| 1. |
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| 2. |
- Malmelöv, Andreas, et al.
(författare)
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History Reduction by Lumping for Time-Efficient Simulation of Additive Manufacturing
- 2020
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Ingår i: Metals. - : MDPI. - 2075-4701. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Additive manufacturing is the process by which material is added layer by layer. In most cases, many layers are added, and the passes are lengthy relative to their thicknesses and widths. This makes finite element simulations of the process computationally demanding owing to the short time steps and large number of elements. The classical lumping approach in computational welding mechanics, popular in the 80s, is therefore, of renewed interest and is evaluated in this work. The method of lumping means that welds are merged. This allows fewer time steps and a coarser mesh. It was found that the computation time can be reduced considerably, with retained accuracy for the resulting temperatures and deformations. The residual stresses become, to a certain degree, smaller. The simulations were validated against a directed energy deposition (DED) experiment with alloy 625.
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| 3. |
- Malmelöv, Andreas
(författare)
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History Reduction Techniques for Simulation of Additive Manufacturing and Physically based Material Modeling
- 2020
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, finite element (FE) simulations of additive manufacturing (AM) and physically based material modeling are presented. AM is a process where the component is built layer-wise. The material undergoes repeated heating and cooling cycles when layers are added, which may result in undesired deformation and residual stress in the built component. The choice of process parameters and scan strategy affect the resulting residual stress. Simulations can be used to support the experimental determination of process parameters and scan strategy. AM processes often comprise many added layers, and the passes are lengthy relative to their thicknesses and widths. This makes the FE simulations computationally expensive, with many elements and time steps. In this work, AM processes have been simulated with the FE-method using a lumping technique. This technique allows fewer time steps and a coarser mesh. Thermal behavior, deformation, and residual stresses have been simulated and compared with experiments. The simulations show that, by using the lumping technique, the computational effort can be reduced significantly with retained accuracy for the resulting temperature and deformations. The residual stresses become somewhat smaller. Alloy 625 is a nickel-based superalloy used in high-temperature applications owing to the hightemperature strength. The material is difficult to manufacture by conventional machining owing to excessive tool wear and low material removal rates. Thus alloy 625 is a material appropriate for the AM technology with its near-net shape potential. An existing, physically based flow stress model has been further developed to fit the mechanisms typical for alloy 625. This model gives an accurate mechanical behavior and capture viscoplasticity, creep, and relaxation. The physically based model has been calibrated versus compression tests and validated with a stress relaxation test performed in a Gleeble 3800 machine. The predicted relaxation was in good agreement with the measured relaxation. The usage of this kind of material model is expected to improve the prediction of the material behavior during the AM process and, thereby, the overall prediction of the AM process.
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| 4. |
- Malmelöv, Andreas, et al.
(författare)
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Mechanism based flow stress model for Alloy 625 and Alloy 718
- 2020
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Ingår i: Materials. - : MDPI. - 1996-1944. ; 13:24
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Tidskriftsartikel (refereegranskat)abstract
- To predict the final geometry in thermo-mechanical processes, the use of modeling tools is of great importance. One important part of the modeling process is to describe the response correctly. A previously published mechanism-based flow stress model has been further developed and adapted for the nickel-based superalloys, alloy 625, and alloy 718. The updates include the implementation of a solid solution strengthening model and a model for high temperature plasticity. This type of material model is appropriate in simulations of manufacturing processes where the material undergoes large variations in strain rates and temperatures. The model also inherently captures stress relaxation. The flow stress model has been calibrated using compression strain rate data ranging from 0.01 to 1 s−1 with a temperature span from room temperature up to near the melting temperature. Deformation mechanism maps are also constructed which shows when the different mechanisms are dominating. After the model has been calibrated, it is validated using stress relaxation tests. From the parameter optimization, it is seen that many of the parameters are very similar for alloy 625 and alloy 718, although it is two different materials. The modeled and measured stress relaxation are in good agreement.
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| 5. |
- Malmelöv, Andreas, et al.
