Influence of timing on CSF tests value for Creutzfeldt-Jakob disease diagnosis

Background: The analysis of markers in the cerebrospinal fluid (CSF) is useful in the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). However, the time at which the study of these markers is most sensitive remains controversal. Objective: To assess the influence of time of sampling on the value of CSF tests in the diagnosis of sCJD. Method: In the framework of a multinational European study, we studied the results of 14-3-3, S100b, neurone specific enolase (NSE) and tau protein in 833 CSF samples from sCJD patients at different stages of disease and in 66 sequentially repeated lumbar punctures (LP). Results: 14-3-3 and tau protein tended to increase in sensitivity from onset (88%, 81%) to the advanced stage (91%, 90%). This was significant only in the methionine-valine (MV) heterozygous group of patients at codon 129. The absolute levels of S100b (p < 0.05), NSE and tau protein increased in the last stage of disease. High levels of tau protein, NSE and S100b were associated with shorter survival times (p < 0.01). Sixty-six sCJD patients underwent repeated LP. These sCJD patients were younger, had longer disease durations and were more frequently MV at codon 129 (p < 0.001) than the whole group. 14-3-3 sensitivity increased from 64% to 82% in the second LP (p = 0.025) and 88% sCJD patients had at least one positive result. Conclusions: Sensitivity and absolute levels of CJD markers increased with disease progression and were modulated by the codon 129 genotype. Early negative results should be inter-preted with caution, especially in young patients or those who are MV at codon 129

Brain-derived proteins in the CSF, do they correlate with brain pathology in CJD?

BACKGROUND: Brain derived proteins such as 14-3-3, neuron-specific enolase (NSE), S 100b, tau, phosphorylated tau and Aβ(1–42 )were found to be altered in the cerebrospinal fluid (CSF) in Creutzfeldt-Jakob disease (CJD) patients. The pathogenic mechanisms leading to these abnormalities are not known, but a relation to rapid neuronal damage is assumed. No systematic analysis on brain-derived proteins in the CSF and neuropathological lesion profiles has been performed. METHODS: CSF protein levels of brain-derived proteins and the degree of spongiform changes, neuronal loss and gliosis in various brain areas were analyzed in 57 CJD patients. RESULTS: We observed three different patterns of CSF alteration associated with the degree of cortical and subcortical changes. NSE levels increased with lesion severity of subcortical areas. Tau and 14-3-3 levels increased with minor pathological changes, a negative correlation was observed with severity of cortical lesions. Levels of the physiological form of the prion protein (PrP(c)) and Aβ(1–42 )levels correlated negatively with cortical pathology, most clearly with temporal and occipital lesions. CONCLUSION: Our results indicate that the alteration of levels of brain-derived proteins in the CSF does not only reflect the degree of neuronal damage, but it is also modified by the localization on the brain pathology. Brain specific lesion patterns have to be considered when analyzing CSF neuronal proteins

Urinary α1-Antichymotrypsin: A Biomarker of Prion Infection

The occurrence of blood-borne prion transmission incidents calls for identification of potential prion carriers. However, current methods for intravital diagnosis of prion disease rely on invasive tissue biopsies and are unsuitable for large-scale screening. Sensitive biomarkers may help meeting this need. Here we scanned the genome for transcripts elevated upon prion infection and encoding secreted proteins. We found that α1-antichymotrypsin (α1-ACT) was highly upregulated in brains of scrapie-infected mice. Furthermore, α1-ACT levels were dramatically increased in urine of patients suffering from sporadic Creutzfeldt-Jakob disease, and increased progressively throughout the disease. Increased α1-ACT excretion was also found in cases of natural prion disease of animals. Therefore measurement of urinary α1-ACT levels may be useful for monitoring the efficacy of therapeutic regimens for prion disease, and possibly also for deferring blood and organ donors that may be at risk of transmitting prion infections

