Abstract Aging and the interaction between genetic and environmental factors are believed to be involved in chronic Parkinson's Disease (PD) progression. Abnormal aggregated α-synuclein is the main component of Lewy body in PD patients. The intranasal route is believed to be a gate way to the brain which facilitates entry of environmental neurotoxin into the brain and account for the smell loss in early PD. In this study, we chronically applied intranasal lipopolysaccharides (LPS) exposure on 4-month-old, 8-month-old, 12-month-old and 16-month-old A53T-α-synuclein (A53T-α-Syn) transgenic C57BL/6 mice every other day for 2 months to evaluate the behavioral, pathological, biochemical changes as well as microglial activation in these mice. We observed intranasal LPS exposed A53T-α-Syn mice displayed a robust progressive olfactory disorder, hypokinesia, selective loss of dopaminergic neurons, reduction in striatal dopamine (DA) content, and accelerated α-synuclein aggregation in the SN in an age-dependent way. Furthermore, we found obvious NF-кB activation, Nurr1 inhibition, IL-1β and TNF-α generation in microglia in the SN. By contrast, these PD-like changes were mild in WT and moderate in A53T-α-Syn mice in old-aged mice. This study demonstrated the synergistic effect of intranasal LPS and α-synuclein burden on PD progression. The potential mechanism was attributed to the inhibition of Nurr1 in microglial cells and the amplified neuroinflammation in the CNS. These multi-hit animals (aging, α-synuclein mutation and neuroinflammation) might help us to investigate the mechanisms through which mutant α-synuclein and inflammation work in concert to mediate PD neurodegeneration.
Abstract Global profile of gene expression at single-cell resolution remains to be determined for primates. Using a recently developed technology (“Stereo-seq”), we have obtained a comprehensive single-cell spatial transcriptome map at the whole-brain level for cynomolgus monkeys, with ∼600 genes per cell for 10 μm-thick coronal sections (up to 15 cm 2 in size). Large-scale single-nucleus RNA-seq analysis for ∼1 million cells helped to identify cell types corresponding to Stereo-seq gene expression profiles, providing a 3-D cell type atlas of the monkey brain. Quantitative analysis of Stereo-seq data revealed molecular fingerprints that mark distinct neocortical layers and subregions, as well as domains within subcortical structures including hippocampus, thalamus, striatum, cerebellum, hypothalamus and claustrum. Striking whole-brain topography and coordinated patterns were found in the expression of genes encoding receptors and transporters for neurotransmitters and neuromodulators. These results pave the way for cellular and molecular understanding of organizing principles of the primate brain.
Sulfur speciation under the influence of sample pretreatment and sewage sludge (SS) application in a continuously SS‐amended soil was assessed by wet‐chemical fractionation and S K ‐edge XANES spectroscopy. Distinct differences in S speciation among the following pretreatments including fresh, air‐drying, anoxic freeze‐drying, oven‐drying, and conditioning (incubation at room temperature and 75% of water holding capacity for 2 wk) were detected in both topsoils and subsoils. Air‐drying significantly increased available S content but decreased C‐bonded S content in the soils compared with anoxic freeze‐drying. Oven‐drying and conditioning pretreatments showed a similar effect on S fractions to air‐drying in the soils but to a lesser extent. X‐ray adsorption near‐edge structure analysis showed that both reduced and intermediate organic S tended to decrease while oxidized S obviously increased in the air‐dried samples. In contrast, the conditioning pretreatment facilitated the transformation of intermediate S into reduced organic S. Continuous application of SS significantly increased total soil S, C‐bonded S, and residual S contents but decreased available S content in the topsoil. Meanwhile, XANES analysis indicated that reduced organic S was markedly increased (over 50% of total S) in the SS‐amended topsoil. No obvious effect of the application of SS on S speciation in the subsoil was observed except for the facilitated transportation of S into lower depth. Overall, our results suggest that anoxic atmospheres during the entire pretreatment process from sampling to drying, grinding, and analysis is crucial for the accurate speciation analysis of S in soils, and the anoxic freeze‐drying is, therefore, highly recommended.
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