| 91381. |
|
|
| 91382. |
- Lande, Aasulv
(författare)
-
A New History of Shinto
- 2010
-
Ingår i: Japanese Journal of Religious Studies. - 0304-1042. ; 37:2, s. 385-388
-
Recension (övrigt vetenskapligt/konstnärligt)
|
|
| 91383. |
- Landeck, Natalie, et al.
(författare)
-
A novel multiplex assay for simultaneous quantification of total and S129 phosphorylated human alpha-synuclein
- 2016
-
Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Alpha-synuclein (asyn) has been shown to play an important role in the neuropathology of Parkinson's disease (PD). In the diseased brain, classic intraneuronal inclusions called Lewy bodies contain abnormal formations of asyn protein which is mostly phosphorylated at serine 129 (pS129 asyn). This suggests that post-translational modifications may play a role in the pathogenic process. To date, several uniplex assays have been developed in order to quantify asyn not only in the brain but also in cerebrospinal fluid and blood samples in order to correlate asyn levels to disease severity and progression. Notably, only four assays have been established to measure pS129 asyn specifically and none provide simultaneous readout of the total and pS129 species. Therefore, we developed a sensitive high-throughput duplex assay quantifying total and pS129 human asyn (h-asyn) in the same well hence improving accuracy as well as saving time, consumables and samples. Results: Using our newly established duplex assay we measured total and pS129 h-asyn in vitro showing that polo-like kinase 2 (PLK2) can phosphorylate asyn up to 41 % in HEK293 cells and in vivo the same kinase phosphorylated h-asyn up to 17 % in rat ventral midbrain neurons. Interestingly, no increase in phosphorylation was observed when PLK2 and h-asyn were co-expressed in rat striatal neurons. Furthermore, using this assay we investigated h-asyn levels in brain tissue samples from patients with PD as well as PD dementia and found significant differences in pS129 h-asyn levels not only between disease tissue and healthy control samples but also between the two distinct disease states especially in hippocampal tissue samples. Conclusions: These results demonstrate that our duplex assay for simultaneous quantification is a useful tool to study h-asyn phosphorylation events in biospecimens and will be helpful in studies investigating the precise causative link between post-translational modification of h-asyn and PD pathology.
|
|
| 91384. |
- Landeck, Natalie
(författare)
-
Pathogenic effects of alpha-synuclein: modifications and toxicity
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Accumulation of intraneuronal inclusions, containing mainly a protein called alpha-synuclein (asyn), is thought to play a critical role in neurodegenerative disorders such as Parkinson's disease (PD). In these so called Lewy bodies, the majority of asyn is phosphorylated at serine 129 (pS129) suggesting that post-translational modifications may play a critical role in the process of aggregate formation. To date, the precise pathological aspects and molecular mechanisms underlying asyn aggregation remain unclear. Previous studies have aimed to elucidate which region of human asyn (h-asyn) is influencing its aggregation properties and therefore possibly its toxicity towards neuronal cells. By investigating truncated h-asyn as well as naturally occurring asyn variants, it has been shown that synuclein lacking the central hydrophobic region is less prone to aggregate in vitro, although not all experimental studies support this view.To address this critical issue, we directly compared several human and rodent synuclein variants in a dose-depended manner to determine their toxic effects in vivo. Interestingly, we found that all human variants followed the same toxicity profile while rat asyn (r-asyn) did not induce neurodegeneration. Whereas phosphorylation levels of h-asyn was greater than that of r-asyn, increasing the amount of endogenous pS129 r-asyn did not result in neurotoxicity. Additionally, using our newly established duplexing assay to measure total and pS129 asyn simultaneously, we showed that endogenous pS129 h-asyn levels are naturally higher than that of r-asyn. This could point to phosphorylation being a side effect of h-asyn accumulation.Interestingly, both rat and mouse asyn are 95% homologous to h-asyn but show no accumulation or neurotoxicity over time in vivo. Furthermore, rodent asyn naturally contains a threonine at position 53 (T53), which in humans causes familial PD. To investigate why rodent asyn is less toxic especially when containing a T53 residue, we altered two C-terminally located amino acids of h-asynA53T to the mouse asyn (m-asyn) sequence and could demonstrate that dopaminergic neurodegeneration was reduced in the rat nigra. Moreover, mutating the C-terminal region of m-asyn to the human amino acids results in an increase of toxicity in vivo. These changes in the neurotoxicity profile could be due to the alterations we observed in the membrane-induced aggregation and vesicle disruption property of asyn.Taken together, these findings not only have an impact on our understanding of the formation and toxicity of asyn aggregates but could also lead to the development of novel therapeutic strategies targeting specifically the C-terminal region of h-asyn in PD.
|
|
| 91385. |
- Landeck, Natalie, et al.
