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  • 1.
    Abelein, Axel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Modulation of Alzheimer's amyloid β peptide self-assembly: Insights into molecular mechanisms of peptide aggregation associated with Alzheimer's disease2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Misfolding of proteins and peptides is closely linked to several neurodegenerative disorders, among them Alzheimer's disease (AD), the most prominent example of brain diseases. The self-assembly of the amyloid β peptide (Aβ) into amyloid fibrils is one histologic hallmark of AD. A detailed knowledge about the underlying mechanism(s) of Aβ aggregation is crucial for advances toward a fundamental understanding of the disease, which may promote the search for and design of efficient therapeutics. The work presented in this thesis deals with modulation of the aggregation process by various compounds, i.e. small organic molecules (e.g. lacmoid and Congo red), surfactants and metal ions. These results provide insight into the molecular mechanism of modulator interactions and interference with Aβ and its aggregation pathways. Applying a combination of kinetic and dynamic studies as well as structural investigations we characterized the molecular interactions between Aβ and aggregation modulators in terms of microscopic rate constants, conformational preferences and thermodynamics. An important conclusion is that these modulators form highly dynamic complexes with Aβ, with life-times on the timescale of milliseconds. Despite the similar exchange dynamics, the effect on peptide aggregation is modulator-specific and fibril formation can be accelerated, retarded or inhibited by their interactions. In summary, Aβ self-assembly is governed by microscopic kinetic and dynamic processes that can be altered by aggregation modulators. Further elucidation of these mechanisms is beneficial for the understanding and therapeutic intervention of amyloid diseases.

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  • 2.
    Abelein, Axel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Modulation of amyloid β peptide self-assembly: Aggregation mechanisms associated with Alzheimer's disease2013Licentiate thesis, comprehensive summary (Other academic)
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  • 3.
    Abelein, Axel
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The zinc ion – a minimal chaperone mimicking agent forretardation of amyloid β peptide fibril formationManuscript (preprint) (Other academic)
  • 4.
    Abelein, Axel
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lang, Lisa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lendel, Christofer
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Corrigendum to “Transient small molecule interactions kinetically modulate amyloid β peptide self-assembly” [FEBS Lett. 586 (2012) 3991–3995]2013In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 587, no 9, p. 1452-1452Article in journal (Other academic)
  • 5. Abelein, Axel
    et al.
    Lang, Lisa
    Lendel, Christofer
    Gräslund, Astrid
    Danielsson, Jens
    Transient small molecule interactions kinetically modulate amyloid β peptide self-assembly.2012In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 586, no 22, p. 3991-3995, article id S0014-5793(12)00757-0Article in journal (Refereed)
    Abstract [en]

    Small organic molecules, like Congo red and lacmoid, have been shown to modulate the self-assembly of the amyloid β peptide (Aβ). Here, we show that Aβ forms NMR invisible non-toxic co-aggregates together with lacmoid as well as Congo red. We find that the interaction involves two distinct kinetic processes and at every given time point only a small fraction of Aβ is in the co-aggregate. These weak transient interactions kinetically redirect the aggregation prone Aβ from self-assembling into amyloid fibrils. These findings suggest that even such weak binders might be effective as therapeutics against pathogenic protein aggregation.

  • 6.
    Abidine, Yara
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Liu, Lifeng
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Wallén, Oskar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Trybala, Edward
    Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Olofsson, Sigvard
    Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Bergström, Tomas
    Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Cellular Chondroitin Sulfate and the Mucin-like Domain of Viral Glycoprotein C Promote Diffusion of Herpes Simplex Virus 1 While Heparan Sulfate Restricts Mobility2022In: Viruses, E-ISSN 1999-4915, Vol. 14, no 8, article id 1836Article in journal (Refereed)
    Abstract [en]

    The diffusion of viruses at the cell membrane is essential to reach a suitable entry site and initiate subsequent internalization. Although many viruses take advantage of glycosaminoglycans (GAG) to bind to the cell surface, little is known about the dynamics of the virus–GAG interactions. Here, single-particle tracking of the initial interaction of individual herpes simplex virus 1 (HSV-1) virions reveals a heterogeneous diffusive behavior, regulated by cell-surface GAGs with two main diffusion types: confined and normal free. This study reports that different GAGs can have competing influences in mediating diffusion on the cells used here: chondroitin sulfate (CS) enhances free diffusion but hinders virus attachment to cell surfaces, while heparan sulfate (HS) promotes virus confinement and increases entry efficiency. In addition, the role that the viral mucin-like domains (MLD) of the HSV-1 glycoprotein C plays in facilitating the diffusion of the virus and accelerating virus penetration into cells is demonstrated. Together, our results shed new light on the mechanisms of GAG-regulated virus diffusion at the cell surface for optimal internalization. These findings may be extendable to other GAG-binding viruses.

