Transmissibility of Atypical Scrapie in Ovine Transgenic Mice: Major Effects of Host Prion Protein Expression and Donor Prion Genotype

Atypical scrapie or Nor98 has been identified as a transmissible spongiform encephalopathy (TSE) that is clearly distinguishable from classical scrapie and BSE, notably regarding the biochemical features of the protease-resistant prion protein PrPres and the genetic factors involved in susceptibility to the disease. In this study we transmitted the disease from a series of 12 French atypical scrapie isolates in a transgenic mouse model (TgOvPrP4) overexpressing in the brain ∼0.25, 1.5 or 6× the levels of the PrPARQ ovine prion protein under the control of the neuron-specific enolase promoter. We used an approach based on serum PrPc measurements that appeared to reflect the different PrPc expression levels in the central nervous system. We found that transmission of atypical scrapie, much more than in classical scrapie or BSE, was strongly influenced by the PrPc expression levels of TgOvPrP4 inoculated mice. Whereas TgOvPrP4 mice overexpressing ∼6× the normal PrPc level died after a survival periods of 400 days, those with ∼1.5× the normal PrPc level died at around 700 days. The transmission of atypical scrapie in TgOvPrP4 mouse line was also strongly influenced by the prnp genotypes of the animal source of atypical scrapie. Isolates carrying the AF141RQ or AHQ alleles, associated with increased disease susceptibility in the natural host, showed a higher transmissibility in TgOvPrP4 mice. The biochemical analysis of PrPres in TgOvPrP4 mouse brains showed a fully conserved pattern, compared to that in the natural host, with three distinct PrPres products. Our results throw light on the transmission features of atypical scrapie and suggest that the risk of transmission is intrinsically lower than that of classical scrapie or BSE, especially in relation to the expression level of the prion protein

The Physical Relationship between Infectivity and Prion Protein Aggregates Is Strain-Dependent

Prions are unconventional infectious agents thought to be primarily composed of PrPSc, a multimeric misfolded conformer of the ubiquitously expressed host-encoded prion protein (PrPC). They cause fatal neurodegenerative diseases in both animals and humans. The disease phenotype is not uniform within species, and stable, self-propagating variations in PrPSc conformation could encode this ‘strain’ diversity. However, much remains to be learned about the physical relationship between the infectious agent and PrPSc aggregation state, and how this varies according to the strain. We applied a sedimentation velocity technique to a panel of natural, biologically cloned strains obtained by propagation of classical and atypical sheep scrapie and BSE infectious sources in transgenic mice expressing ovine PrP. Detergent-solubilized, infected brain homogenates were used as starting material. Solubilization conditions were optimized to separate PrPSc aggregates from PrPC. The distribution of PrPSc and infectivity in the gradient was determined by immunoblotting and mouse bioassay, respectively. As a general feature, a major proteinase K-resistant PrPSc peak was observed in the middle part of the gradient. This population approximately corresponds to multimers of 12–30 PrP molecules, if constituted of PrP only. For two strains, infectivity peaked in a markedly different region of the gradient. This most infectious component sedimented very slowly, suggesting small size oligomers and/or low density PrPSc aggregates. Extending this study to hamster prions passaged in hamster PrP transgenic mice revealed that the highly infectious, slowly sedimenting particles could be a feature of strains able to induce a rapidly lethal disease. Our findings suggest that prion infectious particles are subjected to marked strain-dependent variations, which in turn could influence the strain biological phenotype, in particular the replication dynamics

Photocatalytic degradation of organic pollutants in water and in air. An analytical approach

Arsac, F. Bianchi, D. Chovelon, J. M. Conchon, P. Ferronato, C. Lair, A. Sleirnan, M. 5th Maghreb/Europe Meeting on Materials and Their Applications for Devices and Physical, Chemical and Biological Sensors (MADICA 2006) OCT 30-NOV 01, 2006 Mahdia, TUNISIA Sp. Iss. SIThis paper reports on the development of three specific methods allowing to better understand the mechanism of the photocatalytic degradation of organic pollutants both in air and in gas phases. The first method uses a home made IR cell to study the TiO2 surface during the photocatalytic degradation. The second method uses an ATD/GC/MS system to study the gas phase at a ppbv level during the degradation while the third one uses an HPLC/NMR system to discriminate between different positional isomers. (c) 2007 Elsevier B.V. All rights reserved

Different methods in TiO2 photodegradation mechanism studies: Gaseous and TiO2-adsorbed phases

