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- Grontvedt, GR, et al.
(författare)
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Association of Klotho Protein Levels and KL-VS Heterozygosity With Alzheimer Disease and Amyloid and Tau Burden
- 2022
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Ingår i: JAMA network open. - : American Medical Association (AMA). - 2574-3805. ; 5:11, s. e2243232-
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Tidskriftsartikel (refereegranskat)abstract
- Identification of proteins and genetic factors that reduce Alzheimer disease (AD) pathology is of importance when searching for novel AD treatments. Heterozygosity of the KL-VS haplotype has been associated with reduced amyloid and tau burden. Whether this association is mediated by the Klotho protein remains unclear.ObjectivesTo assess concentrations of Klotho in cerebrospinal fluid (CSF) and plasma among cognitively healthy controls and patients with AD and to correlate these findings with KL-VS heterozygosity status and amyloid and tau burden.Design, Setting, and ParticipantsThis case-control study combined 2 independent case-control AD cohorts consisting of 243 referred patients with AD and volunteer controls recruited from January 1, 2009, to December 31, 2018. Klotho levels were measured in CSF and plasma and correlated with KL-VS heterozygosity status and levels of CSF amyloid-β 42 (Aβ42), total tau, and phosphorylated tau. Statistical analysis was performed from January 1, 2021, to March 1, 2022.Main Outcomes and MeasuresAssociations of Klotho levels in CSF and plasma with levels of CSF biomarkers were analyzed using linear regression. Association analyses were stratified separately by clinical groups, APOE4 status, and KL-VS heterozygosity. Pearson correlation was used to assess the correlation between CSF and plasma Klotho levels.ResultsA total of 243 participants were included: 117 controls (45 men [38.5%]; median age, 65 years [range, 41-84 years]), 102 patients with mild cognitive impairment due to AD (AD-MCI; 59 men [57.8%]; median age, 66 years [range, 46-80 years]), and 24 patients with dementia due to AD (AD-dementia; 12 men [50.0%]; median age, 64.5 years [range, 54-75 years]). Median CSF Klotho levels were higher in controls (1236.4 pg/mL [range, 20.4-1726.3 pg/mL]; β = 0.103; 95% CI, 0.023-0.183; P = .01) and patients with AD-MCI (1188.1 pg/mL [range, 756.3-1810.3 pg/mL]; β = 0.095; 95% CI, 0.018-0.172; P = .02) compared with patients with AD-dementia (1073.3 pg/mL [range, 698.2-1661.4 pg/mL]). Higher levels of CSF Klotho were associated with lower CSF Aβ42 burden (β = 0.519; 95% CI, 0.201-0.836; P < .001) and tau burden (CSF total tau levels: β = −0.884; 95% CI, 0.223 to −0.395; P < .001; CSF phosphorylated tau levels: β = −0.672; 95% CI, −1.022 to −0.321; P < .001) independent of clinical, KL-VS heterozygosity, or APOE4 status. There was a weak correlation between Klotho CSF and plasma levels among the entire cohort (Pearson correlation r = 0.377; P < .001).Conclusions and RelevanceThe findings of this case-control study suggest that Klotho protein levels were associated with clinical stages of AD, cognitive decline, and amyloid and tau burden and that these outcomes were more clearly mediated by the protein directly rather than the KL-VS heterozygosity variant. When selecting individuals at risk for clinical trials, the Klotho protein level and not only the genetic profile should be considered.
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- Skarpengland, T, et al.
(författare)
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Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice
- 2016
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 28337-
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Tidskriftsartikel (refereegranskat)abstract
- Increasing evidence suggests that oxidative DNA damage accumulates in atherosclerosis. Recently, we showed that a genetic variant in the human DNA repair enzyme NEIL3 was associated with increased risk of myocardial infarction. Here, we explored the role of Neil3/NEIL3 in atherogenesis by both clinical and experimental approaches. Human carotid plaques revealed increased NEIL3 mRNA expression which significantly correlated with mRNA levels of the macrophage marker CD68. Apoe−/−Neil3−/− mice on high-fat diet showed accelerated plaque formation as compared to Apoe−/− mice, reflecting an atherogenic lipid profile, increased hepatic triglyceride levels and attenuated macrophage cholesterol efflux capacity. Apoe−/−Neil3−/− mice showed marked alterations in several pathways affecting hepatic lipid metabolism, but no genotypic alterations in genome integrity or genome-wide accumulation of oxidative DNA damage. These results suggest a novel role for the DNA glycosylase Neil3 in atherogenesis in balancing lipid metabolism and macrophage function, potentially independently of genome-wide canonical base excision repair of oxidative DNA damage.
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- Andersen, Casper W., et al.
(författare)
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OPTIMADE, an API for exchanging materials data
- 2021
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Ingår i: Scientific Data. - : Nature Portfolio. - 2052-4463. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- The Open Databases Integration for Materials Design (OPTIMADE) consortium has designed a universal application programming interface (API) to make materials databases accessible and interoperable. We outline the first stable release of the specification, v1.0, which is already supported by many leading databases and several software packages. We illustrate the advantages of the OPTIMADE API through worked examples on each of the public materials databases that support the full API specification.
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- Barrett, Aidan, et al.
(författare)
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Role of estrogen signaling in fibroblastic reticular cells for innate and adaptive immune responses in antigen-induced arthritis
- 2024
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Ingår i: IMMUNOLOGY AND CELL BIOLOGY. - 0818-9641 .- 1440-1711.
