42 research outputs found
Insights in the Regional Distribution and Physiological Role of the Cellular Prion Protein in the Central Nervous System of Mammalian Organisms
The cellular form of the prion protein (PrPC) is a sialoglycoprotein ubiquitously expressed in the central nervous system (CNS) of mammalian species along the neurodevelopment and in the adulthood. The PrPC localization in the brain has attracted interest because of its involvement in fatal neurodegenerative disorders, denoted as transmissible spongiform encephalopathies. In mammals, PrPC is expressed early in embryogenesis, and in the adulthood it reaches its highest levels in the neurons of the encephalon and spinal cord. The protein is also found at lower levels in glial cells of the CNS, as well as in almost all peripheral cell types. By combining in situ hybridization and immunohistochemical techniques, we show the earliest expression of the protein in mouse hippocampus, thalamus and hypothalamus. In particular, specific white matter fiber tracts in mouse CNS (the hippocampal fimbria, the stria terminalis, and the fasciculus retroflexus) show the highest expression of the protein. To extend our understanding of varying PrPC expression profiles in different mammals, we carried out a detailed expression analysis of PrPC distribution along the neurodevelopment of the metatherian South American short-tailed opossum (Monodelphis domestica). No naturally occurring prion diseases have been reported yet for this species. Compared with mice, in opossums we detected lower levels of PrPC in the white matter fiber bundles of the CNS. This result might offer new insights into a possible involvement of PrPC in the varying susceptibility to prion diseases for different mammals. The different distribution of PrPC in the hippocampal layers of mammals led us to hypothesize a different physiological relevance of PrPC in this region. To better understand this issue, we used PrP knock-out mice, in which PrPC is not expressed in the hippocampal strata. We observed that the absence of PrPC impairs the signaling pathway promoted by Reelin, a protein of the extracellular matrix expressed in the stratum lacunosum molecolare and hippocampus of the early postnatal mouse. Overall, our findings suggest a possible role for PrPC in the modulation of the events triggered by the Reelin-signaling pathway in the developmental mouse hippocampus
Le tre Europe di Ralf Dahrendorf
Reflecting on Dahrendorfâs visions and observations on first, second and third Europe opens new fascinating avenues for the understanding of the present state of the Union and the future of liberalism. His political involvement in Germany and Bruxelles since the late 1960s, and his role as public intellectual and leader of prominent academic institutions, were experienced by Dahrendorf as opportunities to test his ideas of liberal societies, of European cooperation (and democratic deficit) and of the return to democracy of Eastern Central Europe. This essay recontructs and comments on two major historical processes that Dahrendorf witnessed and became involved with: 1) the transformation of first Europe in a much broader project, geographically and politically (la seconda Europa) and the connected process pursuing both widening and deepening on the road of third Europe. 2) the return to West of Communist Eastern Europe leading to 1989: a triumph of the liberal order for Dahrendorf but also a process leading into a deep valley of tears and eventually, in the end, to a democratic post-communist reality. This essay is both a reassessment of Dahrendorf initiatives and ideas in these areas and an attempt at reading present developments on the basis of his thinking.
Humanâspecific transcriptome of ventral and dorsal midbrain dopamine neurons
Objective
Neuronal loss in the substantia nigra pars compacta (SNpc) in Parkinson's disease (PD) is not uniform as dopamine neurons from the ventral tier are lost more rapidly than those of the dorsal tier. Identifying the intrinsic differences that account for this differential vulnerability may provide a key for developing new treatments for PD.
Method
Here we compared the RNAâsequenced transcriptomes of ~100 laser captured microâdissected SNpc neurons from each tier from seven healthy controls.
Results
Expression levels of dopaminergic markers were similar across the tiers while markers specific to the neighbouring ventral tegmental area were virtually undetected. After accounting for unwanted sources of variation, we identified one hundred and six differentially expressed genes (DEGs) between the SNpc tiers. The genes higher in the dorsal/resistant SNpc tier neurons displayed coordinated patterns of expression across the human brain, their protein products had more interactions than expected by chance and they demonstrated evidence of functional convergence. No significant shared functionality was found for genes higher in the ventral/vulnerable SNpc tier.
Surprisingly but importantly, none of the identified DEGs were among the familial PD genes or genomeâwide associated loci. Finally, we found some DEGs in opposite tier orientation between human and analogous mouse populations.
