| 1. |
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| 2. |
- Hjerpe, Karin, et al.
(författare)
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Utsläpp av växthusgaser från torvmark
- 2014
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Dikad torvmark i Sverige avgav sammanlagt drygt 11,4 miljoner ton koldioxidekvivalenter år 2012, enligt den senaste klimatrapporteringen. Denna mängd kan jämföras med de totala svenska utsläppen av växthusgaser, som beräknades uppgå till 57,6 miljoner ton koldioxidekvivalenter samma år. En åtgärd som skulle kunna minska utsläppen av växthusgaser från dikad torvmark är att återställa marken till våtmark, vilket minskar avgången av koldioxid och lustgas från marken. Samtidigt ökar avgången av metan, men minskningen av koldioxid- och lustgasutsläppen är större, vilket innebär att utsläppen av växthusgaser från marken totalt sett minskar. Om de ekonomiska resurserna för att återställa dikad torvmark till våtmark är begränsade bör man i första hand återställa dikade torvmarker som är stora källor för växthusgaser till våtmark. Studier av växthusgasutsläpp från dikade torvmarker som används för skogsproduktion visar att näringsrika och väldränerade marker är större källor för växthusgaser än näringsfattigare, fuktigare marker. Vi bedömer därför att det ur ett klimatperspektiv är viktigast att återställa dikad skogsmark med en kol:kväve-kvot under 25 som är frisk-fuktig eller torrare. Dikad torvmark som används för naturbete avger mindre växthusgaser än åkermark på dikad torvmark och därför är det viktigare att återställa åkermark till våtmark. Avgången av växthusgaser varierar mycket mellan olika åkrar på dikad torvmark. Det är dock inte möjligt att identifiera åkrar på dikad torvmark som är stora källor för växthusgaser utifrån markfuktighet eller kol:kväve-kvot, och inte heller utifrån några andra faktorer som är enkla att mäta. Detta beror sannolikt på att åkermarken generellt är så pass väldränerad och näringsrik att varken syreeller kvävetillgången är begränsande för avgången av koldioxid och lustgas. I ett längre tidsperspektiv kommer dikad torvmark att avge koldioxid och lustgas så länge det finns ett syresatt torvlager. Därför bedömer vi att det är viktigast att återställa dikad åkermark med tjockt torvlager till våtmark. Därtill bör mark som inte längre aktivt brukas prioriteras framför mark som fortfarande är i bruk. Utsläppen av växthusgaser verkar inte automatiskt minska när brukandet upphör och även om marken sannolikt kommer att försumpas på sikt, vilket innebär att utsläppen av växthusgaser minskar, kan det ta väldigt lång tid. Dessutom borde kostnaderna för att återställa marken till våtmark i genomsnitt bli lägre om marken inte längre används. Hur mycket avgången av växthusgaser minskar när dikad torvmark återställs till våtmark beror inte bara på hur stor avgången av växthusgaser från den dikade marken var utan också på hur stor avgången från den anlagda våtmarken blir. Utsläppen från våtmarken påverkas av hur den anläggs och sköts. För att våtmarken ska avge så lite växthusgaser som möjligt bör grundvattennivån höjas så mycket att förhållandena före dikningen återskapas. Om våtmarken anläggs på mark som använts för jordbruksproduktion bör dessutom vegetationen tas bort före återställandet. Anläggning av våtmarker kan också ge andra nyttor – våtmarkerna kan bland annat gynna biologisk mångfald och minska näringsläckaget till våra sjöar och vattendrag. När en våtmark ska anläggas och skötas behöver man ta hänsyn till alla dessa aspekter så att våtmarken ger så stor nytta som möjligt.
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| 3. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 4. |
- Jurasinski, Gerald, et al.
(författare)
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Active afforestation of drained peatlands is not a viable option under the EU Nature Restoration Law
- 2024
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Ingår i: AMBIO. - 0044-7447 .- 1654-7209. ; 53:7, s. 970-983
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Tidskriftsartikel (refereegranskat)abstract
- The EU Nature Restoration Law (NRL) is critical for the restoration of degraded ecosystems and active afforestation of degraded peatlands has been suggested as a restoration measure under the NRL. Here, we discuss the current state of scientific evidence on the climate mitigation effects of peatlands under forestry. Afforestation of drained peatlands without restoring their hydrology does not fully restore ecosystem functions. Evidence on long-term climate benefits is lacking and it is unclear whether CO2 sequestration of forest on drained peatland can offset the carbon loss from the peat over the long-term. While afforestation may offer short-term gains in certain cases, it compromises the sustainability of peatland carbon storage. Thus, active afforestation of drained peatlands is not a viable option for climate mitigation under the EU Nature Restoration Law and might even impede future rewetting/restoration efforts. Instead, restoring hydrological conditions through rewetting is crucial for effective peatland restoration.
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| 5. |
- Kjær, Lene Jung, et al.