(författare)
-
Toxic effects of human and rodent variants of alpha-synuclein in vivo
- 2017
-
Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 45:4, s. 536-547
-
Tidskriftsartikel (refereegranskat)abstract
- In Parkinson's disease, abnormal alpha-synuclein (asyn) accumulation leads to the formation of soluble oligomeric species thought to be toxic to cells as well as intraneuronal inclusions. To date, the precise mechanisms leading to aggregation of asyn in the brain is not well-understood. Previous studies in yeast, drosophila, and transgenic mice suggested that a non-A beta component depleted version of human asyn [h-asyn(D70-83)] or human beta-synuclein (h-bsyn), naturally lacking this centrally located hydrophobic region, are less prone to form aggregates in vitro and are expected to be less toxic compared to h-asyn in vivo, although not all experimental studies unequivocally support the latter view. To address this outstanding issue, we directly compared the neurotoxicity of human asyn against that of h-asyn(D70-83), h-bsyn as well as rat asyn using an adeno-associated viral vector to express these proteins in a dose-response study where the vector load was varied over two orders of magnitude. By quantifying the neurodegeneration of rat substantia nigra dopamine neurons here we show that h-asyn, h-bsyn, and h-asyn(D70-83) display comparable neurotoxicity across the vector doses tested. On the other hand, rat asyn and GFP control vectors displayed a different profile, where no detectable neurodegeneration was seen except at the highest vector titer. Thus, the two main conclusions of our study are that (i) deletion of the central hydrophobic region in h-asyn is not sufficient to alter its neurotoxic properties and (ii) expression of the widely used GFP control protein can cause measurable neurodegeneration at high titers.
|
|
| 91386. |
- Landeck, Natalie, et al.
(författare)
-
Two C-terminal sequence variations determine differential neurotoxicity between human and mouse α-synuclein
- 2020
-
Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 15:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: α-Synuclein (aSyn) aggregation is thought to play a central role in neurodegenerative disorders termed synucleinopathies, including Parkinson's disease (PD). Mouse aSyn contains a threonine residue at position 53 that mimics the human familial PD substitution A53T, yet in contrast to A53T patients, mice show no evidence of aSyn neuropathology even after aging. Here, we studied the neurotoxicity of human A53T, mouse aSyn, and various human-mouse chimeras in cellular and in vivo models, as well as their biochemical properties relevant to aSyn pathobiology. Methods: Primary midbrain cultures transduced with aSyn-encoding adenoviruses were analyzed immunocytochemically to determine relative dopaminergic neuron viability. Brain sections prepared from rats injected intranigrally with aSyn-encoding adeno-associated viruses were analyzed immunohistochemically to determine nigral dopaminergic neuron viability and striatal dopaminergic terminal density. Recombinant aSyn variants were characterized in terms of fibrillization rates by measuring thioflavin T fluorescence, fibril morphologies via electron microscopy and atomic force microscopy, and protein-lipid interactions by monitoring membrane-induced aSyn aggregation and aSyn-mediated vesicle disruption. Statistical tests consisted of ANOVA followed by Tukey's multiple comparisons post hoc test and the Kruskal-Wallis test followed by a Dunn's multiple comparisons test or a two-tailed Mann-Whitney test. Results: Mouse aSyn was less neurotoxic than human aSyn A53T in cell culture and in rat midbrain, and data obtained for the chimeric variants indicated that the human-to-mouse substitutions D121G and N122S were at least partially responsible for this decrease in neurotoxicity. Human aSyn A53T and a chimeric variant with the human residues D and N at positions 121 and 122 (respectively) showed a greater propensity to undergo membrane-induced aggregation and to elicit vesicle disruption. Differences in neurotoxicity among the human, mouse, and chimeric aSyn variants correlated weakly with differences in fibrillization rate or fibril morphology. Conclusions: Mouse aSyn is less neurotoxic than the human A53T variant as a result of inhibitory effects of two C-terminal amino acid substitutions on membrane-induced aSyn aggregation and aSyn-mediated vesicle permeabilization. Our findings highlight the importance of membrane-induced self-assembly in aSyn neurotoxicity and suggest that inhibiting this process by targeting the C-terminal domain could slow neurodegeneration in PD and other synucleinopathy disorders.
|
|
| 91387. |
- Landegren, Finn, et al.