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  • 7.
    Abramenkovs, Andris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity2017In: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 188, no 6, p. 597-604Article in journal (Refereed)
    Abstract [en]

    Uncontrolled generation of DNA double-strand breaks (DSBs) in cells is regarded as a highly toxic event that threatens cell survival. Radiation-induced DNA DSBs are commonly measured by pulsed-field gel electrophoresis, microscopic evaluation of accumulating DNA damage response proteins (e.g., 53BP1 or gamma-H2AX) or flow cytometric analysis of gamma-H2AX. The advantage of flow cytometric analysis is that DSB formation and repair can be studied in relationship to cell cycle phase or expression of other proteins. However, gamma-H2AX is not able to monitor repair kinetics within the first 60 min postirradiation, a period when most DSBs undergo repair. A key protein in non-homologous end joining repair is the catalytic subunit of DNA-dependent protein kinase. Among several phosphorylation sites of DNA-dependent protein kinase, the threonine at position 2609 (T2609), which is phosphorylated by ataxia telangiectasia mutated (ATM) or DNA-dependent protein kinase catalytic subunit itself, activates the end processing of DSB. Using flow cytometry, we show here that phosphorylation at T2609 is faster in response to DSBs than gamma-H2AX. Furthermore, flow cytometric analysis of T2609 resulted in a better representation of fast repair kinetics than analysis of gamma-H2AX. In cells with reduced ligase IV activity, and wild-type cells where DNA-dependent protein kinase activity was inhibited, the reduced DSB repair capacity was observed by T2609 evaluation using flow cytometry. In conclusion, flow cytometric evaluation of DNA-dependent protein kinase T2609 can be used as a marker for early DSB repair and gives a better representation of early repair events than analysis of gamma-H2AX.

  • 8.
    Adhikari, Deepak
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Flohr, Gilian
    Hogeschool Leiden, Zernikedreef 11,2333 CK Leiden, The Netherlands.
    Gorre, Nagaraju
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Shen, Yan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Yang, Hairu
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lan, Zijian
    University of Louisville Health Sciences Center, Louisville, Kentucky, USA.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles2009In: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 15, no 12, p. 765-770Article in journal (Refereed)
    Abstract [en]

    To maintain the length of reproductive life in a woman, it is essential that most of her ovarian primordial follicles are maintained in a quiescent state to provide a continuous supply of oocytes. However, our understanding of the molecular mechanisms that control the quiescence and activation of primordial follicles is still in its infancy. In this study, we provide some genetic evidence to show that the tumor suppressor tuberous sclerosis complex 2 (Tsc2), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the dormancy of primordial follicles. In mutant mice lacking the Tsc2 gene in oocytes, the pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in oocytes. This results in depletion of follicles in early adulthood, causing premature ovarian failure (POF). Our results suggest that the Tsc1-Tsc2 complex mediated suppression of mTORC1 activity is indispensable for maintenance of the dormancy of primordial follicles, thus preserving the follicular pool, and that mTORC1 activity in oocytes promotes follicular activation. Our results also indicate that deregulation of Tsc/mTOR signaling in oocytes may cause pathological conditions of the ovary such as infertility and POF.

  • 9.
    Adler, Jeremy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Parmryd, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Quantification of Colocalisation; Co-Occurrence, Correlation, Empty Voxels, Regions of Interest and Thresholding2014In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 2, p. 602A-602AArticle in journal (Other academic)
    Abstract [en]

    Measuring colocalisation is not straightforward with a plethora of coefficients that encapsulate different definitions. Measurements may also be implemented differently. Not only do measurements differ; interconversion is impossible making comparisons challenging. There is a need to cull coefficients and for clear definitions of what precisely is meant by colocalisation in individual studies. Colocalisation can be considered to have two components; co-occurrence which reports whether the fluorophores are found together and correlation which reports on the similarity in their patterns of intensity.

