Trial of Deferiprone in Parkinson’s Disease Devos, David; Labreuche, Julien; Rascol, Olivier ...
The New England journal of medicine,
12/2022, Letnik:
387, Številka:
22
Journal Article
Recenzirano
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Iron deposition in the substantia nigra has been implicated in Parkinson’s disease. Chelation with deferiprone reduced brain iron content but led to worse scores on scales of the movement disorder at ...36 weeks.
Genetic instability, a heritable increase in the rate of genetic mutation, accelerates evolutionary adaptation
and is widespread in cancer
. In mammals, instability can arise from damage to both ...copies of genes involved in DNA metabolism and cell cycle regulation
or from inactivation of one copy of a gene whose product is present in limiting amounts (haploinsufficiency
); however, it has proved difficult to determine the relative importance of these two mechanisms. In Escherichia coli
, the application of repeated, strong selection enriches for genetic instability. Here we have used this approach to evolve genetic instability in diploid cells of the budding yeast Saccharomyces cerevisiae, and have isolated clones with increased rates of point mutation, mitotic recombination, and chromosome loss. We identified candidate, heterozygous, instability-causing mutations; engineering these mutations, as heterozygotes, into the ancestral diploid strain caused genetic instability. Mutations that inactivated one copy of haploinsufficient genes were more common than those that dominantly altered the function of the mutated gene copy. The mutated genes were enriched for genes functioning in transport, protein quality control, and DNA metabolism, and have revealed new targets for genetic instability
, including essential genes. Although only a minority (10 out of 57 genes with orthologues or close homologues) of the targets we identified have homologous human genes that have been implicated in cancer
, the remainder are candidates to contribute to human genetic instability. To test this hypothesis, we inactivated six examples in a near-haploid human cell line; five of these mutations increased instability. We conclude that single genetic events cause genetic instability in diploid yeast cells, and propose that similar, heterozygous mutations in mammalian homologues initiate genetic instability in cancer.
The effects of microwave (MW) pretreatment, staging and digestion temperature on anaerobic digestion were investigated in a setup of ten reactors. A mesophilic reactor was used as a control. Its ...performance was compared to single-stage mesophilic and thermophilic reactors treating pretreated and non-pretreated sludge, temperature-phased (TPAD) thermophilic-mesophilic reactors treating pretreated and non-pretreated sludge and thermophilic–thermophilic reactors also treating pretreated and non-pretreated sludge. Four different sludge retention times (SRTs) (20, 15, 10 and 5 d) were tested for all reactors. Two-stage thermo–thermo reactors treating pretreated sludge produced more biogas than all other reactors and removed more volatile solids. Maximum volatile solids (VS) removal was 53.1% at an SRT of 15 d and maximum biogas increase relative to control was 106% at the shortest SRT tested. Both the maximum VS removal and biogas relative increase were measured for a system with thermophilic acidogenic reactor and thermophilic methanogenic reactor. All the two-stage systems treating microwaved sludge produced sludge free of pathogen indicator bacteria, at all tested conditions even at a total system SRT of only 5 d. MW pretreatment and staging reactors allowed the application of very short SRT (5 d) with no significant decrease in performance in terms of VS removal in comparison with the control reactor. MW pretreatment caused the solubilization of organic material in sludge but also allowed more extensive hydrolysis of organic material in downstream reactors. The association of MW pretreatment and thermophilic operation improves dewaterability of digested sludge.
► We tested two different strategies for anaerobic digestion improvement. ► Microwaving alone produces better results than physical and temperature staging. ► The combination of Microwaving and TPAD increases the biogas production, solids removal and the applied loads without degradation in efficiency. ► MW and TPAD produce sludge with good pathogen removal.
This study addresses one of the limiting factors for producing micro and nanofibrillated cellulose (MNFC)-containing papers: poor water removal properties. We focus on the sheet sealing phenomenon ...during dewatering. A modified dynamic drainage analyzer (DDA) is used to examine both multilayer and single layer forming of MNFC and pulp mixtures. It was found that a thin layer of pulp fibers on the exit layer with the grammage as low as 5 gsm was enough to significantly improve the dewatering of MNFC. For example, the dewatering rate of a furnish with 50% MNFC increased from 0.6 mL/s for a mixed system to 2 mL/s for multilayer system. However, the sheet sealing behavior was completely different when a lower proportion of MNFC was used. For the furnishes with less than 20% MNFC content, the mixed furnishes dewatered faster because the high amount of pulp fibers were able to prevent MNFC from enriching on the exit layer. Surprisingly, we found that very high final solids content (couch solids) could sometimes be achieved when MNFC was used. The highest solids contents achieved were 34 and 29% for the mixed systems. This compares to the 15–20% range typical of standard papermaking furnishes without MNFC. Overall, the results show that contrary to current thinking MNFC containing papers may lead, under some circumstances, to enhanced wire section dewatering.
Parkinson's disease (PD) is a progressive neurodegenerative disorder known for the typical motor features associated. Pathologically, it is characterized by the intracellular accumulation of ...alpha-synuclein (aSyn) in Lewy bodies and Lewy neurites. Currently, there are no established biochemical markers for diagnosing or for following disease progression, a major limitation for the clinical practice. Posttranslational modifications (PTMs) in aSyn have been identified and implicated on its pathobiology. Since aSyn is abundant in blood erythrocytes, we aimed to evaluate whether PTMs of aSyn in the blood might hold value as a biomarker for PD. We examined 58 patients with PD and 30 healthy age-matched individuals. We found that the levels of Y125 phosphorylated, Y39 nitrated, and glycated aSyn were increased in PD, while those of SUMO were reduced. A combinatory analysis of the levels of these PTMs resulted in an increased sensitivity, with an area under curve (AUC) of 0.843 for PD versus healthy controls, and correlated with disease severity and duration. We conclude that the levels of these selected PTMs hold strong potential as biochemical markers for PD. Ultimately, our findings might facilitate the monitoring of disease progression in clinical trials, opening the possibility for developing more effective therapies against PD.
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