| 1. |
- Kehoe, Laura, et al.
(author)
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Make EU trade with Brazil sustainable
- 2019
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Journal article (other academic/artistic)
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| 2. |
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| 3. |
- Andrén, Anna, et al.
(author)
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Miscommunication influences how women act when fetal movements decrease : An interview study with Swedish Somali migrant women
- 2023
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In: Midwifery. - 0266-6138 .- 1532-3099. ; 126
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To explore how Swedish Somali migrant women perceive fetal movements, process information about fetal movements, and take actions if decreased fetal activity occurs.DESIGN: A qualitative study based on individual semi-structured interviews. The interviews were analysed using content analysis.SETTING: The study was conducted in Sweden.PARTICIPANTS: Swedish Somali migrant women (n=15) pregnant in their third trimester or recently given birth.FINDINGS: The analysis led to the main category: tailored information about fetal movements enhances the possibility to seek care if the movements decrease. The results are described in the generic categories: explanatory models determine action; and understand and interpret information.KEY CONCLUSIONS: Miscommunication on fetal movements can be a hurdle for Swedish Somali migrant women that may have impact on stillbirth prevention and the quality of care. Improved communication and information tailored to individual needs is essential to achieve equality for women and their newborns.IMPLICATIONS FOR PRACTICE: The midwife can be used as a hub for reassuring that adequate information about fetal movements reaches each individual woman in antenatal care. Individualised information on fetal movements based on the women's own understanding is suggested to increase the possibility that the pregnant woman will seek care if the movements decrease. Somali women's verbal communication can be used to spread accurate information in the Somali community on the importance of seeking care if fetal movements decrease.
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| 4. |
- Andrén, Anna, et al.
(author)
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One size does not fit all : Perspectives from Swedish midwives on fetal movement counselling
- 2024
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In: Women and Birth. - 1871-5192 .- 1878-1799. ; 37:4
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Journal article (peer-reviewed)abstract
- PROBLEM: Migration continues to play a role in determining health outcomes related to pregnancy and childbirth in Sweden.BACKGROUND: Migrant women have, compared to Swedish-born women, increased risks of adverse birth outcomes. Previous research suggests that migrant women seek care for decreased fetal movements less than Swedish-born women. Given these documented risks, understanding midwives' perspectives in this context is crucial to address maternal health inequities.AIM: To explore midwives' experiences conveying information about fetal movement to migrant women in antenatal healthcare settings.METHODS: Semi-structured, individual interviews with midwives (n=15) experienced in providing information about fetal movements to migrant women. The interviews were analysed using reflexive thematic analysis.FINDINGS: The midwives' efforts to compensate for the deficiencies within the antenatal healthcare organisation and to ensure that all women received access to information and care regarding fetal movements are described in four themes: (a) building a trusting relationship; (b) empowering women through guidance and support; (c) overcoming communication challenges; and d) navigating safety measures.DISCUSSION: Our findings suggest that the standard antenatal care programme does not support midwives to provide holistic and individualised care that aligns with midwifery care philosophy.CONCLUSION: To reduce health inequities for migrant women, this study highlights the need for more flexible guidelines within the standard antenatal care programme. These guidelines should prioritise the individual woman's needs over institutional protocols, acknowledge the midwife-woman relationship as the core of midwifery practice and support midwives to build a partnership with women through continuity of care.
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| 5. |
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| 6. |
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| 7. |
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| 8. |
- Rostami, Jinar, et al.
