L'approccio giapponese alla politica ambientale: una storia di successi e di contraddizioni

L'approccio giapponese alla politica ambientale: una storia di successi e di contraddizion

Artgame. Il videogame come medium artistico.

In seguito a un dibattito durato poco più di un decennio, il videogame è ormai riconosciuto come uno dei più potenti media artistici attualmente disponibili ed è stato protagonista di numerose mostre nei più prestigiosi musei del mondo, tra i quali il MoMA di New York. Molti studiosi, nel tempo, hanno approfondito il rapporto tra cinema e videogame, giungendo a interessanti conclusioni che tuttavia valgono solo per un certo tipo di videogioco, quasi sempre mainstream. Esiste tuttavia un panorama di sviluppatori indipendenti che utilizzano il medium per creare prodotti videoludici artisticamente validi che, anche per la loro resistenza alle categorie e agli strumenti posseduti dallo storico e dal critico d'arte, rimangono perlopiù argomento per qualche articolo pubblicato su riviste specializzate. In seguito a una breve introduzione storica, ho riportato i momenti più salienti del dibattito che ha visto schierati da una parte gli studiosi di nuovi media sostenitori delle potenzialità artistiche del videogame (Henry Jenkins, Aaron Smuts, Felan Parker e altri), e dall'altra i critici cinematografici appartenenti alla vecchia guardia che hanno posto l'accento sulla superiorità comunicativa del cinema (in particolare Roger Ebert). Prima di procedere con l'analisi di numerose opere d'arte videoludica da punti di vista inusuali o del tutto originali, ho ritenuto necessario definire la categoria degli artgame, già abbozzata nel corso del dibattito sui videogame come forma d'arte ma ancora fortemente indefinita e priva di confini netti. In seguito, ho elaborato una collocazione degli artgame nel panorama artistico contemporaneo, accostandoli alla videoarte e rifiutando generi creati ad hoc come quello della Game Art teorizzata da Matteo Bittanti che, comunque, ho tenuto in considerazione come spunto per le mie riflessioni. Come anticipato poco sopra, l'ultimo capitolo del mio elaborato è dedicato all'analisi delle opere. Vista la penuria di saggi dedicati all'argomento non è stato facile orientarmi nell'universo degli artgame e dei videogame indipendenti, e dunque ho indirizzato la mia scelta verso opere che presentano soluzioni originali o che veicolano messaggi o significati profondi, dividendole per argomento. Non potendo seguire alcuna linea guida, non ho utilizzato uno schema fisso ma ho adattato la mia analisi a seconda dei casi, tralasciando volutamente gli aspetti tecnici. Ho dedicato particolare attenzione alle opere e alle riflessioni dei maggiori rappresentanti del movimento artistico indipendente, come i Tale of Tales, Jason Rorher o la Molleindustria, senza però tralasciare artisti meno noti che ho ritenuto comunque particolarmente interessanti

Distinct higher-order alpha-synuclein oligomers induce intracellular aggretation

Misfolding and aggregation of alpha-synuclein (α-syn) into Lewy bodies (LB) is associated with a range of neurological disorders, including Parkinson's disease (PD). The cell to cell transmission of α-syn pathology has been linked to soluble amyloid oligomer populations that preceded LB formation. Oligomers produced in vitro under certain conditions have been demonstrated to induce intracellular aggregation in cell culture models. Here we characterize, by electrospray ionisation - ion mobility spectrometry - mass spectrometry (ESI-IMS-MS), a specific population of α-syn oligomers. These mass spectrometry compatible oligomers were compared with oligomers with known seeding and pore forming capabilities and were shown to have the ability to induce intracellular aggregation. Each oligomer type was shown to have distinct epitope profiles that correlated with their toxic gain of function. Structurally the mass spectrometry compatible oligomers populated a range of species from dimers through to hexamers. Lower order oligomers were structurally diverse and consistent with unstructured assemblies. Higher order oligomers were shown to be compact with ring-like structures. The observation of this compact state may explain how this natively disordered protein is able to transfer pathology from cell to cell and avoid degradation by cellular proteases