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Tidskriftsartikel (refereegranskat)abstract
- Women are more prone to develop rheumatoid arthritis, with peak incidence occurring around menopause. Estrogen has major effects on the immune system and is protective against arthritis. We have previously shown that treatment with estrogen inhibits inflammation and joint destruction in murine models of arthritis, although the mechanisms involved remain unclear. Fibroblastic reticular cells (FRCs) are specialized stromal cells that generate the three-dimensional structure of lymph nodes (LNs). FRCs are vital for coordinating immune responses from within LNs and are characterized by the expression of the chemokine CCL19, which attracts immune cells. The aim of this study was to determine whether the influence of estrogen on innate and adaptive immune cells in arthritis is mediated by estrogen signaling in FRCs. Conditional knockout mice lacking estrogen receptor alpha (ER alpha) in CCL19-expressing cells (Ccl19-CreER alpha fl/fl) were generated and tested. Ccl19-CreER alpha fl/fl mice and littermate controls were ovariectomized, treated with vehicle or estradiol and subjected to the 28-day-long antigen-induced arthritis model to enable analyses of differentiated T- and B-cell populations and innate cells in LNs by flow cytometry. The results reveal that while the response to estradiol treatment in numbers of FRCs per LN is significantly reduced in mice lacking ER alpha in FRCs, estrogen does not inhibit joint inflammation or markedly affect immune responses in this arthritis model. Thus, this study validates the Ccl19-CreER alpha fl/fl strain for studying estrogen signaling in FRCs within inflammatory diseases, although the chosen arthritis model is deemed unsuitable for addressing this question. This study investigated the influence of signaling through estrogen receptor alpha (ER alpha) in fibroblastic reticular cells (FRCs) on innate and adaptive immune responses using a mouse model where ER alpha was conditionally deleted in CCL19-expressing cells. The results reveal that the deletion of ER alpha in FRCs does not affect the FRC phenotype or LN architecture at steady state while the response of FRCs to estrogen treatment during experimental arthritis is significantly reduced in the conditional knock-out mice. However, ER alpha signaling via FRCs does not inhibit joint inflammation or markedly affect immune responses in the antigen-induced arthritis model. image
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- Brockstedt, Sara, et al.
(författare)
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SchnelleMagnetresonanz-Bildgebung
- 2002
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Ingår i: Radiologie Up2Date. - : Georg Thieme Verlag KG. - 1616-0681 .- 1617-8300. ; :4, s. 413-438
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Tidskriftsartikel (refereegranskat)abstract
- Abstract in German Die Verkürzung der Untersuchungszeiten bei der klinischen Magnetresonanztomographie (MRT) bietet für den Patienten den Vorteil einer angenehmeren und schnelleren Untersuchung und erhöht gleichzeitig den Patientendurchsatz. Dies erfordert schnelle und robuste Aufnahmetechniken, welche beispielsweise auch bei der Aufnahme bewegter Organe oder für atemangehaltene Messungen eingesetzt werden können. Durch die Entwicklung leistungsfähiger Gradientensysteme konnten in den letzten Jahren neue und schnelle Pulssequenzen entwickelt werden. Die rasante Entwicklung neuer Aufnahmemethoden und Rekonstruktionstechniken macht es für den Anwender immer wichtiger, die grundlegenden Prinzipien schneller Aufnahmetechniken zu verstehen. In diesem Übersichtsartikel wird versucht, die Grundlagen der schnellen Pulssequenzen und deren klinische Anwendungsbereiche darzustellen. Dies beinhaltet die schnelle Spin-Echo-Technik und deren Kombination mit selektiven Präparationstechniken, die schnelle und ultraschnelle Gradienten-Echo-Technik sowie die echoplanare Bildgebung. Abschließend werden kurz neueste Entwicklungen wie die parallele Bildgebung beschrieben.Zusammenfassung auf S. 434
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- Corciulo, Carmen, et al.
(författare)
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Physiological levels of estradiol limit murine osteoarthritis progression
- 2022
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Ingår i: The Journal of endocrinology. - 0022-0795 .- 1479-6805. ; 255:2, s. 39-51
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Tidskriftsartikel (refereegranskat)abstract
- Among patients with knee osteoarthritis (OA), postmenopausal women are over-represented. The purpose of this study was to determine whether deficiency of female sex steroids affects OA progression and to evaluate the protective effect of treatment with a physiological dose of 17β-estradiol (E2) on OA progression using a murine model. Ovariectomy (OVX) of female mice was used to mimic a postmenopausal state. OVX or sham-operated mice underwent surgery for destabilization of the medial meniscus (DMM) to induce OA. E2 was administered in a pulsed manner for 2 and 8 weeks. OVX of OA mice did not influence the cartilage phenotype or synovial thickness, while both cortical and trabecular subchondral bone mineral density (BMD) decreased after OVX compared with sham-operated mice at 8 weeks post-DMM surgery. Additionally, OVX mice displayed decreased motor activity, reduced threshold of pain sensitivity, and increased number of T cells in the inguinal lymph nodes compared to sham-operated mice 2 weeks after OA induction. Eight weeks of treatment with E2 prevented cartilage damage and thickening of the synovium in OVX OA mice. The motor activity was improved after E2 replacement at the 2 weeks time point, which was also associated with lower pain sensitivity in the OA paw. E2 treatment protected against OVX-induced loss of subchondral trabecular bone. The number of T cells in the inguinal lymph nodes was reduced by E2 treatment after 8 weeks. This study demonstrates that treatment with a physiological dose of E2 exerts a protective role by reducing OA symptoms.
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