| 1. |
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| 2. |
- Buntgen, U., et al.
(author)
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Tree rings reveal globally coherent signature of cosmogenic radiocarbon events in 774 and 993 CE
- 2018
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
-
Journal article (peer-reviewed)abstract
- Though tree-ring chronologies are annually resolved, their dating has never been independently validated at the global scale. Moreover, it is unknown if atmospheric radiocarbon enrichment events of cosmogenic origin leave spatiotemporally consistent fingerprints. Here we measure the 14C content in 484 individual tree rings formed in the periods 770–780 and 990–1000 CE. Distinct 14C excursions starting in the boreal summer of 774 and the boreal spring of 993 ensure the precise dating of 44 tree-ring records from five continents. We also identify a meridional decline of 11-year mean atmospheric radiocarbon concentrations across both hemispheres. Corroborated by historical eye-witness accounts of red auroras, our results suggest a global exposure to strong solar proton radiation. To improve understanding of the return frequency and intensity of past cosmic events, which is particularly important for assessing the potential threat of space weather on our society, further annually resolved 14C measurements are needed.
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| 3. |
- Hudson, Thomas J., et al.
(author)
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International network of cancer genome projects
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Journal article (peer-reviewed)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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| 4. |
- Luyssaert, S., et al.
(author)
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CO2 balance of boreal, temperate, and tropical forests derived from a global database
- 2007
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In: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 13:12, s. 2509-2537
-
Research review (peer-reviewed)abstract
- Terrestrial ecosystems sequester 2.1 Pg of atmospheric carbon annually. A large amount of the terrestrial sink is realized by forests. However, considerable uncertainties remain regarding the fate of this carbon over both short and long timescales. Relevant data to address these uncertainties are being collected at many sites around the world, but syntheses of these data are still sparse. To facilitate future synthesis activities, we have assembled a comprehensive global database for forest ecosystems, which includes carbon budget variables (fluxes and stocks), ecosystem traits (e.g. leaf area index, age), as well as ancillary site information such as management regime, climate, and soil characteristics. This publicly available database can be used to quantify global, regional or biome-specific carbon budgets; to re-examine established relationships; to test emerging hypotheses about ecosystem functioning [e.g. a constant net ecosystem production (NEP) to gross primary production (GPP) ratio]; and as benchmarks for model evaluations. In this paper, we present the first analysis of this database. We discuss the climatic influences on GPP, net primary production (NPP) and NEP and present the CO2 balances for boreal, temperate, and tropical forest biomes based on micrometeorological, ecophysiological, and biometric flux and inventory estimates. Globally, GPP of forests benefited from higher temperatures and precipitation whereas NPP saturated above either a threshold of 1500 mm precipitation or a mean annual temperature of 10 degrees C. The global pattern in NEP was insensitive to climate and is hypothesized to be mainly determined by nonclimatic conditions such as successional stage, management, site history, and site disturbance. In all biomes, closing the CO2 balance required the introduction of substantial biome-specific closure terms. Nonclosure was taken as an indication that respiratory processes, advection, and non-CO2 carbon fluxes are not presently being adequately accounted for.
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| 5. |
- Allentoft, M. E., et al.
(author)
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Population genomics of Bronze Age Eurasia
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 522:7555
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Journal article (peer-reviewed)abstract
- The Bronze Age of Eurasia (around 3000-1000 BC) was a period of major cultural changes. However, there is debate about whether these changes resulted from the circulation of ideas or from human migrations, potentially also facilitating the spread of languages and certain phenotypic traits. We investigated this by using new, improved methods to sequence low-coverage genomes from 101 ancient humans from across Eurasia. We show that the Bronze Age was a highly dynamic period involving large-scale population migrations and replacements, responsible for shaping major parts of present-day demographic structure in both Europe and Asia. Our findings are consistent with the hypothesized spread of Indo-European languages during the Early Bronze Age. We also demonstrate that light skin pigmentation in Europeans was already present at high frequency in the Bronze Age, but not lactose tolerance, indicating a more recent onset of positive selection on lactose tolerance than previously thought.
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| 6. |
- Kenny, J. G., et al.
