1,367 research outputs found
The immunobiology of prion diseases
No full textIndividuals infected with prions succumb to brain damage, and prion infections continue to be inexorably lethal. However, many crucial steps in prion pathogenesis occur in lymphatic organs and precede invasion of the central nervous system. In the past two decades, a great deal has been learnt concerning the cellular and molecular mechanisms of prion lymphoinvasion. These properties are diagnostically useful and have, for example, facilitated preclinical diagnosis of variant Creutzfeldt-Jakob disease in the tonsils. Moreover, the early colonization of lymphoid organs can be exploited for post-exposure prophylaxis of prion infections. As stromal cells of lymphoid organs are crucial for peripheral prion infection, the dedifferentiation of these cells offers a powerful means of hindering prion spread in infected individuals. In this Review, we discuss the current knowledge of the immunobiology of prions with an emphasis on how basic discoveries might enable translational strategies
Altered monoaminergic systems and depressive-like behavior in congenic prion protein nnock-out mice
Full text linkCells and prions: A license to replicate
Full text linkPrion diseases are neurodegenerative, infectious disorders characterized by the aggregation of a misfolded isoform of the cellular prion protein (PrP(C)). The infectious agent - termed prion - is mainly composed of misfolded PrP(Sc). In addition to the central nervous system prions can colonize secondary lymphoid organs and inflammatory foci. Follicular dendritic cells are important extraneural sites of prion replication. However, recent data point to a broader range of cell types that can replicate prions. Here, we review the state of the art in regards to peripheral prion replication, neuroinvasion and the determinants of prion replication competence
Prion pathogenesis in the absence of NLRP3/ASC inflammasomes
Full text linkThe accumulation of the scrapie prion protein PrPSc, a misfolded conformer of the cellular prion protein PrPC, is a crucial feature of prion diseases. In the central nervous system, this process is accompanied by conspicuous microglia activation. The NLRP3 inflammasome is a multi-molecular complex which can sense heterogeneous pathogen-associated molecular patterns and culminates in the activation of caspase 1 and release of IL 1β. The NLRP3 inflammasome was reported to be essential for IL 1β release after in vitro exposure to the amyloidogenic peptide PrP106-126 and to recombinant PrP fibrils. We therefore studied the role of the NLRP3 inflammasome in a mouse model of prion infection. Upon intracerebral inoculation with scrapie prions (strain RML), mice lacking NLRP3 (Nlrp3-/-) or the inflammasome adaptor protein ASC (Pycard-/-) succumbed to scrapie with attack rates and incubation times similar to wild-type mice, and developed the classic histologic and biochemical features of prion diseases. Genetic ablation of NLRP3 or ASC did not significantly impact on brain levels of IL 1β at the terminal stage of disease. Our results exclude a significant role for NLRP3 and ASC in prion pathogenesis and invalidate their claimed potential as therapeutic target against prion diseases
COMPOSER-LEGISLATORS IN FASCIST ITALY: DISTINGUISHING THE PERSONAL AND LEGISLATIVE VOICES OF ADRIANO LUALDI
No full textIn addition to a list of Lualdi's written works, appendices include a facing English translation of Alceo Toni, et al., “Travagli spirituali del nostro tempo: un manifesto di musicisti italiani per la tradizione dell’arte romantica dell’800,” La stampa, December 17, 1932, 3.During Italy’s fascist period, the government appointed Adriano Lualdi to the
Chamber of Deputies. The once prominent composer, author, and music critic
represented the Fascist Union of Musicians in the chamber and had roles in the
administration of government-subsidized festivals. Although little is written about the
composer-legislator, what is available depicts him as opportunistic and self-serving.
