The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the "REGISTRY" cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis.

Prevalence of paunch calf syndrome carriers in Italian Romagnola cattle.

The term 'paunch calf syndrome' encompasses the multi-organic lethal developmental dysplasia reported in the Romagnola breed of cattle and is characterised by facial deformities, an enlarged and floating abdomen containing considerable abdominal effusion, and hepatic fibrosis. Paunch calf syndrome is caused by a missense mutation in the KDM2B gene (c.2503G>A) that is thought to lead to an amino acid exchange (p.D835N). In this study, the prevalence of carriers of the mutant KDM2B allele (and thus the frequency of the allele) was assessed in selected subpopulations of Romagnola cattle. The prevalence of carriers within top-ranked Romagnola sires over the years 2007-2012 was 29.3% (allele frequency 14.6%). In young bull calves, 30.9% were carriers with an allele frequency of 15.4%.

Italian Hebrew Literature

by Sabato Morais. Ed. by Julius H. Greenstone. With a foreword by Henry Morais

Efficiency of frost-cracking processes through space and time: An example from the eastern Italian Alps

It is widely accepted that climate has a strong impact and exerts important feedbacks on erosional processes and sediment transport mechanisms. However, the extent at which climate influences erosion is still a matter of debate. In this paper we test whether frost-cracking processes and related temperature variations can influence the sediment production and surface erosion in a small catchment situated in the eastern Italian Alps. To this extent, we first present a geomorphic map of the region that we complement with published 10Be-based denudation rates. We then apply a preexisting heat-flow model in order to analyze the variations of the frost-cracking intensity (FCI) in the study area, which could have controlled the sediment production in the basin. Finally, we compare the model results with the pattern of denudation rates and Quaternary deposits in the geomorphic map. The model results, combined with field observations, mapping, and quantitative geomorphic analyses, reveal that frost-cracking processes have had a primary role in the production of sediment where the intensity of sediment supply has been dictated and limited by the combined effect of temperature variations and conditions of bedrock preservation. These results highlight the importance of a yet poorly understood process for the production of sediment in mountain areas.

Geological map of the Scalaro Valley ��� Sesia Zone (Italian Western Alps)

In the Sesia Zone (Italian Western Alps), slivers of continental crust characterised by an Alpine high-pressure imprint are intermingled with abundant mafic rocks and Mesozoic metasediments. An extensive study of the central Sesia Zone was undertaken to identify and reconstruct the lithological setting of the mono-cyclic sediments of the Scalaro Unit. A new geological map (1:5000) and schematic cross sections across the Scalaro Unit and the adjoining Eclogitic Micaschist Complex are presented here. In order to delimit the size and shape of the mono-metamorphic unit and understand its internal geometry with respect to the poly-metamorphic basement, an integrated approach was used. Linking observations and data across a range of scales, from kilometres in the field down to petrological and chronological data obtained at micrometre scale, we define for the first time the real size and internal geometry of the Scalaro Unit, as well as its large-scale structural context.

Otium et negotium. Reading processes and their cultural backgrounds in early Italian and German humanism

Reading and reading habits have radically changed in the digital age. Readers are no longer physically bound to textual objects and libraries, they deal with texts by copying, altering, and annotating them, and they mix established textual forms with other semiotic systems such as pictograms, icons and images. These circumstances also provoke a renewed research interest in the history of reading. In this talk, I will concentrate on reading processes as to how they were enacted and practised in early Italian and German humanism. I will start with some paradigmatic scenes described in Petrarch���s letters (among others the famous visit of the Mont Ventoux, where Petrarch, after having enjoyed a spectacular panorama, withdraws into the contemplative reading of St-Augustine). The transmission of Petrarch���s writings in humanist circles of Southern Germany (e.g. with the Schedel and Gossembrot families in Nurnberg, Augsburg and Strasburg) will then lead to specific reading practices documented in manuscripts that once belonged to coherent libraries and are nowadays spread all over Europe. In the case of the former tradesman and mayor Sigismund Gossembrot, complex habits of textual annotating and cross-referencing can be observed. The dichotomy of the Latin terms otium (���rest��� and ���leisure���) and negotium (���activity���, but also ���practice���, ���negotiation���, ���circulation of social energy��� in the sense of New Historicism) will be used as an ideal-type outline to describe the occurring processes of reading.

