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| 2. |
- Nandadasa, Sumeda, et al.
(författare)
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Vascular dimorphism ensured by regulated proteoglycan dynamics favors rapid umbilical artery closure at birth
- 2020
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Ingår i: eLife. - 2050-084X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The umbilical artery lumen closes rapidly at birth, preventing neonatal blood loss, whereas the umbilical vein remains patent longer. Here, analysis of umbilical cords from humans and other mammals identified differential arterial-venous proteoglycan dynamics as a determinant of these contrasting vascular responses. The umbilical artery, but not the vein, has an inner layer enriched in the hydrated proteoglycan aggrecan, external to which lie contraction-primed smooth muscle cells (SMC). At birth, SMC contraction drives inner layer buckling and centripetal displacement to occlude the arterial lumen, a mechanism revealed by biomechanical observations and confirmed by computational analyses. This vascular dimorphism arises from spatially regulated proteoglycan expression and breakdown. Mice lacking aggrecan or the metalloprotease ADAMTS1, which degrades proteoglycans, demonstrate their opposing roles in umbilical vascular dimorphism, including effects on SMC differentiation. Umbilical vessel dimorphism is conserved in mammals, suggesting that differential proteoglycan dynamics and inner layer buckling were positively selected during evolution.
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| 3. |
- Wang, Tianyan, et al.
(författare)
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PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer
- 2022
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media S.A.. - 2296-634X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- PIP5K1α has emerged as a promising drug target for the treatment of castration-resistant prostate cancer (CRPC), as it acts upstream of the PI3K/AKT signaling pathway to promote prostate cancer (PCa) growth, survival and invasion. However, little is known of the molecular actions of PIP5K1α in this process. Here, we show that siRNA-mediated knockdown of PIP5K1α and blockade of PIP5K1α action using its small molecule inhibitor ISA-2011B suppress growth and invasion of CRPC cells. We demonstrate that targeted deletion of the N-terminal domain of PIP5K1α in CRPC cells results in reduced growth and migratory ability of cancer cells. Further, the xenograft tumors lacking the N-terminal domain of PIP5K1α exhibited reduced tumor growth and aggressiveness in xenograft mice as compared to that of controls. The N-terminal domain of PIP5K1α is required for regulation of mRNA expression and protein stability of PIP5K1α. This suggests that the expression and oncogenic activity of PIP5K1α are in part dependent on its N-terminal domain. We further show that PIP5K1α acts as an upstream regulator of the androgen receptor (AR) and AR target genes including CDK1 and MMP9 that are key factors promoting growth, survival and invasion of PCa cells. ISA-2011B exhibited a significant inhibitory effect on AR target genes including CDK1 and MMP9 in CRPC cells with wild-type PIP5K1α and in CRPC cells lacking the N-terminal domain of PIP5K1α. These results indicate that the growth of PIP5K1α-dependent tumors is in part dependent on the integrity of the N-terminal sequence of this kinase. Our study identifies a novel functional mechanism involving PIP5K1α, confirming that PIP5K1α is an intriguing target for cancer treatment, especially for treatment of CRPC.
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| 4. |
- Alim, MA, et al.