(author)
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Mannitol Utilisation is Required for Protection of Staphylococcus aureus from Human Skin Antimicrobial Fatty Acids
- 2013
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In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
-
Journal article (peer-reviewed)abstract
- Mannitol (Mtl) fermentation, with the subsequent production of acid, is a species signature of Staphylococcus aureus, and discriminates it from most other members of the genus. Inactivation of the gene mtlD, encoding Mtl-1-P dehydrogenase was found to markedly reduce survival in the presence of the antimicrobial fatty acid, linoleic acid. We demonstrate that the sugar alcohol has a potentiating action for this membrane-acting antimicrobial. Analysis of cellular metabolites revealed that, during exponential growth, the mtlD mutant accumulated high levels of Mtl and Mtl-P. The latter metabolite was not detected in its isogenic parent strain or a deletion mutant of the entire mtlABFD operon. In addition, the mtlD mutant strain exhibited a decreased MIC for H2O2, however virulence was unaffected in a model of septic arthritis.
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| 7. |
- Charpentier Ljungqvist, Fredrik, 1982-, et al.
(author)
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Regional Patterns of Late Medieval and Early Modern European Building Activity Revealed by Felling Dates
- 2022
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In: Frontiers in Ecology and Evolution. - : Frontiers Media SA. - 2296-701X. ; 9
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Journal article (peer-reviewed)abstract
- Although variations in building activity are a useful indicator of societal well-being and demographic development, historical datasets for larger regions and longer periods are still rare. Here, we present 54,045 annually precise dendrochronological felling dates from historical construction timber from across most of Europe between 1250 and 1699 CE to infer variations in building activity. We use geostatistical techniques to compare spatiotemporal dynamics in past European building activity against independent demographic, economic, social and climatic data. We show that the felling dates capture major geographical patterns of demographic trends, especially in regions with dense data coverage. A particularly strong negative association is found between grain prices and the number of felling dates. In addition, a significant positive association is found between the number of felling dates and mining activity. These strong associations, with well-known macro-economic indicators from pre-industrial Europe, corroborate the use of felling dates as an independent source for exploring large-scale fluctuations of societal well-being and demographic development. Three prominent examples are the building boom in the Hanseatic League region of northeastern Germany during the 13th century, the onset of the Late Medieval Crisis in much of Europec. 1300, and the cessation of building activity in large parts of central Europe during armed conflicts such as the Thirty Years’ War (1618–1648 CE). Despite new insights gained from our European-wide felling date inventory, further studies are needed to investigate changes in construction activity of high versus low status buildings, and of urban versus rural buildings, and to compare those results with a variety of historical documentary sources and natural proxy archives.
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| 8. |
- Foster, William J., et al.
(author)
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Suppressed competitive exclusion enabled the proliferation of Permian/Triassic boundary microbialites
- 2020
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In: Depositional Record. - : Wiley. - 2055-4877. ; 6:1, s. 62-74
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Journal article (peer-reviewed)abstract
- During the earliest Triassic microbial mats flourished in the photic zones of marginal seas, generating widespread microbialites. It has been suggested that anoxic conditions in shallow marine environments, linked to the end-Permian mass extinction, limited mat-inhibiting metazoans allowing for this microbialite expansion. The presence of a diverse suite of proxies indicating oxygenated shallow sea-water conditions (metazoan fossils, biomarkers and redox proxies) from microbialite successions have, however, challenged the inference of anoxic conditions. Here, the distribution and faunal composition of Griesbachian microbialites from China, Iran, Turkey, Armenia, Slovenia and Hungary are investigated to determine the factors that allowed microbialite-forming microbial mats to flourish following the end-Permian crisis. The results presented here show that Neotethyan microbial buildups record a unique faunal association due to the presence of keratose sponges, while the Palaeotethyan buildups have a higher proportion of molluscs and the foraminifera Earlandia. The distribution of the faunal components within the microbial fabrics suggests that, except for the keratose sponges and some microconchids, most of the metazoans were transported into the microbial framework via wave currents. The presence of both microbialites and metazoan associations were limited to oxygenated settings, suggesting that a factor other than anoxia resulted in a relaxation of ecological constraints following the mass extinction event. It is inferred that the end-Permian mass extinction event decreased the diversity and abundance of metazoans to the point of significantly reducing competition, allowing photosynthesis-based microbial mats to flourish in shallow water settings and resulting in the formation of widespread microbialites.