  • 10.
    Adler, Jeremy
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sintorn, Ida-Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Strand, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Parmryd, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Conventional analysis of movement on non-flat surfaces like the plasma membrane makes Brownian motion appear anomalous2019In: Communications Biology, E-ISSN 2399-3642, Vol. 2, article id 12Article in journal (Refereed)
  • 11. Ahn, Young O.
    et al.
    Mahinthichaichan, Paween
    Lee, Hyun Ju
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ouyang, Hanlin
    Kaluka, Daniel
    Yeh, Syun-Ru
    Arjona, Davinia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Rousseau, Denis L.
    Tajkhorshid, Emad
    Ädelroth, Pia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gennis, Robert B.
    Conformational coupling between the active site and residues within the K-C-channel of the Vibrio cholerae cbb(3)-type (C-family) oxygen reductase2014In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 42, p. E4419-E4428Article in journal (Refereed)
    Abstract [en]

    The respiratory chains of nearly all aerobic organisms are terminated by proton-pumping heme-copper oxygen reductases (HCOs). Previous studies have established that C-family HCOs contain a single channel for uptake from the bacterial cytoplasm of all chemical and pumped protons, and that the entrance of the K-C-channel is a conserved glutamate in subunit III. However, the majority of the K-C-channel is within subunit I, and the pathway from this conserved glutamate to subunit I is not evident. In the present study, molecular dynamics simulations were used to characterize a chain of water molecules leading from the cytoplasmic solution, passing the conserved glutamate in subunit III and extending into subunit I. Formation of the water chain, which controls the delivery of protons to the K-C-channel, was found to depend on the conformation of Y241(Vc), located in subunit I at the interface with subunit III. Mutations of Y241(Vc) (to A/F/H/S) in the Vibrio cholerae cbb(3) eliminate catalytic activity, but also cause perturbations that propagate over a 28-angstrom distance to the active site heme b(3). The data suggest a linkage between residues lining the KC-channel and the active site of the enzyme, possibly mediated by transmembrane helix alpha 7, which contains both Y241(Vc) and the active site crosslinked Y255(Vc), as well as two Cu-B histidine ligands. Other mutations of residues within or near helix alpha 7 also perturb the active site, indicating that this helix is involved in modulation of the active site of the enzyme.

  • 12.
    Akkuratov, Evgeny E.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    The Biophysics of Na+,K+-ATPase in neuronal health and disease2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Na+,K+-ATPase is one of the most important proteins in the mammalian cell. It creates sodium and potassium gradients which are fundamental for the membrane potential and sodium-dependent secondary active transport. It has a second role in the cell as a receptor that by binding chemicals from the cardiotonic steroids family, the most knowledgeable of them is ouabain, triggers various signaling pathways in the cell which regulate gene activation, proliferation, apoptosis, etc. It has been shown that several severe neurological diseases are associated with mutations in the Na+,K+-ATPase encoding genes. Although Na+,K+-ATPase was discovered already in 1957 by the Danish scientist Jens Skou, the knowledge about the function of this enzyme  is still not complete.

     

    In the studies included in the thesis, we have learned more about the function of Na+,K+-ATPase in different aspects of health and disease. In study I we showed a mechanism of ouabain-dependent regulation of the NMDA receptor, one of the most important receptors in the nervous system, via binding with Na+,K+-ATPase. This allows us to look at the Na+,K+-ATPase as regulator via protein-protein interaction. In study II we investigated a different aspect of Na+,K+-ATPase functioning – to look at how binding of ouabain to Na+,K+-ATPase activates a number of signaling cascades by looking at the phosphoproteome status of the cells. This allows us to see the whole picture of ouabain-mediated cascades and further characterize them. In study III we focused on the role of Na+,K+-ATPase in severe epileptic encephalopathy caused by a mutation in the ATP1A1 gene. We performed a molecular and cellular study to describe how mutations affects protein structure and function and found that this mutation converts the ion pump to a nonspecific leak channel. In study IV we performed a translational study of the most common mutation for rapid-onset dystonia-parkinsonism. We studied how this mutation affects the nervous system on the protein-, cellular-, and organism level and found that the complete absence of ultraslow afterhyperpolarization (usAHP) could explain gait disturbances found in patients. In the on-going study we showed that Na+,K+-ATPase can oligomerize and that this effect is triggered by ouabain binding to the Na+,K+-ATPase. In this study, we utilized a novel fluorescence labelling approach and used biophysical techniques with single molecule sensitivity to track Na+,K+-ATPase interactions.

     

    In summary, we applied biophysical and molecular methods to study different aspects of the function of Na+,K+-ATPase, and gained insights that could be helpful not only for answering fundamental questions about Na+,K+-ATPase but also to find a treatment for patients with diseases associated with mutations in this protein.

