On fractional p-Laplacian problems with weight

We investigate the existence of nonnegative solutions for a nonlinear problem involving the fractional p-Laplacian operator. The problem is set on a unbounded domain, and compactness issues have to be handled.Comment: 10 page

Asymptotically linear fractional Schrodinger equations

By exploiting a variational technique based upon projecting over the Pohozaev manifold, we prove existence of positive solutions for a class of nonlinear fractional Schrodinger equations having a nonhomogenous nonautonomous asymptotically linear nonlinearity.Comment: 24 page

On fractional Choquard equations

We investigate a class of nonlinear Schrodinger equations with a generalized Choquard nonlinearity and fractional diffusion. We obtain regularity, existence, nonexistence, symmetry as well as decays properties.Comment: revised version, 22 page

Diffeomorphism-invariant properties for quasi-linear elliptic operators

For quasi-linear elliptic equations we detect relevant properties which remain invariant under the action of a suitable class of diffeomorphisms. This yields a connection between existence theories for equations with degenerate and non-degenerate coerciveness.Comment: 16 page

Privilegi librari nell’Italia del Rinascimento

L'avvento della stampa a caratteri mobili a met\ue0 del Quattrocento rappresent\uf2 per l'Europa un punto cardine non solo sul piano culturale ma anche economico con la rapida espansione di un settore produttivo completamente nuovo. Il libro a stampa era veicolo comunicativo di contenuti testuali e, per questo, materia delicata anche sul piano politico-religioso. Con il progressivo sviluppo e consolidamento dell'industria tipografica, divenne strategico da parte degli Stati territoriali regolamentare il settore dotandolo di adeguati strumenti giuridici. Uno di questi fu l'istituto del privilegio librario, precursore ideale del moderno copyright letterario e artistico. Nella prospettiva delle autorit\ue0 territoriali, il privilegio di stampa rappresentava un mezzo per strutturare la neonata industria promuovendone lo sviluppo e ponendola allo stesso tempo entro argini normativi di controllo e validazione dei contenuti testuali diffusi. Nell'ottica degli operatori del settore, anzitutto autori e stampatori, il privilegio librario rappresentava invece uno strumento di protezione giuridica impiegato a tutela degli sforzi profusi e dei capitali investiti, assicurando una posizione temporanea di vantaggio commerciale. Prendendo a campione, in una prospettiva comparata, alcuni dei maggiori centri di produzione libraria dell'Italia nella prima et\ue0 moderna, la presente raccolta di studi esamina il ruolo che il privilegio librario ebbe nello sviluppo dell'editoria italiana e nella crescente attenzione verso il settore da parte delle istituzioni

Dissecting the genetic overlap between severe mental disorders and markers of cellular aging: Identification of pleiotropic genes and druggable targets

Patients with severe mental disorders such as bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD) show a substantial reduction in life expectancy, increased incidence of comorbid medical conditions commonly observed with advanced age and alterations of aging hallmarks. While severe mental disorders are heritable, the extent to which genetic predisposition might contribute to accelerated cellular aging is not known. We used bivariate causal mixture models to quantify the trait-specific and shared architecture of mental disorders and 2 aging hallmarks (leukocyte telomere length [LTL] and mitochondrial DNA copy number), and the conjunctional false discovery rate method to detect shared genetic loci. We integrated gene expression data from brain regions from GTEx and used different tools to functionally annotate identified loci and investigate their druggability. Aging hallmarks showed low polygenicity compared with severe mental disorders. We observed a significant negative global genetic correlation between MDD and LTL (rg = −0.14, p = 6.5E−10), and no significant results for other severe mental disorders or for mtDNA-cn. However, conditional QQ plots and bivariate causal mixture models pointed to significant pleiotropy among all severe mental disorders and aging hallmarks. We identified genetic variants significantly shared between LTL and BD (n = 17), SCZ (n = 55) or MDD (n = 19), or mtDNA-cn and BD (n = 4), SCZ (n = 12) or MDD (n = 1), with mixed direction of effects. The exonic rs7909129 variant in the SORCS3 gene, encoding a member of the retromer complex involved in protein trafficking and intracellular/intercellular signaling, was associated with shorter LTL and increased predisposition to all severe mental disorders. Genetic variants underlying risk of SCZ or MDD and shorter LTL modulate expression of several druggable genes in different brain regions. Genistein, a phytoestrogen with anti-inflammatory and antioxidant effects, was an upstream regulator of 2 genes modulated by variants associated with risk of MDD and shorter LTL. While our results suggest that shared heritability might play a limited role in contributing to accelerated cellular aging in severe mental disorders, we identified shared genetic determinants and prioritized different druggable targets and compounds