(författare)
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Numerical modeling and synchrotron diffraction measurements of residual stresses in laser powder bed fusion manufactured alloy 625
- 2022
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Ingår i: Materials & design. - : Elsevier. - 0264-1275 .- 1873-4197. ; 216
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Tidskriftsartikel (refereegranskat)abstract
- Residual stresses in metal additive manufactured components are a well-known problem. It causes distortion of the samples when removing them from the build plate, as well as acting detrimental with regard to fatigue. The understanding of how residual stresses in a printed sample are affected by process parameters is crucial to allow manufacturers to tune their process parameters, or the design of their component, to limit the negative influence of residual stresses. In this paper, residual stresses in additive manufactured samples are simulated using a thermo-mechanical finite element model. The elasto-plastic behavior of the material is described by a mechanism-based material model that accounts for microstructural and relaxation effects. The heat source in the finite element model is calibrated by fitting the model to experimental data. The residual stress field from the finite element model is compared with experimental results attained from synchrotron X-ray diffraction measurements. The results from the model and measurement give the same trend in the residual stress field. In addition, it is shown that there is no significant difference in trend and magnitude of the resulting residual stresses for an alternation in laser power and scanning speed.
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| 6. |
- Malmelöv, Andreas
(författare)
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Simulation of additive manufacturing using a mechanism based plasticity model
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis presents finite element (FE) simulations of additive manufacturing (AM) and physically based material modeling of alloy 625 and alloy 718. In recent years, there has been an increasing interest in AM and there has been a dramatic increase in publications in the field. AM can be beneficial compared to conventional manufacturing methods in many applications. The method offers short component lead times and large design freedom with the possibility to create complex components. Alloy 625 and alloy 718 are nickel-based superalloys used in high-temperature applications owing to their high-temperature strength. The materials are difficult to manufacture by conventional machining due to rapid tool wear and low material removal rates. Thus, the alloys are appropriate for the AM technology with its near-net shape potential.Owing to the rapid heating and solidification in the AM process, residual stresses are induced in the component. This is a well-known problem and causes distortion of the samples when removing them from the build plate. The residual stresses may also deteriorate the fatigue properties. It is important for the manufacturer to understand how the choice of process parameters and scanning strategy affect the residual stresses to minimize those and improve the quality of the components. Simulation can be used as a tool while developing the process parameters and support the experimental efforts. FEM is generally the preferred method for simulation of deformations and residual stresses in AM. The simulation technique used when modeling AM has its origin from welding simulations that was performed already since the beginning of 1970. However, it is not possible in practice to simulate an AM process in the traditional way due to a large number of elements and time increments to be calculated. This is especially true for the laser-based powder bed fusion (PBF-LB) process where the process of a full-scale part may comprise many thousands of added layers, and the passes are lengthy relative to their thicknesses and widths.The aim of this thesis work is to develop FE simulation techniques that reduce the computational effort when modeling residual stresses in AM processes to enable simu-lation of full-scale parts. This has been done with thermo-mechanical FE-models using different lumping techniques e.g., lumping of layers and lumping of hatches. Lumping of layers and hatches means that several physical layers, or several physical hatches, are merged and added in one modeled layer or hatch respectively. Lumping allows fewer time steps and a coarser mesh which reduces the computational effort. An existing mechanism based flow stress model has been developed to fit the mechanisms typical for alloy 625 and alloy 718 and implemented in the FE model. Also, synchrotron X-ray diffraction was performed to measure the residual stress for comparison with the models. The stress was extracted from the diffraction data using the full Debye ring fitting method.In this work, using the lumping techniques described above, it was possible to simu-late AM processes with up to physical 1500 layers. For different process parameter sets and scan strategies, thermal behavior, deformation and residual stresses have been mod-eled and compared with experiments. Using the lumping of layer technique resulted in modeled residual stresses showing the same trend as measured stresses from synchrotron X-ray diffraction for two different process parameter sets. Utilizing lumping of hatches, the resulting deflection in a part was modeled successfully for different scanning strate-gies. In the modeling, the larger deflection was seen for the samples printed with the scanning direction parallel to the long-side which was also shown experimentally.The results in this work shows that the presented lumping approaches are promising when it comes to modeling of the deformations and residual stresses in AM. Using lumping approaches, it is also possible to simulate different scanning strategies for processes of larger parts. The description of the mechanical behavior of the material is improved, using the mechanism based material model, compared to when the flow stress was modeled with tabulated data, since it takes mechanisms as viscoplasticity and stress relaxation into account. The mechanism based model includes microstructural information as grain size and solutes and can thus more easily be combined with a microstructure model. The combination of the mechanism based material model and the use of lumping techniques is thus an advance in the development of predictive models of the AM process.