Interpretation
Our results highlight functional enrichments of vesicular trafficking, ion transport/homeostasis and oxidative stress genes showing higher expression in the resistant neurons of the SNpc dorsal tier. Furthermore, the comparison of gene expression variation in human and mouse SNpc populations strongly argues for the need of humanâfocused Omics studies
Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies
Several studies have confirmed α-synuclein real-time quaking-induced conversion (αSyn-RT-QuIC) assay to have high sensitivity and specificity for Parkinson's disease. However, whether the assay can be used as a robust, quantitative measure to monitor disease progression, stratify different synucleinopathies and predict disease conversion in patients with idiopathic REM sleep behaviour disorder remains undetermined. The aim of this study was to assess the diagnostic value of CSF aSyn-RT-QuIC quantitative parameters in regard to disease progression, stratification, and conversion in synucleinopathies. We performed αSyn-RT-QuIC in the CSF samples from 74 Parkinson's disease, 24 multiple system atrophy and 45 idiopathic REM sleep behaviour disorder patients alongside 55 healthy controls, analysing quantitative assay parameters in relation to clinical data. αSyn-RT-QuIC showed 89% sensitivity and 96% specificity for Parkinson's disease. There was no correlation between RT-QuIC quantitative parameters and Parkinson's disease clinical scores (e.g. UPDRS motor) but RT-QuIC positivity and some quantitative parameters (e.g. Vmax) differed across the different phenotype clusters. RT-QuIC parameters also added value alongside standard clinical data in diagnosing Parkinson's disease. The sensitivity in multiple system atrophy was 75%, and CSF samples showed longer T50 and lower Vmax compared to Parkinson's disease. All RT-QuIC parameters correlated with worse clinical progression of multiple system atrophy (e.g. change in UMSARS). The overall sensitivity in idiopathic REM sleep behaviour disorder was 64%. In three of the four longitudinally followed idiopathic REM sleep behaviour disorder cohorts, we found around 90% sensitivity, but in one sample (DeNoPa) diagnosing idiopathic REM sleep behaviour disorder earlier from the community cases, this was much lower 39%. During follow-up, 14 of 45 (31%) idiopathic REM sleep behaviour disorder patients converted to synucleinopathy with 9/14 (64%) of convertors showing baseline RT-QuIC positivity. In summary, our results showed that αSyn-RT-QuIC adds value in diagnosing Parkinson's disease and may provide a way to distinguish variations within Parkinson's disease phenotype. The quantitative parameters however did not correlate with disease severity in Parkinson's disease. The assay distinguished multiple system atrophy patients from Parkinson's disease patients and in contrast to Parkinson's disease, the quantitative parameters correlated with disease progression of multiple system atrophy. Our results also provided further evidence for αSyn-RT-QuIC having potential as an early biomarker detecting synucleinopathy in idiopathic REM sleep behaviour disorder patients prior to conversion. Further analysis of longitudinally followed idiopathic REM sleep behaviour disorder patients is needed to better understand the relationship between αSyn-RT-QuIC signature and the progression from prodromal to different synucleinopathies
Cerebrospinal fluid real-time quaking-induced conversion is a robust and reliable test for sporadic creutzfeldtâjakob disease:An international study
Real-time quaking-induced conversion (RT-QuIC) has been proposed as a sensitive diagnostic test for sporadic Creutzfeldt\u2013Jakob disease; however, before this assay can be introduced into clinical practice, its reliability and reproducibility need to be demonstrated. Two international ring trials were undertaken in which a set of 25 cerebrospinal fluid samples were analyzed by a total of 11 different centers using a range of recombinant prion protein substrates and instrumentation. The results show almost complete concordance between the centers and demonstrate that RT-QuIC is a suitably reliable and robust technique for clinical practice. Ann Neurol 2016;80:160\u2013165
Mapping the prion protein distribution in marsupials: insights from comparing opossum with mouse CNS