Cost–utility analysis of pharmacogenetic testing based on CYP2C19 or CYP2D6 in major depressive disorder: assessing the drivers of different cost-effectiveness levels from an Italian societal perspective

Background and Objectives Major depressive disorder (MDD) is a common and severe psychiatric disorder that has enor- mous economical and societal costs. As pharmacogenetics is one of the key tools of precision psychiatry, we analyze the cost–utility of test screening of CYP2C19 and CYP2D6 for patients suffering from major depressive disorder (MDD) and try to understand the main drivers that influence the cost–utility. Methods We developed two pharmacoeconomic nonhomogeneous Markov models to test the cost–utility, from an Ital- ian societal perspective, of pharmacogenetic testing genetic to characterize the metabolizing profiles of cytochrome P450 (CYP) 2C19 and CYP2D6 in a hypothetical case study of patients suffering from major depressive disorder (MDD). The model considers different scenarios of adjustment of antidepressant treatment according to the patient’s metabolizing profile or treatment over a period of 18 weeks. The uncertainty of model parameters is tested through both a probabilistic sensitivity analysis and a one-way deterministic sensitivity analysis, and these results are used in a post-hoc analysis to understand the main drivers of three alternative cost-effectiveness levels (“poor,” “standard,” and “high”). These drivers are first evaluated from an exploratory multidimensional perspective and next from a predictive perspective as the probability that a patient belongs to a specific cost-effectiveness level is estimated on the basis of a restricted set of parameters used in the original pharmacoeconomic model. Results The models for CYP2C19 and CYP2D6 indicate that screening has an incremental cost-effectiveness ratio of 60,000€ and 47,000€ per quality-adjusted life year (QALY), respectively. The probabilistic sensitivity analysis shows that the treat- ments are cost-effective for a 75,000€ willingness to pay (WTP) threshold in 58% and 63% of the Monte Carlo replications, respectively. The post-hoc analysis highlights the factors that allow us to clearly discriminates poor cost-effectiveness from high cost-effectiveness scenarios and demonstrates that it is possible to predict with reasonable accuracy the cost-effectiveness of a genetic test and the associated therapeutic pattern. Conclusions Our findings suggest that screenings for both CYP2C19 and CYP2D6 enzymes for patients with MDD are cost-effective for a WTP threshold of 75,000€ per QALY, and provide relevant suggestions about the most important aspects to be further explored in clinical studies aimed at addressing the cost-effectiveness of genetic testing for patients diagnosed with MDD

RGS2 expression predicts amyloid-β sensitivity, MCI and Alzheimer's disease: genome-wide transcriptomic profiling and bioinformatics data mining

Alzheimer's disease (AD) is the most frequent cause of dementia. Misfolded protein pathological hallmarks of AD are brain deposits of amyloid-β (Aβ) plaques and phosphorylated tau neurofibrillary tangles. However, doubts about the role of Aβ in AD pathology have been raised as Aβ is a common component of extracellular brain deposits found, also by in vivo imaging, in non-demented aged individuals. It has been suggested that some individuals are more prone to Aβ neurotoxicity and hence more likely to develop AD when aging brains start accumulating Aβ plaques. Here, we applied genome-wide transcriptomic profiling of lymphoblastoid cells lines (LCLs) from healthy individuals and AD patients for identifying genes that predict sensitivity to Aβ. Real-time PCR validation identified 3.78-fold lower expression of RGS2 (regulator of G-protein signaling 2; P=0.0085) in LCLs from healthy individuals exhibiting high vs low Aβ sensitivity. Furthermore, RGS2 showed 3.3-fold lower expression (P=0.0008) in AD LCLs compared with controls. Notably, RGS2 expression in AD LCLs correlated with the patients' cognitive function. Lower RGS2 expression levels were also discovered in published expression data sets from postmortem AD brain tissues as well as in mild cognitive impairment and AD blood samples compared with controls. In conclusion, Aβ sensitivity phenotyping followed by transcriptomic profiling and published patient data mining identified reduced peripheral and brain expression levels of RGS2, a key regulator of G-protein-coupled receptor signaling and neuronal plasticity. RGS2 is suggested as a novel AD biomarker (alongside other genes) toward early AD detection and future disease modifying therapeutics

On the stability of standing waves of Klein-Gordon equations in a semiclassical regime

We investigate the orbital stability and instability of standing waves for two classes of Klein-Gordon equations in the semi-classical regime.Comment: 9 page