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- Mäe, Maarja Andaloussi, et al.
(författare)
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Single-Cell Analysis of Blood-Brain Barrier Response to Pericyte Loss
- 2021
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Ingår i: Circulation Research. - : Lippincott Williams & Wilkins. - 0009-7330 .- 1524-4571. ; 128:4, s. E46-E62
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described in several brain disorders, and genetically induced pericyte deficiency in the brain leads to increased macromolecular leakage across the blood-brain barrier (BBB). However, the molecular details of the endothelial response to pericyte deficiency remain elusive.Objective: To map the transcriptional changes in brain endothelial cells resulting from lack of pericyte contact at single-cell level and to correlate them with regional heterogeneities in BBB function and vascular phenotype.Methods and Results: We reveal transcriptional, morphological, and functional consequences of pericyte absence for brain endothelial cells using a combination of methodologies, including single-cell RNA sequencing, tracer analyses, and immunofluorescent detection of protein expression in pericyte-deficient adult Pdgfb(ret/ret) mice. We find that endothelial cells without pericyte contact retain a general BBB-specific gene expression profile, however, they acquire a venous-shifted molecular pattern and become transformed regarding the expression of numerous growth factors and regulatory proteins. Adult Pdgfb(ret/ret) brains display ongoing angiogenic sprouting without concomitant cell proliferation providing unique insights into the endothelial tip cell transcriptome. We also reveal heterogeneous modes of pericyte-deficient BBB impairment, where hotspot leakage sites display arteriolar-shifted identity and pinpoint putative BBB regulators. By testing the causal involvement of some of these using reverse genetics, we uncover a reinforcing role for angiopoietin 2 at the BBB.Conclusions: By elucidating the complexity of endothelial response to pericyte deficiency at cellular resolution, our study provides insight into the importance of brain pericytes for endothelial arterio-venous zonation, angiogenic quiescence, and a limited set of BBB functions. The BBB-reinforcing role of ANGPT2 (angiopoietin 2) is paradoxical given its wider role as TIE2 (TEK receptor tyrosine kinase) receptor antagonist and may suggest a unique and context-dependent function of ANGPT2 in the brain.
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- Faithfull, C. L., et al.
(författare)
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Restoring charophytes is still a challenge: A call for developing successful methods
- 2024
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Ingår i: AQUATIC BOTANY. - 0304-3770 .- 1879-1522. ; 193
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Tidskriftsartikel (refereegranskat)abstract
- Submerged aquatic vegetation, and especially charophytes, which are an important habitat for many species, have declined in the Baltic Sea due to changes in light climate, eutrophication and physical disturbance. Physical disturbance in the form of small-scale dredging activities is commonplace in Sweden due to land uplift, but causes fragmentation of coastal habitats. Here we test three planting methods for restoration of the charophyte Chara aspera on an area of deposited sediment, and a single method for restoration of C. tomentosa in a dredged area. We found that none of the planting methods tested was more successful than natural recolonization of C. aspera on the deposited sediment. C. tomentosa planting was unsuccessful in the dredged area and was likely outcompeted for light by taller species. The C. aspera meadow was resilient to smaller disturbances, as experimental removal of up to 2.5% of C. aspera and sediment from the donor area did not reduce C. aspera coverage a month after removal. Even after an uncontrolled event that removed up to 50% of C. aspera in the experimental plots, C. aspera coverage had returned to pre-removal levels a year after the disturbance. We suggest future restoration experiments test transplanting sediment rich in oocytes and bulbils into areas with suitable light climates and low competition with other species. Restoration efforts are costly and highly uncertain of success, therefore we recommend discontinuing dredging activities in charophyte meadows to protect this important habitat.
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- Fall, Magnus, 1941, et al.
(författare)
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Hunner lesion disease differs in diagnosis, treatment and outcome from bladder pain syndrome: an ESSIC working group report
- 2020
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Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 54:2, s. 91-98
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: There is confusion about the terms of bladder pain syndrome (BPS) and Interstitial Cystitis (IC). The European Society for the Study of IC (ESSIC) classified these according to objective findings [9]. One phenotype, Hunner lesion disease (HLD or ESSIC 3C) differs markedly from other presentations. Therefore, the question was raised as to whether this is a separate condition or BPS subtype. Methods: An evaluation was made to explore if HLD differs from other BPS presentations regarding symptomatology, physical examination findings, laboratory tests, endoscopy, histopathology, natural history, epidemiology, prognosis and treatment outcomes. Results: Cystoscopy is the method of choice to identify Hunner lesions, histopathology the method to confirm it. You cannot distinguish between main forms of BPS by means of symptoms, physical examination or laboratory tests. Epidemiologic data are incomplete. HLD seems relatively uncommon, although more frequent in older patients than non-HLD. No indication has been presented of BPS and HLD as a continuum of conditions, one developing into the other. Conclusions: A paradigm shift in the understanding of BPS/IC is urgent. A highly topical issue is to separate HLD and BPS: treatment results and prognoses differ substantially. Since historically, IC was tantamount to Hunner lesions and interstitial inflammation in the bladder wall, still, a valid definition, the term IC should preferably be reserved for HLD patients. BPS is a symptom syndrome without specific objective findings and should be used for other patients fulfilling the ESSIC definitions.