(författare)
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Pleckstrin Levels Are Increased in Patients with Chronic Periodontitis and Regulated via the MAP Kinase-p38α Signaling Pathway in Gingival Fibroblasts
- 2022
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 12, s. 801096-
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Tidskriftsartikel (refereegranskat)abstract
- Chronic periodontitis (CP) is a bacteria-driven inflammatory disease characterized by the breakdown of gingival tissue, the periodontal ligament, and alveolar bone, leading ultimately to tooth loss. We previously reported the pleckstrin gene (PLEK) to be highly upregulated in gingival tissue of patients with CP and the only gene concurrently upregulated in other inflammatory diseases including rheumatoid arthritis and cardiovascular diseases. Using saliva from 169 individuals diagnosed with CP and healthy controls, we investigated whether pleckstrin could serve as a novel biomarker of periodontitis. Additionally, we explored signal pathways involved in the regulation of PLEK using human gingival fibroblasts (HGFs). Pleckstrin levels were significantly higher (p < 0.001) in the saliva samples of patients with CP compared to controls and closely associated with CP severity. Immunohistochemical analysis revealed the expression of pleckstrin in inflammatory cells and gingival fibroblasts of CP patients. To explore the signal pathways involved in pleckstrin regulation, we stimulated HGFs with either interleukin-1β (IL-1β) or lipopolysaccharides (LPS) alone, or in combination with inhibitors targeting c-Jun N-terminal kinase, tyrosine kinase, protein kinase C, or p38 MAP kinase. Results showed that IL-1β and LPS significantly increased PLEK mRNA and pleckstrin protein levels. VX-745, the p38 MAP kinase inhibitor significantly decreased IL-1β- and LPS-induced pleckstrin levels at both the mRNA and the protein level. Together, these findings show that pleckstrin could serve as a salivary biomarker for the chronic inflammatory disease periodontitis and a regulator of inflammation via the p38 MAP kinase pathway.
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| 5. |
- Bhutada, Sumit, et al.
(författare)
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Identification of protein biomarkers associated with congenital diaphragmatic hernia in human amniotic fluid
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Congenital diaphragmatic hernia (CDH) is a severe birth defect frequently associated with pulmonary hypoplasia, pulmonary hypertension, and heart failure. Since amniotic fluid comprises proteins of both fetal and maternal origin, its analysis could provide insights on mechanisms underlying CDH and provide biomarkers for early diagnosis, severity of pulmonary changes and treatment response. The study objective was to identify proteomic changes in amniotic fluid consistently associated with CDH. Amniotic fluid was obtained at term (37–39 weeks) from women with normal pregnancies (n = 5) or carrying fetuses with CDH (n = 5). After immuno-depletion of the highest abundance proteins, off-line fractionation and high-resolution tandem mass spectrometry were performed and quantitative differences between the proteomes of the groups were determined. Of 1036 proteins identified, 218 were differentially abundant. Bioinformatics analysis showed significant changes in GP6 signaling, in the MSP–RON signaling in macrophages pathway and in networks associated with cardiovascular system development and function, connective tissue disorders and dermatological conditions. Differences in selected proteins, namely pulmonary surfactant protein B, osteopontin, kallikrein 5 and galectin-3 were validated by orthogonal testing using ELISA in larger cohorts and showed statistically significant differences aiding in the diagnosis and prediction of CDH. The findings provide potential tools for clinical management of CDH.
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| 6. |
- Cai, Zongye, et al.
(författare)
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Kynurenine metabolites predict survival in pulmonary arterial hypertension : A role for IL-6/IL-6Rα
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Activation of the kynurenine pathway (KP) has been reported in patients with pulmonary arterial hypertension (PAH) undergoing PAH therapy. We aimed to determine KP-metabolism in treatment-naïve PAH patients, investigate its prognostic values, evaluate the effect of PAH therapy on KP-metabolites and identify cytokines responsible for altered KP-metabolism. KP-metabolite levels were determined in plasma from PAH patients (median follow-up 42 months) and in rats with monocrotaline- and Sugen/hypoxia-induced PH. Blood sampling of PAH patients was performed at the time of diagnosis, six months and one year after PAH therapy. KP activation with lower tryptophan, higher kynurenine (Kyn), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA), and anthranilic acid was observed in treatment-naïve PAH patients compared with controls. A similar KP-metabolite profile was observed in monocrotaline, but not Sugen/hypoxia-induced PAH. Human lung primary cells (microvascular endothelial cells, pulmonary artery smooth muscle cells, and fibroblasts) were exposed to different cytokines in vitro. Following exposure to interleukin-6 (IL-6)/IL-6 receptor α (IL-6Rα) complex, all cell types exhibit a similar KP-metabolite profile as observed in PAH patients. PAH therapy partially normalized this profile in survivors after one year. Increased KP-metabolites correlated with higher pulmonary vascular resistance, shorter six-minute walking distance, and worse functional class. High levels of Kyn, 3-HK, QA, and KA measured at the latest time-point were associated with worse long-term survival. KP-metabolism was activated in treatment-naïve PAH patients, likely mediated through IL-6/IL-6Rα signaling. KP-metabolites predict response to PAH therapy and survival of PAH patients.