The cellular form of the prion protein (PrP(C)) is a sialoglycoprotein widely expressed in the central nervous system (CNS) of mammalian species during neurodevelopment and in adulthood. The location of the protein in the CNS may play a role in the susceptibility of a species to fatal prion diseases, which are also known as the transmissible spongiform encephalopathies (TSEs). To date, little is known about PrP(C) distribution in marsupial mammals, for which no naturally occurring prion diseases have been reported. To extend our understanding of varying PrP(C) expression profiles in different mammals we carried out a detailed expression analysis of PrP(C) distribution along the neurodevelopment of the metatherian South American short-tailed opossum (Monodelphis domestica). We detected lower levels of PrP(C) in white matter fiber bundles of opossum CNS compared to mouse CNS. This result is consistent with a possible role for PrP(C) in the distinct neurodevelopment and neurocircuitry found in marsupials compared to other mammalian species
Prion-specific and surrogate CSF biomarkers in Creutzfeldt-Jakob disease:diagnostic accuracy in relation to molecular subtypes and analysis of neuropathological correlates of p-tau and A beta 42 levels
The differential diagnosis of Creutzfeldt-Jakob disease (CJD) from other, sometimes treatable, neurological disorders is challenging, owing to the wide phenotypic heterogeneity of the disease. Real-time quaking-induced prion conversion (RT-QuIC) is a novel ultrasensitive in vitro assay, which, at variance with surrogate neurodegenerative biomarker assays, specifically targets the pathological prion protein (PrPSc). In the studies conducted to date in CJD, cerebrospinal fluid (CSF) RT-QuIC showed good diagnostic sensitivity (82\u201396%) and virtually full specificity. In the present study, we investigated the diagnostic value of both prion RT-QuIC and surrogate protein markers in a large patient population with suspected CJD and then evaluated the influence on CSF findings of the CJD type, and the associated amyloid-\u3b2 (A\u3b2) and tau neuropathology. RT-QuIC showed an overall diagnostic sensitivity of 82.1% and a specificity of 99.4%. However, sensitivity was lower in CJD types linked to abnormal prion protein (PrPSc) type 2 (VV2, MV2K and MM2C) than in typical CJD (MM1). Among surrogate proteins markers (14-3-3, total (t)-tau, and t-tau/phosphorylated (p)-tau ratio) t-tau performed best in terms of both specificity and sensitivity for all sCJD types. Sporadic CJD VV2 and MV2K types demonstrated higher CSF levels of p-tau when compared to other sCJD types and this positively correlated with the amount of tiny tau deposits in brain areas showing spongiform change. CJD patients showed moderately reduced median A\u3b242 CSF levels, with 38% of cases having significantly decreased protein levels in the absence of A\u3b2 brain deposits. Our results: (1) support the use of both RT-QuIC and t-tau assays as first line laboratory investigations for the clinical diagnosis of CJD; (2) demonstrate a secondary tauopathy in CJD subtypes VV2 and MV2K, correlating with increased p-tau levels in the CSF and (3) provide novel insight into the issue of the accuracy of CSF p-tau and A\u3b242 as markers of brain tauopathy and \u3b2-amyloidosis
Does Public Diplomacy matter? The Debate on Issues and Actors of Public Diplomacy Engagement
Depending on how we define public diplomacy (PD), its roots can be traced back to the interwar period, to the 1940s, or more recently, to the 1960s and the post-Cold War era. At present, politicians, diplomats and scholars are increasingly attracted, concerned by and involved in the practice and theory of this challenging and extremely fast developing field. Academia as well as the world of politics and diplomacy, are striving to understand on the one hand, shape and influence on the other, the flow of public diplomatic engagement that can launch and sustain multiple dialogues with foreign publics in an unprecedented two way street, but also, inevitably, allows the dark side of misinformation and propaganda to take advantage of such an increasingly digitalised diplomatic environment
Trovare un ruolo, fare una scelta: riflessioni sulla collocazione internazionale della Gran Bretagna contemporanea.
L'articolo fa il punto del dibattito storiografico e politico sulla Gran Bretagna in Europa alla luce della recente uscita del paese dalla U
Diplomazia della transizione. Gli alleati e il problema del trattato di pace italiano (1945-1947)
Il libro ha affrontato per la prima volta, grazie a un approfondito lavoro d'archivio in Italia, Stati Uniti e Gran Bretagna, la questione di come la politica, la diplomazia e le relazioni internazionali hanno inciso sul negoziato di pace per l'Italia nella fase di transizione successiva alla fine della seconda guerra mondiale. Il libro pone il negoziato di pace al centro della storiografia sulle origini della guerra fredda