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| 7. |
- Andersson, Carl, et al.
(författare)
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Modeling the Evolution of Grain Texture during Solidification of Laser-Based Powder Bed Fusion Manufactured Alloy 625 Using a Cellular Automata Finite Element Model
- 2023
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Ingår i: Metals. - : MDPI. - 2075-4701. ; 13:11
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Tidskriftsartikel (refereegranskat)abstract
- The grain texture of the as-printed material evolves during the laser-based powder bed fusion (PBF-LB) process. The resulting mechanical properties are dependent on the obtained grain texture and the properties vary depending on the chosen process parameters such as scan velocity and laser power. A coupled 2D Cellular Automata and Finite Element model (2D CA-FE) is developed to predict the evolution of the grain texture during solidification of the nickel-based superalloy 625 produced by PBF-LB. The FE model predicts the temperature history of the build, and the CA model makes predictions of nucleation and grain growth based on the temperature history. The 2D CA-FE model captures the solidification behavior observed in PBF-LB such as competitive grain growth plus equiaxed and columnar grain growth. Three different nucleation densities for heterogeneous nucleation were studied, 1 × 1011, 3 × 1011, and 5 × 1011. It was found that the nucleation density 3 × 1011 gave the best result compared to existing EBSD data in the literature. With the selected nucleation density, the aspect ratio and grain size distribution of the simulated grain texture also agrees well with the observed textures from EBSD in the literature.
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| 8. |
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| 9. |
- Lindwall, Johan
(författare)
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Modelling of laser-based powder bed fusion for bulk metallic glass formation
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The work presented in this thesis aims to develop a modelling approach to predict crystalline phase evolution in bulk metallic glass during additive manufacturing with laser-based powder bed fusion (PBF-LB). Metallic glasses are non-crystalline metallic materials that generally possess exceptional properties because of its amorphous struc-ture. Manufacturing of metallic glass is possible by rapid cooling of a liquid metal alloy. The required cooling rates to avoid crystallisation generally limits traditional manufac-turing techniques to small/thin samples. The desirable properties of metallic glasses motivate manufacturing of larger samples. PBF-LB is one promising method by which bulk metallic glass potentially can be produced without size limitation. Cooling rates in this process are generally several orders of magnitude higher than critical cooling rates to bypass crystallisation in glass forming alloys. Crystalline structures may still evolve within the solid material because of thermal cycling during the manufacturing process. Numerical simulation can assist development of process for bulk metallic glass formation by predicting the phase evolution. Simulations can also help to increase the understand-ing of where and when crystalline structures develop with respect to process parameters and scanning strategy. Simulation of bulk metallic glass formation during PBF-LB is a challenge. The thermodynamic and kinetic properties of the material and the large variations in time and length scales in the process makes accurate simulations difficult. This thesis address these challenges by developing a modelling approach for simulation of the temperature history and crystalline phase evolution. The objective is to assist the development of process parameters for bulk metallic glass formation. The approach includes finite element modelling to compute the temperature history in the heat affected zone. The modelling includes approximations of the energy input and approaches to sim-ulate the large variations in time and length scales associated with PBF-LB. Computed temperature histories acts as input in calculations of the crystalline phase evolution in the metallic glass. The phase transformation modelling approach includes a modified isothermal model and classical nucleation and growth theory. The result is a coupled thermal and phase transformation model that can predict the trend in crystalline phase evolution in a bulk metallic glass with respect to the process parameters. The predictions show very good agreement to experimental estimates of the crystalline volume fraction. Comparison of simulations makes it possible to evaluate the process parameters in terms of crystalline size distribution. The model is a powerful tool that help the development and fine tuning of process parameters to produce bulk metallic glass.
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| 10. |
- Lindwall, Johan, et al.
