Aminoacid substitutions in the glycine zipper affect the conformational stability of amyloid beta fibrils

The aggregation of amyloid-beta peptides is associated with the pathogenesis of Alzheimer’s disease. The hydrophobic core of the amyloid beta sequence contains a GxxxG repeated motif, called glycine zipper, which involves crucial residues for assuring stability and promoting the process of fibril formation. Mutations in this motif lead to a completely different oligomerization pathway and rate of fibril formation. In this work, we have tested G33L and G37L residue substitutions by molecular dynamics simulations. We found that both protein mutations may lead to remarkable changes in the fibril conformational stability. Results suggest the disruption of the glycine zipper as a possible strategy to reduce the aggregation propensity of amyloid beta peptides. On the basis of our data, further investigations may consider this key region as a binding site to design/discover novel effective inhibitors. Communicated by Ramaswamy H. Sarma

Association between age of cannabis initiation and gray matter covariance networks in recent onset psychosis

Cannabis use during adolescence is associated with an increased risk of developing psychosis. According to a current hypothesis, this results from detrimental effects of early cannabis use on brain maturation during this vulnerable period. However, studies investigating the interaction between early cannabis use and brain structural alterations hitherto reported inconclusive findings. We investigated effects of age of cannabis initiation on psychosis using data from the multicentric Personalized Prognostic Tools for Early Psychosis Management (PRONIA) and the Cannabis Induced Psychosis (CIP) studies, yielding a total sample of 102 clinically-relevant cannabis users with recent onset psychosis. GM covariance underlies shared maturational processes. Therefore, we performed source-based morphometry analysis with spatial constraints on structural brain networks showing significant alterations in schizophrenia in a previous multisite study, thus testing associations of these networks with the age of cannabis initiation and with confounding factors. Earlier cannabis initiation was associated with more severe positive symptoms in our cohort. Greater gray matter volume (GMV) in the previously identified cerebellar schizophrenia-related network had a significant association with early cannabis use, independent of several possibly confounding factors. Moreover, GMV in the cerebellar network was associated with lower volume in another network previously associated with schizophrenia, comprising the insula, superior temporal, and inferior frontal gyrus. These findings are in line with previous investigations in healthy cannabis users, and suggest that early initiation of cannabis perturbs the developmental trajectory of certain structural brain networks in a manner imparting risk for psychosis later in life

Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation

Acetylcholine (ACh) has been shown to modulate neuronal differentiation during early development. Both muscarinic and nicotinic acetylcholine receptors (AChRs) regulate a wide variety of physiological responses, including apoptosis, cellular proliferation and neuronal differentiation. However, the intracellular mechanisms underlying these effects of AChR signaling are not fully understood. It is known that activation of AChRs increase cellular proliferation and neurogenesis and that regulation of intracellular calcium through AChRs may underlie the many functions of ACh. Intriguingly, activation of diverse signaling molecules such as Ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase-Akt, protein kinase C and c-Src is modulated by AChRs. Here we discuss the roles of ACh in neuronal differentiation, cell proliferation and apoptosis. We also discuss the pathways involved in these processes, as well as the effects of novel endogenous AChRs agonists and strategies to enhance neuronal-differentiation of stem and neural progenitor cells. Further understanding of the intracellular mechanisms underlying AChR signaling may provide insights for novel therapeutic strategies, as abnormal AChR activity is present in many diseases

Il diritto internazionale: diritto per gli Stati e diritto per gli individui. Parti speciali.

Il volume tratta di quei principi e di quelle norme, consuetudinarie e convenzionali, che disciplinano le relazioni interstatali al fine di permettere la convivenza tra entità statali che, essendo sovrane, si relazionano tra di loro sul presupposto del rispetto e della garanzia reciproca della loro sovranità, in termini di sfera e di manifestazione della sovranità stessa. Secondo questa linea, la prima parte del volume è dedicata allo studio della sovranità dello Stato e dei suoi limiti c.d. classici perché discendono dal contemperamento tra diverse sfere di sovranità secondo un approccio sinallagmatico. Ma nella prima parte del volume ci si sofferma anche sul rilievo assunto, in contrapposizione e come limite alla piena ed assoluta discrezionalità della sovranità statale, dagli interessi di individui, sia singolarmente intesi (tutela internazionale dei diritti umani e delle libertà fondamentali) sia in quanto popoli (diritto all’autodeterminazione). Nella parte seconda e nella parte terza del volume la sovranità statale è invece affrontata con riferimento alla sfera spaziale della sua esplicazione che si è progressivamente estesa agli spazi marini, anche a quelli più lontani dalle coste degli Stati, ed allo spazio atmosferico sovrastante il territorio dello Stato, talora attraverso l’elaborazione di nuovi concetti, più adatti a soddisfare gli interessi degli Stati nello sfruttamento delle risorse di questi spazi. Questo processo ha dato luogo allo sviluppo di regimi giuridici innovativi, come, ad esempio, quello vigente per l’Antartide o quello elaborato, principalmente in sede UNESCO, a tutela del patrimonio culturale e naturale mondiale. Infine, nella parte quarta, si è voluto affrontare il tema della sovranità economica dello Stato, della quale forse oggi si parla anche troppo od in modo impreciso a livello di società civile, per il forte impatto culturale, sociale e politico che ha avuto la liberalizzazione commerciale e la progressiva interdipendenza economica e finanziaria tra gli Stati quale conseguenza della mondializzazione o della globalizzazione dell’economia