Idiopathic Parkinson's disease is characterized by a progressive loss of dopaminergic neurons, but the exact disease aetiology remains largely unknown. To date, Parkinson's disease research has ...mainly focused on nigral dopaminergic neurons, although recent studies suggest disease-related changes also in non-neuronal cells and in midbrain regions beyond the substantia nigra. While there is some evidence for glial involvement in Parkinson's disease, the molecular mechanisms remain poorly understood. The aim of this study was to characterize the contribution of all cell types of the midbrain to Parkinson's disease pathology by single-nuclei RNA sequencing and to assess the cell type-specific risk for Parkinson's disease using the latest genome-wide association study. We profiled >41 000 single-nuclei transcriptomes of post-mortem midbrain from six idiopathic Parkinson's disease patients and five age-/sex-matched controls. To validate our findings in a spatial context, we utilized immunolabelling of the same tissues. Moreover, we analysed Parkinson's disease-associated risk enrichment in genes with cell type-specific expression patterns. We discovered a neuronal cell cluster characterized by CADPS2 overexpression and low TH levels, which was exclusively present in idiopathic Parkinson's disease midbrains. Validation analyses in laser-microdissected neurons suggest that this cluster represents dysfunctional dopaminergic neurons. With regard to glial cells, we observed an increase in nigral microglia in Parkinson's disease patients. Moreover, nigral idiopathic Parkinson's disease microglia were more amoeboid, indicating an activated state. We also discovered a reduction in idiopathic Parkinson's disease oligodendrocyte numbers with the remaining cells being characterized by a stress-induced upregulation of S100B. Parkinson's disease risk variants were associated with glia- and neuron-specific gene expression patterns in idiopathic Parkinson's disease cases. Furthermore, astrocytes and microglia presented idiopathic Parkinson's disease-specific cell proliferation and dysregulation of genes related to unfolded protein response and cytokine signalling. While reactive patient astrocytes showed CD44 overexpression, idiopathic Parkinson's disease microglia revealed a pro-inflammatory trajectory characterized by elevated levels of IL1B, GPNMB and HSP90AA1. Taken together, we generated the first single-nuclei RNA sequencing dataset from the idiopathic Parkinson's disease midbrain, which highlights a disease-specific neuronal cell cluster as well as 'pan-glial' activation as a central mechanism in the pathology of the movement disorder. This finding warrants further research into inflammatory signalling and immunomodulatory treatments in Parkinson's disease.
An experimental and theoretical study of forced unsteady-state operation of trickle-bed reactors in comparison to the steady-state operation is the subject of this paper. It is well known that ...changes in the control variables influence the regime and the performance of trickle-bed reactors. In this study as one example for a forced periodic operation of a trickle-bed reactor an unsteady-state technique was used in which the catalyst bed is contacted periodically with different liquid flow rates. The unsteady-state operation was considered as square-waves cycling liquid flow rate at the reactor inlet. The hydrogenation of alpha-methylstyrene to cumene: C
6
H
5
(CH
3
)=CH
2
(
L
)
+ H
2
(
G
)
→
C
6
H
5
CH(CH
3
)
2
(
L
)
over a Palladium-catalyst (0.7% Pd/
γ
-Al
2
O
3
) was selected as a model reaction. The experimental results of the alpha-methylstyrene hydrogenation in a laboratory-scale trickle-bed reactor showed, that the reactor performance can be significantly improved by feed liquid flow modulation.
The simulation studies demonstrate that the liquid flow variation has a strong influence on the liquid hold-up oscillation and on the catalyst wetting efficiency. Consequently the time average alpha-methylstyrene conversion will be increased, because the mass transfer resistance between the phases (gas–liquid, gas–solid and liquid–solid) affect the overall reaction rate and consequently the conversion will be improved.
Adsorptive reactors represent a promising application of the multifunctional reactor concept for process intensification. The deliberate manipulation of concentration and temperature profiles ...resulting from the integration of an additional adsorptive functionality with heterogeneous catalytic activity can be impeded significantly by mass transfer limitations. If the multifunctionality is extended down to the particle level by using a multifunctional catalyst design the mass transfer bottleneck can be circumvented. Structured multifunctional catalyst particles offer an additional degree of freedom in reactor design. The enhancement in performance from multifunctional catalysts with integrated adsorption sites was evaluated for two reaction systems of industrial relevance using a rigorous dynamic model. Significant improvements were found when mass transfer limitations were present and a simple design procedure is presented for selecting the optimal particle structure of multifunctional catalysts.
The design of periodically operated trickle-bed reactors requires extensive knowledge of the complex underlying processes occurring at various scales. The development of dynamic models offers ...detailed insights into system behaviour and allows quantitative investigations over a wide range of operating conditions without the expense of comprehensive experimental studies. The description of the dynamic behaviour of periodically wetted catalyst particles is an important element in the overall multi-scale model architecture. Unfortunately, very little information is available on the influence of various model assumptions to aid selection of appropriate unsteady-state models. A systematic evaluation of dynamic particle-scale modelling approaches based on various intra-particle concentration profiles and periodic wetting of the external particle surface is presented.
Process intensification using periodic operation of trickle bed reactors (TBRs) is still a long way from replacing conventional steady-state operation in industrial use, despite the numerous benefits ...described in the literature. Complex interactions between hydrodynamics, mass transfer and reaction phenomena make the design of periodically operated TBRs an almost insurmountable challenge. The development of hydrodynamic models able to provide reliable quantitative predictions of flow behaviour and possessing a sound physical basis, is an essential prerequisite for obtaining the necessary insights into this complexity. In this work, the two-phase pressure drop and dynamic liquid hold-up during max/min and on/off periodical operation were predicted using a model based on the relative permeability concept. In order to demonstrate the utility of this approach, a systematic investigation of the quantitative influence of the liquid-phase physical properties was carried out. The results obtained show that the modelling of the hydrodynamics in periodically operated TBRs using the relative permeability concept is feasible. By selecting suitable permeability parameters, unsteady-state hydrodynamics for different periodic operating modes can be predicted successfully.
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