(författare)
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Potential drivers of human tick-borne encephalitis in the Örebro region of Sweden, 2010-2021
- 2023
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Incidence of tick-borne encephalitis (TBE) has increased during the last years in Scandinavia, but the underlying mechanism is not understood. TBE human case data reported between 2010 and 2021 were aggregated into postal codes within Örebro County, south-central Sweden, along with tick abundance and environmental data to analyse spatial patterns and identify drivers of TBE. We identified a substantial and continuing increase of TBE incidence in Örebro County during the study period. Spatial cluster analyses showed significant hotspots (higher number of cases than expected) in the southern and northern parts of Örebro County, whereas a cold spot (lower number of cases than expected) was found in the central part comprising Örebro municipality. Generalised linear models showed that the risk of acquiring TBE increased by 12.5% and 72.3% for every percent increase in relative humidity and proportion of wetland forest, respectively, whereas the risk decreased by 52.8% for every degree Celsius increase in annual temperature range. However, models had relatively low goodness of fit (R2 < 0.27). Results suggest that TBE in Örebro County is spatially clustered, however variables used in this study, i.e., climatic variables, forest cover, water, tick abundance, sheep as indicator species, alone do not explain this pattern.
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| 6. |
- Lagou, Vasiliki, et al.
(författare)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 7. |
- Lindgren, Amelie, et al.
(författare)
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Extensive loss of past permafrost carbon but a net accumulation into present-day soils
- 2018
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 560:7717, s. 219-222
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Tidskriftsartikel (refereegranskat)abstract
- Atmospheric concentrations of carbon dioxide increased between the Last Glacial Maximum (LGM, around 21,000 years ago) and the preindustrial era(1). It is thought that the evolution of this atmospheric carbon dioxide (and that of atmospheric methane) during the glacial-to-interglacial transition was influenced by organic carbon that was stored in permafrost during the LGM and then underwent decomposition and release following thaw(2,3). It has also been suggested that the rather erratic atmospheric delta C-13 and Delta C-14 signals seen during deglaciation(1.4) could partly be explained by the presence of a large terrestrial inert LGM carbon stock, despite the biosphere being less productive (and therefore storing less carbon)(5,6). Here we present an empirically derived estimate of the carbon stored in permafrost during the LGM by reconstructing the extent and carbon content of LGM biomes, peatland regions and deep sedimentary deposits. We find that the total estimated soil carbon stock for the LGM northern permafrost region is smaller than the estimated present-day storage (in both permafrost and non-permafrost soils) for the same region. A substantial decrease in the permafrost area from the LGM to the present day has been accompanied by a roughly 400-petagram increase in the total soil carbon stock. This increase in soil carbon suggests that permafrost carbon has made no net contribution to the atmospheric carbon pool since the LGM. However, our results also indicate potential postglacial reductions in the portion of the carbon stock that is trapped in permafrost, of around 1,000 petagrams, supporting earlier studies(7). We further find that carbon has shifted from being primarily stored in permafrost mineral soils and loess deposits during the LGM, to being roughly equally divided between peatlands, mineral soils and permafrost loess deposits today.
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| 8. |
- Lindgren, Amelie, et al.
(författare)
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GIS-based Maps and Area Estimates of Northern Hemisphere Permafrost Extent during the Last Glacial Maximum
- 2016
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Ingår i: Permafrost and Periglacial Processes. - : Wiley. - 1045-6740 .- 1099-1530. ; 27:1, s. 6-16
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Tidskriftsartikel (refereegranskat)abstract
- This study presents GIS-based estimates of permafrost extent in the northern circumpolar region during the Last Glacial Maximum (LGM), based on a review of previously published maps and compilations of field evidence in the form of ice-wedge pseudomorphs and relict sand wedges. We focus on field evidence localities in areas thought to have been located along the past southern border of permafrost. We present different reconstructions of permafrost extent, with areal estimates of exposed sea shelf, ice sheets and glaciers, to assess areas of minimum, likely and maximum permafrost extents. The GIS-based mapping of these empirical reconstructions allows us to estimate the likely area of northern permafrost during the LGM as 34.5 million km(2) (which includes 4.7 million km(2) of permafrost on exposed coastal sea shelves). The minimum estimate is 32.7 million km(2) and the maximum estimate is 35.3 million km(2). The extent of LGM permafrost is estimated to have been between c. 9.1 to 11.7 million km(2) larger than its current extent on land (23.6 million km(2)). However, 2.4 million km(2) of the lost land area currently remains as subsea permafrost on the submerged coastal shelves. The LGM permafrost extent in the northern circumpolar region during the LGM was therefore about 33 percent larger than at present. The net loss of northern permafrost since the LGM is due to its disappearance in large parts of Eurasia, which is not compensated for by gains in North America in areas formerly covered by the Laurentide ice sheet.
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| 9. |
- Lindgren, Amelie, et al.
(författare)
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Millennial-scale analysis of land >23 ˚N as a carbon source and sink since the Last Glacial Maximum
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The transfers of carbon between land, ocean and atmosphere, and their relation to temperature variability over glacial and interglacial cycles continue to intrigue the scientific community. Over the past four decades, many have focused on the role of the Southern Ocean to explain the atmospheric carbon dioxide (CO2) patterns seen in ice core records, but recent advances also include mentions of a possible terrestrial component. We quantify important terrestrial organic soil carbon (C) stocks north of 23˚, using palaeo-data and modeled climate to reconstruct terrestrial C dynamics from the Last Glacial Maximum until present at millennial time steps. During the deglaciation, C storage declined to reach a minimum around 10 kyr BP, a trend which then turned and led to progressively higher soil C stocks during the Holocene. Net changes in mineral soil C stocks are small, even though significant geographic shifts occurred; instead, deglacial and interglacial terrestrial C stock dynamics are dominated by losses from permafrost loess, inundation of continental shelves and gains in peatlands, processes commonly overlooked in complex Earth System Models.
