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- Järver, Peter, et al.
(författare)
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Single-Stranded Nucleic Acids Regulate TLR3/4/7 Activation through Interference with Clathrin-Mediated Endocytosis
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Recognition of nucleic acids by endosomal Toll-like receptors (TLR) is essential to combat pathogens, but requires strict control to limit inflammatory responses. The mechanisms governing this tight regulation are unclear. We found that single-stranded oligonucleotides (ssON) inhibit endocytic pathways used by cargo destined for TLR3/4/7 signaling endosomes. Both ssDNA and ssRNA conferred the endocytic inhibition, it was concentration dependent, and required a certain ssON length. The ssON-mediated inhibition modulated signaling downstream ofTLRs that localized within the affected endosomal pathway. We further show that injection of ssON dampens dsRNA-mediated inflammatory responses in the skin of non-human primates. These studies reveal a regulatory role for extracellular ssON in the endocytic uptake of TLR ligands and provide a mechanistic explanation of their immunomodulation. The identified ssON-mediated interference of endocytosis (SOMIE) is a regulatory process that temporarily dampens TLR3/4/7 signaling, thereby averting excessive immune responses.
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| 6. |
- Muñoz-Alarcón, Andrés, et al.
(författare)
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Modulating Anti-MicroRNA-21 Activity and Specificity Using Oligonucleotide Derivatives and Length Optimization
- 2012
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Ingår i: ISRN Pharmaceutics. - : Hindawi Limited. - 2090-6145 .- 2090-6153. ; 2012
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs are short, endogenous RNAs that direct posttranscriptional regulation of gene expression vital for many developmental and cellular functions. Implicated in the pathogenesis of several human diseases, this group of RNAs provides interesting targets for therapeutic intervention. Anti-microRNA oligonucleotides constitute a class of synthetic antisense oligonucleotides used to interfere with microRNAs. In this study, we investigate the effects of chemical modifications and truncations on activity and specificity of anti-microRNA oligonucleotides targeting microRNA-21. We observed an increased activity but reduced specificity when incorporating locked nucleic acid monomers, whereas the opposite was observed when introducing unlocked nucleic acid monomers. Our data suggest that phosphorothioate anti-microRNA oligonucleotides yield a greater activity than their phosphodiester counterparts and that a moderate truncation of the anti-microRNA oligonucleotide improves specificity without significantly losing activity. These results provide useful insights for design of anti-microRNA oligonucleotides to achieve both high activity as well as efficient mismatch discrimination.
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- Twardek, W. M., et al.
(författare)
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Field assessments of heart rate dynamics during spawning migration of wild and hatchery-reared Chinook salmon
- 2021
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Ingår i: Philosophical Transactions of the Royal Society B-Biological Sciences. - : The Royal Society. - 0962-8436 .- 1471-2970. ; 376:1830
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Tidskriftsartikel (refereegranskat)abstract
- During spawning, adult Pacific salmonids (Oncorhynchus spp.) complete challenging upriver migrations during which energy and oxygen delivery must be partitioned into activities such as locomotion, maturation and spawning behaviours under the constraints of an individual's cardiac capacity. To advance our understanding of cardiac function in free-swimming fishes, we implanted migrating adult Chinook salmon (Oncorhynchus tshawytscha) collected near the mouth of the Sydenham River, Ontario, with heart rate (f(H)) biologgers that recorded f(H) every 3 min until these semelparous fish expired on spawning grounds several days later. Fundamental aspects of cardiac function were quantified, including resting, routine and maximum f(H), as well as scope for f(H) (maximum-resting f(H)). Predictors of f(H) were explored using generalized least-squares regression, including water temperature, discharge, fish size and fish origin (wild versus hatchery). Heart rate was positively correlated with water temperature, which aligned closely with daily and seasonal shifts. Wild fish had slower resting heart rates than hatchery fish, which led to significantly higher scope for f(H). Our findings suggest that wild salmon may have better cardiac capacity during migration than hatchery fish, potentially promoting migration success in wild fish. This article is part of the theme issue 'Measuring physiology in free-living animals (Part I)'.