(author)
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Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates
- 2021
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In: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 18:1
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Journal article (peer-reviewed)abstract
- BackgroundAlzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by brain accumulation of aggregated amyloid-beta (Aβ) and alpha-synuclein (αSYN), respectively. In order to develop effective therapies, it is crucial to understand how the Aβ/αSYN aggregates can be cleared. Compelling data indicate that neuroinflammatory cells, including astrocytes and microglia, play a central role in the pathogenesis of AD and PD. However, how the interplay between the two cell types affects their clearing capacity and consequently the disease progression remains unclear.MethodsThe aim of the present study was to investigate in which way glial crosstalk influences αSYN and Aβ pathology, focusing on accumulation and degradation. For this purpose, human-induced pluripotent cell (hiPSC)-derived astrocytes and microglia were exposed to sonicated fibrils of αSYN or Aβ and analyzed over time. The capacity of the two cell types to clear extracellular and intracellular protein aggregates when either cultured separately or in co-culture was studied using immunocytochemistry and ELISA. Moreover, the capacity of cells to interact with and process protein aggregates was tracked using time-lapse microscopy and a customized “close-culture” chamber, in which the apical surfaces of astrocyte and microglia monocultures were separated by a <1 mm space.ResultsOur data show that intracellular deposits of αSYN and Aβ are significantly reduced in co-cultures of astrocytes and microglia, compared to monocultures of either cell type. Analysis of conditioned medium and imaging data from the “close-culture” chamber experiments indicate that astrocytes secrete a high proportion of their internalized protein aggregates, while microglia do not. Moreover, co-cultured astrocytes and microglia are in constant contact with each other via tunneling nanotubes and other membrane structures. Notably, our live cell imaging data demonstrate that microglia, when attached to the cell membrane of an astrocyte, can attract and clear intracellular protein deposits from the astrocyte.ConclusionsTaken together, our data demonstrate the importance of astrocyte and microglia interactions in Aβ/αSYN clearance, highlighting the relevance of glial cellular crosstalk in the progression of AD- and PD-related brain pathology.
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| 9. |
- Rostami, Jinar, et al.
(author)
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Prolyl oligopeptidase inhibition by KYP-2407 increases alpha-synuclein fibril degradation in neuron-like cells
- 2020
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In: Biomedicine and Pharmacotherapy. - : Elsevier BV. - 0753-3322 .- 1950-6007. ; 131
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Journal article (peer-reviewed)abstract
- Growing evidence emphasizes insufficient clearance of pathological alpha-synuclein (αSYN) aggregates in the progression of Parkinson's disease (PD). Consequently, cellular degradation pathways represent a potential therapeutic target. Prolyl oligopeptidase (PREP) is highly expressed in the brain and has been suggested to increase αSYN aggregation and negatively regulate the autophagy pathway. Inhibition of PREP with a small molecule inhibitor, KYP-2407, stimulates autophagy and reduces the oligomeric species of αSYN aggregates in PD mouse models. However, whether PREP inhibition has any effects on intracellular αSYN fibrils has not been studied before. In this study, the effect of KYP2407 on αSYN preformed fibrils (PFFs) was tested in SH-SY5Y cells and human astrocytes. Immunostaining analysis revealed that both cell types accumulated αSYN PFFs intracellularly but KYP-2047 decreased intracellular αSYN deposits only in SH-SY5Y cells, as astrocytes did not show any PREP activity. Western blot analysis confirmed the reduction of high molecular weight αSYN species in SH-SY5Y cell lysates, and secretion of αSYN from SH-SY5Y cells also decreased in the presence of KYP-2407. Accumulation of αSYN inside the SH-SY5Y cells resulted in an increase of the auto-lysosomal proteins p62 and LC3BII, as well as calpain 1 and 2, which have been shown to be associated with PD pathology. Notably, treatment with KYP-2407 significantly reduced p62 and LC3BII levels, indicating an increased autophagic flux, and calpain 1 and 2 levels returned to normal in the presence of KYP-2407. Our findings indicate that PREP inhibition can potentially be used as therapy to reduce the insoluble intracellular αSYN aggregates.
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| 10. |
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| 11. |
- Sravani, Musunuri, 1987-, et al.