Evaluation of humoral and cellular response to third dose of BNT162b2 mRNA COVID-19 vaccine in patients treated with B-cell depleting therapy

Objective: to investigate the responses to mRNA COVID-19 vaccines in a cohort of immunosuppressed patients affected by immune-mediated inflammatory diseases (IMID). Methods: we have measured humoral and cellular immunity using quantitative IgG anti-SARS-CoV-2 Spike antibody (anti-S-IgG), neutralization assays and specific interferon-gamma (IFN-g) release assay (IGRA) before and after the third dose of BNT162b2. The response of those on anti-CD20 (n = 18) was then compared with healthy controls (HC, n = 18) and IMID naïve to anti-CD20 drugs (n = 13). Results: a third BNT162b2 dose is highly immunogenic in IMID patients naïve to anti-CD20, as 100% of the subjects seroconverted compared to the 55% in anti-CD20. The rate of IGRA response was of 79% in anti-CD20, 50% in IMID naïve to anti-CD20, 100% in HC. Among those who have seroconverted, IMID patients had significantly reduced anti-S-IgG and neutralization titers compared to HC, whereas no significant difference was observed when comparing anti-CD20 and HC. Furthermore, 13% of anti-CD20 and 7.7% of IMID were simultaneously negative for both neutralizing antibodies and IGRA after three doses. Conclusion: these data draw attention to the immunogenicity of COVID-19 vaccination in treated IMID, taking specific groups into consideration for vaccination program

Evaluation of antibody response to BNT162b2 mRNA COVID-19 vaccine in patients affected by immune-mediated inflammatory diseases up to 5 months after vaccination

SARS-CoV-2 vaccination with mRNA product BNT162b2 elicited high immunogenicity in healthy subjects in trials. This study aims to better understand the factors that influence the humoral immune response to vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). We enrolled patients and healthy healthcare workers control group (HCW) that underwent mRNA BNT162b2 vaccination and measured the serum IgG anti-S-RBD response at booster dose (T1), one month after booster dose (T2) and up to 5 months (T3). Demographic, disease-specific and vaccination data were recorded. Vaccination response of 551 participants naïve to SARS-CoV-2 infection were included in HCW and 102 in the IMID group, analyzing separately those on anti-CD20. At T2 all naïve HCW developed anti-S-RBD-IgG, while 94% of IMID responded (p < 0.001). IMID patients had a significantly different level of IgG than HCW at both T1 (p = 0.031), T2 (p < 0.001), while there was no significant difference at T3. There were no statistically significant differences according to the IMID type or to ongoing treatment with immunosuppressants, corticosteroids or biological drugs other than anti-CD20. The proportion and magnitude of response was significantly lower in IMID treated with anti-CD20 drugs. There was a correlation with age at T1 and at T2 but not at T3, stronger in patients than in HCW. Immune response close after BNT162b2 vaccination is reduced in patients with IMID, but there is no significant difference at 5 months. The measured reduction is related to age and the disease itself rather than treatments, with the exception of anti-CD20 drugs

The N-Terminal residues 43 to 60 form the interface for dopamine mediated α-synuclein dimerisation

α-synuclein (α-syn) is a major component of the intracellular inclusions called Lewy bodies, which are a key pathological feature in the brains of Parkinson's disease patients. The neurotransmitter dopamine (DA) inhibits the fibrillisation of α-syn into amyloid, and promotes α-syn aggregation into SDS-stable soluble oligomers. While this inhibition of amyloid formation requires the oxidation of both DA and the methionines in α-syn, the molecular basis for these processes is still unclear. This study sought to define the protein sequences required for the generation of oligomers. We tested N- (α-syn residues 43-140) and C-terminally (1-95) truncated α-syn, and found that similar to full-length protein both truncated species formed soluble DA: α-syn oligomers, albeit 1-95 had a different profile. Using nuclear magnetic resonance (NMR), and the N-terminally truncated α-syn 43-140 protein, we analysed the structural characteristics of the DA:α-syn 43-140 dimer and α-syn 43-140 monomer and found the dimerisation interface encompassed residues 43 to 60. Narrowing the interface to this small region will help define the mechanism by which DA mediates the formation of SDS-stable soluble DA:α-syn oligomers