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| 13. |
- Fransson, Emma, PhD, 1973-, et al.
(författare)
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Differentiated mental health patterns in pregnancy during COVID-19 first two waves in Sweden : a mixed methods study using digital phenotyping
- 2022
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- To utilize modern tools to assess depressive and anxiety symptoms, wellbeing and life conditions in pregnant women during the first two waves of the COVID-19 pandemic in Sweden. Pregnant women (n = 1577) were recruited through the mobile application Mom2B. Symptoms of depression, anxiety and wellbeing were assessed during January 2020–February 2021. Movement data was collected using the phone’s sensor. Data on Google search volumes for “Corona” and Covid-related deaths were obtained. Qualitative analysis of free text responses regarding maternity care was performed. Two peaks were seen for depressive symptoms, corresponding to the two waves. Higher prevalence of anxiety was only noted during the first wave. A moderating effect of the two waves in the association of depression, anxiety, and well-being with Covid deaths was noted; positive associations during the first wave and attenuated or became negative during the second wave. Throughout, women reported on cancelled healthcare appointments and worry about partners not being allowed in hospital. The association of mental health outcomes with relevant covariates may vary during the different phases in a pandemic, possibly due to adaptation strategies on a personal and societal/healthcare level. Digital phenotyping can help healthcare providers and governmental bodies to in real time monitor high-risk groups during crises, and to adjust the support offered.
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| 14. |
- Hurrell, T, et al.
(författare)
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Human Liver Spheroids as a Model to Study Aetiology and Treatment of Hepatic Fibrosis
- 2020
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 9:4
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver disease affects approximately one billion adults worldwide. Non-alcoholic steatohepatitis (NASH) is a progressive disease and underlies the advancement to liver fibrosis, cirrhosis, and hepatocellular carcinoma, for which there are no FDA-approved drug therapies. We developed a hetero-cellular spheroid system comprised of primary human hepatocytes (PHH) co-cultured with crude fractions of primary human liver non-parenchymal cells (NPC) from several matched or non-matched donors, to identify phenotypes with utility in investigating NASH pathogenesis and drug screening. Co-culture spheroids displayed stable expression of hepatocyte markers (albumin, CYP3A4) with the integration of stellate (vimentin, PDGFRβ), endothelial (vWF, PECAM1), and CD68-positive cells. Several co-culture spheroids developed a fibrotic phenotype either spontaneously, primarily observed in PNPLA3 mutant donors, or after challenge with free fatty acids (FFA), as determined by COL1A1 and αSMA expression. This phenotype, as well as TGFβ1 expression, was attenuated with an ALK5 inhibitor. Furthermore, CYP2E1, which has a strong pro-oxidant effect, was induced by NPCs and FFA. This system was used to evaluate the effects of anti-NASH drug candidates, which inhibited fibrillary deposition following 7 days of exposure. In conclusion, we suggest that this system is suitable for the evaluation of NASH pathogenesis and screening of anti-NASH drug candidates.
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| 20. |
- Xiang, Menglan, et al.
(författare)
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A Single-Cell Transcriptional Roadmap of the Mouse and Human Lymph Node Lymphatic Vasculature
- 2020
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Ingår i: Frontiers in Cardiovascular Medicine. - : FRONTIERS MEDIA SA. - 2297-055X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Single-cell transcriptomics promise to revolutionize our understanding of the vasculature. Emerging computational methods applied to high-dimensional single-cell data allow integration of results between samples and species and illuminate the diversity and underlying developmental and architectural organization of cell populations. Here, we illustrate these methods in the analysis of mouse lymph node (LN) lymphatic endothelial cells (LEC) at single-cell resolution. Clustering identifies five well-delineated subsets, including two medullary sinus subsets not previously recognized as distinct. Nearest neighbor alignments in trajectory space position the major subsets in a sequence that recapitulates the known features and suggests novel features of LN lymphatic organization, providing a transcriptional map of the lymphatic endothelial niches and of the transitions between them. Differences in gene expression reveal specialized programs for (1) subcapsular ceiling endothelial interactions with the capsule connective tissue and cells; (2) subcapsular floor regulation of lymph borne cell entry into the LN parenchyma and antigen presentation; and (3) pathogen interactions and (4) LN remodeling in distinct medullary subsets. LEC of the subcapsular sinus floor and medulla, which represent major sites of cell entry and exit from the LN parenchyma respectively, respond robustly to oxazolone inflammation challenge with enriched signaling pathways that converge on both innate and adaptive immune responses. Integration of mouse and human single-cell profiles reveals a conserved cross-species pattern of lymphatic vascular niches and gene expression, as well as specialized human subsets and genes unique to each species. The examples provided demonstrate the power of single-cell analysis in elucidating endothelial cell heterogeneity, vascular organization, and endothelial cell responses. We discuss the findings from the perspective of LEC functions in relation to niche formations in the unique stromal and highly immunological environment of the LN.
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