| 1. |
- Adelöf, Julia, 1990, et al.
(författare)
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Conclusions from a behavioral aging study on male and female F2 hybrid mice on age-related behavior, buoyancy in water-based tests, and an ethical method to assess lifespan.
- 2019
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Ingår i: Aging. - : Impact Journals, LLC. - 1945-4589. ; 11:17, s. 7150-7168
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Tidskriftsartikel (refereegranskat)abstract
- Due to strain-specific behavioral idiosyncrasies, inbred mouse strains are suboptimal research models for behavioral aging studies. The aim of this study is to determine age-related behavioral changes of F2 hybrid C57BL/6NxBALB/c male and female mice. Lifespan was followed (nmales=48, nfemales=51) and cohorts of mature adult (7 months), middle-aged (15 months), and old mice (22 months of age; n=7-12 per group) were assessed regarding open-field activity, exploration, passive avoidance learning/memory, and depressive-like behavior. We found that both males and females demonstrated decreased exploratory behavior with age, while memory and depressive-like behavior were maintained. Females exhibited enhanced depressive-like behavior compared to males; however, a correlation between fat mass and swimming activity in the test directly accounted for 30-46% of this behavioral sex difference. In addition, we suggest a method to qualitatively estimate natural lifespan from survival analyses in which animals with signs of pain or severe disease are euthanized. This is, to our knowledge, the first behavioral study to consider both sex and aging in hybrid mice. We here define decreased exploratory behavior as a conserved hallmark of aging independent of sex, highlight the effect of buoyancy in water tests, and provide a method to assay lifespan with reduced animal suffering.
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| 2. |
- Adelöf, Julia, 1990, et al.
(författare)
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PA28α overexpressing female mice maintain exploratory behavior and capacity to prevent protein aggregation in hippocampus as they age.
- 2021
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Ingår i: Aging cell. - : Wiley. - 1474-9726 .- 1474-9718. ; 4:29
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Tidskriftsartikel (refereegranskat)abstract
- With age, protein damage accumulates and increases the risk of age-related diseases. The proteasome activator PA28αβ is involved in protein damage clearance during early embryogenesis and has demonstrated protective effects against proteinopathy. We have recently discovered that adult female mice overexpressing PA28α (PA28αOE) have enhanced learning and memory, and protein extracts from their hippocampi prevent aggregation more efficiently than wild type. In this study, we investigated the effect of overexpressing PA28α on aging using C57BL/6N×BALB/c F2 hybrid mice. We found that the hippocampal anti-aggregation effect was maintained in young adult (7 months) to middle-aged (15 months) and old (22 months) PA28αOE females. While the PA28αOE influence on learning and memory gradually decreased with aging, old PA28αOE females did not display the typical drop in explorative behavior-a behavioral hallmark of aging-but were as explorative as young mice. PA28αOE lowered PA28-dependent proteasome capacity in both heart and hippocampus, and there was no indication of lower protein damage load in PA28αOE. The life span of PA28αOE was also similar to wild type. In both wild type and PA28αOE, PA28-dependent proteasome capacity increased with aging in the heart, while 26S and 20S proteasome capacities were unchanged in the timepoints analyzed. Thus, PA28αOE females exhibit improved hippocampal ability to prevent aggregation throughout life and enhanced cognitive capabilities with different behavioral outcomes dependent on age; improved memory at early age and a youth-like exploration at old age. The cognitive effects of PA28αβ combined with its anti-aggregation molecular effect highlight the therapeutical potential of PA28αβ in combating proteinopathies.
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| 3. |
- Adelöf, Julia, 1990, et al.
(författare)
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PA28αβ overexpression enhances learning and memory of female mice without inducing 20S proteasome activity
- 2018
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Ingår i: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The proteasome system plays an important role in synaptic plasticity. Induction and maintenance of long term potentiation is directly dependent on selective targeting of proteins for proteasomal degradation. The 20S proteasome activator PA28αβ activates hydrolysis of small nonubiquitinated peptides and possesses protective functions upon oxidative stress and proteinopathy. The effect of PA28αβ activity on behavior and memory function is, however, not known. We generated a mouse model that overexpresses PA28α (PA28αOE) to understand PA28αβ function during healthy adult homeostasis via assessment of physiological and behavioral profiles, focusing on female mice. RESULTS: PA28α and PA28β protein levels were markedly increased in all PA28αOE tissues analyzed. PA28αOE displayed reduced depressive-like behavior in the forced swim test and improved memory/learning function assessed by intersession habituation in activity box and shuttle box passive avoidance test, with no significant differences in anxiety or general locomotor activity. Nor were there any differences found when compared to WT for body composition or immuno-profile. The cognitive effects of PA28αOE were female specific, but could not be explained by alterations in estrogen serum levels or hippocampal regulation of estrogen receptor β. Further, there were no differences in hippocampal protein expression of neuronal or synaptic markers between PA28αOE and WT. Biochemical analysis of hippocampal extracts demonstrated that PA28α overexpression did not increase PA28-20S peptidase activity or decrease K48-polyubiquitin levels. Instead, PA28αOE exhibited elevated efficiency in preventing aggregation in the hippocampus. CONCLUSIONS: This study reveals, for the first time, a connection between PA28αβ and neuronal function. We found that PA28α overexpressing female mice displayed reduced depressive-like behavior and enhanced learning and memory. Since the positive effects of PA28α overexpression arose without an activation of 20S proteasome capacity, they are likely independent of PA28αβ's role as a 20S proteasome activator and instead depend on a recognized chaperone-like function. These findings suggest that proteostasis in synaptic plasticity is more diverse than previously reported, and demonstrates a novel function of PA28αβ in the brain.