(författare)
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Simulation of phase evolution in a Zr-based glass forming alloy during multiple laser remelting
- 2022
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Ingår i: Journal of Materials Research and Technology. - : Elsevier. - 2238-7854 .- 2214-0697. ; 16, s. 1165-1178
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Tidskriftsartikel (refereegranskat)abstract
- Additive manufacturing by laser-based powder bed fusion is a promising technique for bulk metallic glass production. But, reheating by deposition of subsequent layers may cause local crystallisation of the alloy. To investigate the crystalline phase evolution during laser scanning of a Zr-based metallic glass-forming alloy, a simulation strategy based on the finite element method and the classical nucleation theory has been developed and compared with experimental results from multiple laser remelting of a single-track. Multiple laser remelting of a single-track demonstrates the crystallisation behaviour by the influence of thermal history in the reheated material. Scanning electron microscopy and transmission electron microscopy reveals the crystalline phase evolution in the heat affected zone after each laser scan. A trend can be observed where repeated remelting results in an increased crystalline volume fraction with larger crystals in the heat affected zone, both in simulation and experiment. A gradient of cluster number density and mean radius can also be predicted by the model, with good correlation to the experiments. Prediction of crystallisation, as presented in this work, can be a useful tool to aid the development of process parameters during additive manufacturing for bulk metallic glass formation.
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| 11. |
- Lindwall, Johan, et al.
(författare)
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Virtual Development of Process Parameters for Bulk Metallic Glass Formation in Laser-Based Powder Bed Fusion
- 2022
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Ingår i: Materials. - : MDPI. - 1996-1944. ; 15:2
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Tidskriftsartikel (refereegranskat)abstract
- The development of process parameters and scanning strategies for bulk metallic glass formation during additive manufacturing is time-consuming and costly. It typically involves trials with varying settings and destructive testing to evaluate the final phase structure of the experimental samples. In this study, we present an alternative method by modelling to predict the influence of the process parameters on the crystalline phase evolution during laser-based powder bed fusion (PBF-LB). The methodology is demonstrated by performing simulations, varying the following parameters: laser power, hatch spacing and hatch length. The results are compared in terms of crystalline volume fraction, crystal number density and mean crystal radius after scanning five consecutive layers. The result from the simulation shows an identical trend for the predicted crystalline phase fraction compared to the experimental estimates. It is shown that a low laser power, large hatch spacing and long hatch lengths are beneficial for glass formation during PBF-LB. The absolute values show an offset though, over-predicted by the numerical model. The method can indicate favourable parameter settings and be a complementary tool in the development of scanning strategies and processing parameters for additive manufacturing of bulk metallic glass.
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| 12. |
- Lundholm, Erik
(författare)
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On the relationship between microstructure, process parameters and mechanical properties of boron steels
- 2023
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The continuous development of the press hardening technology has led to stronger, lighter and more environmentally friendly components. Utilising the varying properties of boron steel at different temperatures enables great design freedom, while also attaining high strength in the final component. This is achieved by heating the initial material to an austenitic state, where it has good formability, followed by forming and quenching using pressing tools. However, in order to simulate this thermo-mechanical process the microstructure evolution must be understood. Research has been performed using various initial material states, evaluating possible effects on the final mechanical properties. Studies have also been performed to evaluate the grain growth during austenitisation. The influence of the initial material and the evolution of the austenite morphology during austenitisation has previously been less researched compared to other parts of the process.In this work, samples from commercially available materials have been heat treated to create test specimens, which subsequently have been used for mechanical testing and microstructure analysis. Digital image correlation was used to determine local fracture strains and anisotropic properties during plastic deformation. Samples were also heat treated using varying process parameters in order to study the grain growth during austenitisation. It was found that if hot rolled, cold rolled and soft annealed cold rolled samples were compared after hardening, their mechanical properties only exhibited minor variations. However, all samples displayed anisotropic properties during plastic deformation. There is therefore some microstructural trace from the production which is unaffected by soft annealing, austenitisation and subsequent quenching. The grain growth observed during the austenitisation was consistent within a temperature range not exceeding 930 ◦C. Using data retrieved from isothermal experiments a model could be fitted which described the growth using the temperature and current grain size. At 960 ◦C the microstructure was irregular, with large single grains and considerable variations in the average grain size within the same sample. The bending performance was not affected in a major way by the austenitisation temperature.The lack of variation of the mechanical properties due to the initial microstructure or parent austenite grain size is a testament to the robustness of the process. It should be noted however, that all samples were rapidly quenched. If the microstructure is formed through diffusion dependent phase transformations, the final mechanical properties could be more sensitive to process parameters. Further research is needed to fully understand the microstructural evolution and thus the mechanical properties where a more general thermal cycle can be used.
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| 13. |
- Widén, Åsa, et al.