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  • 13.
    Akkuratov, Evgeny E.
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Sorrell, Frankie
    Souza, Vasco
    Paukar, Martin
    Picton, Laurence
    Jans, Daniel
    Andersson, Magnus
    Fritz, Nicolas
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Zhang, Xiaoqun
    Liebmann, Thomas
    KTH.
    Lindskog, Maria
    KTH.
    Svenningsson, Per
    Miles, Gareth
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Aperia, Anita
    KTH.
    Mechanisms by which the T613M mutation causes mobility and gait disturbances in Rapid-Onset Dystonia-ParkinsonismManuscript (preprint) (Other academic)
  • 14.
    Akkuratov, Evgeny E.
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Westin, Linda
    Vazquez-Juarez, Erika
    de Marothy, Minttu
    Melnikova, Aleksandra K
    Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia, 119234.
    Blom, Hans
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lindskog, Maria
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Aperia, Anita
    Ouabain Modulates the Functional Interaction Between Na,K-ATPase and NMDA Receptor.2020In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 57, no 10, p. 4018-4030Article in journal (Refereed)
    Abstract [en]

    The N-methyl-D-aspartate (NMDA) receptor plays an essential role in glutamatergic transmission and synaptic plasticity and researchers are seeking for different modulators of NMDA receptor function. One possible mechanism for its regulation could be through adjacent membrane proteins. NMDA receptors coprecipitate with Na,K-ATPase, indicating a potential interaction of these two proteins. Ouabain, a mammalian cardiotonic steroid that specifically binds to Na,K-ATPase and affects its conformation, can protect from some toxic effects of NMDA receptor activation. Here we have examined whether NMDA receptor activity and downstream effects can be modulated by physiological ouabain concentrations. The spatial colocalization between NMDA receptors and the Na,K-ATPase catalytic subunits on dendrites of cultured rat hippocampal neurons was analyzed with super-resolution dSTORM microscopy. The functional interaction was analyzed with calcium imaging of single hippocampal neurons exposed to 10 μM NMDA in presence and absence of ouabain and by determination of the ouabain effect on NMDA receptor-dependent long-term potentiation. We show that NMDA receptors and the Na,K-ATPase catalytic subunits alpha1 and alpha3 exist in same protein complex and that ouabain in nanomolar concentration consistently reduces the calcium response to NMDA. Downregulation of the NMDA response is not associated with internalization of the receptor or with alterations in its state of Src phosphorylation. Ouabain in nanomolar concentration elicits a long-term potentiation response. Our findings suggest that ouabain binding to a fraction of Na,K-ATPase molecules that cluster with the NMDA receptors will, via a conformational effect on the NMDA receptors, cause moderate but consistent reduction of NMDA receptor response at synaptic activation.

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  • 15.
    Akpe, Victor
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Photophysical and Chemical Approaches to Cellular Biophysics2008Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    The central theme in this thesis is reversibility. Two main attempts has been made to approach reversibility in cellular systems from both chemical and physical points of view. Reversibility of immunolabeling of proteins on the cell surface has been adressed by development of new fluorescent substances optimized for CALI (Chromophore-Assisted Laser Inactivation of protein). Aluminum phthalocyanine (AlPc) is here identified to be a good candidate for a new generation of fluorophores for efficient hydroxyl radical generation. It is shown that cells can be reversibly labeled with antibody-AlPc conjugates. In experiments on living cells the AlPcs were not only active as classic fluorophores but also as photocatalytic substances with destaining properties. Reversibility of cell immobilization is also reported, where cells cultured in microstructures were immobilized and 3D supported using hydrogels. Hydrogel formulation and application was optimized to achieve a system where both viability and ease of use was satisfied. Gel reversibility was actualized with pH and enzyme treatment. The developped method offers the possibility of stop flow culturing cells in controlled and reusable 3D environments.

