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  • Public defence: 2024-08-30 09:00 A1:111a, Uppsala
    Balboa Ramilo, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Exploring Preclinical Targets in Abdominal Aortic Aneurysm2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Abdominal Aortic Aneurysm (AAA) is a vascular disease characterised by the progressive and permanent dilation of the aorta, culminating in rupture and death, if not intervened. It affects 5% of men over the age of 65 years with a history of smoking. No pharmacological options are available to treat this disease. This thesis aims to investigate the role of glucose metabolism and mitochondrial function (Studies I-III) and microRNAs (Study IV) in experimental AAA and evaluate their potential as treatment targets.

    In Study I, angiotensin II (angII)-infused Apolipoprotein E (ApoE) deficient mice received intraperitoneal injections of the glycolysis inhibitor PFK15, for three weeks, starting one week after disease induction. Treatment with PFK15 reduced aneurysm formation compared with the control group and prevented the decrease in α-smooth cell actin/vimentin gene expression ratio caused by angII. Glycolysis inhibition with PFK15 prevents AAA growth by favouring the maintenance of a contractile phenotype of vascular smooth muscle cells.

    In Study II, angII-infused ApoE deficient mice received daily subcutaneous injections of the glucagon-like peptide 1 receptor analogue semaglutide, for four weeks, starting simultaneously with disease induction. Treatment with semaglutide prevented death by aortic rupture in the first seven days of disease development and the loss of collagen in the aortic wall. Semaglutide thereby prevents aortic dissection and rupture likely by promoting the maintenance of collagen in the aortic wall. 

    In Study III, mice received angII or saline infusion for four weeks. Mitochondrial function was evaluated ex vivo in whole aortic tissue, by high-resolution respirometry. Aortas of angII-infused mice had a reduced capacity to increase oxygen consumption, in response to ADP and succinate, compared to control. These results demonstrate that it is possible to measure mitochondrial function in whole aneurysmal tissue ex vivo, and, importantly, that mitochondrial function is impaired in AAA. 

    In Study IV, angII-infused ApoE deficient mice received four intraperitoneal injections of miR-10b, starting three days before disease induction and continuing for four weeks. Treatment with miR-10b promoted AAA development, growth and rupture, associated with an increased elastin degradation. miR-10b has an active role in promoting experimental AAA progression by boosting aortic wall degradation. 

    In conclusion, glucose metabolism, mitochondrial function and microRNA are important pathways in the pathophysiology of AAA and promising targets for pharmacological modulation. 

    List of papers
    1. Parallel Murine and Human Aortic Wall Genomics Reveals Metabolic Reprogramming as Key Driver of Abdominal Aortic Aneurysm Progression
    Open this publication in new window or tab >>Parallel Murine and Human Aortic Wall Genomics Reveals Metabolic Reprogramming as Key Driver of Abdominal Aortic Aneurysm Progression
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    2021 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, E-ISSN 2047-9980, Vol. 10, no 17, article id e020231Article in journal (Refereed) Published
    Abstract [en]

    Background: While numerous interventions effectively interfered with abdominal aortic aneurysm (AAA) formation/progression in preclinical models, none of the successes translated into clinical success. Hence, a systematic exploration of parallel and divergent processes in clinical AAA disease and its 2 primary models (the porcine pancreatic elastase and angiotensin-II infusion [AngII] murine model) was performed to identify mechanisms relevant for aneurysm disease.

    Methods and Results: This study combines Movat staining and pathway analysis for histological and genomic comparisons between clinical disease and its models. The impact of a notable genomic signal for metabolic reprogramming was tested in a rescue trial (AngII model) evaluating the impact of 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15)-mediated interference with main glycolytic switch PFKFB3. Histological evaluation characterized the AngII model as a dissection model that is accompanied by adventitial fibrosis. The porcine pancreatic elastase model showed a transient inflammatory response and aortic dilatation, followed by stabilization and fibrosis. Normalization of the genomic responses at day 14 confirmed the self-limiting nature of the porcine pancreatic elastase model. Clear parallel genomic responses with activated adaptive immune responses, and particularly strong signals for metabolic switching were observed in human AAA and the AngII model. Rescue intervention with the glycolysis inhibitor PFK15 in the AngII model showed that interference with the glycolytic switching quenches aneurysm formation.

    Conclusions: Despite clear morphological contrasts, remarkable genomic parallels exist for clinical AAA disease and the AngII model. The metabolic response appears causatively involved in AAA progression and provides a novel therapeutic target. The clear transient genomic response classifies the porcine pancreatic elastase model as a disease initiation model.

    Place, publisher, year, edition, pages
    John Wiley & SonsWILEY, 2021
    Keywords
    abdominal aortic aneurysm, angiotensin II model, elastase model, gene expression, glycolysis, human, metabolic reprogramming
    National Category
    Surgery Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:uu:diva-456512 (URN)10.1161/JAHA.120.020231 (DOI)000693361200070 ()34420357 (PubMedID)
    Funder
    Swedish Research Council, 2019-01673Swedish Heart Lung Foundation, 20190556
    Available from: 2021-10-25 Created: 2021-10-25 Last updated: 2024-07-04Bibliographically approved
    2. Semaglutide Prevents Aortic Rupture and Dissection in the Angiotensin II Mouse Model
    Open this publication in new window or tab >>Semaglutide Prevents Aortic Rupture and Dissection in the Angiotensin II Mouse Model
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-527737 (URN)
    Available from: 2024-05-06 Created: 2024-05-06 Last updated: 2024-05-06
    3. Impaired Mitochondrial Function in Whole Abdominal Aortic Aneurysm
    Open this publication in new window or tab >>Impaired Mitochondrial Function in Whole Abdominal Aortic Aneurysm
    (English)Manuscript (preprint) (Other academic)
    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-527739 (URN)
    Available from: 2024-05-06 Created: 2024-05-06 Last updated: 2024-05-06
    4. miR-10b promotes aortic aneurysm formation and aortic rupture in angiotensin II-induced ApoE-deficient mice
    Open this publication in new window or tab >>miR-10b promotes aortic aneurysm formation and aortic rupture in angiotensin II-induced ApoE-deficient mice
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    2021 (English)In: Vascular pharmacology, ISSN 1537-1891, E-ISSN 1879-3649, Vol. 141, article id 106927Article in journal (Refereed) Published
    Abstract [en]

    Abdominal aortic aneurysm (AAA) is associated with increased plasma levels of microRNA (miR) -10b. 5 nmols of miR-10b or miR control was administrated to Apolipoprotein E-deficient mice three days prior implantation of osmotic mini-pumps containing angiotensin II, and for three additional times once a week, which increased expression of miR-10b in plasma. Animals receiving miR-10b had a mortality rate due to aortic rupture of 61% compared to 11% in the miR controls (p < 0.05). Further, miR- 10b resulted in an increased aneurysm formation and growth (p < 0.05), which was accompanied by increased elastin degradation, neutrophil and mast cell markers (p < 0.05). In conclusion, miR-10b is functionally affecting aneurysm development and rupture and not only a marker of AAA. More mechanistic studies are required to better understand miR-10b's role in AAA formation.

    Place, publisher, year, edition, pages
    Elsevier, 2021
    Keywords
    Aneurysm, Aorta, Treatment, miR-10b, microRNA
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:uu:diva-459191 (URN)10.1016/j.vph.2021.106927 (DOI)000756079500018 ()34715373 (PubMedID)
    Funder
    Swedish Research Council, 2019-01673Swedish Heart Lung Foundation, 2019-0556
    Note

    De två första författarna delar förstaförfattarskapet.