(author)
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Increased Levels of Extracellular Microvesicle Markers and Decreased Levels of Endocytic/Exocytic Proteins in the Alzheimer's Disease Brain
- 2016
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 54:4, s. 1671-1686
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Journal article (peer-reviewed)abstract
- Background: Alzheimer's disease (AD) is a chronic neurodegenerative disorder accounting for more than 50% of all dementia cases. AD neuropathology is characterized by the formation of extracellular plaques and intracellular neurofibrillary tangles consisting of aggregated amyloid-beta and tau, respectively. The disease mechanism has only been partially elucidated and is believed to also involve many other proteins. Objective: This study intended to perform a proteomic profiling of post mortem AD brains and compare it with control brains as well as brains from other neurological diseases to gain insight into the disease pathology. Methods: Here we used label-free shotgun mass spectrometry to analyze temporal neocortex samples from AD, other neurological disorders, and non-demented controls, in order to identify additional proteins that are altered in AD. The mass spectrometry results were verified by antibody suspension bead arrays. Results: We found 50 proteins with altered levels between AD and control brains. The majority of these proteins were found at lower levels in AD. Pathway analyses revealed that several of the decreased proteins play a role in exocytic and endocytic pathways, whereas several of the increased proteins are related to extracellular vesicles. Using antibody-based analysis, we verified the mass spectrometry results for five representative proteins from this group of proteins (CD9, HSP72, PI42A, TALDO, and VAMP2) and GFAP, a marker for neuroinflammation. Conclusions: Several proteins involved in exo-endocytic pathways and extracellular vesicle functions display altered levels in the AD brain. We hypothesize that such changes may result in disturbed cellular clearance and a perturbed cell-to-cell communication that may contribute to neuronal dysfunction and cell death in AD.
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| 12. |
- Streubel-Gallasch, Linn, et al.
(author)
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Parkinson's Disease-Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance
- 2021
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In: Molecular Neurobiology. - : Springer Nature. - 0893-7648 .- 1559-1182. ; 58:7, s. 3119-3140
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Journal article (peer-reviewed)abstract
- Parkinson's disease (PD) is a neurodegenerative, progressive disease without a cure. To prevent PD onset or at least limit neurodegeneration, a better understanding of the underlying cellular and molecular disease mechanisms is crucial. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent one of the most common causes of familial PD. In addition, LRRK2 variants are risk factors for sporadic PD, making LRRK2 an attractive therapeutic target. Mutations in LRRK2 have been linked to impaired alpha-synuclein (alpha-syn) degradation in neurons. However, in which way pathogenic LRRK2 affects alpha-syn clearance by astrocytes, the major glial cell type of the brain, remains unclear. The impact of astrocytes on PD progression has received more attention and recent data indicate that astrocytes play a key role in alpha-syn-mediated pathology. In the present study, we aimed to compare the capacity of wild-type astrocytes and astrocytes carrying the PD-linked G2019S mutation in Lrrk2 to ingest and degrade fibrillary alpha-syn. For this purpose, we used two different astrocyte culture systems that were exposed to sonicated alpha-syn for 24 h and analyzed directly after the alpha-syn pulse or 6 days later. To elucidate the impact of LRRK2 on alpha-syn clearance, we performed various analyses, including complementary imaging, transmission electron microscopy, and proteomic approaches. Our results show that astrocytes carrying the G2019S mutation in Lrrk2 exhibit a decreased capacity to internalize and degrade fibrillar alpha-syn via the endo-lysosomal pathway. In addition, we demonstrate that the reduction of alpha-syn internalization in the Lrrk2 G2019S astrocytes is linked to annexin A2 (AnxA2) loss of function. Together, our findings reveal that astrocytic LRRK2 contributes to the clearance of extracellular alpha-syn aggregates through an AnxA2-dependent mechanism.
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| 13. |
- Zysk, Marlena, et al.