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| 10. |
- Lindgren, Amelie, 1987-
(författare)
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Northern Permafrost Region Soil Carbon Dynamics since the Last Glacial Maximum : a terrestrial component in the glacial to interglacial carbon cycle
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- At the Last Glacial Maximum (LGM), after ~100,000 years of relatively cold temperatures and progressively lower atmospheric carbon dioxide (CO2) concentrations, CO2 levels reached ~180 ppm, which is less than half of what we see today in a much warmer world (~400 ppm). Although much of this increase since the LGM is due to human-induced emissions, about 100 ppm of this increase can be attributed to natural variations seen over glacial to interglacial cycles. The sources for this natural CO2 rise remain unclear despite considerable efforts to constrain its origin. This thesis attempts to describe and quantify the role of soil carbon in this context, with emphasis on the permafrost hypothesis, which states that a shift from glacial to interglacial conditions released permafrost soil carbon to the atmosphere during the deglaciation. We present empirical estimates of the change in the Northern permafrost area between the LGM and present, and the associated soil carbon stock changes. We also partition these soil carbon stock changes at millennial intervals to capture not only the size but the timing of change. We find that the soil carbon stocks north of the Tropics decreased after the LGM to reach a minimum around 10,000 years ago, after which stocks increased to more than compensate for past losses. This may present part of a solution to untangle the marine and atmospheric 13C record, where the marine records suggest that the terrestrial carbon stock has grown since the LGM, while the atmospheric record also indicates terrestrial losses. To estimate the mineral soil carbon stocks, we have relied on vegetation reconstructions. Some of these reconstructions were created with a novel data-driven machine learning approach. This method may facilitate robust vegetation reconstruction when evidence of past conditions is readily available. Results in this thesis highlight the importance of permafrost, loess deposits and peatlands when considering the soil carbon cycle over long time scales.
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| 11. |
- Lindgren, Amelie, et al.
(författare)
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Reconstructing Past Global Vegetation With Random Forest Machine Learning, Sacrificing the Dynamic Response for Robust Results
- 2021
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Ingår i: Journal of Advances in Modeling Earth Systems. - 1942-2466. ; 13:2
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Tidskriftsartikel (refereegranskat)abstract
- Vegetation is an important component in the Earth system, providing a direct link between the biosphere and atmosphere. As such, a representative vegetation pattern is needed to accurately simulate climate. We attempt to model global vegetation (biomes) with a data‐driven approach, to test if this allows us to create robust global and regional vegetation patterns. This not only provides quantitative reconstructions of past vegetation cover as a climate forcing, but also improves our understanding of past land cover‐climate interactions which have important implications for the future. By using a Random Forest (RF) machine learning tool, we train the vegetation reconstruction with available biomized pollen data of present and past conditions to produce broad‐scale vegetation patterns for the preindustrial (PI), the mid‐Holocene (MH, ∼6,000 years ago), and the Last Glacial Maximum (LGM, ∼21,000 years ago). We test the method's robustness by introducing a systematic temperature bias based on existing climate model spread and compare the result with that of LPJ‐GUESS, an individual‐based dynamic global vegetation model. The results show that the RF approach is able to produce robust patterns for periods and regions well constrained by evidence (the PI and the MH), but fails when evidence is scarce (the LGM). The apparent robustness of this method is achieved at the cost of sacrificing the ability to model dynamic vegetation response to a changing climate.
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| 12. |
- Lindgren, Amelie, et al.
(författare)
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Reconstructing past vegetation with Random Forest Machine Learning, sacrificing the dynamic response for robust results
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Vegetation is an important feature in the Earth system, providing a direct link between the biosphere and atmosphere. As such, a representative vegetation pattern is needed to accurately simulate climate. We attempt to reconstruct past and present vegetation with a data driven approach, to test if this allows us to create robust global and regional vegetation patterns. The motivation for this stems from the possibility of avoiding circular arguments when studying past time periods where vegetation is used to reconstruct climate, and climate is used to construct vegetation. By using the Random Forest machine learning tool, we train the vegetation reconstruction with available biomized pollen data of present and past conditions and are able to produce reasonable broad-scale vegetation patterns for the Pre-Industrial and the Mid-Holocene together with a few modeled climate variables. We test the methods robustness by introducing a systematic temperature bias based on existing climate model spread and compare the result with that of LPJ-GUESS, a process-based dynamic global vegetation model. Results prove that the Random Forest approach is able to produce robust patterns for periods and regions well constrained by evidence, but fails when evidence is scarce. The robustness is achieved by sacrificing a dynamic vegetation response to a changing climate.
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| 13. |
- Lindgren, Amelie, et al.