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| 4. |
- Begley, Cecily, 1954, et al.
(författare)
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Evaluation of an intervention to increase vaginal birth after caesarean section through enhanced women-centred care: The OptiBIRTH randomised trial (ISRCTN10612254)
- 2017
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Ingår i: 31th ICM Triennial Congress.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Vaginal birth after a previous caesarean (VBAC) is a safe alternative to repeat caesarean section (CS), is the preferred option of most women and may reduce overall CS rates.1 However, VBAC rates vary; e.g., rates in Germany, Ireland and Italy are considerably lower (29-36%) than those in the Netherlands, Sweden and Finland (45-55%). Purpose/Objective: To evaluate the effectiveness of an intervention to maximise VBAC rates. The OptiBIRTH Project was funded by a European Union Grant: FP7-HEALTH-2012-INNOVATION-1-HEALTH.2012.3.2-1. Agreement No:305208 Method: A cluster randomised trial was used. A sample size of 12 maternity units was required, each recruiting 120 consenting women, to detect an absolute 15% difference in successful VBACs (increase from 25% in control to 40% in intervention groups), using an ICC of 0.05, with power of >80% and an alpha of 0.05. To allow for loss to follow-up, 15 trial units were randomised across three countries with low VBAC rates (Germany, Ireland and Italy) and the trial commenced April 2014. An evidence-based intervention was introduced in all intervention sites. Control sites had usual care. Interim analysis by an independent Data Monitoring Committee at mid-point permitted continuation. Data were analysed using intention to treat. Key Findings: Recruitment closed October 2015, with the last babies born in December 2015, and data analysis will be completed in April 2016. The primary outcome, comparison of annual VBAC rates for each hospital before and after introduction of the intervention will be presented, and selected secondary outcomes for the recruited women including: mode of birth, perineal trauma, breastfeeding, uterine rupture, wound breakdown, perinatal mortality, Apgar scores, and admission to neonatal intensive care unit. Discussion: If the OptiBIRTH intervention increases VBAC rates safely, its introduction across Europe could prevent 160,000 unnecessary CSs every year, saving maternity services >€150 million annually and contributing to the normalisation of birth for thousands of women. References: 1 Cunningham et al (2010). National Institute of Health Consensus Development Conference Statement: Vaginal birth after caesarean. Obstet & Gynecol 115(6): 1279-1295. 2 EURO-PERISTAT 2008: CD006066.EURO-PERISTAT Project (2008). European Perinatal Health Report. (www.europeristat.com).
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| 5. |
- Clarke, Mike, et al.
(författare)
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OptiBIRTH: a cluster randomised trial of acomplex intervention to increase vaginalbirth after caesarean section
- 2020
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Ingår i: BMC Pregnancy and Childbirth. - : Springer Science and Business Media LLC. - 1471-2393 .- 1471-2393.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite evidence supporting the safety of vaginal birth after caesarean section (VBAC), rates are lowin many countries.Methods: OptiBIRTH investigated the effects of a woman-centred intervention designed to increase VBAC ratesthrough an unblinded cluster randomised trial in 15 maternity units with VBAC rates < 35% in Germany, Ireland andItaly. Sites were matched in pairs or triplets based on annual birth numbers and VBAC rate, and randomised, 1:1 or 2:1, intervention versus control, following trial registration. The intervention involved evidence-based education ofclinicians and women with one previous caesarean section (CS), appointment of opinion leaders, audit/peer review,and joint discussions by women and clinicians. Control sites provided usual care. Primary outcome was annualhospital-level VBAC rates before the trial (2012) versus final year of the trial (2016). Between April 2014 and October2015, 2002 women were recruited (intervention 1195, control 807), with mode-of-birth data available for 1940women.Results: The OptiBIRTH intervention was feasible and safe across hospital settings in three countries. There was nostatistically significant difference in the change in the proportion of women having a VBAC between interventionsites (25.6% in 2012 to 25.1% in 2016) and control sites (18.3 to 22.3%) (odds ratio adjusted for differences betweenintervention and control groups (2012) and for homogeneity in VBAC rates at sites in the countries: 0.87, 95% CI:0.67, 1.14, p = 0.32 based on 5674 women (2012) and 5284 (2016) with outcome data. Among recruited womenwith birth data, 4/1147 perinatal deaths > 24 weeks gestation occurred in the intervention group (0.34%) and 4/782in the control group (0.51%), and two uterine ruptures (one per group), a rate of 1:1000.Conclusions: Changing clinical practice takes time. As elective repeat CS is the most common reason for CS inmultiparous women, interventions that are feasible and safe and that have been shown to lead to decreasingrepeat CS, should be promoted. Continued research to refine the best way of promoting VBAC is essential. Thismay best be done using an implementation science approach that can modify evidence-based interventions inresponse to changing clinical circumstances.Trial registration: The OptiBIRTH trial was registered on 3/4/2013. Trial registration number ISRCTN10612254.