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| 9. |
- Gut, Urs, et al.
(author)
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No systematic effects of sampling direction on climate-growth relationships in a large-scale, multi-species tree-ring data set
- 2019
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In: Dendrochronologia. - : Elsevier BV. - 1125-7865 .- 1612-0051. ; 57
-
Journal article (peer-reviewed)abstract
- Ring-width series are important for diverse fields of research such as the study of past climate, forest ecology, forest genetics, and the determination of origin (dendro-provenancing) or dating of archaeological objects. Recent research suggests diverging climate-growth relationships in tree-rings due to the cardinal direction of extracting the tree cores (i.e. direction-specific effect). This presents an understudied source of bias that potentially affects many data sets in tree-ring research. In this study, we investigated possible direction-specific growth variability based on an international (10 countries), multi-species (8 species) tree-ring width network encompassing 22 sites. To estimate the effect of direction-specific growth variability on climate-growth relationships, we applied a combination of three methods: An analysis of signal strength differences, a Principal Component Gradient Analysis and a test on the direction-specific differences in correlations between indexed ring-widths series and climate variables. We found no evidence for systematic direction-specific effects on tree radial growth variability in high-pass filtered ring-width series. In addition, direction-specific growth showed only marginal effects on climate-growth correlations. These findings therefore indicate that there is no consistent bias caused by coring direction in data sets used for diverse dendrochronological applications on relatively mesic sites within forests in flat terrain, as were studied here. However, in extremely dry, warm or cold environments, or on steep slopes, and for different life-forms such as shrubs, further research is advisable.
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| 10. |
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| 11. |
- Oishi, Yumiko, et al.
(author)
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SREBP1 Contributes to Resolution of Pro-inflammatory TLR4 Signaling by Reprogramming Fatty Acid Metabolism
- 2017
-
In: Cell Metabolism. - Cambridge, MA, United States : Cell Press. - 1550-4131 .- 1932-7420. ; 25:2, s. 412-427
-
Journal article (peer-reviewed)abstract
- Macrophages play pivotal roles in both the induction and resolution phases of inflammatory processes. Macrophages have been shown to synthesize anti-inflammatory fatty acids in an LXR-dependent manner, but whether the production of these species contributes to the resolution phase of inflammatory responses has not been established. Here, we identify a biphasic program of gene expression that drives production of anti-inflammatory fatty acids 12-24 hr following TLR4 activation and contributes to downregulation of mRNAs encoding pro-inflammatory mediators. Unexpectedly, rather than requiring LXRs, this late program of anti-inflammatory fatty acid biosynthesis is dependent on SREBP1 and results in the uncoupling of NFκB binding from gene activation. In contrast to previously identified roles of SREBP1 in promoting production of IL1β during the induction phase of inflammation, these studies provide evidence that SREBP1 also contributes to the resolution phase of TLR4-induced gene activation by reprogramming macrophage lipid metabolism.
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| 12. |
- Rodriguez, Henry, et al.
(author)
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Recommendations from the 2008 International Summit on Proteomics Data Release and Sharing Policy : The Amsterdam Principles
- 2009
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In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 8:7, s. 3689-3692
-
Journal article (peer-reviewed)abstract
- Policies supporting the rapid and open sharing of genomic data have directly fueled the accelerated pace of discovery in large-scale genomics research. The proteomics community is starting to implement analogous policies and infrastructure for making large-scale proteomics data widely available on a precompetitive basis. On August 14, 2008, the National Cancer Institute (NCI) convened the "International Summit on Proteomics Data Release and Sharing Policy" in Amsterdam, The Netherlands, to identify and address potential roadblocks to rapid and open access to data. The six principles agreed upon by key stakeholders at the summit addressed issues surrounding (1) timing, (2) comprehensiveness, (3) format, (4) deposition to repositories, (5) quality metrics, and (6) responsibility for proteomics data release. This summit report explores various approaches to develop a framework of data release and sharing principles that will most effectively fulfill the needs of the funding agencies and the research community.
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| 13. |
- Büntgen, Ulf, et al.