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| 7. |
- Foox, Jonathan, et al.
(författare)
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The SEQC2 epigenomics quality control (EpiQC) study
- 2021
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Ingår i: Genome Biology. - : BioMed Central (BMC). - 1465-6906 .- 1474-760X. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCytosine modifications in DNA such as 5-methylcytosine (5mC) underlie a broad range of developmental processes, maintain cellular lineage specification, and can define or stratify types of cancer and other diseases. However, the wide variety of approaches available to interrogate these modifications has created a need for harmonized materials, methods, and rigorous benchmarking to improve genome-wide methylome sequencing applications in clinical and basic research. Here, we present a multi-platform assessment and cross-validated resource for epigenetics research from the FDA’s Epigenomics Quality Control Group.ResultsEach sample is processed in multiple replicates by three whole-genome bisulfite sequencing (WGBS) protocols (TruSeq DNA methylation, Accel-NGS MethylSeq, and SPLAT), oxidative bisulfite sequencing (TrueMethyl), enzymatic deamination method (EMSeq), targeted methylation sequencing (Illumina Methyl Capture EPIC), single-molecule long-read nanopore sequencing from Oxford Nanopore Technologies, and 850k Illumina methylation arrays. After rigorous quality assessment and comparison to Illumina EPIC methylation microarrays and testing on a range of algorithms (Bismark, BitmapperBS, bwa-meth, and BitMapperBS), we find overall high concordance between assays, but also differences in efficiency of read mapping, CpG capture, coverage, and platform performance, and variable performance across 26 microarray normalization algorithms.ConclusionsThe data provided herein can guide the use of these DNA reference materials in epigenomics research, as well as provide best practices for experimental design in future studies. By leveraging seven human cell lines that are designated as publicly available reference materials, these data can be used as a baseline to advance epigenomics research.
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| 8. |
- García-Antúnez, Oriol, et al.
(författare)
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The contradictions of youth participation for intergenerational justice in urban environmental planning
- 2023
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Ingår i: Frontiers in Sustainable Cities. - Lausanne : Frontiers Media S.A.. - 2624-9634. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Intergenerational justice (IGJ) has long been utilized in academic contexts such as philosophy and political theory. However, IGJ has increasingly become politicized. That is, it has been translated into more tangible ideas and discourses for public scrutiny, contestation, and action. This politicization is strongly represented by youth activism, which has utilized the concept to demand urgent political action and to defend the right to be included and represented in decision-making processes, particularly regarding climate change-related issues. The central topic of discussion in this perspective article is the strategic identification of youth inclusion with IGJ, and specifically the risks involved in accepting this identification. In this article we focus on urban environmental planning and argue that it is important to separate the practice of youth inclusion and the concept of IGJ to address these concerns and explore alternative strategies for incorporating IGJ in urban environmental planning. We then proceed to explore potential urban environmental planning approaches that are more intergenerationally just and conclude by critically reflecting on how the current political economy enables or hinders a more intergenerationally just approach to urban environmental planning.
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| 9. |
- Golovliov, Igor, 1958-, et al.