(författare)
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Sveriges torrfåror : geografi, naturvärden och metoder för miljöförbättringar
- 2022
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Syftet med projektet var att ta fram metoder för att underlätta beslut om minimitappning och andra miljöförbättringsåtgärder för torrfåror, d.v.s. vattendragssträckor där vatten letts bort via kanaler eller tunnlar för att passera genom vattenkraftverks turbiner. Ibland sker även överledning från ett vattendrag till ett annat för att på så sätt öka produktionen av vattenkraft i vissa kraftverksanläggningar. Detta lämnar den ursprungliga fåran helt eller delvis torrlagd under stora delar av året. Vi har i denna rapport valt att använda begreppet ”torrfåror” för att indikera att det mest utmärkande draget är den reducerade vattenföringen. Många av dessa sträckor var ursprungligen forsar, och ekosystem och arter knutna till forsar har blivit sällsynta. Vi kartlade förekomsten av torrfåror i Sverige, och totalt identifierades och verifierades 972 torrfåror i en databas. 366 av dessa är belägna i Götaland, 323 i Svealand och 283 i Norrland. Den absoluta majoriteten av Sveriges torrfåror saknar bestämmelser om minimitappning. För de 622 torrfåror där vi hittat uppgifter om vattenföring, saknar 481 (77%) en tilldömd minimitappning. De 137 torrfårorna med minimitappning hade i genomsnitt en medelminimitappning på årsbasis på endast 3,6% av den naturliga årsmedelvattenföringen. I 63% av torrfårorna med minimitappning var denna lika med eller mindre än 5% av den naturliga årsmedelvattenföringen, och 48% var flödet lika med eller mindre än 0,5 m3/s. Analyser av fiskfaunan baserat på elfiskedata visar att torrfåror hade i genomsnitt lägre andel fiskar som hör till typiskt sett strömlevande arter och lägre total fiskabundans jämfört med av vattenkraft opåverkade referenslokaler. Torrfåror med minimitappning hade bättre status vad gäller fiskfaunan än de utan minimitappning vad gäller andel strömlevande arter, total fiskabundans och artrikedom av fisk. Andel individer av strömlevande fiskarter, total fiskabundans och fiskartrikedom ökade med ökande minimitappning i torrfårorna, men sambanden var icke-linjära och planade ut med ökande minimitappning. Torrfårornas medellutning var relativt hög (3,6%), och de representerar till övervägande del strömmande och forsande miljöer som helt eller delvis har torrlagts. Torrfårorna var i genomsnitt 1317 m, medan medianlängden endast var 319 m. De korta (50-100 m) och mycket korta (<50 m) torrfårorna var framför allt belägna i södra Sverige, medan långa (1-10 km) och mycket långa (>10 km) var vanligare i Norrlands inland. Majoriteten av torrfårorna i Sverige låg i vattendragens nedströmsdelar, i vattendragsordning 1 eller 2 räknat från mynningen. Miljöförbättringsåtgärder av olika slag, som mer naturliga vattenflöden, fiskvägar eller biotopvårdande åtgärder, har utförts vid 10% av torrfårorna sedan 1970. Av de 574 torrfåror där överensstämmelsen med vattenförekomster i VISS var god var 434 klassade som naturliga och 140 som kraftigt modifierade. I det senare fallet var den ekologiska potentialen enligt Vattendirektivet alltid klassificerad som måttlig eller sämre. Av de 434 som definierades som naturliga vattenförekomster hade de flesta givits måttlig ekologisk status. De största problemen i vattenförekomster som helt eller delvis motsvarar torrfåror är brister i konnektivitet och att den hydrologiska regimen är förändrad. Våra resultat visar att kortare torrfåror, som bara omfattar en del av en vattenförekomst, ofta förbises vid statusklassningen enligt Vattendirektivet, och att torrfåran ges samma ekologisk status som vattenförekomsten i stort. För att kunna välja ut vilka torrfåror som ska restaureras och genomföra restaureringsprojekt i torrfåror är fungerande samverkansprocess mellan berörda parter (t.ex. verksamhetsutövare, myndigheter, konsulter och ideella organisationer) viktig för att underlätta vägen från kartläggning till genomförande. Vi presenterar aspekter som underlättar, och kompetenser som behövs hos för att processen ska bli lyckosam. För att underlätta genomförandet av miljöförbättringsåtgärder i torrfåror presenterar vi ett metodiskt och strukturerat arbetssätt som ger en komplett kartläggning av torrfåran samt dess omgivande dämningsområden med biflöden, som leder fram till analyser av påverkansgraden, brister jämfört med opåverkade