N-Acetylcholinesterase-Induced Apoptosis in Alzheimer's Disease

Background: Alzheimer’s disease (AD) involves loss of cholinergic neurons and Tau protein hyper-phosphorylation. Here, we report that overexpression of an N-terminally extended ‘‘synaptic’ ’ acetylcholinesterase variant, N-AChE-S is causally involved in both these phenomena. Methodology and Principal Findings: In transfected primary brain cultures, N-AChE-S induced cell death, morphological impairments and caspase 3 activation. Rapid internalization of fluorescently labeled fasciculin-2 to N-AChE-S transfected cells indicated membranal localization. In cultured cell lines, N-AChE-S transfection activated the Tau kinase GSK3, induced Tau hyper-phosphorylation and caused apoptosis. N-AChE-S-induced cell death was suppressible by inhibiting GSK3 or caspases, by enforced overexpression of the anti-apoptotic Bcl2 proteins, or by AChE inhibition or silencing. Moreover, inherent N-AChE-S was upregulated by stressors inducing protein misfolding and calcium imbalances, both characteristic of AD; and in cortical tissues from AD patients, N-AChE-S overexpression coincides with Tau hyper-phosphorylation. Conclusions: Together, these findings attribute an apoptogenic role to N-AChE-S and outline a potential value to ACh

Prolonged Testing of Metal Mobility in Mining-Impacted Soils Amended with Phosphate Fertilisers

The aim of the study was to determine whether the application of superphosphate fertiliser to soils contaminated with mine wastes can inhibit metal and metalloid mobility (Cu, Pb, Zn, Cd, Fe, Mn, As, Sb) in the long term. Contaminated soils contained sulfide- and sulfate-rich waste materials from the Broken Hill and Mt Isa mining centres. Results of long-term (10 months) column experiments demonstrate that fertiliser amendment had highly variable effects on the degree of metal and metalloid mobilisation and capture. Rapid release of metals from a sulfate-rich soil showed that phosphate amendment was ineffective in stabilising highly soluble metal-bearing phases. In a sulfide-rich soil with abundant organic matter, complexing of metals with soluble organic acids led to pronounced metal (mainly Cd, Cu and Zn) release from fertiliser-amended soils. The abundance of pyrite, as well as the addition of fertiliser, caused persistent acid production over time, which prevented the formation of insoluble metal phosphate phases and instead fostered an increased mobility of both metals and metalloids (As, Cd, Cu, Sb, Zn). By contrast, fertiliser application to a sulfide-rich soil with low organic carbon content and a sufficient acid buffering capacity to maintain near-neutral pH resulted in the immobilisation of Pb in the form of newly precipitated Pb phosphate phases. Thus, phosphate stabilisation was ineffective in suppressing metal and metalloid mobility from soils that were rich in organic matter, contained abundant pyrite and had a low acid buffering capacity. Phosphate stabilisation appears to be more effective for the in situ treatment of sulfide-rich soils that are distinctly enriched in Pb and contain insignificant concentrations of organic matter and other metals and metalloids

Integrated longitudinal multiomics study identifies immune programs associated with acute COVID-19 severity and mortality

BACKGROUNDPatients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity.METHODSWe performed deep immunophenotyping and conducted longitudinal multiomics modeling, integrating 10 assays for 1,152 Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study participants and identifying several immune cascades that were significant drivers of differential clinical outcomes.RESULTSIncreasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, formation of neutrophil extracellular traps, and T cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma Igs and B cells and dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to failure of viral clearance in patients with fatal illness.CONCLUSIONOur longitudinal multiomics profiling study revealed temporal coordination across diverse omics that potentially explain the disease progression, providing insights that can inform the targeted development of therapies for patients hospitalized with COVID-19, especially those who are critically ill.TRIAL REGISTRATIONClinicalTrials.gov NCT04378777.FUNDINGNIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI122220); and National Science Foundation (DMS2310836)