    Available from: 2021-11-22 Created: 2021-11-22 Last updated: 2024-06-13Bibliographically approved
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  • Public defence: 2024-08-30 09:15 lecture room Sonja Lyttkens, Uppsala
    Wrede, Sina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Interfaces in Dye-Sensitized Electrodes: From Fundamental Understanding to Devices2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Renewable energy solutions are vital in realising a more equitable and sustainable future. Among several solar light harvesting and storage technologies, dye-sensitized electrodes offer a cost-effective and flexible solution for solar cells or solar fuel devices. In order to enhance their solar conversion efficiency, however, the understanding of charge transfer pathways, particularly at the dye-sensitized surface, is crucial. Surface properties and interfacial processes have a great effect on the final device and are the overarching theme of this thesis.

    Firstly, intermolecular charge transfer across dye-sensitized surfaces was investigated, which play a role in both facilitating charge accumulation and affecting recombination rates and are therefore pivotal factors influencing solar cell efficiencies. Specifically, investigations on nickel oxide (NiO) and ZrO2 surfaces elucidate charge transfer mechanisms across the surface and their dependence on solvent properties, offering possible pathways for optimizing device performance.

    Due to their significance on dye-sensitized photocathodes, the chemical nature of NiO surface states was explored as they are known to affect charge recombination and the dye-regeneration processes. Spectroscopic insights during controlled atmosphere experiments highlight the influence of surface species generated by oxygen and water molecules on the electronic properties of NiO, particularly of hydroxide and oxygen-related species.

    Thirdly, the design and characterization of the first reported solid-state p-n tandem dye-sensitized solar cell was demonstrated. Such a cell can surpass the voltage limitations observed in liquid tandem cells and could achieve an open-circuit voltage of 1.4 V. These tandem cells hold promise for applications in solar fuel production, where high potential differences are essential for driving chemical reactions.

    List of papers
    1. Electron-hopping across dye-sensitized mesoporous NiO surfaces
    Open this publication in new window or tab >>Electron-hopping across dye-sensitized mesoporous NiO surfaces
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    2022 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 24, no 48, p. 29850-29861Article in journal (Refereed) Published
    Abstract [en]

    To gain a deeper understanding of the underlying charge processes in dye sensitized photocathodes, lateral electron hopping across dye-sensitized NiO photocathodes was investigated. For dye-sensitized systems, hole hopping across photoanodes has been studied extensively in the literature but no expansive studies on electron hopping in sensitized photocathodes exist today. Therefore, an organic p-type dye (TIP) with donor–linker–acceptor design, showing high stability and electrochemical reversibility, was used to study the electron transfer dynamics (electron-hopping) between dyes with temperature dependent spectroelectrochemistry and computational simulations. Besides intermolecular electron-hopping across the surface with a rate constant in the order of 105 s−1, our results show a second electron hopping pathway between NiO surface states with a rate constant in the order of 107 s−1, which precedes the electron hopping between the dyes. Upon application of a potential step negative enough to reduce both the dye and NiO surface states, the majority of NiO surface states need to be reduced before intermolecular electron transfer can take place. The results indicate that, in contrast to sensitized photoanodes where intermolecular charge transfer is known to influence recombination kinetics, intermolecular charge transport processes in TIP dye sensitized NiO photocathodes is less relevant because the fast electron transport between NiO surface states likely dominates recombination kinetics.

    Place, publisher, year, edition, pages
    Royal Society of Chemistry, 2022
    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-492680 (URN)10.1039/d2cp03249j (DOI)000894747500001 ()36468421 (PubMedID)
    Funder
    Swedish Energy Agency, 49278-1Linköpings universitet
    Available from: 2023-01-10 Created: 2023-01-10 Last updated: 2024-05-03Bibliographically approved
    2. Lateral Electron and Hole Hopping between Dyes on Mesoporous ZrO2: Unexpected Influence of Solvents with a Low Dielectric Constant
    Open this publication in new window or tab >>Lateral Electron and Hole Hopping between Dyes on Mesoporous ZrO2: Unexpected Influence of Solvents with a Low Dielectric Constant
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    2023 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 145, no 21, p. 11472-11476Article in journal (Refereed) Published
    Abstract [en]

    Lateral intermolecular charge transfer between photosensitizers on metal oxide substrates is important for the understanding on the overall working principles of dye-sensitized systems. Such studies usually concentrate on either hole or electron transfer separately and are conducted in solvents with a high dielectric constant (εs) that are known, however, to show a drastic decrease of the local dielectric constant close to the metal oxide surface. In the present study, both hole and electron hopping between organic donor–acceptor photosensitizers was experimentally investigated on PB6 dye-sensitized mesoporous ZrO2 films. The donor (close to the surface) and acceptor (away from surface) subunit of the PB6 dye were observed to be involved in hole and electron hopping, respectively. Hole and electron transfer kinetics were found to differ remarkably in high-εs solvents, but similar in solvents with εs < 12. This finding indicates that low-εs solvents maintain similar local dielectric constant values close to, and further away from, the semiconductor surface, which is different from the previously observed behavior of high dielectric constant solvents at a metal oxide interface.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2023
    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-510941 (URN)10.1021/jacs.3c01333 (DOI)000984202100001 ()37127024 (PubMedID)
    Funder
    Swedish Energy Agency, 49278-1Knut and Alice Wallenberg Foundation, KAW 2019.0071Wenner-Gren Foundations, UPD2021-0151
    Available from: 2023-09-13 Created: 2023-09-13 Last updated: 2024-05-03Bibliographically approved
    3. Insights into the surface of mesoporous nickel oxide and its interaction with oxygen and water
    Open this publication in new window or tab >>Insights into the surface of mesoporous nickel oxide and its interaction with oxygen and water
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-527655 (URN)
    Available from: 2024-05-03 Created: 2024-05-03 Last updated: 2024-05-03
    4. A solid-state p–n tandem dye-sensitized solar cell
    Open this publication in new window or tab >>A solid-state p–n tandem dye-sensitized solar cell
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    2024 (English)In: Sustainable Energy & Fuels, E-ISSN 2398-4902, Vol. 8, no 5, p. 1004-1011Article in journal (Refereed) Published
    Abstract [en]

    The development of p–n tandem dye-sensitized solar cells (t-DSCs) offers the potential for substantial open-circuit voltages, holding great promise for a wide range of applications, particularly in the fields of photovoltaics and photoelectrochemical devices. Most reported t-DSCs are liquid-based, and suffer from unsatisfactory stability due to the leakage of liquid electrolytes and photovoltage that is limited to the energy difference of the two utilized semiconductors. In this study, we present the first realization of a solid-state p–n tandem dye-sensitized solar cell that incorporates both p-type and n-type solid-state dye-sensitized solar cells (ssDSCs) by using a transparent indium-doped tin oxide (ITO) back contact for both sides. Notably, this tandem system shows a remarkable open-circuit voltage of 1.4 V, surpassing the constraints of its liquid-based counterparts. Although the performance variations between p-ssDSCs and n-ssDSCs hint at challenges related to charge recombination and the efficiency of p-ssDSCs, this study underscores the significant potential inherent in solid-state tandem configurations

    National Category
    Physical Chemistry Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-527654 (URN)10.1039/d3se01461d (DOI)
    Funder
    Swedish Energy Agency, 49278-1Swedish Research Council, 2019-00207
    Available from: 2024-05-03 Created: 2024-05-03 Last updated: 2024-05-03
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  • Public defence: 2024-08-30 10:15 Polhemsalen, Uppsala
    Eriksson, Gustav
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing.
    Robust and efficient discretizations of wave-dominated problems2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Partial differential equations appear in mathematical models that describe a wide range of physical phenomena, such as sound pressure waves in the air, the vibrations of solid structures, and the flow of fluids. Unfortunately, most of these problems can not be solved analytically using pen and paper. Instead, we turn to numerical methods and computer simulations to obtain approximate solutions. In this thesis, the focus is on high-order accurate finite difference methods for wave propagation and fluid dynamical problems. High-order finite difference methods are conceptually simple to design and implement efficiently on modern computers. However, special care must be taken close to boundaries to obtain robust and stable schemes. In this thesis, a class of finite difference operators with summation-by-parts (SBP) properties is used. These operators satisfy a discrete equivalent to intergration-by-parts which, when the boundary conditions are correctly imposed, enables a stability proof for the discretized scheme. Two such methods for imposing boundary conditions are studied and compared in the thesis, the simultaneous-approximation-term (SAT) method and the projection (P) method.

