Prion Protein Misfolding Affects Calcium Homeostasis and Sensitizes Cells to Endoplasmic Reticulum Stress

Prion-related disorders (PrDs) are fatal neurodegenerative disorders characterized by progressive neuronal impairment as well as the accumulation of an abnormally folded and protease resistant form of the cellular prion protein, termed PrPRES. Altered endoplasmic reticulum (ER) homeostasis is associated with the occurrence of neurodegeneration in sporadic, infectious and familial forms of PrDs. The ER operates as a major intracellular calcium store, playing a crucial role in pathological events related to neuronal dysfunction and death. Here we investigated the possible impact of PrP misfolding on ER calcium homeostasis in infectious and familial models of PrDs. Neuro2A cells chronically infected with scrapie prions showed decreased ER-calcium content that correlated with a stronger upregulation of UPR-inducible chaperones, and a higher sensitivity to ER stress-induced cell death. Overexpression of the calcium pump SERCA stimulated calcium release and increased the neurotoxicity observed after exposure of cells to brain-derived infectious PrPRES. Furthermore, expression of PrP mutants that cause hereditary Creutzfeldt-Jakob disease or fatal familial insomnia led to accumulation of PrPRES and their partial retention at the ER, associated with a drastic decrease of ER calcium content and higher susceptibility to ER stress. Finally, similar results were observed when a transmembrane form of PrP was expressed, which is proposed as a neurotoxic intermediate. Our results suggest that alterations in calcium homeostasis and increased susceptibility to ER stress are common pathological features of both infectious and familial PrD models

Balanced Synaptic Input Shapes the Correlation between Neural Spike Trains

Stimulus properties, attention, and behavioral context influence correlations between the spike times produced by a pair of neurons. However, the biophysical mechanisms that modulate these correlations are poorly understood. With a combined theoretical and experimental approach, we show that the rate of balanced excitatory and inhibitory synaptic input modulates the magnitude and timescale of pairwise spike train correlation. High rate synaptic inputs promote spike time synchrony rather than long timescale spike rate correlations, while low rate synaptic inputs produce opposite results. This correlation shaping is due to a combination of enhanced high frequency input transfer and reduced firing rate gain in the high input rate state compared to the low state. Our study extends neural modulation from single neuron responses to population activity, a necessary step in understanding how the dynamics and processing of neural activity change across distinct brain states

Cross-oncopanel study reveals high sensitivity and accuracy with overall analytical performance depending on genomic regions

BackgroundTargeted sequencing using oncopanels requires comprehensive assessments of accuracy and detection sensitivity to ensure analytical validity. By employing reference materials characterized by the U.S. Food and Drug Administration-led SEquence Quality Control project phase2 (SEQC2) effort, we perform a cross-platform multi-lab evaluation of eight Pan-Cancer panels to assess best practices for oncopanel sequencing.ResultsAll panels demonstrate high sensitivity across targeted high-confidence coding regions and variant types for the variants previously verified to have variant allele frequency (VAF) in the 5-20% range. Sensitivity is reduced by utilizing VAF thresholds due to inherent variability in VAF measurements. Enforcing a VAF threshold for reporting has a positive impact on reducing false positive calls. Importantly, the false positive rate is found to be significantly higher outside the high-confidence coding regions, resulting in lower reproducibility. Thus, region restriction and VAF thresholds lead to low relative technical variability in estimating promising biomarkers and tumor mutational burden.ConclusionThis comprehensive study provides actionable guidelines for oncopanel sequencing and clear evidence that supports a simplified approach to assess the analytical performance of oncopanels. It will facilitate the rapid implementation, validation, and quality control of oncopanels in clinical use.Peer reviewe

Conoscenze e percezioni sull'utilizzo delle sostanze per l'aumento della performance: un survey negli utenti delle palestre

KNOWLEDGE AND PERCEPTIONS ON THE USE OF PERFORMANCE-ENHANCING SUBSTANCES: A SUR- VEY OF GYM GOERS BACKGROUND: The use of performance-enhancing substances is not limited to professional athletes but can also be found in gyms amongst young amateur sports people. There is very little evidence in favour of taking such substances, and there are certainly health-related risks. This study aims to investigate awareness of the risks associated with energyenhancing substances. METHODS: This is a cross-sectional study made of a self-administered questionnaire handed out to amateur athletes in gyms and fitness centers in Naples and its province. RESULTS: 159 people took part in the study; 63.3% confirmed their use of various types of substance, including sports supplements and pharmaceutical products. We see the emergence of a clear pattern of beliefs in the positive effects of taking such substances. It was also possible to ascertain a good level of awareness of the risks associated with the taking of performance-enhancing substances. CONCLUSIONS: Sportsmen who welcome the idea of improving their performance with “external assistance” is on the increase. A better understanding of the problems associated with the taking of ergogenic substances requires effective measuresaimed at preventing abuse above all among young people, via educational campaigns which promote a healthy life style

Market Prices and Institutional Values - Comparison for Tax Purposes Through GIS Instrument

In Italy, the institutional analysis of the real estate market values is carried out by the Inland Revenue (government agency), through the Observatory of the Real Estate Market (OMI). In the last ten years, the average values (for types of real estates: houses, warehouses, garages, etc.) reported by the OMI are much closer to the market prices really recorded through the housing market sale contracts. Therefore, the reform of taxes on the real estate, recently strongly required by the European Commission, intends to take as reference the OMI values to increase the level of equalization in the taxation. This measure wants to correlate taxes to the real market value of the property and not to the land register value, which is completely distant from the real prices: this is true both for historical reasons (the latest update of land register values dates to several years ago) and for the evolution that the market has suffered especially in the big cities because of metropolitan and transport infrastructure development. This paper intends to verify the reliability of the OMI values compared to actual market prices and, at the same time, intends to control the possibility to equalize the fiscal mechanism considering the same tax revenue, as the Government claims to be able to do. The intent is to avoid the sacrifice of the less affluent segments of the population benefiting the lobbies of high-quality property owners using these modern mechanisms of the tax system. In this model, has been implemented an informative dataset in GIS mode. The use of GIS instrument makes it easier to verify the differential between government data and market prices

Feasibility of the Dutch ICF Activity Inventory: a pilot study

<p>Abstract</p> <p>Background</p> <p>Demographic ageing will lead to increasing pressure on visual rehabilitation services, which need to be efficiently organised in the near future. The Dutch ICF Activity Inventory (D-AI) was developed to assess the rehabilitation needs of visually impaired persons. This pilot study tests the feasibility of the D-AI using a computer-assisted telephone interview.</p> <p>Methods</p> <p>In addition to the regular intake, the first version of the D-AI was assessed in 20 patients. Subsequently, patients and intake assessors were asked to fill in an evaluation form. Based on these evaluations, a new version of the D-AI was developed.</p> <p>Results</p> <p>Mean administration time of the D-AI was 88.8 (± 41.0) minutes. Overall, patients and assessors were positive about the D-AI assessment. However, professionals and 60% of the patients found the administration time to be too long. All included items were considered relevant and only minor adjustments were recommended.</p> <p>Conclusion</p> <p>The systematic character of the revised D-AI will prevent topics from being overlooked and indicate which needs have the highest priority from a patient-centred perspective. Moreover, ongoing assessment of the D-AI will enhance evaluation of the rehabilitation process. To decrease administration time, in the revised D-AI only the top priority goals will be fully assessed. Using the D-AI, a rehabilitation plan based on individual needs can be developed for each patient. Moreover, it enables better evaluation of the effects of rehabilitation. A larger validation study is planned.</p