Otium et negotium. Reading processes and their cultural backgrounds in early Italian and German humanism

Reading and reading habits have radically changed in the digital age. Readers are no longer physically bound to textual objects and libraries, they deal with texts by copying, altering, and annotating them, and they mix established textual forms with other semiotic systems such as pictograms, icons and images. These circumstances also provoke a renewed research interest in the history of reading. In this talk, I will concentrate on reading processes as to how they were enacted and practised in early Italian and German humanism. I will start with some paradigmatic scenes described in Petrarch���s letters (among others the famous visit of the Mont Ventoux, where Petrarch, after having enjoyed a spectacular panorama, withdraws into the contemplative reading of St-Augustine). The transmission of Petrarch���s writings in humanist circles of Southern Germany (e.g. with the Schedel and Gossembrot families in Nurnberg, Augsburg and Strasburg) will then lead to specific reading practices documented in manuscripts that once belonged to coherent libraries and are nowadays spread all over Europe. In the case of the former tradesman and mayor Sigismund Gossembrot, complex habits of textual annotating and cross-referencing can be observed. The dichotomy of the Latin terms otium (���rest��� and ���leisure���) and negotium (���activity���, but also ���practice���, ���negotiation���, ���circulation of social energy��� in the sense of New Historicism) will be used as an ideal-type outline to describe the occurring processes of reading.

European mobility and local political incorporation: The case of British and Romanian residents in Spain

This paper analyses the impact of European mobility in the field of the political nomination of intra-EU migrants in local elections. The study contributes to the debates in the literature related to immigrant nomination and representation by showing how group resources and political opportunities in the country of residence interact with the political opportunities of the European citizenship regime. It argues that the symbolic and legal status of European identity, representation in the European Parliament and strong links between political institutions in the countries of destination and origin play a positive role in boosting immigrant political entrepreneurs��� visibility vis-��-vis host country political actors. In order to illustrate these findings, the paper provides a qualitative comparison of British and Romanian residents in Spain.

NADPH-CYTOCHROME P-450 REDUCTASE: EVIDENCE FOR TWO SEPARATE STRUCTURAL DOMAINS AND ISOLATION AND CHARACTERIZATION OF THE MEMBRANE ASSOCIATED SEGMENT