    In Paper I a high-order accurate finite difference discretization of the incompressible Navier-Stokes equations is presented, where the projection method is found to be more suitable for wall boundary conditions. In Paper II the SBP-SAT and SBP-P methods are compared for boundary and interface conditions to the dynamic beam equation and the dynamic Kirchoff-Love plate equation. A new SBP-P and hybrid SBP-P-SAT method is developed for non-conforming interface conditions to the second-order wave equation in Paper III. In Paper IV shape optimization problems constrained by the second-order wave equation are solved using high-order SBP-P-SAT finite difference discretizations. Theoretical aspects of the projection method are discussed in Paper V. In Paper VI SBP operators defined on Gauss-Lobatto quadrature points are used to derive an efficient and robust scheme for the Laplacian on complex geometries.

    List of papers
    1. Weak Versus Strong Wall Boundary Conditions for the Incompressible Navier-Stokes Equations
    Open this publication in new window or tab >>Weak Versus Strong Wall Boundary Conditions for the Incompressible Navier-Stokes Equations
    2022 (English)In: Journal of Scientific Computing, ISSN 0885-7474, E-ISSN 1573-7691, Vol. 92, no 3, article id 81Article in journal (Refereed) Published
    Abstract [en]

    The pressure-velocity formulation of the incompressible Navier-Stokes equations is solved using high-order finite difference operators satisfying a summation-by-parts property. Two methods for imposing Dirichlet boundary conditions (one strong and one weak) are presented and proven stable using the energy method. Additionally, novel diagonal-norm second-derivative finite difference operators are derived with highly improved boundary accuracy. Accuracy and convergence measurements are presented and verified against theoretical expectations. Numerical experiments also show that subtle effects close to solid walls are more efficiently captured with strong boundary condition imposition methods rather than weak (less degrees of freedom required).

    Place, publisher, year, edition, pages
    Springer NatureSpringer Nature, 2022
    Keywords
    Navier-Stokes, Wall boundary conditions, Incompressibility, Finite difference methods, High order accuracy
    National Category
    Computational Mathematics
    Research subject
    Scientific Computing with specialization in Numerical Analysis
    Identifiers
    urn:nbn:se:uu:diva-481940 (URN)10.1007/s10915-022-01941-5 (DOI)000830056900006 ()
    Funder
    Swedish Research Council, SNIC 2021/22-70Swedish Research Council, 2018-05973
    Available from: 2022-08-18 Created: 2022-08-18 Last updated: 2024-05-01Bibliographically approved
    2. Boundary and interface methods for energy stable finite difference discretizations of the dynamic beam equation
    Open this publication in new window or tab >>Boundary and interface methods for energy stable finite difference discretizations of the dynamic beam equation
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    2023 (English)In: Journal of Computational Physics, ISSN 0021-9991, E-ISSN 1090-2716, Vol. 476, article id 111907Article in journal (Refereed) Published
    Abstract [en]

    We consider energy stable summation by parts finite difference methods (SBP-FD) for the homogeneous and piecewise homogeneous dynamic beam equation (DBE). Previously the constant coefficient problem has been solved with SBP-FD together with penalty terms (SBP-SAT) to impose boundary conditions. In this work, we revisit this problem and compare SBP-SAT to the projection method (SBP-P). We also consider the DBE with discontinuous coefficients and present novel SBP-SAT, SBP-P, and hybrid SBP-SAT-P discretizations for imposing interface conditions. To demonstrate the methodology for two-dimensional problems, we also present a discretization of the piecewise homogeneous dynamic Kirchoff-Love plate equation based on the hybrid SBP-SAT-P method. Numerical experiments show that all methods considered are similar in terms of accuracy, but that SBP-P can be more computationally efficient (less restrictive time step requirement for explicit time integration methods) for both the constant and piecewise constant coefficient problems.

    Place, publisher, year, edition, pages
    Elsevier, 2023
    Keywords
    Dynamic beam equation, Boundary treatment, Summation by parts, Finite differences, High order methods
    National Category
    Computational Mathematics
    Research subject
    Scientific Computing with specialization in Numerical Analysis
    Identifiers
    urn:nbn:se:uu:diva-500751 (URN)10.1016/j.jcp.2023.111907 (DOI)000976854500001 ()
    Funder
    Swedish Research Council Formas, 2018-00925Swedish Research Council, 2017-04626
    Available from: 2023-04-24 Created: 2023-04-24 Last updated: 2024-05-01Bibliographically approved
    3. Non-conforming Interface Conditions for the Second-Order Wave Equation
    Open this publication in new window or tab >>Non-conforming Interface Conditions for the Second-Order Wave Equation
    2023 (English)In: Journal of Scientific Computing, ISSN 0885-7474, E-ISSN 1573-7691, Vol. 95, article id 92Article in journal (Refereed) Published
    Abstract [en]

    Imposition methods of interface conditions for the second-order wave equation with non-conforming grids is considered. The spatial discretization is based on high order finite differences with summation-by-parts properties. Previously presented solution methods for this problem, based on the simultaneous approximation term (SAT) method, have shown to introduce significant stiffness. This can lead to highly inefficient schemes. Here, two new methods of imposing the interface conditions to avoid the stiffness problems are presented: (1) a projection method and (2) a hybrid between the projection method and the SAT method. Numerical experiments are performed using traditional and order-preserving interpolation operators. Both of the novel methods retain the accuracy and convergence behavior of the previously developed SAT method but are significantly less stiff.

    Place, publisher, year, edition, pages
    Springer, 2023
    Keywords
    Summation-by-parts, High order, Non-conforming interface, Projection
    National Category
    Computational Mathematics
    Research subject
    Scientific Computing with specialization in Numerical Analysis
    Identifiers
    urn:nbn:se:uu:diva-502512 (URN)10.1007/s10915-023-02218-1 (DOI)000986400100001 ()
    Funder
    Swedish Research Council Formas, 2018-00925Uppsala University
    Available from: 2023-05-26 Created: 2023-05-26 Last updated: 2024-05-01Bibliographically approved
    4. Acoustic shape optimization using energy stable curvilinear finite differences
    Open this publication in new window or tab >>Acoustic shape optimization using energy stable curvilinear finite differences
    (English)Manuscript (preprint) (Other academic)
    National Category
    Computational Mathematics
    Identifiers
    urn:nbn:se:uu:diva-514581 (URN)10.48550/arXiv.2310.11956 (DOI)
    Funder
    Swedish Research Council Formas, 2018-00925Swedish Research Council, 2017-04626 VR
    Available from: 2023-10-18 Created: 2023-10-18 Last updated: 2024-05-01
    5. Operator-based analysis of summation-by-parts methods
    Open this publication in new window or tab >>Operator-based analysis of summation-by-parts methods
    (English)Manuscript (preprint) (Other academic)
    National Category
    Computational Mathematics
    Identifiers
    urn:nbn:se:uu:diva-527429 (URN)
    Available from: 2024-04-30 Created: 2024-04-30 Last updated: 2024-05-01
    6. Efficient discretization of the Laplacian on complex geometries
    Open this publication in new window or tab >>Efficient discretization of the Laplacian on complex geometries
    (English)Manuscript (preprint) (Other academic)
    National Category
    Computational Mathematics
    Identifiers
    urn:nbn:se:uu:diva-527427 (URN)
    Available from: 2024-04-30 Created: 2024-04-30 Last updated: 2024-05-01
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  • Public defence: 2024-08-30 13:00 Humanistiska teatern, 22-0008, Engelska parken, Uppsala
    Lindgren-Ciampi, Pontus
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Languages, Department of Modern Languages, Slavic Languages.
    Purism and National Identity: The construction of language and national identity in Serbian and Bulgarian nineteenth-century purist discourse2024Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The aim of this thesis is to analyse how the Serbian and Bulgarian nineteenth-century intellectual elites constructed concepts of national identity in media-discourses on linguistic purity, as well as how these purist discourses were situated within their unique Balkan cultural-historical contexts. The dissertation places itself in the field of historical sociolinguistics which suggests a contextual approach to language change in the past and the discourses shaping them. Nevalainen (2015) has subsumed this approach under the integrationist notion of “layered simultaneity”. This notion implies that the meanings which a specific sociocultural community—the Balkan nineteenth-century intellectuals, in the case of this study—simultaneously produces in discourse, are always the outcome of an infinitely complex interplay of historical, social, political, ideological, and cultural contingencies, relations, and entanglements.        

