| 1. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 2. |
- Gyhlesten Back, Jessica
(författare)
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Modelling and Characterisation of the Martensite Formation in Low Alloyed Carbon Steels
- 2017
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The current work contains experimental and theoretical work about the formation of martensite from the austenitic state of the steel Hardox 450. Simulation of rolling and subsequent quenching of martensitic steel plates requires a model that can account for previous deformation, current stresses and the temperature history, therefore dilatometry experiments were performed, with and without deformation. Two austenitization schedules were used and in the standard dilatometry the cooling rates varied between 5-100 °C/s, in order to find the minimum cooling rate that gives a fully martensitic microstructure. Cooling rates larger than 40°C/s gave a fully martensitic microstructure. The cooling rate of 100 °C/s was used in the deformation dilatometry tests where the uniaxial deformation varied from 5-50 %. The theoretical work involved modelling of the martensite formation and the thermal/transformation strains they cause in the steel. Characterizations were done using light optical microscopy, hardness tests and electron backscatter diffraction technique. The parent austenite grains of the martensitic structure were reconstructed using the orientation relationship between the parent austenite and the martensite. Kurdjumov-Sachs orientation relationships have previously been proven to work well for low-carbon steels and was therefore selected.The standard implementation of the Koistinen-Marburger equation for martensite formation and a more convenient approach were compared. The latter approach does not require the storage of initial austenite fraction at start of martensite formation. The comparison shows that the latter model works equally well for the martensite formation. The results showed that the use of martensite start and finish temperatures calibrated versus experiments for Hardox 450 works better when computing thermal expansion than use of general relations based on the chemistry of the steel.The results from deformation dilatometry showed that deformation by compressive uniaxial stresses impedes the martensite transformation. The simplified incremental model works well for deformation with 5 % and 10 %. However, the waviness in the experimental curve for deformation 50 % does not fit the model due vi to large barrelling effect and the large relative expansion for the material that the sample holders are made of.Crystallographic reconstruction of parent austenite grains were performed on a hot-rolled as-received reference sample and dilatometry samples cooled with 60 °C/s and 100 °C/s. The misorientation results showed that the samples match with the Kurdjumov-Sachs orientation relationship in both hot rolled product and dilatometry samples. When misorientation between adjacent pixels are between 15° and 48°, then the boundary between them was considered as a parent austenite grain. The austenitic grain boundaries of the sample cooled at 100 °C/s is in general identical with the hot rolled sample when considering high angle boundaries (15°-48°). The results from the hardness tests showed that the rolled product exhibits higher hardness as compared to samples cooled by 100 °C/s and 60 °C/s. This can be attributed to the formation of transition-iron-carbides in the hot rolled product due to longer exposure of coiling temperature.
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| 3. |
- Lejon, Erik
(författare)
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Information Integration in Computer Aided Design
- 2014
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Information management during product development and over the lifecycle of products has become central to enable competitiveness in the engineering industry. Reuse and integration of information is essential to avoid duplicating efforts. This need for methods and tools which effectively enable capture, retrieval, representation, and reuse of information.The research presented in this thesis is based on investigations of information management at two companies in the engineering industry in Sweden. One case at each company was identified. The cases focused on the methods and tools with which product-related information is captured, retrieved represented, and reused.The challenge lies in ensuring that pertinent product information can be efficiently captured and, once stored, can be understood, used, and reused by both systems and individuals.To address the challenge, an approach for integrating information in Product Development was developed, implemented, and evaluated. One of the bases of the approach is the information architecture used to provide easy access to product information in an integrated and customizable way. Information is stored in a main source, a Product Lifecycle Management (PLM) system tightly integrated with other sources. These tightly integrated information sources together form a PLM solution. The data model of the PLM system becomes the unified data model for the product information. The approach allows for redundancy-free storage that ensures that the information provided is up-to-date and valid. Ease of access to the information is provided by utilizing a service-oriented architecture to provide Web applications and integrations.Close collaboration between researchers and users has been essential throughout the entire process of investigation, implementation, and evaluation.Feedback from the evaluation showed that the prescribed approach was preferred to the old approach and that the participants from both companies agree that it will likely provide value to both authors and consumers of the information.
