphibole and clinopyroxene) and the acid melt. The occurrence of chemically homogeneous amphiboles in associated granites suggests that “contact” hybridisation comprised also a process of gradient-induced chemical diffusion

Petrogenesis of Early Permian olivine-bearing cumulates and associated basalt dykes from Bocca di Tenda (Northern Corsica): Implications for post-collisional Variscan evolution

The Early Permian gabbroic sequence of Bocca di Tenda (Northern Corsica) intrudes a plutonic suite made of hornblende-granitoids and is crosscut by basalt dykes with chilled margins. The gabbroic sequence includes olivine-gabbronorite cumulates that consist mainly of euhedral olivine (Fo78-72) and plagioclase (An68-61), and poikilitic clinopyroxene (Mg# = 0.85-0.80), orthopyroxene and Ti-pargasite. Pyroxenes from the olivinegabbronorites have δ18O values of +6.3‰ to +6.7‰, which are evidence for the involvement of a crustal component in the petrogenesis of these rocks. The basalts have Mg# values of 57 to 53 and chondrite-normalised patterns characterised by a steady decrease from LREE to HREE. Relative to modern N-MORB, they show also moderate enrichment of Nb and Ta over Zr and Hf, which are in turn slightly enriched over Y and HREE. The olivine-gabbronorites and basalts show overlapping Nd isotopic compositions (initial εNd of +2.4 to +1.4 and of +3.0 to +1.5, respectively) and have clinopyroxenes with nearly parallel incompatible trace element patterns, thus revealing that these two rock types formed by melts with similar compositions. Most likely, the primary melts of Bocca di Tenda gabbroic sequence were slightly enriched in most incompatible elements and Nd isotopic compositions relative to modern N-MORB