(author)
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Recent European drought extremes beyond Common Era background variability
- 2021
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In: Nature Geoscience. - : Springer Science and Business Media LLC. - 1752-0894 .- 1752-0908. ; 14:4, s. 190-196
-
Journal article (peer-reviewed)abstract
- Europe's recent summer droughts have had devastating ecological and economic consequences, but the severity and cause of these extremes remain unclear. Here we present 27,080 annually resolved and absolutely dated measurements of tree-ring stable carbon and oxygen (delta C-13 and delta O-18) isotopes from 21 living and 126 relict oaks (Quercus spp.) used to reconstruct central European summer hydroclimate from 75 bce to 2018 ce. We find that the combined inverse delta C-13 and delta O-18 values correlate with the June-August Palmer Drought Severity Index from 1901-2018 at 0.73 (P < 0.001). Pluvials around 200, 720 and 1100 ce, and droughts around 40, 590, 950 and 1510 ce and in the twenty-first century, are superimposed on a multi-millennial drying trend. Our reconstruction demonstrates that the sequence of recent European summer droughts since 2015 ce is unprecedented in the past 2,110 years. This hydroclimatic anomaly is probably caused by anthropogenic warming and associated changes in the position of the summer jet stream. European summer droughts in recent years are anomalously severe compared with those of the previous 2,000 years, according to a synthesis of annually resolved tree-ring carbon and oxygen isotope records.
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| 14. |
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| 15. |
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| 16. |
- Kingham, Paul J, et al.
(author)
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Stimulating the neurotrophic and angiogenic properties of human adipose-derived stem cells enhances nerve repair
- 2014
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In: Stem Cells and Development. - : Mary Ann Liebert Inc. - 1547-3287 .- 1557-8534. ; 23:7, s. 741-754
-
Journal article (peer-reviewed)abstract
- In future, adipose-derived stem cells (ASC) might be used to treat neurological disorders. In this study, the neurotrophic and angiogenic properties of human ASC were evaluated, and their effects in a peripheral nerve injury model were determined. In vitro growth factor stimulation of the cells resulted in increased secretion of brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), vascular endothelial growth factor-A (VEGF-A), and angiopoietin-1 proteins. Conditioned medium from stimulated cells increased neurite outgrowth of dorsal root ganglia (DRG) neurons. Similarly, stimulated cells showed an enhanced ability to induce capillary-like tube formation in an in vitro angiogenesis assay. ASC were seeded into a fibrin conduit that was used to bridge a 10 mm rat nerve gap. After 2 weeks, the animals treated with control or stimulated ASC showed an enhanced axon regeneration distance. Stimulated cells evoked more total axon growth. Analysis of regeneration and apoptosis-related gene expression showed that both ASC and stimulated ASC enhanced GAP-43 and activating transcription factor 3 (ATF-3) expression in the spinal cord and reduced c-jun expression in the DRG. Caspase-3 expression in the DRG was reduced by stimulated ASC. Both ASC and stimulated ASC also increased the vascularity of the fibrin nerve conduits. Thus, ASC produce functional neurotrophic and angiogenic factors, creating a more desirable microenvironment for nerve regeneration.
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| 17. |
- Kirdyanov, Alexander, et al.
(author)
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Notes towards an optimal sampling strategy in dendroclimatology
- 2018
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In: Dendrochronologia. - : Elsevier BV. - 1125-7865 .- 1612-0051. ; 52, s. 162-166
-
Journal article (peer-reviewed)abstract
- Though the extraction of increment cores is common practice in tree-ring research, there is no standard for the number of samples per tree, or trees per site needed to accurately describe the common growth pattern of a discrete population of trees over space and time. Tree-ring chronologies composed of living, subfossil and archaeological material often combine an uneven distribution of increment cores and disc samples. The effects of taking one or two cores per tree, or even the inclusion of multiple radii measurements from entire discs, on chronology development and quality remain unreported. Here, we present four new larch (Larix cajanderi Mayr) ring width chronologies from the same 20 trees in northeastern Siberia that have been independently developed using different combinations of core and disc samples. Our experiment reveals: i) sawing is much faster than coring, with the latter not always hitting the pith; ii) the disc-based chronology contains fewer locally absent rings, extends further back in time and exhibits more growth coherency; iii) although the sampling design has little impact on the overall chronology behaviour, lower frequency information is more robustly obtained from the disc measurements that also tend to reflect a slightly stronger temperature signal. In quantifying the influence of sampling strategy on the quality of tree-ring width chronologies, and their suitability for climate reconstructions, this study provides useful insights for optimizing fieldwork campaigns, as well as for developing composite chronologies from different wood sources.