Previous scholarship claims that he used his position in the fascist bureaucracy to his own
advantage by pushing his aesthetic philosophy through legislation. These claims are
substantiated by Lualdi’s private communications and published works which detail his
opinions on musical aesthetics. Comparing Lualdi’s political records to his publications
shows that his personal opinions on aesthetics did not interfere with legislation to the
degree that past scholarship suggests. I argue that previous scholarship conflates Lualdi’s
legislative voice with his personal voice, offering a distorted, and therefore incomplete
version of Adriano Lualdi as a historical figure
Prion pathogenesis is unaltered in the absence of SIRPα-mediated "don't-eat-me" signaling
Full text linkPrion diseases are neurodegenerative conditions caused by misfolding of the prion protein, leading to conspicuous neuronal loss and intense microgliosis. Recent experimental evidence point towards a protective role of microglia against prion-induced neurodegeneration, possibly through elimination of prion-containing apoptotic bodies. The molecular mechanisms by which microglia recognize and eliminate apoptotic cells in the context of prion diseases are poorly defined. Here we investigated the possible involvement of signal regulatory protein α (SIRPα), a key modulator of host cell phagocytosis; SIRPα is encoded by the Sirpa gene that is genetically linked to the prion gene Prnp. We found that Sirpa transcripts are highly enriched in microglia cells within the brain. However, Sirpa mRNA levels were essentially unaltered during the course of experimental prion disease despite upregulation of other microglia-enriched transcripts. To study the involvement of SIRPα in prion pathogenesis in vivo, mice expressing a truncated SIRPα protein unable to inhibit phagocytosis were inoculated with rodent-adapted scrapie prions of the 22L strain. Homozygous and heterozygous Sirpa mutants and wild-type mice experienced similar incubation times after inoculation with either of two doses of 22L prions. Moreover, the extent of neuronal loss, microgliosis and abnormal prion protein accumulation was not significantly affected by Sirpa genotypes. Collectively, these data indicate that SIRPα-mediated phagocytosis is not a major determinant in prion disease pathogenesis. It will be important to search for additional candidates mediating prion phagocytosis, as this mechanism may represent an important target of antiprion therapies
Tilgher Adriano
No full textDopo un primo accostamento all’idealismo fichtiano, Adriano Tilgher elaborò una concezione della filosofia come tensione irrisolvibile tra opzioni morali e visioni del mondo, rifiutando ogni totalità sistematica. Sul piano religioso, per Tilgher il problema fondamentale di ogni religione è il problema del male: di fronte ad esso, se il buddismo ha proposto di fuggire il mondo, il cristianesimo «ha sempre considerato il mondo, la vita, la società come campi di combattimento e preparazione del cielo». Le soluzioni religiose tradizionali, compreso il cristianesimo, sono, però, afferma Tilgher, in grave crisi, dato l’indebolimento della credenza nell’involucro mitico che le sosteneva, ma il tema del male resta non certo meno pressante del passato e l’autore si mostra estremamente critico anche con le ideologie politiche che hanno preteso di sostituire le tradizioni religiose, non certo risolvendo e anzi aumentando ancora l’entità del male.
Parole chiave: Adriano Tilgher, problema del male, dramma del cristianesimo, mito e religione, anti-totalismo
After an initial approach to Fichtean idealism, Adriano Tilgher developed a conception of philosophy as an irreconcilable tension between moral options and worldviews, rejecting any systematic totality. On a religious level, for Tilgher, the fundamental problem of every religion is the problem of evil: in the face of it, while Buddhism has proposed to escape the world, Christianity "has always regarded the world, life, and society as fields of battle and preparation for heaven." However, traditional religious solutions, including Christianity, are, Tilgher asserts, in serious crisis due to the weakening of belief in the mythical framework that supported them. Yet, the theme of evil remains no less pressing than in the past, and the author is extremely critical of political ideologies that have sought to replace religious traditions, which have not resolved the issue but rather exacerbated the extent of evil.
Keywords: Adriano Tilgher, problem of evil, drama of Christianity, myth and religion, anti-totalis
Constitutive Restrictions for Deformable Simple Media that are Heat Conducting and Electrically Polarizable
Full text linkWe present the constitutive restrictions for a deformable simple medium that is heat conducting, electrically polarizable and interacting with the electric field, either of elastic type or with a fading memory.
The used theory is an extension of the well known Green-Naghdi thermo-mechanical theories of continua, mainly devoted to thermoelastic bodies or rigid conductors. Hence the theory that is used here is based on an entropy balance law rather than an entropy imbalance, uses the notion of thermal displacement, and predicts
heat propagation by thermal waves at finite speed
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