(författare)
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Towards new reporting of drained organic soils under the UNFCCC : assessment of emission factors and areas in Sweden
- 2014
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The 2013 Supplement to the 2006 Guidelines for National Greenhouse Gas Inventories: Wetlands (Wetlands Supplement), hereafter called WL GL, was adopted and accepted at the 37th Session of the IPCC in October 2013. This study assesses how to adapt the WL GL for Swedish conditions and available data sources. This includes both the assessment of emission factors and the possibility to obtain relevant activity data for the categories included in the WL GL. The report focuses on land use categories in the Land use, Land use change and Forestry sector (LULUCF) where emissions from drained organic soils occur, and the rewetting of these organic soils. Table 2 summarizes the recommended emission factors described throughout the sections in this report, and the total impact of the new emission factors on the emissions from a land-use area (IEF). See relevant sections for discussion on the choice of emission factors. The emission factors presented here are only representative for land remaining within a category and not for land use change between categories, except rewetting. These results show that drained organic Cropland has the highest impact per area. Swedish Forest land contributes with the highest CO2 -eq emissions due to the large area. The total emissions from the land-use categories described in table 2 are 10.63 Mt CO2 eq.
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| 14. |
- Lindgren, Georg A., et al.
(författare)
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Inland subsurface water system role for coastal nitrogen load dynamics and abatement responses
- 2007
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Ingår i: Environmental Science & Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 41:7, s. 2159-2164
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Tidskriftsartikel (refereegranskat)abstract
- We simulate and analyze long-term dynamics of coastalnitrogen (N) loading and the inland source changes andprocesses that may have determined its development overthe past 60-year period and may govern its possiblefuture responses to variousNsource management scenarios.With regard to processes, the results show that averagebasin-scale N delivery fractions to the coast may not berepresentative of the coastal impacts of either diffuse orpoint inland sources. The effects of inland source changesmay be greatly redistributed in space-time and delayedby slow N transport and mass transfer processes in thesubsurface water system of coastal catchments. Extrapolationof current N transport-attenuation conditionsfor quantification of future abatement effects may thereforebe misleading if the extrapolation models do not realisticallyrepresent delayed long-term influences of slow subsurfaceprocesses. With regard to policy, the results show that andwhy national Swedish and international Baltic Searegion policies for coastal N load abatement may bedifficult or impossible to achieve by inland source abatementonly. Large mitigation of both point and diffuse sourcesmay be necessary to achieve targeted coastal N loadreductions fast and maintain them also in the long term.
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| 15. |
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| 16. |
- Lindgren, Joel, 1982-, et al.
(författare)
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A GLP-1 receptor agonist conjugated to an albumin-binding domain for extended half-life
- 2014
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Ingår i: Biopolymers. - : Wiley. - 0006-3525 .- 1097-0282. ; 102:3, s. 252-259
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon-like peptide 1 (GLP-1) and related peptide agonists have been extensively investigated for glycaemic control in Type 2 diabetes, and may also have therapeutic applications for other diseases. Due to the short half-life (t1/2<2 min) of the endogenous peptide, caused by proteolytic degradation and renal clearance, different strategies for half-life extension and sustained release have been explored. In the present study, conjugates between a GLP-1 analogue and a 5 kDa albumin-binding domain (ABD) derived from streptococcal protein G have been chemically synthesized and evaluated. ABD binds with high affinity to human serum albumin, which is highly abundant in plasma and functions as a drug carrier in the circulation. Three different GLP-1-ABD conjugates, with the two peptides connected by linkers of two, four, and six PEG units, respectively, were synthesized and tested in mouse pancreatic islets at high (11 mM) and low (3 mM) glucose concentration. Insulin release upon stimulation was shown to be glucose-dependent, showing no significant difference between the three different GLP-1-ABD conjugates and unconjugated GLP-1 analogue. The biological activity, in combination with the high affinity binding to albumin, make the GLP-1-ABD conjugates promising GLP-1 receptor agonists expected to show extended in vivo half-life.
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| 17. |
- Lindgren, Joel, et al.
(författare)
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A Native Chemical Ligation Approach for Combinatorial Assembly of Affibody Molecules
- 2012
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Ingår i: ChemBioChem. - : Wiley. - 1439-4227 .- 1439-7633. ; 13:7, s. 1024-1031
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Tidskriftsartikel (refereegranskat)abstract
- Affinity molecules labeled with different reporter groups, such as fluorophores or radionuclides, are valuable research tools used in a variety of applications. One class of engineered affinity proteins is Affibody molecules, which are small (6.5 kDa) proteins that can be produced by solid phase peptide synthesis (SPPS), thereby allowing site-specific incorporation of reporter groups during synthesis. The Affibody molecules are triple-helix proteins composed of a variable part, which gives the protein its binding specificity, and a constant part, which is identical for all Affibody molecules. In the present study, native chemical ligation (NCL) has been applied for combinatorial assembly of Affibody molecules from peptide fragments produced by Fmoc SPPS. The concept is demonstrated for the synthesis of three different Affibody molecules. The cysteine residue introduced at the site of ligation can be used for directed immobilization and does not interfere with the function of the investigated proteins. This strategy combines a high-yield production method with facilitated preparation of proteins with different C-terminal modifications.