Homogenous detergent-solubilized NADPH-Cytochrome P-450 reductase was incorporated into microsomes and liposomes. This binding occurred spontaneously at temperatures between 4(DEGREES) and 37(DEGREES) and appeared to involve hydrophobic forces as the binding was not disrupted by 0.5 M sodium chloride. This exogenously-added reductase was active catalytically towards native cytochrome P-450, suggesting an association with the microsomal membrane similar to endogenous reductase. Homogeneous detergent-solubilized reductase was disaggregated by Renex-690 micelles, confirming the presence of a hydrophobic combining region on the enzyme. In contrast to these results, steapsin protease-solubilized reductase was incapable of microsomal attachment and did not interact with Renex-690 micelles. Detergent-solubilized reductase (76,500 daltons) was converted into a form with the electrophoretic mobility of steapsin protease-solubilized reductase (68,000 daltons) and a 12,500 dalton peptide (as determined by polyacrylamide-SDS gel electrophoresis) when the liposomal-incorporated enzyme was incubated with steapsin protease. The 68,000 dalton fragment thus obtained had properties identical with steapsin protease-solubilized reductase, i.e. it was catalytically active towards cytochrome c but inactive towards cytochrome P-450 and did not bind liposomes. The 12,500 dalton fragment remained associated with the liposomes when the digest was fractionated by gel filtration, suggesting that this is the segment of the enzyme which is embedded in the phospholipid bilayer. Thus, detergent-solubilized reductase appears to contain a soluble catalytic domain and a separate and separable membrane-binding domain. This latter domain is required for attaching the enzyme to the membrane and also to facilitate the catalytic interaction between the reductase and its native electron acceptor, cytochrome P-450. The membrane-binding segment of the reductase was isolated by preparative gel electrophoresis in SDS following its generation by proteolytic treatment of liposome-incorporated reductase. The peptide has a molecular weight of 6,400 as determined by gel filtration in 8 M guanidine hydrochloride and has an amino acid composition which is not especially hydrophobic. Following removal of SDS and dialysis out of 6 M urea, the membrane-binding peptide was unable to inhibit the activity of a reconstituted system containing purified reductase and cytochrome P-450. Moreover, when reductase and cytochrome P-450 were added to liposomes which contained the membrane-binding peptide, it was determined that mixed function oxidase activity was reconstituted as effectively as when vesicles without the membrane-binding peptide were used. Thus, the membrane-binding peptide was ineffective as an inhibitor of mixed function oxidase activity, suggesting perhaps that it facilitates catalysis by anchoring the catalytic domain of the reductase proximal to cytochrome P-450 (i.e. in the same mixed micelle) rather than through a specific interaction with cytochrome P-450. ^

DRUG METABOLISM IN LIVER TUMORS: PURIFICATION AND CHARACTERIZATION OF NADPH-CYTOCHROME-P450 REDUCTASE AND THE RESOLUTION OF MULTIPLE FORMS OF CYTOCHROME P-450

The hydroxylation of N- and O-methyl drugs and a polycyclic hydrocarbon has been demonstrated in microsomes prepared from two transplantable Morris hepatomas (i.e., 7288C. t.c. and 5123 t.c.(H). The hydroxylation rates of the drug benzphetamine and the polycyclic hydrocarbon benzo {(alpha)} pyrene by tumor microsomes were inducible 2 to 3-fold and 2-fold, respectively by pretreatment of rats with phenobarbital/hydrocortisone. Hepatoma 5123t.c.(h) microsomal hydroxylation activities were more inducible after these pretreatments than hepatoma 7288C.t.c. Two chemotherapeutic drugs (cyclophosphamide and isophosphamide) were shown to be mutagenic after activation by the tumor hemogenate with the TA100 strain of Salmonella typhimurium bacteria. NADPH-cytochrome P-450 was purified from phenobarbital/hydrocortisone treated rat hepatoma 5123t.c.(H) microsomes 353-fold with a specific activity 63.6 nmol of cytochrome c reduced per min per mg of protein. The purified enzyme, has an apparent molecular weight of 79,500 daltons, and contained an equal molar ratio of FMN and FAD, with a total flavin content of 16.4 nmol per mg of protein. The purified enzyme also catalyzed electron transfer to artificial electron acceptors with the K(,m) values of the hepatoma reductase similar to those of purified liver reductase. The K(,m) value of the hepatoma reductase (13 uM) for NADPH was similar to that of purified liver reductase (5.0 uM). In addition the purified hepatoma reductase was immunochemically similar to the liver reductase.^ Hepatoma cytochrome P-450, the hemeprotein component of the hepatoma microsomes of rats pretreated with phenobarbital/hydrocortisone. The resolution of the six forms was achieved by the DE-53 ion-exchange chromatography, and further purified by hydroxyapatite. The six different fractions that contained P-450 activity, had specific contents from 0.47 to 1.75 nmol of cytochrome P-450 per mg of protein, and indicated a 2 to 9-fold purification as compared to the original microsomes. In addition, difference spectra, molecular weights and immunological results suggest there are at least six different forms of cytochrome P-450 in hepatoma 5123 t.c.(H). ^