(author)
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Protective effects of voltage-gated calcium channel antagonists against zinc toxicity in SN56 neuroblastoma cholinergic cells
- 2018
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:12
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Journal article (peer-reviewed)abstract
- One of the pathological site effects in excitotoxic activation is Zn2+ overload to postsynaptic neurons. Such an effect is considered to be equivalent to the glutamate component of excitotoxicity. Excessive uptake of Zn2+ by active voltage-dependent transport systems in these neurons may lead to significant neurotoxicity. The aim of this study was to investigate whether and which antagonists of the voltage gated calcium channels (VGCC) might modify this Zn2+-induced neurotoxicity in neuronal cells. Our data demonstrates that depolarized SN56 neuronal cells may take up large amounts of Zn2+ and store these in cytoplasmic and mitochondrial sub-fractions. The mitochondrial Zn2+ excess suppressed pyruvate uptake and oxidation. Such suppression was caused by inhibition of pyruvate dehydrogenase complex, aconitase and NADP-isocitrate dehydrogenase activities, resulting in the yielding of acetyl-CoA and ATP shortages. Moreover, incoming Zn2+ increased both oxidized glutathione and malondialdehyde levels, known parameters of oxidative stress. In depolarized SN56 cells, nifedipine treatment (L-type VGCC antagonist) reduced Zn2+ uptake and oxidative stress. The treatment applied prevented the activities of PDHC, aconitase and NADP-IDH enzymes, and also yielded the maintenance of acetyl-CoA and ATP levels. Apart from suppression of oxidative stress, N- and P/Q-type VGCCs presented a similar, but weaker protective influence. In conclusion, our data shows that in the course of excitotoxity, impairment to calcium homeostasis is tightly linked with an excessive neuronal Zn2+ uptake. Hence, the VGCCs types L, N and P/Q share responsibility for neuronal Zn2+ overload followed by significant energy-dependent neurotoxicity. Moreover, Zn2+ affects the target tricarboxylic acid cycle enzymes, yields acetyl-CoA and energy deficits as well.
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| 14. |
- Almandoz-Gil, Leire, et al.
(author)
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In situ proximity ligation assay reveals co-localization of alpha-synuclein and SNARE proteins in murine primary neurons
- 2018
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In: Frontiers in Neurology. - : Frontiers Media S.A.. - 1664-2295. ; 9
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Journal article (peer-reviewed)abstract
- The aggregation of alpha-synuclein (alpha Syn) is the pathological hallmark of Parkinson's disease, dementia with Lewy bodies and related neurological disorders. However, the physiological function of the protein and how this function relates to its pathological effects remain poorly understood. One of the proposed roles of aSyn is to promote the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to VAMP-2. The objective of this study was to visualize the co-localization between aSyn and the SNARE proteins (VAMP-2, SNAP-25, and syntaxin-1) for the first time using in situ proximity ligation assay (PLA). Cortical primary neurons were cultured from either non-transgenic or transgenic mice expressing human aSyn with the A30P mutation under the Thy-1 promoter. With an antibody recognizing both mouse and human aSyn, a PLA signal indicating close proximity between aSyn and the three SNARE proteins was observed both in the soma and throughout the processes. No differences in the extent of PLA signals were seen between non-transgenic and transgenic neurons. With an antibody specific against human aSyn, the PLA signal was mostly located to the soma and was only present in a few cells. Taken together, in situ PLA is a method that can be used to investigate the co-localization of aSyn and the SNARE proteins in primary neuronal cultures
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| 15. |
- Andersson, Karin, 1972, et al.
(author)
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Inflammation in the hippocampus affects IGF1 receptor signaling and contributes to neurological sequelae in rheumatoid arthritis.
- 2018
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 115:51
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Journal article (peer-reviewed)abstract
- Rheumatoid arthritis (RA) is an inflammatory joint disease with a neurological component including depression, cognitive deficits, and pain, which substantially affect patients' quality of daily life. Insulin-like growth factor 1 receptor (IGF1R) signaling is one of the factors in RA pathogenesis as well as a known regulator of adult neurogenesis. The purpose of this study was to investigate the association between IGF1R signaling and the neurological symptoms in RA. In experimental RA, we demonstrated that arthritis induced enrichment of IBA1+ microglia in the hippocampus. This coincided with inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) and up-regulation of IGF1R in the pyramidal cell layer of the cornus ammoni and in the dentate gyrus, reproducing the molecular features of the IGF1/insulin resistance. The aberrant IGF1R signaling was associated with reduced hippocampal neurogenesis, smaller hippocampus, and increased immobility of RA mice. Inhibition of IGF1R in experimental RA led to a reduction of IRS1 inhibition and partial improvement of neurogenesis. Evaluation of physical functioning and brain imaging in RA patients revealed that enhanced functional disability is linked with smaller hippocampus volume and aberrant IGF1R/IRS1 signaling. These results point to abnormal IGF1R signaling in the brain as a mediator of neurological sequelae in RA and provide support for the potentially reversible nature of hippocampal changes.