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- Cooke, Steven J., et al.
(författare)
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Animal migration in the Anthropocene : threats and mitigation options
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Ingår i: Biological Reviews. - 1464-7931.
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Tidskriftsartikel (refereegranskat)abstract
- Animal migration has fascinated scientists and the public alike for centuries, yet migratory animals are facing diverse threats that could lead to their demise. The Anthropocene is characterised by the reality that humans are the dominant force on Earth, having manifold negative effects on biodiversity and ecosystem function. Considerable research focus has been given to assessing anthropogenic impacts on the numerical abundance of species/populations, whereas relatively less attention has been devoted to animal migration. However, there are clear linkages, for example, where human-driven impacts on migration behaviour can lead to population/species declines or even extinction. Here, we explore anthropogenic threats to migratory animals (in all domains – aquatic, terrestrial, and aerial) using International Union for the Conservation of Nature (IUCN) Threat Taxonomy classifications. We reveal the diverse threats (e.g. human development, disease, invasive species, climate change, exploitation, pollution) that impact migratory wildlife in varied ways spanning taxa, life stages and type of impact (e.g. from direct mortality to changes in behaviour, health, and physiology). Notably, these threats often interact in complex and unpredictable ways to the detriment of wildlife, further complicating management. Fortunately, we are beginning to identify strategies for conserving and managing migratory animals in the Anthropocene. We provide a set of strategies that, if embraced, have the potential to ensure that migratory animals, and the important ecological functions sustained by migration, persist.
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- Din, Lennox, et al.
(författare)
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Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes
- 2019
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Ingår i: Genetic Epidemiology. - : WILEY. - 0741-0395 .- 1098-2272. ; 43:7, s. 844-863
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p =.0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.
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| 10. |
- Holder, Peter E., et al.
(författare)
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Preparing for a changing future in recreational fisheries : 100 research questions for global consideration emerging from a horizon scan
- 2020
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Ingår i: Reviews in Fish Biology and Fisheries. - : Springer Science and Business Media LLC. - 0960-3166 .- 1573-5184. ; 30:1, s. 137-151
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Forskningsöversikt (refereegranskat)abstract
- Recreational fisheries hold immense ecological, social, and economic value. The management of these fisheries is increasingly important as we move forward in the Anthropocene. Recreational fisheries managers face several challenges as fisheries often involve diverse social and ecological systems comprised of complex feedback and stakeholder motivations and needs. Here, we used a horizon scanning exercise to yield 100 research questions related to recreational fisheries science and management in the Anthropocene. Initial research questions (n = 205) were collected from recreational fisheries experts (i.e., stakeholders, managers, researchers) from various sectors (i.e., industry, government, NGOs) and geographic locations (14 countries: Australia, Brazil, Canada, Czech Republic, Germany, Italy, New Zealand, Norway, South Africa, Spain, Sweden, Switzerland, United Kingdom, USA). These questions were subsequently categorized, thematized, and refined by our authorship team, eventually yielding what we considered to be the top 100 research questions of relevance to management of recreational fisheries. The key themes include: human dimensions; bioeconomics; resource monitoring and data acquisition; governance; management-regulatory actions; management-stock and habitat enhancement; catch-and-release; impacts of recreational fisheries on populations, communities and ecosystems; threats and sustainability; and angler outreach, education and engagement. It is our intention that this comprehensive and forward-looking list will create a framework to guide future research within this field, and contribute to evidence-based recreational fisheries management and policy.
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| 12. |
- Lennox, J.A., et al.