Copper binding to the Alzheimer’s disease amyloid precursor protein

Alzheimer’s disease is the fourth biggest killer in developed countries. Amyloid precursor protein (APP) plays a central role in the development of the disease, through the generation of a peptide called Aβ by proteolysis of the precursor protein. APP can function as a metalloprotein and modulate copper transport via its extracellular copper binding domain (CuBD). Copper binding to this domain has been shown to reduce Aβ levels and hence a molecular understanding of the interaction between metal and protein could lead to the development of novel therapeutics to treat the disease. We have recently determined the three-dimensional structures of apo and copper bound forms of CuBD. The structures provide a mechanism by which CuBD could readily transfer copper ions to other proteins. Importantly, the lack of significant conformational changes to CuBD on copper binding suggests a model in which copper binding affects the dimerisation state of APP leading to reduction in Aβ production. We thus predict that disruption of APP dimers may be a novel therapeutic approach to treat Alzheimer’s disease

Metal Ionophore Treatment Restores Dendritic Spine Density and Synaptic Protein Levels in a Mouse Model of Alzheimer's Disease

We have previously demonstrated that brief treatment of APP transgenic mice with metal ionophores (PBT2, Prana Biotechnology) rapidly and markedly improves learning and memory. To understand the potential mechanisms of action underlying this phenomenon we examined hippocampal dendritic spine density, and the levels of key proteins involved in learning and memory, in young (4 months) and old (14 months) female Tg2576 mice following brief (11 days) oral treatment with PBT2 (30 mg/kg/d). Transgenic mice exhibited deficits in spine density compared to littermate controls that were significantly rescued by PBT2 treatment in both the young (+17%, p<0.001) and old (+32%, p<0.001) animals. There was no effect of PBT2 on spine density in the control animals. In the transgenic animals, PBT2 treatment also resulted in significant increases in brain levels of CamKII (+57%, p = 0.005), spinophilin (+37%, p = 0.04), NMDAR1A (+126%, p = 0.02), NMDAR2A (+70%, p = 0.05), pro-BDNF (+19%, p = 0.02) and BDNF (+19%, p = 0.04). While PBT2-treatment did not significantly alter neurite-length in vivo, it did increase neurite outgrowth (+200%, p = 0.006) in cultured cells, and this was abolished by co-incubation with the transition metal chelator, diamsar. These data suggest that PBT2 may affect multiple aspects of snaptic health/efficacy. In Alzheimer's disease therefore, PBT2 may restore the uptake of physiological metal ions trapped within extracellular β-amyloid aggregates that then induce biochemical and anatomical changes to improve cognitive function

Amyloid Precursor Protein Is Required for Normal Function of the Rod and Cone Pathways in the Mouse Retina

Amyloid precursor protein (APP) is a transmembrane glycoprotein frequently studied for its role in Alzheimer's disease. Our recent study in APP knockout (KO) mice identified an important role for APP in modulating normal neuronal development in the retina. However the role APP plays in the adult retina and whether it is required for vision is unknown. In this study we evaluated the role of APP in retinal function and morphology comparing adult wildtype (WT) and APP-KO mice. APP was expressed on neuronal cells of the inner retina, including horizontal, cone bipolar, amacrine and ganglion cells in WT mice. The function of the retina was assessed using the electroretinogram and although the rod photoreceptor responses were similar in APP-KO and WT mice, the post-photoreceptor, inner retinal responses of both the rod and cone pathways were reduced in APP-KO mice. These changes in inner retinal function did not translate to a substantial change in visual acuity as assessed using the optokinetic response or to changes in the gross cellular structure of the retina. These findings indicate that APP is not required for basic visual function, but that it is involved in modulating inner retinal circuitry