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| 16. |
- Avelin, Pernilla, et al.
(author)
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Make the stillborn baby and the loss real for the siblings : parents' advice on how the siblings of a stillborn baby can be supported
- 2012
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In: Journal of Perinatal Education. - : Springer Publishing Company. - 1058-1243 .- 1548-8519. ; 21:2, s. 90-98
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Journal article (peer-reviewed)abstract
- This study aimed to investigate parents' advice to other parents on the basis of their own experiences of siblings' taking leave of a stillborn sister or brother. The study was a Web questionnaire study of 411 parents. The thematic content analysis resulted in two categories: "Make the stillborn baby and the loss real for the siblings" and "Take the siblings' resources and prerequisites into account." Parents' advised that siblings should see and hold the stillborn baby and, thus, be invited and included into the leave-taking process with respect to the siblings' feelings, resources, and prerequisites. Based on these findings, professional caregivers can usefully be proactive in their approach to facilitate and encourage the involvement of siblings.
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| 17. |
- Becker, K., et al.
(author)
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Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
- 2021
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In: EBioMedicine. - : Elsevier B.V.. - 2352-3964. ; 73
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Journal article (peer-reviewed)abstract
- Background: The clinical-stage drug candidate EBL-1003 (apramycin) represents a distinct new subclass of aminoglycoside antibiotics for the treatment of drug-resistant infections. It has demonstrated best-in-class coverage of resistant isolates, and preclinical efficacy in lung infection models. However, preclinical evidence for its utility in other disease indications has yet to be provided. Here we studied the therapeutic potential of EBL-1003 in the treatment of complicated urinary tract infection and acute pyelonephritis (cUTI/AP). Methods: A combination of data-base mining, antimicrobial susceptibility testing, time-kill experiments, and four murine infection models was used in a comprehensive assessment of the microbiological coverage and efficacy of EBL-1003 against Gram-negative uropathogens. The pharmacokinetics and renal toxicology of EBL-1003 in rats was studied to assess the therapeutic window of EBL-1003 in the treatment of cUTI/AP. Findings: EBL-1003 demonstrated broad-spectrum activity and rapid multi-log CFU reduction against a phenotypic variety of bacterial uropathogens including aminoglycoside-resistant clinical isolates. The basicity of amines in the apramycin molecule suggested a higher increase in positive charge at urinary pH when compared to gentamicin or amikacin, resulting in sustained drug uptake and bactericidal activity, and consequently in potent efficacy in mouse infection models. Renal pharmacokinetics, biomarkers for toxicity, and kidney histopathology in adult rats all indicated a significantly lower nephrotoxicity of EBL-1003 than of gentamicin. Interpretation: This study provides preclinical proof-of-concept for the efficacy of EBL-1003 in cUTI/AP. Similar efficacy but lower nephrotoxicity of EBL-1003 in comparison to gentamicin may thus translate into a higher safety margin and a wider therapeutic window in the treatment of cUTI/API. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section. © 2021 The Author(s)
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| 18. |
- Behere, Anish, et al.