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| 4. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 5. |
- Yan, Chunli, 1978-
(författare)
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Developing digital support for learning and diagnostic reasoning in clinical practice
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The two main purposes of clinical decision-support systems (CDSSs) are to provide healthcare professionals decision-making support based on evidence-based medical knowledge, and a continuing medical education. This thesis focuses on both purposes and shows how fundamental theory in the field of artificial intelligence can be developed, adapted and implemented in a CDSS for supporting learning and diagnostic reasoning in clinical practice. The main research problems addressed in this thesis are how to represent and manage uncertain, incomplete, inconsistent and distributed knowledge in automated reasoning and decision-making with the clinicians in the loop, how to facilitate the knowledge engineering and maintenance process, and how to detect and support learning and skill development in CDSS users.Research contributions include theories, methods, and algorithms based on possibilistic logic and formal argumentation for representing and managing uncertain, incomplete, inconsistent and distributed medical knowledge, and for supporting reasoning and decision-making when using a CDSS. The clinician is provided potentially conflicting arguments and their strength based on different diagnostic criteria and the available patient information in order to make an informed decision. The theoretical results were implemented in the Dementia Diagnosis and Management Support System - Web version (DMSS-W), in a multi-agent hypothesis-driven inquiry dialogue system, and in an inference engine serving as a module of ACKTUS.CDSS maintenance is challenging since new knowledge about diseases and treatments are continuously developed. Typically, knowledge and software engineers are needed to bridge medical experts and CDSSs, leading to time-consuming system development. ACKTUS (Activity-Centered Knowledge and Interaction Tailored to Users) was, as part of this research, further developed as a generic web-based platform for knowledge management and end-user development of CDSSs. It includes the inference engine and a content management system that the medical expert can use to manage knowledge, design and evaluate CDSSs. A graphical user interface generator synchronizes the interface to the ontology serving as the knowledge base. ACKTUS was used for developing DMSS-W, and facilitated the system development and maintenance.To offer person-tailored support for the clinician's learning, reasoning and decision-making, the CDSS design was based on theories of how novices and experts reason and make decisions. Pilot case studies involving physicians with different levels of expertise who applied DMSS-W in patient cases were conducted in clinical practice to explore methods for detecting skill levels and whether learning is taking place. The results indicated that the skill levels can be detected using the method. The novice was seen to develop reasoning strategies similar to an expert's, indicating that learning was taking place. In future work, tailored educational support will be developed, and evaluated using the methods.
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| 6. |
- Babu, Bijish, Tec. Lic. 1979-
(författare)
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Mechanism-based flow stress model for Ti-6Al-4V : applicable for simulation of additive manufacturing and machining
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ti-6Al-4V has remarkable properties such as high specific mechanical properties (viz. stiffness, strength, toughness, fatigue resistance), corrosion resistance, biocompatibility etc. These properties make it attractive for applications in aerospace, chemical industry, energy production, surgical implants, etc. Many of these applications have to satisfy high requirements on mechanical properties, which are directly affected by the microstructure. Therefore, it is essential to understand as well as to model the microstructure evolution during manufacturing as well as in-service. Furthermore, this alloy has a narrow temperature and strain rate window of workability.This work was initiated as part of a project aimed at performing finite element simulations of a manufacturing process chain involving hot forming, welding, machining, additive manufacturing and heat treatment of Ti-6Al-4V components within the aerospace industry. Manufacturing process chain simulations can compute the cumulative effect of the various processes by following the material state through the whole chain and give a realistic prediction of the final component. Capacity to describe material behavior in a wide range of temperatures and strain rates is crucial for this task.A material model based on the dominant deformation mechanisms of the alloy is assumed to have a more extensive range of validity compared to an empirical relationship. Explicit dislocation dynamics based models are not practically feasible for manufacturing process simulation, and therefore the concept of dislocation density, (length of dislocations per unit volume) developed by (Kocks1966; Bergström, 1970) is followed here. This mean field approach provides a representation of the average behavior of a large number of dislocations, grains, etc. Conrad (1981) studied the influence of various factors like solutes, interstitials, strain, strain rate, temperature, etc., on the strength and ductility of titanium systems and proposed a binary additive relationship for its yield strength. The first component relates to long-range interactions and second short-range relates to lattice resistance for dislocation motion. For high strain rate deformation, this short-range term is extended to include the effects of a viscous drag given by phonon and electron drag (Lesuer et al. 2001). Immobilisation of dislocation by pile-ups gives hardening and remobilization/annihilation by dislocation glide and climb gives restoration. Globularization is also considered to restore the material. The material model is calibrated using isothermal compression tests at a wide range of temperatures and strain rates. Compression tests performed using Gleeble thermo-mechanical simulator is used at low-strain rates and split-Hopkins pressure bar is used at high strain rates for calibration.During additive manufacturing depending on the temperature, heating/cooling rates, Ti-6Al-4V undergoes allotropic phase transformation. This transformation results in a variety of textures that can give different mechanical properties. Based on the texture (Semiatin et al., 1999b; Seetharaman and Semiatin, 2002; Thomas et al., 2005) identified few microstructural features that are relevant to the mechanical properties. The three separate alpha phase fractions; Widmanstatten, grain boundary, Martensite, and the beta-phase fraction are included in the current model. However, since the strengthening contributions of these individual alpha phases are not known, a linear rule of mixtures for the total alpha-beta composition is developed. This model is calibrated using continuous cooling tests performed by Malinov et al. 2001 with differential scanning calorimeter at varying cooling rates. This mechanism-based model is formulated in such a way that it can be implemented in any standard finite element software. In the current work, this is implemented as subroutines within MSC Marc and used for simulation of hot-forming and additive manufacturing.