(författare)
-
A hybrid modell for assessing resilience of electricity networks
- 2016
-
Ingår i: EEEIC 2016 - International Conference on Environment and Electrical Engineering. - 9781509023196
-
Konferensbidrag (refereegranskat)abstract
- A hybrid model is used for quantification of three resilience metrics: robustness, rapidity and resilience loss. The approach is demonstrated in a case study on a municipal electricity distribution system. An overall conclusion from the case study is that the suggested method provides an overview of the resilience metrics of the electricity distribution system and that it allows the network operator to see for what levels of strain that they reach their targets concerning system resilience. It is also concluded that the presented approach can enable assessment of how decision variables, relating to the technical network as well as to the repair system, are impacting system resilience.
|
|
| 91388. |
- Landegren, Finn, et al.
(författare)
-
A Method for Assessing Margin and Sensitivity of Electricity Networks With Respect to Repair System Resources
- 2016
-
Ingår i: IEEE Transactions on Smart Grid. - 1949-3061. ; 7:6, s. 2880-2889
-
Tidskriftsartikel (refereegranskat)abstract
- Modern society is becoming increasingly dependent on a continuous supply of electricity. In order to maintain the safety and security of society and its citizens, it is therefore necessary that electricity networks are resilient toward disruptions whether caused by natural disasters, sinister attacks, or other. Margin and sensitivity are two crucial aspects of the resilience concept which have so far been subject to little research. Here a simulation-based method is presented that enables quantitative assessment of margin and sensitivity of electricity networks with respect to repair system resources. A simulation model is used that explicitly takes into account the electricity network as well as the repair teams and materiel necessary for repairing network components. The method is demonstrated for a municipal power distribution system in Sweden which is subjected to disturbances with a severity up to 12 independent failures (N-12). An overall conclusion from the case study is that the suggested method provides an overview of the margin and sensitivity of the electricity distribution system, with respect to repair system resources. This information can form the basis for decisions concerning what amount of resources is appropriate.
|
|
| 91389. |
- Landegren, Finn, et al.
(författare)
-
A Method for Assessing Resilience of Socio-Technical IT-Systems
- 2016
-
Ingår i: Risk, Reliability and Safety: Innovating Theory and Practice. - Taylor & Francis Group, 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742 : CRC Press. - 9781498788984 ; , s. 2199-2206
-
Konferensbidrag (refereegranskat)abstract
- Modern society is increasingly dependent on IT-systems. Due to this dependence it is importantthat IT-networks are designed to be resilient, meaning that they will either maintain or quickly recover theirfunctionality when exposed to strain. Simulation-based methods that consider supply network topology as wellas system responsible for repairing supply network have previously been used and found to be beneficial forassessing resilience of electricity and water distribution systems. A method of this kind is here applied for ITnetworks.The aim of the present research is to test if such a method is applicable for assessing resilience ofIT-systems, meaning that: 1) it is possible to use based on available data, in this case gathered mainly throughinterviews with focus groups, 2) the results are relevant for users/owners/maintainers. The method is tested ina case study on the IT-network of one department of Lund university as well as the university core network.Results show that the method is applicable for the studied IT-network and that we can obtain the resiliencemetrics sought for. It is found that the method can enable system owners to see if and for what levels of strainthey are presently reaching their desired targets concerning system resilience. While applicable to the studiedsystem, feedback from system experts indicates that the method will primarily be useful for IT-systems whosefailure would 1) result in large economic values (e.g. IT-system of major private companies) or 2) lead to lossof health or safety (e.g. IT-systems of governmental organizations and hospitals).
|
|
| 91390. |
- Landegren, Finn, et al.
(författare)
-
Comparing Societal Consequence Measures of Outages in Electrical Distribution Systems
- 2014
-
Ingår i: Safety and Reliability : Methodology and Applications - Proceedings of the European Safety and Reliability Conference, ESREL 2014 - Methodology and Applications - Proceedings of the European Safety and Reliability Conference, ESREL 2014. - : CRC Press. - 9781138026810 - 9780429226823 ; , s. 189-196
-
Konferensbidrag (refereegranskat)abstract
- Quality of supply regulations are today in use in a large number of countries. While these regu-lations are likely to decrease the direct economical consequences from power outages it is less clear to what extent they take into account the societal criticality of consumers. In order to advance knowledge in this area, two different ways of estimating consequences of power outages are here contrasted. In recent years a system, named Styrel, has been introduced in Sweden, intended to enable prioritization of critical power customers from a societal perspective during times of power shortage. The Styrel prioritizations are here used as a proxy for the societal consequences of power outages. The second way of measuring consequences that arise makes use of the Swedish power outage regulation concerning outage compensations to customers. A case study is carried out for a real-life distribution system in Sweden, where failures of different sizes are simulated and the two consequence measures are calculated for each failure scenario. The overall result is that the present power outage regulation poorly mirrors the societal consequences as estimated by the Styrel prioritizations, leading to the conclusion that present day power outage regulation in Sweden is not satisfactorily taking some aspects of societal criticality into account.
|
|