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| 18. |
- Lindgren, Joel, 1982-
(författare)
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Chemical Engineering of Small Affinity Proteins
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Small robust affinity proteins have shown great potential for use in therapy, in vivo diagnostics, and various biotechnological applications. However, the affinity proteins often need to be modified or functionalized to be successful in many of these applications. The use of chemical synthesis for the production of the proteins can allow for site-directed functionalization not achievable by recombinant routes, including incorporation of unnatural building blocks. This thesis focuses on chemical engineering of Affibody molecules and an albumin binding domain (ABD), which both are three-helix bundle proteins of 58 and 46 amino acids, respectively, possible to synthesize using solid phase peptide synthesis (SPPS).In the first project, an alternative synthetic route for Affibody molecules using a fragment condensation approach was investigated. This was achieved by using native chemical ligation (NCL) for the condensation reaction, yielding a native peptide bond at the site of ligation. The constant third helix of Affibody molecules enables a combinatorial approach for the preparation of a panel of different Affibody molecules, demonstrated by the synthesis of three different Affibody molecules using the same helix 3 (paper I).In the next two projects, an Affibody molecule targeting the amyloid-beta peptide, involved in Alzheimer’s disease, was engineered. Initially the N-terminus of the Affibody molecule was shortened resulting in a considerably higher synthetic yield and higher binding affinity to the target peptide (paper II). This improved variant of the Affibody molecule was then further engineered in the next project, where a fluorescently silent variant was developed and successfully used as a tool to lock the amyloid-beta peptide in a β-hairpin conformation during studies of copper binding using fluorescence spectroscopy (paper III).In the last two projects, synthetic variants of ABD, interesting for use as in vivo half-life extending partners to therapeutic proteins, were engineered. In the first project the possibility to covalently link a bioactive peptide, GLP-1, to the domain was investigated. This was achieved by site-specific thioether bridge-mediated cross-linking of the molecules via a polyethylene glycol (PEG)-based spacer. The conjugate showed retained high binding affinity to human serum albumin (HSA) and a biological activity comparable to a reference GLP-1 peptide (paper IV). In the last project, the possibility to increase the proteolytic stability of ABD through intramolecular cross-linking, to facilitate its use in e.g. oral drug delivery applications, was investigated. A tethered variant of ABD showed increased thermal stability and a considerably higher proteolytic stability towards pepsin, trypsin and chymotrypsin, three important proteases found in the gastrointestinal (GI) tract (paper V).Taken together, the work presented in this thesis illustrates the potential of using chemical synthesis approaches in protein engineering.
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| 19. |
- Lindgren, Joel, et al.
(författare)
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Engineered non-fluorescent Affibody molecules facilitate studies of the amyloid-beta (A beta) peptide in monomeric form : Low pH was found to reduce A beta/Cu(II) binding affinity
- 2013
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134 .- 1873-3344. ; 120, s. 18-23
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Tidskriftsartikel (refereegranskat)abstract
- Aggregation of amyloid-beta (A beta) peptides into oligomers and amyloid plaques in the human brain is considered a causative factor in Alzheimer's disease (AD). As metal ions are over-represented in AD patient brains, and as distinct A beta aggregation pathways in presence of Cu(II) have been demonstrated, metal binding to A beta likely affects AD progression. A beta aggregation is moreover pH-dependent, and AD appears to involve inflammatory conditions leading to physiological acidosis. Although metal binding specificity to A beta varies at different pH's, metal binding affinity to A beta has so far not been quantitatively investigated at sub-neutral pH levels. This may be explained by the difficulties involved in studying monomeric peptide properties under aggregation-promoting conditions. We have recently devised a modified Affibody molecule, Z(A beta 3)(12-58), that binds A beta with sub-nanomolar affinity, thereby locking the peptide in monomeric form without affecting the N-terminal region where metal ions bind. Here, we introduce non-fluorescent A beta-binding Affibody variants that keep A beta monomeric while only slightly affecting the A beta peptide's metal binding properties. Using fluorescence spectroscopy, we demonstrate that Cu(II)/A beta(1-40) binding is almost two orders of magnitude weaker at pH 5.0 (apparent K-D = 51 mu M) than at pH 7.3 (apparent K-D = 0.86 mu M). This effect is arguably caused by protonation of the histidines involved in the metal ligandation. Our results indicate that engineered variants of Affibody molecules are useful for studying metal-binding and other properties of monomeric A beta under various physiological conditions, which will improve our understanding of the molecular mechanisms involved in AD.
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| 20. |
- Lindgren, Joel, 1982-, et al.