    The material examined in this study consists of fifteen Serbian and Bulgarian periodicals, four pamphlets, and one book. These publications were either originally published in the periodical press or constituted a vital part of debates that had been initiated in the periodical press. All were published in the period of the Serbian and Bulgarian ‘National Revivals’ (1804–1878) and represent platforms where the members of the expanding bourgeois public sphere debated the questions of purism, language, and national identity. The primary sources stretch from 1830 to 1874. This period was formative for the construction of complex and interacting sets of cultural practices and symbols which were intended to define the nation externally – in relation to other nations and unite it internally. According to the then prevailing Romanticist cultural ideology, language was the prime definer of cultural difference and the utmost expression of the unicity of a people.

    Purist discourses on language and national identity are always embedded in specific historical and cultural contexts and can hardly be understood without taking these dynamic frameworks into consideration. The broad picture that emerges from the results of this thesis shows that the convergences and divergences in the purist discourses of the Serbian and Bulgarian intellectual elites are dependent on several contextual factors. A convergent factor was the common starting point in the Pax Slavia Orthodoxa, where higher cultural meanings were defined by the ideology of the Orthodox churches. Yet, divergent were the historical and cultural contexts in which these elites entered into dialogue with the ideological paradigms of Enlightenment and Romanticism that to such and eminent degree shaped the cultural side of modern European nation-building.               

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  • Public defence: 2024-08-30 13:15 B41, Uppsala
    Centanni, Maddalena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Model-based evaluation of biomarkers for dose-individualization in oncology2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In contemporary cancer care, several issues are garnering increasing attention. First, significant inter-individual variability among patients challenges the effectiveness of a uniform dosing approach. Second, the escalating costs of treatments necessitate careful consideration when selecting doses and other clinical modalities, including biomarkers, while balancing economic constraints. The objective of this thesis was to evaluate techniques for tailoring doses and guiding clinical decisions for cancer patients through the development and implementation of various models, with the aim of improving treatment outcomes in terms of both efficacy and safety. 

    Through a model-based framework integrating sunitinib pharmacokinetics (PK), adverse events, biomarkers, tumor dynamics and their correlation with overall survival, different treatment schedules and biomarkers for dose individualization were explored. Based on the proposed threshold values, neutrophil count (ANC) and the biomarker sVEGFR-3 were identified as offering the best balance between safety and efficacy for sunitinib in gastro-intestinal stromal tumors (GIST) and could thus serve as viable guides for dose individualization in clinical practice. Given its routine measurement, dose adjustments guided by ANC may be preferable in clinical settings. The feasibility of utilizing diastolic blood pressure (dBP) for personalized dose optimization of tyrosine-kinase inhibitors in clinical settings is constrained due to its reliance on repeated measurements taken at consistent intervals. 

    For axitinib and sunitinib, model-based predictions using multiple clinical measurements were more accurate than single sample measurements. For drugs with high unexplained inter-individual variability (IIV), low residual variability (RUV), and low inter-occasional variability (IOV), therapeutic drug monitoring (TDM) provided a more accurate measure of exposure. Conversely, for drugs with low IIV and high RUV and IOV, pharmacogenetic profiling was more suitable. However, the prevalence of pharmacogenetic subtypes and the challenge of measuring exposure metrics like AUC through limited sampling also influence these approaches.

    This research further emphasizes how model structure affects the outcomes of cost-effectiveness analyses and consequently the potential implications for regulatory decisions. Although creating mechanistic models for these analyses demands substantial initial effort, the growing need for model-based analyses in drug approval is likely to make these models more accessible for future compounds. Moreover, such models are expected to be more biologically plausible and therefore more reflective of reality and offer flexibility for exploring alternative dosages with limited additional effort.

    Using model-based assessments, the relationship between the PK and PK-pharmacodynamic (PKPD) profiles of adverse events arising from therapies for acute lymphocytic leukemia were established. For PEG-asparaginase, the PK model categorized 93% of patients who experienced inactivation against PEG-asparaginase as having an increased clearance, and 86% of patients who did not experience hypersensitivity as maintaining stable clearance throughout their asparaginase treatment. This approach marks a potential method for predicting inactivation by identifying early changes in clearance. For vincristine, model-informed precision dosing was shown to reduce the incidence of vincristine-induced peripheral neuropathy (VIPN) from 62.1% to 53.9%, though the clinical impact remains modest.

    List of papers
    1. Model-based Dose Individualization of Sunitinib in Gastrointestinal Stromal Tumors
    Open this publication in new window or tab >>Model-based Dose Individualization of Sunitinib in Gastrointestinal Stromal Tumors
    2020 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 26, no 17, p. 4590-4598Article in journal (Refereed) Published
    Abstract [en]

    Purpose: Various biomarkers have been proposed for sunitinib therapy in gastrointestinal stromal tumor (GIST). However, the lack of "real-life" comparative studies hampers the selection of the most appropriate one. We, therefore, set up a pharmacometric simulation framework to compare each proposed biomarker. Experimental Design: Models describing relations between sunitinib exposure, adverse events (hand-foot syndrome, fatigue, hypertension, and neutropenia), soluble VEGFR (sVEGFR)-3, and overall survival (OS) were connected to evaluate the differences in survival and adverse events under different dosing algorithms. Various fixed dosing regimens [4/2 (weeks on/weeks off) or 2/1 (50 mg), and continuous daily dosing (37.5 mg)] and individualization approaches [concentration-adjusted dosing (CAD), toxicity-adjusted dosing (TAD), and sVEGFR-3-adjusted dosing (VAD)] were explored following earlier suggested blood sampling schedules and dose-reduction criteria. Model-based forecasts of biomarker changes were evaluated for predictive accuracy and the advantage of a model-based dosing algorithm was evaluated for clinical implementation. Results: The continuous daily dosing regimen was predicted to result in the longest survival. TAD (24.5 months) and VAD (25.5 months) increased median OS as compared with a fixed dose schedule (19.9 and 21.5 months, respectively) and CAD (19.7 and 21.3 months, respectively), without markedly raising the risk of intolerable toxicities. Changes in neutrophil count and sVEGFR-3 were accurately forecasted in the majority of subjects (> 65%), based on biweekly blood sampling. Conclusions: Dose adjustments based on the pharmacodynamic biomarkers neutrophil count and sVEGFR-3 can increase OS while retaining drug safety. Future efforts could explore the possibility of incorporating a model-based dose approach in clinical practice to increase dosing accuracy for these biomarkers.