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| 6. |
- Frye, Maike, et al.
(författare)
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EphrinB2-EphB4 signalling provides Rho-mediated homeostatic control of lymphatic endothelial cell junction integrity
- 2020
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Ingår i: eLIFE. - : eLife Sciences Publications, Ltd. - 2050-084X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Endothelial integrity is vital for homeostasis and adjusted to tissue demands. Although fluid uptake by lymphatic capillaries is a critical attribute of the lymphatic vasculature, the barrier function of collecting lymphatic vessels is also important by ensuring efficient fluid drainage as well as lymph node delivery of antigens and immune cells. Here, we identified the transmembrane ligand EphrinB2 and its receptor EphB4 as critical homeostatic regulators of collecting lymphatic vessel integrity. Conditional gene deletion in mice revealed that EphrinB2/EphB4 signalling is dispensable for blood endothelial barrier function, but required for stabilization of lymphatic endothelial cell (LEC) junctions in different organs of juvenile and adult mice. Studies in primary human LECs further showed that basal EphrinB2/EphB4 signalling controls junctional localisation of the tight junction protein CLDN5 and junction stability via Rac1/Rho-mediated regulation of cytoskeletal contractility. EphrinB2/EphB4 signalling therefore provides a potential therapeutic target to selectively modulate lymphatic vessel permeability and function.
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| 7. |
- Hernebring, Malin, 1978, et al.
(författare)
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H2O2-induced cataract as a model of age-related cataract: Lessons learned from overexpressing the proteasome activator PA28αβ in mouse eye lens.
- 2021
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Ingår i: Experimental eye research. - : Elsevier BV. - 1096-0007 .- 0014-4835. ; 203
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Tidskriftsartikel (refereegranskat)abstract
- Cataract, the world-leading cause of blindness, is formed when crystallin aggregates cloud the eye lens. We overexpressed PA28αβ, a proteasome activator with properties protective against aggregation and oxidative stress, and examined whether they are less prone to develop cataract arisen from aging and/or hydrogen peroxide (H2O2) treatment. Another objective of this work was to compare the H2O2-induced cataracts of mouse lenses ex vivo to cataracts formed upon aging in mice. As part of an aging study of F2 hybrid C57BL/6NxBALB/c mice, ocular lenses of mature adult (7 months), middle-aged (15 months), and old (22 months of age) PA28αOE mice and their wildtype littermates (n = 22-44 lenses per group) were dissected and evaluated with regard to their cataractous state. In parallel, ocular lenses from 3 to 4 months old PA28αOE and wildtype C57BL/6 N littermates were treated with 100 μM H2O2 every 24 h for 7 days, with progression of cataract and physical appearance monitored daily. Lenses from both studies were also subjected to analysis of oxidative protein damage (carbonylation) and protein solubility. We found that overexpression of PA28αβ had no effect on neither age-related nor H2O2-induced cataract and conclude that overexpression of PA28αβ does not protect mice from developing cataract. The inefficiency of PA28αβ against cataract could be due to its anti-aggregation activity being already excessively present in the eye lens, exerted by crystallins. Crystallins are likely also constituting the 20-25 kDa proteins that were the dominant carbonyl targets in the eye lens irrespective of cataractous state. Assessment of H2O2-induced cataract in relation to age-related cataract demonstrated that high molecular weight protein carbonylation correlates to cataract both in vivo and ex vivo, while reduced protein solubility is more pronounced in age-related cataract. Furthermore, this work highlights vast dissimilarities in the physical manifestations of cataract upon aging and H2O2 ex vivo treatment. Age-related cataract initiation can take various forms, as a vague general blurriness or as a barely visible demarcated opacity, while H2O2-induced cataractogenesis seems to follow a specific scheme. In mice, this scheme begins with relatively opaque peripheral areas emerging that clear up later on as the lenses start to display a hat-like appearance. This transformation takes place synchronous to swelling of the eye lens, and is likely a result of osmotic disturbances causing a phase separation between the viscous lens cortex and the more solid fibers of the lens nucleus.