(författare)
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Intramolecular thioether crosslinking of therapeutic proteins to increase proteolytic stability
- 2014
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Ingår i: ChemBioChem. - : Wiley. - 1439-4227 .- 1439-7633. ; 15:14, s. 2132-2138
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Protein-based pharmaceuticals typically display high selectivity and low toxicity, but are also characterized by low oral availability, mainly because of enzymatic degradation in the gastrointestinal tract and poor permeability across the intestinal wall. One way to increase the proteolytic stability of peptides and proteins is by intramolecular crosslinking, such as the introduction of disulfide bridges. However, disulfide bridges are at risk of thiol-disulfide exchange or reduction during production, purification, and/or therapeutic use, whereas thioether bridges are expected to be stable under the same conditions. In this study, thioether crosslinking was investigated for a 46 aa albumin-binding domain (ABD) derived from streptococcal protein G. ABD binds with high affinity to human serum albumin (HSA) and has been proposed as a fusion partner to increase the in vivo half-lives of therapeutic proteins. In the study, five ABD variants with single or double intramolecular thioether bridges were designed and synthesized. The binding affinity, secondary structure, and thermal stability of each protein was investigated by SPR-based biosensor analysis and CD spectroscopy. The proteolytic stability in the presence of the major intestinal proteases pepsin (found in the stomach) and trypsin in combination with chymotrypsin (found in pancreatin secreted to the duodenum by the pancreas) was also investigated. The most promising crosslinked variant, ABD_CL1, showed high thermal stability, retained high affinity in binding to HSA, and showed dramatically increased stability in the presence of pepsin and trypsin/chymotrypsin, compared to the ABD reference protein. This suggests that the intramolecular thioether crosslinking strategy can be used to increase the stability towards gastrointestinal enzymes.
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| 21. |
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| 22. |
- Lindgren, Joel, et al.
(författare)
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N-terminal engineering of amyloid-beta-binding Affibody molecules yields improved chemical synthesis and higher binding affinity
- 2010
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Ingår i: Protein Science. - : Wiley. - 0961-8368 .- 1469-896X. ; 19:12, s. 2319-2329
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Tidskriftsartikel (refereegranskat)abstract
- The aggregation of amyloid-beta (A beta) peptides is believed to be a major factor in the onset and progression of Alzheimer's disease Molecules binding with high affinity and selectivity to A beta-peptides are important tools for investigating the aggregation process An A beta-binding Affibody molecule, Z(A beta 3), has earlier been selected by phage display and shown to bind A beta(1-40) with nanomolar affinity and to inhibit A beta-peptide aggregation In this study, we create truncated functional versions of the Z(A beta 3) Affibody molecule better suited for chemical synthesis production Engineered Affibody molecules of different length were produced by solid phase peptide synthesis and allowed to form covalently linked homodimers by S-S-bridges The N-terminally truncated Affibody molecules Z(A beta 3)(12-58), Z(A beta 3)(15-58), and Z(A beta 3)(18-58) were produced in considerably higher synthetic yield than the corresponding full-length molecule Z(A beta 3)(1-58) Circular dichroism spectroscopy and surface plasmon resonance-based biosensor analysis showed that the shortest Affibody molecule, Z(A beta 3)(18-58), exhibited complete loss of binding to the A beta(1-40)-peptide, while the Z(A beta 3)(12-58) and Z(A beta 3)(15-58) Affibody molecules both displayed approximately one order of magnitude higher binding affinity to the A beta(1-40)-peptide compared to the full-length Affibody molecule Nuclear magnetic resonance spectroscopy showed that the structure of A beta(1-40) in complex with the truncated Affibody dimers is very similar to the previously published solution structure of the A beta(1-40)-peptide in complex with the full-length Z(A beta 3) Affibody molecule This indicates that the N-terminally truncated Affibody molecules Z(A beta 3)(12-58) and Z(A beta 3)(15-58) are highly promising for further engineering and future use as binding agents to monomeric A beta(1-40)
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| 23. |
- Lindgren, Joel, et al.
(författare)
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N-terminal engineering of amyloid-β-binding Affibody molecules yields improved chemical synthesis and higher binding affinity
- 2010
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Ingår i: Protein Science. - : Wiley. - 0961-8368 .- 1469-896X. ; 19:12, s. 2319-2329
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Tidskriftsartikel (refereegranskat)abstract
- The aggregation of amyloid-beta (A beta) peptides is believed to be a major factor in the onset and progression of Alzheimer's disease Molecules binding with high affinity and selectivity to A beta-peptides are important tools for investigating the aggregation process An A beta-binding Affibody molecule, Z(A beta 3), has earlier been selected by phage display and shown to bind A beta(1-40) with nanomolar affinity and to inhibit A beta-peptide aggregation In this study, we create truncated functional versions of the Z(A beta 3) Affibody molecule better suited for chemical synthesis production Engineered Affibody molecules of different length were produced by solid phase peptide synthesis and allowed to form covalently linked homodimers by S-S-bridges The N-terminally truncated Affibody molecules Z(A beta 3)(12-58), Z(A beta 3)(15-58), and Z(A beta 3)(18-58) were produced in considerably higher synthetic yield than the corresponding full-length molecule Z(A beta 3)(1-58) Circular dichroism spectroscopy and surface plasmon resonance-based biosensor analysis showed that the shortest Affibody molecule, Z(A beta 3)(18-58), exhibited complete loss of binding to the A beta(1-40)-peptide, while the Z(A beta 3)(12-58) and Z(A beta 3)(15-58) Affibody molecules both displayed approximately one order of magnitude higher binding affinity to the A beta(1-40)-peptide compared to the full-length Affibody molecule Nuclear magnetic resonance spectroscopy showed that the structure of A beta(1-40) in complex with the truncated Affibody dimers is very similar to the previously published solution structure of the A beta(1-40)-peptide in complex with the full-length Z(A beta 3) Affibody molecule This indicates that the N-terminally truncated Affibody molecules Z(A beta 3)(12-58) and Z(A beta 3)(15-58) are highly promising for further engineering and future use as binding agents to monomeric A beta(1-40)
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| 24. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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| 25. |
- Lundblad, Mattias, et al.