Recent updates on the Maser Monitoring Organisation

The Maser Monitoring Organisation (M2O) is a research community of telescope operators, astronomy researchers and maser theoreticians pursuing a joint goal of reaching a deeper understanding of maser emission and exploring its variety of uses as tracers of astrophysical events. These proceedings detail the origin, motivations and current status of the M2O, as was introduced at the 2021 EVN symposium

Characterisation of cell-penetrating peptide-mediated peptide delivery

1. Cell-penetrating peptides such as antennapedia, TAT, transportan and polyarginine have been extensively employed for in vitro and in vivo delivery of biologically active peptides. However, little is known of the relative efficacy, toxicity and uptake mechanism of individual protein transduction domain–peptide conjugates, factors that will be critical in determining the most effective sequence. 2. In the present study, we show by FACS analysis that unconjugated antennapedia, TAT, transportan and polyarginine demonstrate similar kinetic uptake profiles, being maximal at 1–3 h and independent of cell type (HeLa, A549 and CHO cell lines). A comparison of the magnitude of uptake of cell-penetrating peptide conjugates demonstrated that polyarginine=transportan>antennapedia>TAT. 3. However, examination of cellular toxicity showed that antennapedia<TAT<transportan<∩polyarginine, with antennapedia–peptide conjugates having no significant toxicity even at 100 μM. 4. Confocal studies of the mechanism of antennapedia- and TAT-peptide uptake showed that the time course of uptake and their cellular distribution did not correlate with transferrin, a marker of clathrin-mediated endocytosis. In contrast, the peptides co-localised with a marker of lipid rafts domains, cholera toxin, which was attenuated following the disruption of these domains using methyl-β-cyclodextrin. 5. Overall, comparison of the uptake and toxicity suggests that antennapedia provides the optimal cell-penetrating peptide for peptide delivery in vitro and that both antennapedia- and TAT-mediated peptide delivery occurs predominantly via lipid raft-dependent but clathrin-independent endocytosis

Advancing Astrophysics with the Square Kilometre Array

In 2014 it was 10 years since the publication of the comprehensive ‘Science with the Square Kilometre Array’ book and 15 years since the first such volume appeared in 1999. In that time numerous and unexpected advances have been made in the fields of astronomy and physics relevant to the capabilities of the Square Kilometre Array (SKA). The SKA itself progressed from an idea to a developing reality with a baselined Phase 1 design (SKA1) and construction planned from 2017. To facilitate the publication of a new, updated science book, which will be relevant to the current astrophysical context, the meeting "Advancing Astrophysics with the Square Kilometre Array" was held in Giardina Naxos, Sicily. Articles were solicited from the community for that meeting to document the scientific advances enabled by the first phase of the SKA and those pertaining to future SKA deployments, with expected gains of 5 times the Phase 1 sensitivity below 350 MHz, about 10 times the Phase 1 sensitivity above 350 MHz and with frequency coverage extending to ~20 GHz. The chapters listed here are the direct result of that meeting

Advancing Astrophysics with the Square Kilometre Array (AASKA14)

In 2014 it was 10 years since the publication of the comprehensive ‘Science with the Square Kilometre Array’ book and 15 years since the first such volume appeared in 1999. In that time numerous and unexpected advances have been made in the fields of astronomy and physics relevant to the capabilities of the Square Kilometre Array (SKA). The SKA itself progressed from an idea to a developing reality with a baselined Phase 1 design (SKA1) and construction planned from 2017. To facilitate the publication of a new, updated science book, which will be relevant to the current astrophysical context, the meeting "Advancing Astrophysics with the Square Kilometre Array" was held in Giardina Naxos, Sicily. Articles were solicited from the community for that meeting to document the scientific advances enabled by the first phase of the SKA and those pertaining to future SKA deployments, with expected gains of 5 times the Phase 1 sensitivity below 350 MHz, about 10 times the Phase 1 sensitivity above 350 MHz and with frequency coverage extending to ~20 GHz