(author)
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Novel visualization of phosphorylated tau and alpha-synuclein aggregates in the Alzheimer’s disease and Parkinson’s disease brain
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Other publication (other academic/artistic)abstract
- Several neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), display deposits of phosphorylated tau (pTau) and/or alpha-synuclein (pSyn) in affected parts of the brain. However, the pathological and morphological properties of these protein aggregates remain poorly characterized, due to lack of specificity and sensitivity of in situ detection techniques. The aim of this study was to investigate the patho-morphological properties of phosphorylated tau and α-syn aggregates on AD and PD brain tissues with a novel sensitive in situ proximity ligation assay (PLA) technique. We took advantage of the sensitivity and <40 nm resolution of PLA, along with the selectivity of different antibodies directed against pTau and pSyn epitopes. Most notably, multiplex pTauS202, T205-pTauT231, singleplex pTauT231 and pSynS129 PLA recognized more extensive phosphorylated tau and αSyn pathology, compared to conventional immunohistochemistry (IHC) using the same antibodies on adjacent brain sections. Furthermore, singleplex pTauT231 PLA captured additional pathological aggregates compared to the singleplex pTauS202, T205 PLA in late Braak stage AD brains, where traditional IHC failed to distinguish between pTauS202, T205 and pTauT231 pathology. Similarly, in PD brains, singleplex pSynS129 PLA detected novel pathological structures, such as intercellular thick tunneling nanotubes and pre-Lewy body intracytoplasmic aggregates, whereas pSynS129 IHC was limited to the detection of mature Lewy body/neurite pathology. Lastly, we could demonstrate that our dual PLA approach also can be applied to detect co-aggregates of pSyn-pTau.
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| 19. |
- Beretta, Chiara, et al.
(author)
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Amyloid-β deposits in human astrocytes contain truncated and highly resistant proteoforms
- 2024
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In: Molecular and Cellular Neuroscience. - : Elsevier. - 1044-7431 .- 1095-9327. ; 128
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Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) is a neurodegenerative disorder that develops over decades. Glial cells, including astrocytes are tightly connected to the AD pathogenesis, but their impact on disease progression is still unclear. Our previous data show that astrocytes take up large amounts of aggregated amyloid-beta (Aβ) but are unable to successfully degrade the material, which is instead stored intracellularly. The aim of the present study was to analyze the astrocytic Aβ deposits composition in detail in order to understand their role in AD propagation. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated Aβ42 fibrils and magnetic beads. Live cell imaging and immunocytochemistry confirmed that the ingested Aβ aggregates and beads were transported to the same lysosomal compartments in the perinuclear region, which allowed us to successfully isolate the Aβ deposits from the astrocytes. Using a battery of experimental techniques, including mass spectrometry, western blot, ELISA and electron microscopy we demonstrate that human astrocytes truncate and pack the Aβ aggregates in a way that makes them highly resistant. Moreover, the astrocytes release specifically truncated forms of Aβ via different routes and thereby expose neighboring cells to pathogenic proteins. Taken together, our study establishes a role for astrocytes in mediating Aβ pathology, which could be of relevance for identifying novel treatment targets for AD.
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| 20. |
- Beretta, Chiara, 1992-
(author)
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Astrocytes in Alzheimer’s disease : Exploring the impact of amyloid-β pathology on neurotoxicity, metabolism and inflammation.
- 2024
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Doctoral thesis (other academic/artistic)abstract
- Astrocytes play a central role in brain homeostasis, but are also tightly connected to the pathogenesis of Alzheimer’s disease (AD). Yet, their exact role in amyloid-beta (Aβ) pathology and chronic neuroinflammation is unclear. The aim of this thesis was to elucidate the impact of astrocytes in AD progression. For this purpose, astrocytes in different culture set-ups were exposed to soluble Aβ aggregates. The astrocytes engulf and process, but fail to fully degrade the Aβ aggregates, which are instead stored as large intracellular deposits. In Paper I, we show that extracellular vesicles (EVs), secreted from the Aβ-containing cells induce synaptic loss, axonal swelling and vacuolization of primary neurons, which consequently leads to apoptosis. Astrocytes play a central role in the brain’s energy metabolism and we were therefore interested in how Aβ pathology affects their metabolism. In Paper II, we report that Aβ accumulation in astrocytes disrupts mitochondrial fission/fusion homeostasis, resulting in decreased mitochondrial respiration and altered glycolysis. Interestingly, the astrocytes switch to fatty acid β oxidation with the aid of peroxisomes to maintain stable energy production. Another important task is to understand how astrocytes modify the ingested Aβ. In Paper III, we characterized the astrocytic Aβ inclusions by isolating them with magnetic beads. Our analysis showed that the astrocytes truncate and pack together the Aβ aggregates. Moreover, we found that astrocytes release specifically truncated forms of Aβ via different routes.Astrocytes’ involvement in lipid metabolism and inflammation has recently gained much interest, but many questions remain about the connection between these processes. In Paper IV, we show that Aβ pathology causes lipid droplet (LD) accumulation in astrocytes. Moreover, we could show that astrocytes frequently transfer LDs to neighboring cells, both through direct cell-to-cell contacts and via secretion. Astrocytes have previously been reported to express major histocompatibility complex II (MHCII) and have the capacity to perform as professional antigen presenting cells. Interestingly, our results demonstrate that LDs contain MHCII, identifying a link between LDs and inflammation in astrocytes.Taken together, this thesis contributes with important knowledge of the role of astrocytes in AD pathology.