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| 18. |
- Kolar, Matthew J., et al.
(author)
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Faster Protocol for Endogenous Fatty Acid Esters of Hydroxy Fatty Acid (FAHFA) Measurements
- 2018
-
In: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 90:8, s. 5358-5365
-
Journal article (peer-reviewed)abstract
- Fatty acid esters of hydroxy fatty acids (FAHFAs) are a recently discovered class of endogenous lipids with antidiabetic and anti-inflammatory activities. Interest in these lipids is due to their unique biological activites and the observation that insulin-resistant people have lower palmitic acid esters of hydroxystearic acid (PAHSA) levels, suggesting that a FAHFA deficiency may contribute to metabolic disease. Rigorous testing of this hypothesis will require the measurement of many clinical samples; however, current analytical workflows are too slow to enable samples to be analyzed quickly. Here we describe the development of a significantly faster workflow to measure FAHFAs that optimizes the fractionation and chromatography of these lipids. We can measure FAHFAs in 30 min with this new protocol versus 90 min using the older protocol with comparable performance in regioisomer detection and quantitation. We also discovered through this optimization that oleic acid esters of hydroxystearic acids (OAHSAs), another family of FAHFAs, have a much lower background signal than PAHSAs, which makes them easier to measure. Our faster workflow was able to quantify changes in PAHSAs and OAHSAs in mouse tissues and human plasma, highlighting the potential of this protocol for basic and clinical applications.
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| 19. |
- Kolar, Matthew J., et al.
(author)
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Linoleic acid esters of hydroxy linoleic acids are anti-inflammatory lipids found in plants and mammals
- 2019
-
In: Journal of Biological Chemistry. - 0021-9258. ; 294:27, s. 10698-10707
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Journal article (peer-reviewed)abstract
- Fatty acid esters of hydroxy fatty acids (FAHFAs) are a recently discovered class of biologically active lipids. Here we identify the linoleic acid ester of 13-hydroxy linoleic acid (13-LAHLA) as an anti-inflammatory lipid. An oat oil fraction and FAHFA-enriched extract from this fraction showed anti-inflammatory activity in a lipopolysaccharide-induced cytokine secretion assay. Structural studies identified three LAHLA isomers (15-, 13-, and 9-LAHLA) as being the most abundant FAHFAs in the oat oil fraction. Of these LAHLAs, 13-LAHLA is the most abundant LAHLA isomer in human serum after ingestion of liposomes made of fractionated oat oil, and it is also the most abundant endogenous LAHLA in mouse and human adipose tissue. As a result, we chemically synthesized 13-LAHLA for biological assays. 13-LAHLA suppresses lipopolysaccharide-stimulated secretion of cytokines and expression of pro-inflammatory genes. These studies identify LAHLAs as an evolutionarily conserved lipid with anti-inflammatory activity in mammalian cells.
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| 20. |
- Kolar, M.K., et al.
(author)
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Peripheral nerve tissue engineering
- 2014. - 2
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In: Tissue engineering using ceramics and polymers. - : Elsevier. - 9780857097163 - 9780857097125 ; , s. 468-497
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Book chapter (peer-reviewed)abstract
- The chapter summarises the pathophysiological response to peripheral nerve injury and subsequent regeneration reactions, with a particular focus on nerve gap injuries. To repair and bridge the tissue defects, nerve guidance conduits (NGCs) have been proposed as an alternative approach to autografts. Designing optimal NGCs requires development of (i) the conduit body, (ii) intraluminal structures and (iii) addition of regeneration promoting biological components to the lumen. The chapter provides a historical background to this research area and describes the current state of the art with a range of biomaterial constructs, which can be supplemented with Schwann cells or alternatively a variety of stem cells.
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| 21. |
- Kolar, Mallappa K., et al.