    Place, publisher, year, edition, pages
    AMER ASSOC CANCER RESEARCH, 2020
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-421262 (URN)10.1158/1078-0432.CCR-20-0887 (DOI)000567799100021 ()32522885 (PubMedID)
    Funder
    Swedish Cancer Society, CAN 2017/626
    Available from: 2020-10-08 Created: 2020-10-08 Last updated: 2024-05-06Bibliographically approved
    2. Model-Based Biomarker Selection for Dose Individualization of Tyrosine-Kinase Inhibitors
    Open this publication in new window or tab >>Model-Based Biomarker Selection for Dose Individualization of Tyrosine-Kinase Inhibitors
    2020 (English)In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 11, article id 316Article in journal (Refereed) Published
    Abstract [en]

    Tyrosine-kinase inhibitors (TKIs) demonstrate high inter-individual variability with respect to safety and efficacy and would therefore benefit from dose or schedule adjustments. This study investigated the efficacy, safety, and economical aspects of alternative dosing options for sunitinib in gastro-intestinal stromal tumors (GIST) and axitinib in metastatic renal cell carcinoma (mRCC). Dose individualization based on drug concentration, adverse effects, and sVEGFR-3 was explored using a modeling framework connecting pharmacokinetic and pharmacodynamic models, as well as overall survival. Model-based simulations were performed to investigate four different scenarios: (I) the predicted value of high-dose pulsatile schedules to improve clinical outcomes as compared to regular daily dosing, (II) the potential of biomarkers for dose individualizations, such as drug concentrations, toxicity measurements, and the biomarker sVEGFR-3, (III) the cost-effectiveness of biomarker-guided dose-individualizations, and (IV) model-based dosing approaches versus standard sample-based methods to guide dose adjustments in clinical practice. Simulations from the axitinib and sunitinib frameworks suggest that weekly or once every two weeks high-dosing result in lower overall survival in patients with mRCC and GIST, compared to continuous daily dosing. Moreover, sVEGFR-3 appears a safe and cost-effective biomarker to guide dose adjustments and improve overall survival (euro36 784.- per QALY). Model-based estimations were for biomarkers in general found to correctly predict dose adjustments similar to or more accurately than single clinical measurements and might therefore guide dose adjustments. A simulation framework represents a rapid and resource saving method to explore various propositions for dose and schedule adjustments of TKIs, while accounting for complicating factors such as circulating biomarker dynamics and inter-or intra-individual variability.

    Place, publisher, year, edition, pages
    FRONTIERS MEDIA SA, 2020
    Keywords
    tyrosine kinase inhibitor, dose individualization, population modeling, PKPD, pharmacometrics
    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-410893 (URN)10.3389/fphar.2020.00316 (DOI)000525633300001 ()32226388 (PubMedID)
    Funder
    Swedish Cancer Society, CAN 2017/626
    Available from: 2020-05-25 Created: 2020-05-25 Last updated: 2024-05-06Bibliographically approved
    3. Optimization of blood pressure measurement practices for pharmacodynamic analyses of tyrosine-kinase inhibitors
    Open this publication in new window or tab >>Optimization of blood pressure measurement practices for pharmacodynamic analyses of tyrosine-kinase inhibitors
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    2023 (English)In: Clinical and Translational Science, ISSN 1752-8054, E-ISSN 1752-8062, Vol. 16, no 1, p. 73-84Article in journal (Refereed) Published
    Abstract [en]

    Blood pressure measurements form a critical component of adverse event monitoring for tyrosine kinase inhibitors, but might also serve as a biomarker for dose titrations. This study explored the impact of various sources of within-individual variation on blood pressure readings to improve measurement practices and evaluated the utility for individual- and population-level dose selection. A pharmacokinetic-pharmacodynamic modeling framework was created to describe circadian blood pressure changes, inter- and intra-day variability, changes from dipper to non-dipper profiles, and the relationship between drug exposure and blood pressure changes over time. The framework was used to quantitatively evaluate the influence of physiological and pharmacological aspects on blood pressure measurements, as well as to compare measurement techniques, including office-based, home-based, and ambulatory 24-h blood pressure readings. Circadian changes, as well as random intra-day and inter-day variability, were found to be the largest sources of within-individual variation in blood pressure. Office-based and ambulatory 24-h measurements gave rise to potential bias (>5 mmHg), which was mitigated by model-based estimations. Our findings suggest that 5-8 consecutive, home-based, measurements taken at a consistent time around noon, or alternatively within a limited time frame (e.g., 8.00 a.m. to 12.00 p.m. or 12.00 p.m. to 5.00 p.m.), will give rise to the most consistent blood pressure estimates. Blood pressure measurements likely do not represent a sufficiently accurate method for individual-level dose selection, but may be valuable for population-level dose identification. A user-friendly tool has been made available to allow for interactive blood pressure simulations and estimations for the investigated scenarios.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2023
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-501780 (URN)10.1111/cts.13423 (DOI)000869632500001 ()36152309 (PubMedID)
    Funder
    Swedish Cancer Society, 20 1226 PjF
    Available from: 2023-05-16 Created: 2023-05-16 Last updated: 2024-05-06Bibliographically approved
    4. Comparative Analysis of Pharmacoeconomic and Pharmacometric Modeling in the Cost-Effectiveness Evaluation of Sunitinib Therapy with Therapeutic Drug Monitoring for Gastrointestinal Stromal Tumors
    Open this publication in new window or tab >>Comparative Analysis of Pharmacoeconomic and Pharmacometric Modeling in the Cost-Effectiveness Evaluation of Sunitinib Therapy with Therapeutic Drug Monitoring for Gastrointestinal Stromal Tumors
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Cost-effectiveness analyses (CEAs) increasingly use models to predict long-term outcomes and translate trial data to real-world settings. Model structure uncertainty affects these predictions. This study evaluates a pharmacometric modeling approach against traditional pharmacoeconomic models for CEAs of sunitinib in gastrointestinal stromal tumors (GIST).

    Methods: A two-arm trial comparing sunitinib 37.5 mg daily to no treatment was simulated using a pharmacometric model framework. Four existing pharmacoeconomic models (time-to-event (TTE) and Markov models) were applied to the survival data and linked to logistic regression models describing the toxicity data (neutropenia, thrombocytopenia, hypertension, fatigue and hand-foot syndrome (HFS)) to create pharmacoeconomic model frameworks. All five frameworks were used to simulate clinical outcomes and sunitinib treatment costs, including a therapeutic drug monitoring (TDM) scenario.

    Results: The pharmacometric model predicted sunitinib treatment costs an additional 147,065 euro/QALY compared to no treatment, with deviations -23.2% (discrete Markov), -17.8%% (continuous Markov), +3.8% (TTE Weibull) and +27.8% (TTE exponential) from the pharmacoeconomic model frameworks. The pharmacometric models captured the change in toxicity over treatment cycles (e.g. increased HFS incidence until cycle 4 with a decrease thereafter), a pattern not observed in the pharmacoeconomic models (e.g. stable HFS incidence over all treatment cycles). Furthermore, the pharmacoeconomic models excessively forecasted the percentage of patients encountering sub-therapeutic concentrations of sunitinib over the course of time (pharmacoeconomic: 24.6% at cycle 2 to 98.7% at cycle 16, versus pharmacometric: 13.7% at cycle 2 to 34.1% at cycle 16).