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| 8. |
- Martin-Almedina, Silvia, et al.
(författare)
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EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis
- 2016
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 126:8, s. 3080-3088
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Tidskriftsartikel (refereegranskat)abstract
- Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality. Here, we have identified an autosomal dominant, inherited form of lymphatic-related (nonimmune) hydrops fetalis (LRHF). Independent exome sequencing projects on 2 families with a history of in utero and neonatal deaths associated with nonimmune hydrops fetalis uncovered 2 heterozygous missense variants in the gene encoding Eph receptor B4 (EPHB4). Biochemical analysis determined that the mutant EPHB4 proteins are devoid of tyrosine kinase activity, indicating that loss of EPHB4 signaling contributes to LRHF pathogenesis. Further, inactivation of Ephb4 in lymphatic endothelial cells of developing mouse embryos led to defective lymphovenous valve formation and consequent subcutaneous edema. Together, these findings identify EPHB4 as a critical regulator of early lymphatic vascular development and demonstrate that mutations in the gene can cause an autosomal dominant form of LRHF that is associated with a high mortality rate.
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| 9. |
- Morandi, Garrett D., et al.
(författare)
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Elucidating mechanisms of toxic action of dissolved organic chemicals in oil sands process-affected water (OSPW)
- 2017
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Ingår i: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 186, s. 893-900
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Tidskriftsartikel (refereegranskat)abstract
- Oil sands process-affected water (OSPW) is generated during extraction of bitumen in the surface-mining oil sands industry in Alberta, Canada, and is acutely and chronically toxic to aquatic organisms. It is known that dissolved organic compounds in OSPW are responsible for most toxic effects, but knowledge of the specific mechanism(s) of toxicity, is limited. Using bioassay-based effects-directed analysis, the dissolved organic fraction of OSPW has previously been fractionated, ultimately producing refined samples of dissolved organic chemicals in OSPW, each with distinct chemical profiles. Using the Escherichia coli K-12 strain MG1655 gene reporter live cell array, the present study investigated relationships between toxic potencies of each fraction, expression of genes and characterization of chemicals in each of five acutely toxic and one non-toxic extract of OSPW derived by use of effects-directed analysis. Effects on expressions of genes related to response to oxidative stress, protein stress and DNA damage were indicative of exposure to acutely toxic extracts of OSPW. Additionally, six genes were uniquely responsive to acutely toxic extracts of OSPW. Evidence presented supports a role for sulphur- and nitrogen-containing chemical classes in the toxicity of extracts of OSPW.
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| 10. |
- Morandi, Garrett, et al.
(författare)
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Effects of chemical fractions from an oil sands end-pit lake on reproduction of fathead minnows
- 2020
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Ingår i: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 249
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Tidskriftsartikel (refereegranskat)abstract
- Oil sands process-affected water (OSPW) is a byproduct of bitumen extraction in the surface-mining oil sands industry in Alberta, Canada. Organic compounds in OSPW can be acutely or chronically toxic to aquatic organisms, so part of a long-term strategy for remediation of OSPW is ageing of water in artificial lakes, termed end-pit lakes. BaseMine Lake (BML) is the first oil sands end-pit lake, commissioned in 2012. At the time of its establishment, an effects-directed analysis of BML-OSPW showed that naphthenic acids and polar organic chemical species containing sulfur or nitrogen contributed to its acute lethality. However, the chronic toxicity of these same chemical fractions has not yet been investigated. In this work, the short-term fathead minnow reproductive bioassay was used to assess endocrine-system effects of two fractions of BML-OSPW collected in 2015. One of the fractions (F1) contained predominantly naphthenic acids, while the other (F2) contained non-acidic polar organic chemical species. Exposure of minnows to F1 or F2 at concentrations equivalent to 25% (v/v) of the 2015 BML-OSPW sample (5-15% of the 2012 BML-OSPW sample) did not alter reproductive performance, fertilization success, or concentrations of sex steroids in female or male minnows. Additionally, there were no significant differences in fertility, hatching success, or incidence of morphological indices of embryos collected on day 7 or 14 from exposed breeding trios. However, exposure of male fathead minnow to 25% (v/v) intact 2015 BML-OSPW resulted in a significantly greater hepatosomatic index. Exposure of fathead minnow to refined fractions of dissolved organic chemicals in 2015 BML-OSPW, or a 25% (v/v) of the intact mixture did not affect fertility or fecundity as measured by use of the 21-day reproductive bioassay. These data will be useful in setting future threshold criteria for OSPW reclamation and treatment.
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