(författare)
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Adaptive Multiscale Principal Component Analysis for Wastewater Treatment
- 2001
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Ingår i: ; , s. 341-438
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Konferensbidrag (refereegranskat)abstract
- Fault detection and isolation (FDI) are important steps in the monitoring and supervision of industrial processes. Biological wastewater treatment (WWT) plants are difficult to model, and hence to monitor, because of the complexity of the biological reactions and because plant influent and disturbances are highly variable and/or unmeasured. Multivariate statistical models have been developed for a wide variety of situations over the past few decades, proving successful in many applications. In this paper we develop a new monitoring algorithm based on Principal Components Analysis (PCA). It can be seen equivalently as making Multiscale PCA (MSPCA) adaptive, or as a multiscale decomposition of adaptive PCA. Adaptive Multiscale PCA (AdMSPCA) exploits the changing multivariate relationships between variables at different time-scales. Adaptation of scale PCA models over time permits them to follow the evolution of the process, inputs or disturbances. Performance of AdMSPCA and adaptive PCA on a real WWT data set is compared and contrasted. The most significant difference observed was the ability of AdMSPCA to adapt to a much wider range of changes. This was mainly due to the flexibility afforded by allowing each scale model to adapt whenever it did not signal an abnormal event at that scale. Relative detection speeds were examined only summarily, but seemed to depend on the characteristics of the faults/disturbances. The results of the algorithms were similar for sudden changes, but AdMSPCA appeared more sensitive to slower changes.
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| 14. |
- Rosén, Christian, et al.
(författare)
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Multivariate and Multiscale Monitoring of Wastewater Treatment Operation
- 2001
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Ingår i: Water Research. - 1879-2448. ; 35:14, s. 3402-3410
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Tidskriftsartikel (refereegranskat)abstract
- In this work extensions to principal component analysis (PCA) for wastewater treatment (WWT) process monitoring are discussed. Conventional PCA has some limitations when used for WWT monitoring. Firstly, PCA assumes that data are stationary, which is normally not the case in WWT monitoring. Secondly, PCA is most suitable for monitoring data that display events in one time-scale. However, in WWT operation, disturbances and events occur in different time-scales. These two limitations make conventional PCA unsuitable for WWT monitoring. The first limitation can be overcome by use of adaptive PCA. In adaptive PCA, the PCA model is continuously updated using an exponential memory function. Variable mean, variance and co-variance are thus adapted to the changing conditions. The second problem can be solved by time-scale decomposition of data prior to analysis. The time-scale decomposition methodology involves wavelets and multiresolution analysis (MRA) in combination with PCA. MRA provides a tool for investigation and monitoring of process measurement at different time-scales by decomposing measurement data into separate frequency bands. Time-scale decomposition increases the sensitivity of the monitoring, which makes it possible to detect small but significant events in data displaying large variations. Moreover, time-scale information is sometimes important in the interpretation of a disturbance to determine its physical cause. Also, by decomposing data, the problem of changing process conditions is partly solved. All the presented methods are illustrated with examples using real WWT process data.
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| 15. |
- Stuparu, Andreea D., et al.
(författare)
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Mechanisms of Resistance to Prostate-Specific Membrane Antigen-Targeted Radioligand Therapy in a Mouse Model of Prostate Cancer
- 2021
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505. ; 62:7, s. 989-995
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Tidskriftsartikel (refereegranskat)abstract
- Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is effective against prostate cancer (PCa), but all patients relapse eventually. Poor understanding of the underlying resistance mechanisms represents a key barrier to development of more effective RLT. We investigate the proteome and phosphoproteome in a mouse model of PCa to identify signaling adaptations triggered by PSMA RLT. Methods: Therapeutic efficacy of PSMA RLT was assessed by tumor volume measurements, time to progression, and survival in C4-2 or C4-2 TP53-/- tumor-bearing nonobese diabetic scid γ-mice. Two days after RLT, the proteome and phosphoproteome were analyzed by mass spectrometry. Results: PSMA RLT significantly improved disease control in a dose-dependent manner. Proteome and phosphoproteome datasets revealed activation of genotoxic stress response pathways, including deregulation of DNA damage/replication stress response, TP53, androgen receptor, phosphatidylinositol-3-kinase/AKT, and MYC signaling. C4-2 TP53-/- tumors were less sensitive to PSMA RLT than were parental counterparts, supporting a role for TP53 in mediating RLT responsiveness. Conclusion: We identified signaling alterations that may mediate resistance to PSMA RLT in a PCa mouse model. Our data enable the development of rational synergistic RLT-combination therapies to improve outcomes for PCa patients.
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