    Conclusions: Model structure significantly influences CEA predictions. The pharmacometric model more closely represented real-world toxicity trends and drug exposure changes. The relevance of these findings depends on the specific question a CEA seeks to address.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-527636 (URN)
    Available from: 2024-05-03 Created: 2024-05-03 Last updated: 2024-05-06
    5. Pharmacogenetic testing or Therapeutic Drug Monitoring: A Quantitative Framework
    Open this publication in new window or tab >>Pharmacogenetic testing or Therapeutic Drug Monitoring: A Quantitative Framework
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Pharmacogenetic profiling and therapeutic drug monitoring (TDM) have both been proposed to manage inter-individual variability (IIV) in drug exposure. However, determining the most effective approach for estimating exposure for a particular drug remains a challenge. This study aimed to quantitatively assess the circumstances in which pharmacogenetic profiling may outperform TDM in estimating drug exposure, under three sources of variability (IIV, inter-occasion variability (IOV) and residual unexplained variability (RUV)).

    Methods: Pharmacokinetic models were selected from the literature corresponding to drugs for which pharmacogenetic profiling and TDM are both clinically considered approaches for dose-individualization. The models were used to simulate relevant drug exposures (Ctrough or AUC) under varying degrees of IIV, IOV and RUV.

    Results: Six drug cases were selected from the literature. Model-based simulations demonstrated that the percentage of patients for whom pharmacogenetic exposure predictions is superior to TDM differs for each drug case: tacrolimus (11.0%), tamoxifen (12.7%), efavirenz (49.2%), vincristine (49.6%), risperidone (48.1%) and 5-FU (100%). Generally, in the presence of higher unexplained IIV in combination with lower RUV and IOV, exposure was best estimated by TDM, whereas under lower unexplained IIV in combination with higher IOV or RUV, pharmacogenetic profiling was preferred. 

    Conclusions: For the drugs with relatively low RUV and IOV (e.g., tamoxifen and tacrolimus), TDM estimated true exposure the best. Conversely, for drugs with similar or lower unexplained IIV (e.g., efavirenz or 5-FU, respectively) combined with relatively high RUV, pharmacogenetic profiling provided the most accurate estimate for most patients. However, genotype prevalence and the relative influence of genotypes on the PK, as well as the ability of TDM to accurately estimate AUC with a limited number of samples, had an impact. The results could be used to support clinical decision making when considering other factors, such as the probability for severe side effects. 

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-527633 (URN)
    Available from: 2024-05-03 Created: 2024-05-03 Last updated: 2024-05-06
    6. Increase in peg-asparaginase clearance as a predictor for inactivation in patients with acute lymphoblastic leukemia
    Open this publication in new window or tab >>Increase in peg-asparaginase clearance as a predictor for inactivation in patients with acute lymphoblastic leukemia
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    2024 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 38, no 4, p. 712-719Article in journal (Refereed) [Artistic work] Published
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-527127 (URN)10.1038/s41375-024-02153-6 (DOI)
    Funder
    Swedish Childhood Cancer Foundation, PR2021-0064
    Available from: 2024-04-24 Created: 2024-04-24 Last updated: 2024-05-06
    7. Model-Informed Precision Dosing to Reduce Vincristine-Induced Peripheral Neuropathy in Pediatric Patients: A Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis
    Open this publication in new window or tab >>Model-Informed Precision Dosing to Reduce Vincristine-Induced Peripheral Neuropathy in Pediatric Patients: A Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis
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    2023 (English)In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 63, no 2, p. 197-209Article in journal (Refereed) Published
    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-527126 (URN)10.1007/s40262-023-01336-1 (DOI)
    Funder
    Swedish Cancer Society, CAN 20 1226 PjFSwedish Childhood Cancer Foundation, PR2021-0064Uppsala University
    Available from: 2024-04-24 Created: 2024-04-24 Last updated: 2024-05-06
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  • Public defence: 2024-08-30 13:15 Brusewitzsalen, Uppsala
    Sylvan, Siri
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Government.
    Toward a New Democratic Theory of Expertise2024Doctoral thesis, monograph (Other academic)
    Abstract [en]

    In contemporary society, citizens have access to an unprecedented amount of expertise. However, the tremendous growth of scientific knowledge in late modernity has not translated into greater certainty. Instead, citizens are under pressure to become experts themselves, “experts on experts”. How should we understand the democratic problem reflected in the present crisis of expertise, and what could it mean to respond constructively to it? This thesis addresses this overarching question by critically examining the existing normative approaches to expertise in democracy, and by developing a new approach, drawing on the political thought of Hannah Arendt. 

    Scientific knowledge has often been regarded as apolitical and serving a purely functional role in democratic politics. This assumption no longer appears tenable, given the insights from Science and Technology Studies (STS). In this dissertation, I take the theoretical challenge from STS as my starting point to examine existing normative perspectives on the relationship between expertise and democracy. The two predominant approaches, termed ‘the instrumental’ and ‘the procedural approach’, both embody a Kantian notion of public reason as the foundation of universal legitimacy. However, in my critical examination, I find both approaches insufficient, as they overlook the more existential dimension of the relationship between knowledge and politics. 

    To develop a new approach, I turn to the political thought of the 20th-century thinker Hannah Arendt. By unpacking Arendt’s notion of world alienation, I develop a new interpretation of the democratic problem reflected in the contemporary crisis of expertise. According to this interpretation, the fundamental issue is not that citizens could fail in their new role as experts on experts, but rather that they could resign from it completely. 

    In response to this predicament, I examine three of Arendt’s central concepts – authority, the public, and judgment – and show how they can be utilized to construct a new normative approach to expertise. According to this approach, which I call ‘existential’, experts play a crucial role in democracy as world-builders, constructing public spaces for making sense of knowledge. In their role as world-builders, the experts support public judgment – not by providing citizens a critical standard for rationally adjudicating between competing claims, but by constructing the public contexts where the burden of judgment can be experienced as meaningful and tolerable.

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  • Public defence: 2024-08-30 13:19 101195, Heinz-Otto Kreiss, Uppsala
    Shimchenko, Marina
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology.
    Optimizing Energy Efficiency of Concurrent Garbage Collection2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The increasing energy consumption of the Information and Communication Technology sector amid climate change concerns underscores the urgency for energy efficiency improvements in computing. This thesis focuses on optimizing the energy efficiency of Java, a widely used programming language, and its implementation in OpenJDK. Specifically, our focus is on enhancing the energy efficiency of concurrent garbage collection.

    As a starting point for our work, we assessed the energy consumption of various garbage collection algorithms within OpenJDK, establishing concurrent garbage collectors as the least energy-efficient. This prompted further investigation into methods to enhance their energy consumption. We investigated methods like dynamically adjusting the memory size required by an application based on how much of the computer's processors one wants to use for garbage collection. We also looked into scheduling garbage collection tasks to run on specific types of computer cores that use less energy and running these tasks when the computer is not being actively used. 

    We implemented all the abovementioned strategies in one of Java’s concurrent garbage collectors, ZGC. Through our experiments, we showed that these techniques can significantly reduce the amount of energy used by garbage collection without slowing down the performance of the programs running on the computer. Overall, our research contributes to making computing more environmentally friendly by finding ways to use less energy while still getting the same results.

    List of papers
    1. Analysing and Predicting Energy Consumption of Garbage Collectors in OpenJDK
    Open this publication in new window or tab >>Analysing and Predicting Energy Consumption of Garbage Collectors in OpenJDK
    2022 (English)In: MPLR '22: Proceedings of the 19th International Conference on Managed Programming Languages and Runtimes / [ed] Elisa Gonzalez Boix; Tobias Wrigstad, New York: Association for Computing Machinery (ACM), 2022, p. 3-15Conference paper, Published paper (Refereed)
    Abstract [en]

    Sustainable computing needs energy-efficient software. This paper explores the potential of leveraging the nature of software written in managed languages: increasing energy efficiency by changing a program’s memory management strategy without altering a single line of code. To this end, we perform comprehensive energy profiling of 35 Java applications across four benchmarks. In many cases, we find that it is possible to save energy by replacing the default G1 collector with another without sacrificing performance. Furthermore, potential energy savings can be even higher if performance regressions are permitted. Inspired by these results, we study what the most energy-efficient GCs are to help developers prune the search space for energy profiling at a low cost. Finally, we show that machine learning can be successfully applied to the problem of finding an energy-efficient GC configuration for an application, reducing the cost even further.