International audienceThe development of photocatalysis processes offers a significant number of perspectives especially in gaseous phase depollution. It is proved that the photo-oxidizing properties of photocatalyst (TiO2) activated by UV plays an important role in the degradation of volatile organic compounds (VOC). Heterogeneous photocatalysis is based on the absorption of UV radiations by TiO2. This phenomenon leads to the degradation and the oxidation of the compounds, according to a mechanism that associates the pollutant's adsorption on the photocatalyst and radical degradation reactions. The main objective of the study is the understanding of the TiO2-photocatalysis phenomenon including gaseous and adsorbed phase mechanisms. Results obtained with three different apparatus are compared; gaseous phases are analysed and mechanisms at the gaseous phase/photocatalyst interface are identified. This study leads to improve understanding of various mechanisms during pollutant photodegradation: adsorption of pollutants on TiO2 first takes place, then desorption and/or photodegradation, and finally, desorption of degradation products on TiO2. The association of analytical methods and different processes makes the determination of all parameters that affect the photocatalytic process possible. Mastering these parameters is fundamental for the design and construction of industrial size reactors that aim to purify the atmosphere

Causes of early mortality after liver transplantation: A twenty-years single centre experience

Objective. - To define the causes of mortality of patients who died within the first three months after a liver transplantation. Type of study. - Retrospective, observational, and single centre study. Patients and methods. - Between March 1989 and July 2010, all patients who died within three months after a liver transplantation were included. Demographic characteristics, preoperative and peroperative data, donor characteristics, postoperative complications and causes of mortality were collected. Results. - Among the 788 performed liver transplantations, 76 patients died in intensive care unit (11%). The main indications of liver transplantation were alcoholic cirrhosis (30%), hepatitis C (28%), hepatocarcinoma (15%), primitive or secondary biliary cirrhosis (10%). Fifty percent of the patients were categorized as Child C. The main causes of death were non-function or dysfunction with retransplantation contra-indication graft (18%), sepsis (18%), neurological complications (12%), hemorrhagic shock (13%), (9%), multiorgan failures (5%), cardiac complications (6%). Conclusion. In this study, the main causes of mortality were infectious, neurological and hemorrhagic. These results emphasize the necessity for better control of sepsis, haemorrhage and immunosupressors. (C) 2011 Elsevier Masson SAS. All rights reserved

Abnormal accumulation of lipid droplets in neurons induces the conversion of alpha-Synuclein to proteolytic resistant forms in a Drosophila model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein (αSyn) aggregation and associated with abnormalities in lipid metabolism. The accumulation of lipids in cytoplasmic organelles called lipid droplets (LDs) was observed in cellular models of PD. To investigate the pathophysiological consequences of interactions between αSyn and proteins that regulate the homeostasis of LDs, we used a transgenic Drosophila model of PD, in which human αSyn is specifically expressed in photoreceptor neurons. We first found that overexpression of the LD-coating proteins Perilipin 1 or 2 (dPlin1/2), which limit the access of lipases to LDs, markedly increased triacylglyclerol (TG) loaded LDs in neurons. However, dPlin-induced-LDs in neurons are independent of lipid anabolic (diacylglycerol acyltransferase 1/midway, fatty acid transport protein/dFatp) and catabolic (brummer TG lipase) enzymes, indicating that alternative mechanisms regulate neuronal LD homeostasis. Interestingly, the accumulation of LDs induced by various LD proteins (dPlin1, dPlin2, CG7900 or KlarsichtLD-BD) was synergistically amplified by the co-expression of αSyn, which localized to LDs in both Drosophila photoreceptor neurons and in human neuroblastoma cells. Finally, the accumulation of LDs increased the resistance of αSyn to proteolytic digestion, a characteristic of αSyn aggregation in human neurons. We propose that αSyn cooperates with LD proteins to inhibit lipolysis and that binding of αSyn to LDs contributes to the pathogenic misfolding and aggregation of αSyn in neurons

Admission of patients with STEMI since the outbreak of the COVID-19 pandemic: a survey by the European Society of Cardiology

Aims The COVID-19 pandemic required a significant redeployment of worldwide healthcare resources. Fear of infection, national lockdowns and altered healthcare priorities have the potential to impact utilisation of healthcare resources for non-communicable diseases. To survey health professionals’ views of the impact of the COVID-19 pandemic on the rate and timing of admission of patients with ST-elevation myocardial infarction (STEMI), the European Society of Cardiology (ESC) administered an internet-based questionnaire to cardiologists and cardiovascular nurses across 6 continents. Methods and results 3101 responses were received from 141 countries across 6 continents. 88.3% responded that their country was in “total lockdown” and 7.1% in partial lockdown. 78.8% responded that the number of patients presenting with STEMI was reduced since the coronavirus outbreak and 65.2% indicated that the reduction in STEMI presentations was >40%. Approximately 60% of all respondents reported that STEMI patients presented later than usual and 58.5% that >40% of STEMI patients admitted to hospital presented beyond the optimal window for primary percutaneous intervention (PCI) or thrombolysis. Independent predictors of the reported higher rate of delayed STEMI presentation were a country in total lockdown, >100 COVID-19 cases admitted locally, and the complete restructuring of the local cardiology service. Conclusion The survey indicates that the impact of COVID-19 on STEMI presentations is likely to be substantial, with both lower presentations and a higher rate of delayed presentations occurring. This has potentially important ramifications for future healthcare and policy planning in the event of further waves of this pandemic.</p