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| 7. |
- Draxler, Joar
(författare)
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Modeling and Simulation of Weld Hot Cracking
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Several alloy systems are susceptible to weld hot cracking. Weld hot cracking occurs by fracture of liquid films, normally grain boundary liquid films, at the late stage of the solidification of the weld. The cracks can be small and therefore difficult to detect by nondestructive test methods. If hot cracks are not repaired, they can act as sites for initiation of fatigue and stress corrosion cracking, which in turn can lead to catastrophic failure in critical applications such as aerospace engines and nuclear power plants. Therefore, it is of highest importance to design weld processes so that hot cracking can be avoided. Here, numerical simulation can be a powerful tool for optimizing weld speed, heat input, weld path geometry, weld path sequences, weld fixturing, etc., such that the risk for hot cracking can be minimized. In this thesis, we propose a modeling approach for simulating weld hot cracking in sheet metals with low welding speeds and fully penetrating welds. These conditions are assumed to give rise to isolated grain boundary liquid films (GBLFs) whose crack susceptibility can be analyzed using one-dimensional models. The work is divided into four journal papers. The three first papers treat hot cracking that occurs in the fusion zone of the weld while the last paper treats hot cracking in the partially melted zone of the weld. The main content of the four papers are summarized below. In paper A, a pore-based crack criterion for hot cracking has been developed. This criterion states that cracking occurs in a GBLF if the liquid pressure in the film goes below a fracture pressure. The fracture pressure is determined from a pore model as the liquid pressure that is required to balance the surface tension of an axisymmetric pore in a liquid film located between two parallel plates at a given critical pore radius. The fracture pressure depends on the surface tension, the spacing between the parallel plates and the gas concentration in the liquid. In order to evaluate the above pore-based crack criterion in a GBLF the liquid pressure in the film most be known. In paper B, a one-dimensional GBLF pressure model for a columnar dendritic microstructure has been developed. This model is based on a combination of Poiseuille parallel plate flow and Darcy porous flow. Flow induced by mechanical straining of the GBLF is accounted for by a macroscopic mechanical strain field that is localized to the GBLF by a temperature dependent length scale. In paper C, a computational welding mechanics model for a Varestraint test is developed. The model is used to calibrate the crack criterion in paper A and the pressure model in paper B. It is then used to test the crack criterion in Varestraint tests with different augmented strains. Calculated crack locations, orientations, and widths are shown to correlate well to the experimental Varestraint tests. vii Finally, in paper D, a segregation model for predicting the thickness of eutectic bands has been developed. The thickness of eutectic bands affects the degree of liquation in partially melted zone, and therefore is an important factor for hot cracking in this region of the weld.
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| 8. |
- Evangelou, Evangelos, et al.
(författare)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 9. |
- Khurshid, Mansoor, 1986-
(författare)
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Static and fatigue analyses of welded steel structures : some aspects towards lightweight design
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The objectives of this thesis comprise of overcoming the challenges in designing lightweight welded structures such as material selection, choice of fatigue design methods, and increased performance by using improvement techniques. Material selection of welded joints is dependent on the filler and base material strengths. Partially and fully penetrated cruciform and butt welded joints were designed in under-matching, matching, and over-matching filler materials. Base material steel grades were S600MC, S700MC, and S960. Current design rules are developed for welds in steel up to yield strength of 700MPa. Therefore, design rules in Eurocode3, AWS d1.1, and BSK 07 were verified and recommendations for developing design rules for designing welded joints in S960 were concluded. Numerical methodology for estimating static strength of welded joints by simulating heat affected zone was also developed.Another objective of the thesis work was to overcome the challenges in selection of fatigue design methods. The available design curves in standards are developed for uniaxial stress states, however, in real life the welds in mechanical structures are subjected to complex multiaxial stress states. Furthermore; weld toe failures are frequently investigated, weld root failures are seldom investigated. Therefore, in this work the multiaxial fatigue strength of welded joints failing at the weld root was assessed using experiments and various nominal and local stress based approaches. Butt welded joints with different weld seam inclinations with respect to applied uniaxial loading were designed to assess the root fatigue strength in higher multiaxial stress ratio regime. The fatigue strength of multi-pass tube-to-plate welded joints subjected to internal pressure only and combined internal pressure and torsion in and 90° out of phase loading was also investigated. Test data generated in this thesis was evaluated together with the test data collected from literature.Last objective of the thesis included investigation of the increased performance in fatigue strength by post weld treatment methods such as HFMI. The behavior of residual stresses induced due to HFMI treatment during fatigue loading is studied. Numerical residual stress estimations and residual stress relaxation models are developed and the effect of various HFMI treatment process parameters and steel grade on the induced residual stress state is investigated. Specimens studied were non load carrying longitudinal attachments and simple plates. Residual stresses in both test specimens were measured using X-ray diffraction technique.
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| 10. |
- Morris, Andrew P, et al.
(författare)
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Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
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