    Place, publisher, year, edition, pages
    New York: Association for Computing Machinery (ACM), 2022
    Keywords
    Energy, GC, Java, Machine Learning
    National Category
    Computer Sciences
    Research subject
    Computer Science
    Identifiers
    urn:nbn:se:uu:diva-490859 (URN)10.1145/3546918.3546925 (DOI)978-1-4503-9696-7 (ISBN)
    Conference
    MPLR '22: 19th International Conference on Managed Programming Languages and Runtimes, Brussels, Belgium, September 14-15, 2022
    Projects
    JVMReCo
    Funder
    Swedish Foundation for Strategic Research, SM19-0059
    Available from: 2022-12-15 Created: 2022-12-15 Last updated: 2024-05-06Bibliographically approved
    2. Heap Size Adjustment with CPU Control
    Open this publication in new window or tab >>Heap Size Adjustment with CPU Control
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    2023 (English)In: PROCEEDINGS OF THE 20TH ACM SIGPLAN INTERNATIONAL CONFERENCE ON MANAGED PROGRAMMING LANGUAGES AND RUNTIMES, MPLR 2023 / [ed] Moss, E Bruno, R, ASSOC COMPUTING MACHINERY , 2023, p. 114-128Conference paper, Published paper (Refereed)
    Abstract [en]

    This paper explores automatic heap sizing where developers let the frequency of GC expressed as a target overhead of the application's CPU utilisation, control the size of the heap, as opposed to the other way around. Given enough headroom and spare CPU, a concurrent garbage collector should be able to keep up with the application's allocation rate, and neither the frequency nor duration of GC should impact throughput and latency. Because of the inverse relationship between time spent performing garbage collection and the minimal size of the heap, this enables trading memory for computation and conversely, neutral to an application's performance. We describe our proposal for automatically adjusting the size of a program's heap based on the CPU overhead of GC. We show how our idea can be relatively easily integrated into ZGC, a concurrent collector in OpenJDK, and study the impact of our approach on memory requirements, throughput, latency, and energy.

    Place, publisher, year, edition, pages
    ASSOC COMPUTING MACHINERY, 2023
    Keywords
    JVM, Garbage Collection, Heap sizing policy
    National Category
    Computer Sciences
    Identifiers
    urn:nbn:se:uu:diva-523058 (URN)10.1145/3617651.3622988 (DOI)001142913500011 ()979-8-4007-0380-5 (ISBN)
    Conference
    20th ACM SIGPLAN International Conference on Managed Programming Languages and Runtimes (MPLR), OCT 22, 2023, Cascais, PORTUGAL
    Available from: 2024-02-16 Created: 2024-02-16 Last updated: 2024-05-06Bibliographically approved
    3. Scheduling Garbage Collection for Energy Efficiency on Asymmetric Multicore Processors
    Open this publication in new window or tab >>Scheduling Garbage Collection for Energy Efficiency on Asymmetric Multicore Processors
    2024 (English)In: The Art, Science, and Engineering of Programming, E-ISSN 2473-7321, Vol. 8, no 3, article id 10Article in journal (Refereed) Published
    Abstract [en]

    The growing concern for energy efficiency in the Information and Communication Technology (ICT) sector has prompted the exploration of resource management techniques. While hardware architectures, such as single-ISA asymmetric multicore processors (AMP), offer potential energy savings, there is still untapped potential for software optimizations. This paper aims to bridge this gap by investigating the scheduling of garbage collection (GC) activities on a heterogeneous architecture with both performance cores (“p-cores”) and energy cores (“e-cores”) to achieve energy savings.

    Our study focuses on the concurrent ZGC collector in the context of Java Virtual Machines (JVM), as the energy aspect is not well studied in the context of latency-sensitive Java workloads. By comparing the energy efficiency, performance, latency, and memory utilization of executing GC on p-cores versus e-cores, we present compelling findings.

    We demonstrate that scheduling GC work on e-cores overall leads to approximately 3% energy savings without performance and mean latency degradation while requiring no additional effort from developers. Overall energy reduction can increase to 5.3±0.0225% by tuning the number of e-cores (still not changing the program!).

    Our findings highlight the practicality and benefits of scheduling GC on e-cores, showcasing the potential for energy savings in heterogeneous architectures running Java workloads while meeting critical latency requirements. Our research contributes to the ongoing efforts toward achieving a more sustainable and efficient ICT sector.

    Place, publisher, year, edition, pages
    Aspect-Oriented Software Association, 2024
    Keywords
    Energy-efficiency, Java, Garbage Collection, Asymmetric multicore processors
    National Category
    Computer Sciences
    Identifiers
    urn:nbn:se:uu:diva-526870 (URN)10.22152/programming-journal.org/2024/8/10 (DOI)
    Funder
    Swedish Research Council, 2020-05346Swedish Foundation for Strategic Research, SM19-0059
    Available from: 2024-04-19 Created: 2024-04-19 Last updated: 2024-06-28Bibliographically approved
    4. Monk: opportunistic scheduling to delay horizontal scaling
    Open this publication in new window or tab >>Monk: opportunistic scheduling to delay horizontal scaling
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The goal of this work is to explore the opportunistic scheduling of a fully concurrent GC, namely ZGC. The main idea is that scheduling GC threads while the CPU is idle allows for upscaling server workloads at a higher average CPU utilization since latency starts degrading at a higher CPU utilization. We showed that opportunistic scheduling can allow SPECjbb2015 to process up to 15% more requests under 25ms. 

    Keywords
    JVM, Garbage Collection, OS scheduling
    National Category
    Computer Sciences
    Identifiers
    urn:nbn:se:uu:diva-527461 (URN)
    Available from: 2024-05-02 Created: 2024-05-02 Last updated: 2024-05-06
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  • Public defence: 2024-09-13 13:15 Polhemsalen, Uppsala
    Gunnarsson, Viktor
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Electrical Engineering, Signals and Systems.
    Binaural Modeling for High-Fidelity Spatial Audio2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The enjoyment of reproduced sound and music is a prime pleasure for many, and the high-fidelity reproduction of binaural audio is integral to many applications in augmented and virtual reality. This thesis introduces a framework for binaural headphone auralization of sound systems, together with an in-depth analysis and proposed solutions to address sources of coloration within the signal chain.

    The framework includes a novel method for binaural auralization of microphone array impulse responses. Employing a hybrid parametric approach, it utilizes causal multichannel Wiener filtering to synthesize the directional response of the ear, as described by head-related transfer functions (HRTFs), using the microphone array and a model of its acoustic properties. A time-domain polynomial matrix framework is employed for filter computations and direct and reflected sound is treated separately. Results demonstrate a small perceptual difference to reference measured binaural room impulse responses. 

    Additionally, the thesis addresses the impact of binaural measurement uncertainty and proposes a new measurement technique for HRTFs and headphone transfer functions (HpTFs). The method is based on a cardioid microphone array for open ear canal measurements. Results indicate that the method significantly reduces measurement uncertainty compared to omnidirectional measurements in the ear canal.  

    Moreover, a phase pre-processing method for HRTFs is introduced that reduces spatial phase variability of the HRTF set at high frequencies while retaining correct interaural coherence for diffuse sound. It is demonstrated that the HRTF phase pre-processing greatly reduces spectral coloration in headphone simulation of amplitude panning on virtual speakers. The method also improves performance in binaural rendering of microphone array recordings. 