(författare)
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KP-LULUCF
- 2016
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Ingår i: National inventort report Sweden 2016: greenhouse gas emission inventories 1990-2014: submitted under the United Nations framework convention om climate change and the Kyoto protocol. ; , s. 471-500
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Bokkapitel (refereegranskat)
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| 26. |
- Lundblad, Mattias, et al.
(författare)
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KP-LULUCF
- 2015
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Ingår i: National Inventory Report Sweden 2015: Greenhouse Gas Emission Inventories 1990-2013: Submitted under the United Nations Framework Convention on Climate Change and the Kyoto Protocol. ; , s. 440-465
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 27. |
- Lundblad, Mattias, et al.
(författare)
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Land use, land-use change and forestry (CRF sector 4)
- 2015
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Ingår i: National Inventory Report Sweden 2015: Greenhouse Gas Emission Inventories 1990-2013: Submitted under the United Nations Framework Convention on Climate Change and the Kyoto Protocol. ; , s. 326-364
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 28. |
- Lundblad, Mattias, et al.
(författare)
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Land use, land-use change and forestry (CRF sector 4), KP-LULUCF
- 2016
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Ingår i: National inventory report Sweden 2016: greenhouse gas emission inventories 1990-2014: submitted under the United Nations framework convention on climate change and the Kyoto protocol. ; , s. 353-392
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Bokkapitel (refereegranskat)
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| 29. |
- Nilsson, Anders, et al.
(författare)
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Intramolecular Thioether Crosslinking to Increase the Proteolytic Stability of Affibody Molecules
- 2017
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Ingår i: ChemBioChem. - : WILEY-V C H VERLAG GMBH. - 1439-4227 .- 1439-7633. ; 18:20, s. 2056-2062
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Tidskriftsartikel (refereegranskat)abstract
- Protein therapeutics suffer from low oral bioavailability, mainly due to poor membrane permeability and digestion by gastrointestinal proteases. To improve proteolytic stability, intramolecular thioether crosslinks were introduced into a three-helix affibody molecule binding the human epidermal growth factor receptor (EGFR). Solid-phase peptide synthesis was used to produce an unmodified control protein domain and three different crosslinked protein domain variants: one with a thioether crosslink between the N-terminal lysine residue and a cysteine residue in the second loop region (denoted K4), a second with a crosslink between the C-terminal lysine residue and a cysteine residue in the first loop region (denoted K58), and a third with crosslinks in both positions (denoted K4K58). Circular dichroism (CD) and surface-plasmon-resonance-based (SPR-based) biosensor studies of the protein domains showed that the three-helix structure and high-affinity binding to EGFR were preserved in the crosslinked protein domains. In vitro digestion by gastrointestinal proteases demonstrated that the crosslinked protein domains showed increased stability towards pepsin and towards a combination of trypsin and chymotrypsin.
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| 30. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 31. |
- Pervjakova, Natalia, et al.
(författare)
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Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 31:19, s. 3377-3391
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Tidskriftsartikel (refereegranskat)abstract
- Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy (GenDIP) Consortium assembled genome-wide association studies (GWAS) of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (p < 5x10-8) with GDM, mapping to/near MTNR1B (p = 4.3x10-54), TCF7L2 (p = 4.0x10-16), CDKAL1 (p = 1.6 × 10-14), CDKN2A-CDKN2B (p = 4.1x10-9) and HKDC1 (p = 2.9x10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D; and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomisation analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.
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| 32. |
- Tiiman, Ann, et al.
(författare)
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Specific Binding of Cu(II) Ions to Amyloid-Beta Peptides Bound to Aggregation-Inhibiting Molecules or SDS Micelles Creates Complexes that Generate Radical Oxygen Species
- 2016
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 54:3, s. 971-982
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Tidskriftsartikel (refereegranskat)abstract
- Aggregation of the amyloid-beta (A beta) peptide into insoluble plaques is a major factor in Alzheimer's disease (AD) pathology. Another major factor in AD is arguably metal ions, as metal dyshomeostasis is observed in AD patients, metal ions modulate A beta aggregation, and AD plaques contain numerous metals including redox-active Cu and Fe ions. In vivo, A beta is found in various cellular locations including membranes. So far, Cu(II)/A beta interactions and ROS generation have not been investigated in a membrane environment. Here, we study Cu(II) and Zn(II) interactions with A beta bound to SDS micelles or to engineered aggregation-inhibiting molecules (the cyclic peptide CP-2 and the Z(A beta 3)(12-58) Y18L Affibody molecule). In all studied systems the A beta N-terminal segment was found to be unbound, unstructured, and free to bind metal ions. In SDS micelles, A beta was found to bind Cu(II) and Zn(II) with the same ligands and the same K-D as in aqueous solution. ROS was generated in all Cu(II)/A beta complexes. These results indicate that binding of A beta to membranes, drugs, and other entities that do not interact with the A beta N-terminal part, appears not to compromise the N-terminal segment's ability to bind metal ions, nor impede the capacity of N-terminally bound Cu(II) to generate ROS.