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| 21. |
- Beretta, Chiara, et al.
(author)
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Astrocytes with Alzheimer’s disease pathology provoke lipid droplet mediated cell-to-cell propagation of MHC II complexes
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Other publication (other academic/artistic)abstract
- Background. Astrocytes are critical for maintaining brain homeostasis, but are also highly involved in neuroinflammation. In the Alzheimer disease (AD) brain, reactive, inflammatory astrocytes are situated closely around amyloid β (Aβ) plaques. We have previously shown that reactive astrocytes ingest large quantities of soluble Aβ aggregates, but are unable to degrade the material, which leads to intracellular Aβ accumulation and severe cellular stress. A common response to cellular stress is the formation of lipid droplets (LDs). Novel data indicate that LDs play an important role in inflammatory processes. However, the involvement of LDs in AD inflammation and progression remains unclear.Methods. The aim of this study was to investigate how astrocytic Aβ pathology affects lipid metabolism and antigen presentation. For this purpose, human induced pluripotent stem cell (iPSC) derived astrocytes were exposed to soluble Aβ42 aggregates and analyzed over time, using a battery of experimental approaches.Results. Our results show that Aβ exposure induces LD accumulation in astrocytes, although the overall lipid composition remains unchanged. Moreover, astrocytes transfer LDs to neighboring cells via tunneling nanotubes (TNTs) and extracellular vesicle (EVs). Interestingly, we found that the antigen presenting protein major histocompatibility complex II (MHCII) is present inside LDs, suggesting an active role of LDs in astrocytic antigen presentation. Immunohistochemical analysis of human brain tissue verified the presence of LD-loaded MHCII+ astrocytes in AD individuals. Moreover, we found infiltrated CD4+ T cells to be in close contact with astrocytes, confirming an astrocyte T cell cross-talk in the AD brainConclusions. Taken together, our data show that Aβ pathology drastically affects lipid storage in astrocytes, which in turn modulates the astrocytic antigen presentation, indicating a role for astrocytic LDs in T cell responses in the AD brain.
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| 22. |
- Beretta, Chiara, et al.
(author)
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Extracellular vesicles from amyloid-beta exposed cell cultures induce severe dysfunction in cortical neurons
- 2020
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In: Scientific Reports. - : NATURE RESEARCH. - 2045-2322. ; 10
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Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) is characterized by a substantial loss of neurons and synapses throughout the brain. The exact mechanism behind the neurodegeneration is still unclear, but recent data suggests that spreading of amyloid-beta (A beta) pathology via extracellular vesicles (EVs) may contribute to disease progression. We have previously shown that an incomplete degradation of A beta (42) protofibrils by astrocytes results in the release of EVs containing neurotoxic A beta. Here, we describe the cellular mechanisms behind EV-associated neurotoxicity in detail. EVs were isolated from untreated and A beta (42) protofibril exposed neuroglial co-cultures, consisting mainly of astrocytes. The EVs were added to cortical neurons for 2 or 4 days and the neurodegenerative processes were followed with immunocytochemistry, time-lapse imaging and transmission electron microscopy (TEM). Addition of EVs from A beta (42) protofibril exposed co-cultures resulted in synaptic loss, severe mitochondrial impairment and apoptosis. TEM analysis demonstrated that the EVs induced axonal swelling and vacuolization of the neuronal cell bodies. Interestingly, EV exposed neurons also displayed pathological lamellar bodies of cholesterol deposits in lysosomal compartments. Taken together, our data show that the secretion of EVs from A beta exposed cells induces neuronal dysfunction in several ways, indicating a central role for EVs in the progression of A beta -induced pathology.