    Finally, the thesis presents a comprehensive model for addressing coloration at the ear-signal level inherent in amplitude panning on speaker arrays. The analysis focuses on pairwise panning on symmetrical speaker setups and monaural correction filters are proposed that are robust to head movements around the sweet spot. The proposed filters are found to mitigate the phantom source elevation effect in stereophonic panning and enhance the perceived spectral similarity between discrete and panned sound sources, with effectiveness contingent on the speaker setup geometry.

    List of papers
    1. Binaural Auralization of Microphone Array Room Impulse Responses Using Causal Wiener Filtering
    Open this publication in new window or tab >>Binaural Auralization of Microphone Array Room Impulse Responses Using Causal Wiener Filtering
    2021 (English)In: IEEE-ACM TRANSACTIONS ON AUDIO SPEECH AND LANGUAGE PROCESSING, ISSN 2329-9290, Vol. 29, p. 2899-2914Article in journal (Refereed) Published
    Abstract [en]

    Binaural room auralization involves Binaural Room Impulse Responses (BRIRs). Dynamic binaural synthesis (i.e., head-tracked presentation) requires BRIRs for multiple head poses. Artificial heads can be used to measure BRIRs, but BRIR modeling from microphone array room impulse responses (RIRs) is becoming popular since personalized BRIRs can be obtained for any head pose with low extra effort. We present a novel framework for estimating a binaural signal from microphone array signals, using causal Wiener filtering and polynomial matrix formalism. The formulation places no explicit constraints on the geometry of the microphone array and enables directional weighting of the estimation error. A microphone noise model is used for regularization and to balance filter performance and noise gain. A complete procedure for BRIR modeling from microphone array RIRs is also presented, employing the proposed Wiener filtering framework. An application example illustrates the modeling procedure using a 19-channel spherical microphone array. Direct and reflected sound segments are modeled separately. The modeled BRIRs are compared to measured BRIRs and are shown to be waveform-accurate up to at least 1.5 kHz. At higher frequencies, correct statistical properties of diffuse sound field components are aimed for. A listening test indicates small perceptual differences to measured BRIRs. The presented method facilitates fast BRIR data set acquisition for use in dynamic binaural synthesis and is a viable alternative to Ambisonics-based binaural room auralization.

    Place, publisher, year, edition, pages
    Institute of Electrical and Electronics Engineers (IEEE)Institute of Electrical and Electronics Engineers (IEEE), 2021
    Keywords
    Microphone arrays, Estimation, Ear, Speech processing, Acoustics, Array signal processing, Magnetic heads, Beamforming, binaural recording, binaural room impulse response (BRIR), head-related transfer function (HRTF), interaural coherence, MIMO, virtual acoustic environment, virtual artificial head (VAH)
    National Category
    Signal Processing Fluid Mechanics and Acoustics
    Identifiers
    urn:nbn:se:uu:diva-456921 (URN)10.1109/TASLP.2021.3110340 (DOI)000697817100002 ()
    Funder
    Vinnova
    Available from: 2021-10-25 Created: 2021-10-25 Last updated: 2024-05-06Bibliographically approved
    2. Robust Binaural Measurements in the Ear Canal Using a Two-Microphone Array
    Open this publication in new window or tab >>Robust Binaural Measurements in the Ear Canal Using a Two-Microphone Array
    2023 (English)Conference paper, Published paper (Refereed)
    Abstract [en]

    Accurate binaural rendering requires accurate reproduction of binaural signals at the eardrum, which in turn requires adequate binaural technology. We propose a method to measure head-related & headphone transfer functions with a two-microphone array in the ear canal. By implementing a cardioid directional pattern, the forward and reverse propagating sound pressure components are measured separately, thus avoiding the influence of standing waves in the ear canal on the measurements. The method is useful in filter design for individualized binaural rendering that, compared with the blocked-canal method, does not assume acoustically 'open' headphones to be used. The method also mitigates the excessive sensitivity to microphone position of regular open-canal measurements. Validation measurements are conducted using a natural scale replica ear and a MEMS microphone array.

    Place, publisher, year, edition, pages
    The Audio Engineering Society, 2023
    Keywords
    Headphone measurements, HRTFs, Cardioid
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-525352 (URN)
    Conference
    AES 2023 International Conference on Spatial and Immersive Audio, Huddersfield, UK, August 23-25, 2023
    Available from: 2024-03-21 Created: 2024-03-21 Last updated: 2024-05-06Bibliographically approved
    3. A practical method for HRTF phase pre-processing
    Open this publication in new window or tab >>A practical method for HRTF phase pre-processing
    2022 (English)In: Proceedings of the 24th International Congress on Acoustics, International Congress on Acoustics (ICA) , 2022, article id ABS-0222Conference paper, Published paper (Refereed)
    Abstract [en]

    Pre-processing of HRTF phase has proved useful to improve binaural rendering of order-limited spherical harmonics (SH) signals. The adjustment is typically applied at high frequencies and allows to reduce magnitude errors for directional sound field components. This article proposes a practical method for HRTF phase pre-processing using linear phase above a cutoff frequency, and a direction-dependent phase offset to maintain correct diffuse-field interaural coherence. Two applications are discussed - filter design for binaural rendering of microphone array or SH-signals, and reduced coloration in virtual source panning on virtual speaker setups. Factors influencing the perceptual transparency of the phase modification are evaluated subjectively and objectively.

    Place, publisher, year, edition, pages
    International Congress on Acoustics (ICA), 2022
    Keywords
    Auralization, Ambisonics decoding, HRTF interpolation
    National Category
    Media Engineering
    Identifiers
    urn:nbn:se:uu:diva-509587 (URN)
    Conference
    24th International Congress on Acoustics, Gyeongju, Korea, October 24-28, 2022
    Available from: 2023-08-21 Created: 2023-08-21 Last updated: 2024-05-06Bibliographically approved
    4. Spectral Correction of Audio Objects in Stereophonic Rendering
    Open this publication in new window or tab >>Spectral Correction of Audio Objects in Stereophonic Rendering
    2024 (English)In: IEEE/ACM Transactions on Audio, Speech, and Language Processing, ISSN 2329-9290, Vol. 32, p. 3141-3156Article in journal (Refereed) Published
    Abstract [en]

    This paper presents a comprehensive model for ear-signal level coloration in stereo amplitude panning, enabling the calculation of monaural correction filters that equalize the average coloration over a small area around the sweet spot. The model takes into account the speaker setup geometry, listener Head-Related Transfer-Functions (HRTFs), the employed pan-law, the direct-to-reflected sound ratio, and the correlation between the speaker signals at the listening position. Coloration in diffuse sound reproduction is also investigated. The coloration model is validated using binaural room impulse response measurements, and the correction filters are found to effectively reduce the difference in composite ear power spectrum between a discrete and virtual center source. A listening test on the perceived spectral difference between these two cases, with stereo setups in front of and behind the listener, indicate that the correction filter improves timbral similarity between a virtual and discrete center source for rear speaker panning. The test also indicates that remaining unmodeled coloration sources are large, especially for front panning. However, a second listening test finds that the correction filter improves accuracy of perceived direction in front panning by mitigating the phantom image elevation effect.

    Place, publisher, year, edition, pages
    Institute of Electrical and Electronics Engineers (IEEE), 2024
    National Category
    Signal Processing
    Identifiers
    urn:nbn:se:uu:diva-527266 (URN)10.1109/TASLP.2024.3414283 (DOI)001256333200003 ()
    Available from: 2024-04-26 Created: 2024-04-26 Last updated: 2024-07-17Bibliographically approved
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