(författare)
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Long-Term Survival of Virulent Tularemia Pathogens outside a Host in Conditions That Mimic Natural Aquatic Environments
- 2021
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Ingår i: Applied and Environmental Microbiology. - : Elsevier. - 0099-2240 .- 1098-5336. ; 87:6, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Francisella tularensis, the causative agent of the zoonotic disease tularemia, can cause seasonal outbreaks of acute febrile illness in humans with disease peaks in late summer to autumn. Interestingly, its mechanisms for environmental persistence between outbreaks are poorly understood. One hypothesis is that F. tularensis forms biofilms in aquatic environments. We utilized two fully virulent wild-type strains: FSC200 (Francisella tularensis subsp. holarctica) and Schu S4 (Francisella tularensis subsp. tularensis) and three control strains, the attenuated live vaccine strain (LVS; F. tularensis subsp. holarctica), a Schu S4 DwbtI mutant that is documented to form biofilms, and the low-virulence strain U112 of the closely related species Francisella novicida. Strains were incubated in saline solution (0.9% NaCl) microcosms for 24 weeks at both 4°C and 20°C, whereupon viability and biofilm formation were measured. These temperatures were selected to approximate winter and summer temperatures of fresh water in Scandinavia, respectively. U112 and Schu S4 DwbtI formed biofilms, but F. tularensis strains FSC200 and Schu S4 and the LVS did not. All strains exhibited prolonged viability at 4°C compared to 20°C. U112 and FSC200 displayed remarkable long-term persistence at 4°C, with only 1- and 2-fold log reductions, respectively, of viable cells after 24weeks. Schu S4 exhibited lower survival, yielding no viable cells by week 20. At 24weeks, cells from FSC200, but not from Schu S4, were still fully virulent in mice. Taken together, these results demonstrate biofilm-independent, long-term survival of pathogenic F. tularensis subsp. holarctica in conditions that mimic overwinter survival in aquatic environments.
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| 10. |
- Håkansson, Charlotta, 1971-
(författare)
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Greenhouse Gas Fluxes and Carbon Sequestration in Young Norway Spruce Stands : The Effects of Fertilization
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The enormous challenge of climate change is discussed and debated today because of its major impact on life on Earth. The forests have an important role to play as the plants absorb carbon dioxide (CO2) from the atmosphere through their photosynthesis and the growing tree retain carbon (C). Hence, the larger the growth the greater the carbon storage and climate benefit. The demand for wood and wood products is increasing as well as the ongoing debate about forest management. Therefore, alternative management methods to increase wood production is of interest and the effects these methods could have on climate change mitigation. In this context this Thesis deals with the effect of fertilization on carbon balance and growth in young forest as well as flows of the greenhouse gases, CO2, methane (CH4), and nitrous oxide (N2O) from forest land. In addition, it deals also with the reliability and comparability of different measurement methods which are compared with respect to the carbon balance.The studies have been carried out in a young mixed stand of Norway spruce (Picea abies (L.) Karst) and birch (Betula pendula and B.pubescens) on a storm-felled (Gudrun 2005) area in southern Sweden, Kronoberg county. Part of the area was fertilized with 150 kg N ha-1 everysecond year from 2014 and forward, while the other part was kept unfertilized. In the unfertilized part a dose experiment was set up where 0,150, 300, and 450 kg N ha-1 were added to investigate the impact of the different fertilizer levels on forest floor greenhouse gas fluxes. Chamber measurements of forest floor fluxes, eddy-flux measurements of stand net-fluxes and tree measurements of height, diameter and birch leaf biomass were conducted in different, occasionally overlapping, periods in the years 2013-2021.The results show that even if the flows of CO2 from the forest floor increase initially after a first standard fertilization, the effect decreases quickly. The net fluxes show that the stands become carbon sinks already eight years after the storm with a net uptake of about 18 ton CO2 ha-1 yr-1 of. The forest floor fluxes of CH4 and N2O also show a short-term effect of fertilization, however the levels are very low compared to CO2. The fertilization induced increase of total tree biomass growth increased with time. The results show that 12 and 15 years after regeneration, the fertilization compared to the control has increased the tree growth by 3.4 and 6.3 m3 ha-1 yr-1 and carbon storage by 4.7 and 8.7 ton C ha-1 yr-1 respectively.Comparison of measurement results of the Eddy-flux technique's netflows and chamber measurements of soil respiration together with tree growth shows the importance of calibrating the measurement methods when the results are later to be used in modeling future climate scenarios.
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