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| 23. |
- Bogren, Malin, 1970, et al.
(author)
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Facilitators of and barriers to providing high-quality midwifery education in South-East Asia—An integrative review
- 2022
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In: Women and Birth. - : Elsevier BV. - 1871-5192 .- 1878-1799. ; 35:3
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Journal article (peer-reviewed)abstract
- Background: With a diversity in midwifery education across the South-East Asia region, and with the knowledge about the lifesaving competency of the midwife profession, this study's aim is to describe facilitators of and barriers to providing high-quality midwifery education in South-East Asia. Methods: Inspired by Whittemore and Knafl, we conducted a systematic integrative literature review including the five key stages of problem identification, literature search, data evaluation, data analysis, and presentation of results. The literature searches were conducted in October 2020 in the databases CINAHL, PubMed, and Scopus. A deductive data analysis based on global standards was performed. Results: The search identified 1257 articles, 34 of which were included. Countries in South-East Asia did not fully comply with the ICM global standards. Midwifery education was not separated from that of nursing, and educators lacked formal qualifications in midwifery. Curriculum implementation in the clinical area was a key barrier to achieving learning outcomes. Higher academic education for midwifery educators and mentorship programs facilitated the pedagogic and assessment process, focusing on the abilities of critical thinking, reflection, and decision-making. Conclusions: Countries in South-East Asia still have a long way to go before they can provide high-quality midwifery education. The identified facilitators can lead to a difference in students’ academic achievement and confidence in their clinical work. Coordinated actions will enable the progress in achieving competent midwives matching national health priorities. The findings highlight a need for more research on midwifery education in both theory and practice across the region. © 2021 The Author(s)
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| 24. |
- Brolin, Emma, et al.
(author)
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Altered Distribution of SNARE Proteins in Primary Neurons Exposed to Different Alpha-Synuclein Proteoforms
- 2023
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In: Cellular and molecular neurobiology. - : Springer. - 0272-4340 .- 1573-6830. ; 43:6, s. 3023-3035
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Journal article (peer-reviewed)abstract
- Growing evidence indicates that the pathological alpha-synuclein (a-syn) aggregation in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) starts at the synapses. Physiologic a-syn is involved in regulating neurotransmitter release by binding to the SNARE complex protein VAMP-2 on synaptic vesicles. However, in which way the SNARE complex formation is affected by a-syn pathology remains unclear. In this study, primary cortical neurons were exposed to either a-syn monomers or preformed fibrils (PFFs) for different time points and the effect on SNARE protein distribution was analyzed with a novel proximity ligation assay (PLA). Short-term exposure to monomers or PFFs for 24 h increased the co-localization of VAMP-2 and syntaxin-1, but reduced the co-localization of SNAP-25 and syntaxin-1, indicating a direct effect of the added a-syn on SNARE protein distribution. Long-term exposure to a-syn PFFs for 7 d reduced VAMP-2 and SNAP-25 co-localization, although there was only a modest induction of ser129 phosphorylated (pS129) a-syn. Similarly, exposure to extracellular vesicles collected from astrocytes treated with a-syn PFFs for 7 d influenced VAMP-2 and SNAP-25 co-localization despite only low levels of pS129 a-syn being formed. Taken together, our results demonstrate that different a-syn proteoforms have the potential to alter the distribution of SNARE proteins at the synapse.
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