(author)
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Regenerative effects of adipose-tissue-derived stem cells for treatment of peripheral nerve injuries
- 2014
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In: Biochemical Society Transactions. - 0300-5127 .- 1470-8752. ; 42, s. 697-701
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Journal article (peer-reviewed)abstract
- Peripheral nerve injuries are a common occurrence affecting the nerves found outside the central nervous system. Complete nerve transections necessitate surgical re-anastomosis, and, in cases where there is a significant gap between the two ends of the injured nerve, bridging strategies are required to repair the defect. The current clinical gold standard is the nerve graft, but this has a number of limitations, including donor site morbidity. An active area of research is focused on developing other techniques to replace these grafts, by creating tubular nerve-guidance conduits from natural and synthetic materials, which are often supplemented with biological cues such as growth factors and regenerative cells. In the present short review, we focus on the use of adipose-tissue-derived stem cells and the possible mechanisms through which they may exert a positive influence on peripheral nerve regeneration, thereby enabling more effective nerve repair.
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| 22. |
- Kolar, Mallappa Kadappa, et al.
(author)
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The neurotrophic effects of different human dental mesenchymal stem cells
- 2017
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Journal article (peer-reviewed)abstract
- The current gold standard treatment for peripheral nerve injury is nerve grafting but this has disadvantages such as donor site morbidity. New techniques focus on replacing these grafts with nerve conduits enhanced with growth factors and/or various cell types such as mesenchymal stem cells (MSCs). Dental-MSCs (D-MSCs) including stem cells obtained from apical papilla (SCAP), dental pulp stem cells (DPSC), and periodontal ligament stem cells (PDLSC) are potential sources of MSCs for nerve repair. Here we present the characterization of various D-MSCs from the same human donors for peripheral nerve regeneration. SCAP, DPSC and PDLSC expressed BDNF, GDNF, NGF, NTF3, ANGPT1 and VEGFA growth factor transcripts. Conditioned media from D-MSCs enhanced neurite outgrowth in an in vitro assay. Application of neutralizing antibodies showed that brain derived neurotrophic factor plays an important mechanistic role by which the D-MSCs stimulate neurite outgrowth. SCAP, DPSC and PDLSC were used to treat a 10 mm nerve gap defect in a rat sciatic nerve injury model. All the stem cell types significantly enhanced axon regeneration after two weeks and showed neuroprotective effects on the dorsal root ganglia neurons. Overall the results suggested SCAP to be the optimal dental stem cell type for peripheral nerve repair.
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| 23. |
- Kolar, Mallappa K, et al.
(author)
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The therapeutic effects of human adipose derived stem cells in a rat cervical spinal cord injury model
- 2014
-
In: Stem Cells and Development. - : Mary Ann Liebert. - 1547-3287 .- 1557-8534. ; 23:14, s. 1659-1674
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Journal article (peer-reviewed)abstract
- Spinal cord injury triggers a cascade of degenerative changes leading to cell death and cavitation. Severed axons fail to regenerate across the scar tissue and are only capable of limited sprouting. In this study we investigated the effects of adult human adipose derived stem cells (ASC) on axonal regeneration following transplantation into the injured rat cervical spinal cord. ASC did not induce activation of astrocytes in culture and supported neurite outgrowth from adult rat sensory DRG neurons. After transplantation into the lateral funiculus 1mm rostral and caudal to the cervical C3-C4 hemisection, ASC continued to express BDNF, VEGF and FGF-2 for 3 weeks but only in animals treated with cyclosporine A. Transplanted ASC stimulated extensive ingrowth of 5HT-positive raphaespinal axons into the trauma zone with some terminal arborisations reaching the caudal spinal cord. In addition, ASC induced sprouting of raphaespinal terminals in C2 contralateral ventral horn and C6 ventral horn on both sides. Transplanted cells also changed the structure of the lesion scar with numerous astrocytic processes extended into the middle of the trauma zone in a chain-like pattern and in close association with regenerating axons. The density of the astrocytic network was also significantly decreased. Although the transplanted cells had no effect on the density of capillaries around the lesion site, the activity of OX42-positive microglial cells was markedly reduced. However, ASC did not support recovery of forelimb function. The results suggest that transplanted ASC can modify the structure of the glial scar and stimulate axonal sprouting.