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| 33. |
- Voigt, Carolina, et al.
(författare)
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Ecosystem carbon response of an Arctic peatland to simulated permafrost thaw
- 2019
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Ingår i: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 25:5, s. 1746-1764
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Tidskriftsartikel (refereegranskat)abstract
- Permafrost peatlands are biogeochemical hot spots in the Arctic as they store vast amounts of carbon. Permafrost thaw could release part of these long-term immobile carbon stocks as the greenhouse gases (GHGs) carbon dioxide (CO2) and methane (CH4) to the atmosphere, but how much, at which time-span and as which gaseous carbon species is still highly uncertain. Here we assess the effect of permafrost thaw on GHG dynamics under different moisture and vegetation scenarios in a permafrost peatland. A novel experimental approach using intact plant-soil systems (mesocosms) allowed us to simulate permafrost thaw under near-natural conditions. We monitored GHG flux dynamics via high-resolution flow-through gas measurements, combined with detailed monitoring of soil GHG concentration dynamics, yielding insights into GHG production and consumption potential of individual soil layers. Thawing the upper 10-15 cm of permafrost under dry conditions increased CO2 emissions to the atmosphere (without vegetation: 0.74 +/- 0.49 vs. 0.84 +/- 0.60 g CO2-C m(-2) day(-1); with vegetation: 1.20 +/- 0.50 vs. 1.32 +/- 0.60 g CO2-C m(-2) day(-1), mean +/- SD, pre- and post-thaw, respectively). Radiocarbon dating (C-14) of respired CO2, supported by an independent curve-fitting approach, showed a clear contribution (9%-27%) of old carbon to this enhanced post-thaw CO2 flux. Elevated concentrations of CO2, CH4, and dissolved organic carbon at depth indicated not just pulse emissions during the thawing process, but sustained decomposition and GHG production from thawed permafrost. Oxidation of CH4 in the peat column, however, prevented CH4 release to the atmosphere. Importantly, we show here that, under dry conditions, peatlands strengthen the permafrost-carbon feedback by adding to the atmospheric CO2 burden post-thaw. However, as long as the water table remains low, our results reveal a strong CH4 sink capacity in these types of Arctic ecosystems pre- and post-thaw, with the potential to compensate part of the permafrost CO2 losses over longer timescales.
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| 34. |
- Voigt, Carolina, et al.
(författare)
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Increased nitrous oxide emissions from Arctic peatlands after permafrost thaw
- 2017
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 114:24, s. 6238-6243
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Tidskriftsartikel (refereegranskat)abstract
- Permafrost in the Arctic is thawing, exposing large carbon and nitrogen stocks for decomposition. Gaseous carbon release from Arctic soils due to permafrost thawing is known to be substantial, but growing evidence suggests that Arctic soils may also be relevant sources of nitrous oxide (N2O). Here we show that N2O emissions from subarctic peatlands increase as the permafrost thaws. In our study, the highest postthaw emissions occurred from bare peat surfaces, a typical landform in permafrost peatlands, where permafrost thaw caused a fivefold increase in emissions (0.56 +/- 0.11 vs. 2.81 +/- 0.6 mg N2O m(-2) d(-1)). These emission rates match those from tropical forest soils, the world's largest natural terrestrial N2O source. The presence of vegetation, known to limit N2O emissions in tundra, did decrease (by similar to 90%) but did not prevent thaw-induced N2O release, whereas waterlogged conditions suppressed the emissions. We show that regions with high probability for N2O emissions cover one-fourth of the Arctic. Our results imply that the Arctic N2O budget will depend strongly on moisture changes, and that a gradual deepening of the active layer will create a strong noncarbon climate change feedback.
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| 35. |
- Voigt, Carolina, et al.
(författare)
-
Increased nitrous oxide emissions from Arctic peatlands after permafrost thaw
- 2017
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424. ; 114:24, s. 6238-6243
-
Tidskriftsartikel (refereegranskat)abstract
- Permafrost in the Arctic is thawing, exposing large carbon and nitrogen stocks for decomposition. Gaseous carbon release from Arctic soils due to permafrost thawing is known to be substantial, but growing evidence suggests that Arctic soils may also be relevant sources of nitrous oxide (N2O). Here we show that N2O emissions from subarctic peatlands increase as the permafrost thaws. In our study, the highest postthaw emissions occurred from bare peat surfaces, a typical landform in permafrost peatlands, where permafrost thaw caused a fivefold increase in emissions (0.56 ± 0.11 vs. 2.81 ± 0.6 mg N2O m-2 d-1). These emission rates match those from tropical forest soils, the world's largest natural terrestrial N2O source. The presence of vegetation, known to limit N2O emissions in tundra, did decrease (by ∼90%) but did not prevent thaw-induced N2O release, whereas waterlogged conditions suppressed the emissions. We show that regions with high probability for N2O emissions cover one-fourth of the Arctic. Our results imply that the Arctic N2O budget will depend strongly on moisture changes, and that a gradual deepening of the active layer will create a strong noncarbon climate change feedback.
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