ekosystem, och åtgärdsbehov. Behov av åtgärder grundar sig på vilken restaureringspotential som finns baserat på förhållanden innan reglering och opåverkade referenslokaler. När man summerar naturvärden ger det en bild av vad som är möjligt att göra och vad som kan åstadkommas inom rimliga gränser med tanke på vattenkraftsproduktion. Målet är att detektera för vattenkraftsproduktion kostnadseffektiva och i det långa perspektivet resursanpassade åtgärder som gynnar ekosystemet och bevarar eller ökar naturvärdena. Som en grund för att kunna bestämma nivå på minimitappning presenterar vi en lista på vilka flöden eller aspekter av en naturlig flödesregim som krävs för att uppnå olika naturvärden (ökad biologisk mångfald av naturligt förekommande arter på en vattendragssträcka) eller ekosystemfunktioner. Denna kan hjälpa att bedöma vilka aspekter av naturliga flödesregimer som behövs för att erhålla önskade naturvärden, eller omvänt, att kunna ge en prognos för vilka naturvärden som kan förväntas vid en viss flödesregim, allt fokuserat på torrfåror. Vi presenterar också en metodik för att inventera torrfåror med kvantitativa metoder som bygger på att med hjälp av stickprov skatta hur mycket det finns av olika strukturer. Syftet med inventeringen är att kvantifiera strukturer i och kring vattendraget som kan vara viktiga för en bedömning av potentialen för att återskapa naturvärden (både akvatiska och i strandmiljön) vid olika möjliga flöden i torrfåror. Det finns flera fördelar med att ha en sådan samplingdesign (istället för kvalitativa metoder) i studier av ekologiska restaureringsprojekt. Det möjliggör att skatta t.ex. medelvärdet eller storleken på variabler som är av intresse, vare sig det är ytan av ett vegetationsbälte, mängden död ved eller fraktioner av sediment i fåran. Det kanske viktigaste skälet att göra det är att det möjliggör kvantitativ utvärdering av miljöförbättringsåtgärder, och avgöra om åtgärder har haft avsedd effekt. Miljödomar bör utformas för att vara långsiktigt hållbara för torrfårans ekosystem, d.v.s. vara relevanta under flera decennier trots att elsystemet och klimatet förändras. Få föreslagna åtgärder gällande torrfåror har genomförts praktiskt och att utreda genom uppföljning och belägga huruvida genomförda åtgärder faktiskt gett miljönytta är essentiellt. Uppföljning förutsätter att en vetenskaplig förstudie har genomförts (naturvärde, nuläge, påverkans- och bristanalys). Om det finns förstudier så finns goda förutsättningar att utvärdera effekterna, om tillräckligt lång tid efter restaurering har gått för att åtminstone initial ekologisk respons ska ha skett. Sammanfattningsvis konstaterar vi att de allra flesta torrfåror saknar minimitappning eller andra åtgärder för att förbättra den biologiska mångfalden och vattendragsekosystemen, men att det finns stöd för att sådana åtgärder är effektiva. Vår förhoppning är att de metoder vi presenterar ska underlätta beslut och genomförande av miljöförbättringsåtgärder i torrfåror.
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| 14. |
- Zhang, Si Min, et al.
(författare)
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Development of a chemical probe against NUDT15
- 2020
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Ingår i: Nature Chemical Biology. - : Springer Science and Business Media LLC. - 1552-4450 .- 1552-4469. ; 16:10, s. 1120-1128
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Tidskriftsartikel (refereegranskat)abstract
- The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides, but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop small-molecule NUDT15 inhibitors to elucidate its biological functions and potentially to improve NUDT15-dependent chemotherapeutics. Lead compound TH1760 demonstrated low-nanomolar biochemical potency through direct and specific binding into the NUDT15 catalytic pocket and engaged cellular NUDT15 in the low-micromolar range. We also employed thiopurine potentiation as a proxy functional readout and demonstrated that TH1760 sensitized cells to 6-thioguanine through enhanced accumulation of 6-thio-(d)GTP in nucleic acids. A biochemically validated, inactive structural analog, TH7285, confirmed that increased thiopurine toxicity takes place via direct NUDT15 inhibition. In conclusion, TH1760 represents the first chemical probe for interrogating NUDT15 biology and potential therapeutic avenues.
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