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| 24. |
- Kolar, Mallappa K., 1981-
(author)
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Transplantation of mesenchymal stem cells and injections of microRNA as therapeutics for nervous system repair
- 2016
-
Doctoral thesis (other academic/artistic)abstract
- Traumatic injuries to the spinal cord (SCI) and peripheral nerve (PNI) affect several thousand people worldwide every year. At present, there is no effective treatment for SCI and despite continuous improvements in microsurgical reconstructive techniques for PNI, many patients are still left with permanent, devastating neurological dysfunction. This thesis investigates the effects of mesenchymal stem cells (MSC) derived from adipose (ASC) and dental (DSC) tissue and chitosan/microRNA-124 polyplex particles on regeneration after spinal cord and peripheral nerve injury in adult rats. Dental stem cells were obtained from apical papilla, dental pulp, and periodontal ligament. ASC and DSC expressed MSC surface markers (CD73, CD90, CD105 and CD146) and various neurotrophic molecules including BDNF, GDNF, NGF, VEGF-A and angiopoietin-1. Growth factor stimulation of the stem cells resulted in increased secretion of these proteins. Both ASC and DSC supported in vitro neurite outgrowth and in contrast to Schwann cells, ASC did not induce activation of astrocytes. Stimulated ASC also showed an enhanced ability to induce capillary-like tube formation in an in vitro angiogenesis assay. In a peripheral nerve injury model, ASC and DSC were seeded into a fibrin conduit, which was used to bridge a 10 mm rat sciatic nerve gap. After 2 weeks, both ASC and DSC promoted axonal regeneration in the conduit and reduced caspase-3 expression in the dorsal root ganglion (DRG). ASC also enhanced GAP-43 and ATF-3 expression in the spinal cord, reduced c-jun expression in the DRG and increased the vascularity of the implant. After transplantation into injured C3-C4 cervical spinal cord, ASC continued to express neurotrophic factors and laminin and stimulated extensive ingrowth of 5HT-positive raphaespinal axons into the trauma zone. In addition, ASC induced sprouting of raphaespinal terminals in C2 contralateral ventral horn and C6 ventral horn on both sides. Transplanted cells also changed the structure and the density of the astroglial scar. Although the transplanted cells had no effect on the density of capillaries around the lesion site, the reactivity of OX42-positive microglial cells was markedly reduced. However, ASC did not enhance recovery of forelimb function. In order to reduce activation of microglia/macrophages and the secondary tissue damage after SCI, the role of microRNA-124 was investigated. In vitro transfection of chitosan/microRNA-124 polyplex particles into rat microglia resulted in the reduction of reactive oxygen species and TNF-α levels and lowered expression of MHC-II. Upon microinjection into uninjured rat spinal cords, particles formed with Cy3-labeled control sequence RNA, were specifically internalized by OX42 positive macrophages and microglia. Alternatively, particles injected in the peritoneum were transported by macrophages to the site of spinal cord injury. Microinjections of chitosan/microRNA-124 particles significantly reduced the number of ED-1 positive macrophages after SCI. In summary, these results show that human MSC produce functional neurotrophic and angiogenic factors, creating a more desirable microenvironment for neural regeneration after spinal cord and peripheral nerve injury. The data also suggests that chitosan/microRNA-124 particles could be potential treatment technique to reduce neuroinflammation.
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| 25. |
- Louw, Andrew M, et al.
(author)
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Chitosan polyplex mediated delivery of miRNA-124 reduces activation of microglial cells in vitro and in rat models of spinal cord injury
- 2016
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In: Nanomedicine. - : Elsevier BV. - 1549-9634 .- 1549-9642. ; 12:3, s. 643-653
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Journal article (peer-reviewed)abstract
- Traumatic injury to the central nervous system (CNS) is further complicated by an increase in secondary neuronal damage imposed by activated microglia/macrophages. MicroRNA-124 (miR-124) is responsible for mouse monocyte quiescence and reduction of their inflammatory cytokine production. We describe the formulation and ex vivo transfection of chitosan/miR-124 polyplex particles into rat microglia and the resulting reduction of reactive oxygen species (ROS) and TNF-α and lower expression of MHC-II. Upon microinjection into uninjured rat spinal cords, particles formed with Cy3-labeled control sequence RNA, were specifically internalized by OX42 positive macrophages and microglia cells. Alternatively particles injected in the peritoneum were transported by macrophages to the site of spinal cord injury 72h post injection. Microinjections of chitosan/miR-124 particles significantly reduced the number of ED-1 positive macrophages in the injured spinal cord. Taken together, these data present a potential treatment technique to reduce inflammation for a multitude of CNS neurodegenerative conditions.
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