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  • 16.
    Akpe, Victor
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Nyokong, Tebello
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Photophysics and photochemistry of zinc, aluminium and tin octakis (benzylthio) phthalocyanines2008Report (Other academic)
  • 17.
    Akpe, Victor
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Vernet, Erik
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Gräslund, Torbjörn
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Characterization studies of aluminum phthalocyanine binding to antibodies from SKBR 3 cell line2008Report (Other academic)
  • 18.
    Alam, Md Khorshed
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Vinklarek, Ivo
    Gröbner, Gerhard
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Johansson, Lennart B-Å
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sachl, Radek
    Fluorescence Studies of Lipid Distribution in Bilayers under Oxidative Stress2019In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 116, no 3, p. 508A-508AArticle in journal (Other academic)
  • 19.
    Albet-Torres, Nuria
    et al.
    School of Natural Sciences, Linnaeus University, Kalmar, Sweden .
    Gunnarsson, Anders
    Chalmers University of Technology, Dept. of Applied Physics, Gothenburg, Sweden .
    Persson, Malin
    School of Natural Sciences, Linnaeus University, Kalmar, Sweden .
    Balaz, Martina
    School of Natural Sciences, Linnaeus University, Kalmar, Sweden .
    Höök, Fredrik
    Chalmers University of Technology, Dept. of Applied Physics, Gothenburg, Sweden .
    Månsson, Alf
    School of Natural Sciences, Linnaeus University, Kalmar, Sweden .
    Molecular motors on lipid bilayers and silicon dioxide: different driving forces for adsorption2010In: Soft Matter, ISSN 1744-683X, E-ISSN 1744-6848, Vol. 6, no 14, p. 3211-3219Article in journal (Refereed)
    Abstract [en]

    Understanding how different types of interactions govern adsorption of the myosin motor fragment heavy meromyosin (HMM) onto different substrates is important in functional studies of actomyosin and for the development of motor powered lab-on-a-chip applications. In this study, we have combined in vitro motility assays and quartz crystal microbalance with dissipation (QCM-D) monitoring to investigate the underlying adsorption mechanisms of HMM onto supported lipid bilayers in comparison with pure and silanized SiO2. The QCM-D results, combined with data showing actin transportation by HMM adsorbed onto positively charged supported lipid bilayers, suggest reversible HMM surface adsorption via the negatively charged coiled-coil tail region. In contrast, the QCM-D data for HMM adsorption onto negatively charged lipids support a model according to which HMM adsorbs onto negatively charged surfaces largely via the positively charged actin binding regions. Adsorption studies at low (30-65 mM) and high (185-245 mM) ionic strengths onto piranha cleaned SiO2 surfaces (contact angle < 20 degrees) support this general model. However, unlike the situation for charged lipids, rinsing in high ionic strength solution caused only partial HMM desorption from SiO2, without restoration of actin propulsion by the remaining HMM molecules. This suggests that mechanisms other than electrostatic interactions are involved in the tethering of HMM heads to SiO2 surfaces. An expanded model for HMM adsorption is formulated on the basis of the data and the potential of the results for nanotechnological applications of actomyosin is discussed.

  • 20.
    Albet-Torres, Nuria
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Månsson, Alf
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Long-Term Storage of Surface-Adsorbed Protein Machines2011In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 27, no 11, p. 7108-7112Article in journal (Refereed)
    Abstract [en]

    The effective and simple long-term storage of complex functional proteins is critical in achieving commercially viable biosensors. This issue is particularly challenging in recently proposed types of nanobiosensors, where molecular-motor-driven transportation substitutes microfluidics and forms the basis for novel detection schemes. Importantly, therefore, we here describe that delicate heavy meromyosin (HMM)-based nanodevices (HMM motor fragments adsorbed to silanized surfaces and actin bound to HMM) fully maintain their function when stored at -20 degrees C for more than a month. The mechanisms for the excellent preservation of acto-HMM motor function upon repeated freeze thaw cycles are discussed. The results are important to the future commercial implementation of motor-based nanodevices and are of more general value to the long-term storage of any protein-based bionanodevice.

  • 21.
    Alikhani, Nyosha
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Berglund, Anna-Karin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Engmann, Tanja
    Spånning, Erika
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Voegtle, F. -Nora
    Pavlov, Pavel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Meisinger, Chris
    Langer, Thomas
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Targeting Capacity and Conservation of PreP Homologues Localization in Mitochondria of Different Species2011In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 410, no 3, p. 400-410Article in journal (Refereed)
    Abstract [en]

    Mitochondrial presequences and other unstructured peptides are degraded inside mitochondria by presequence proteases (PrePs) identified in Arabidopsis thaliana (AtPreP), humans (hPreP), and yeast (Cym1/Mop112). The presequences of A. thaliana and human PreP are predicted to consist of 85 and 29 amino acids, respectively, whereas the Saccharomyces cerevisiae Cym1/Mop112 presequence contains only 7 residues. These differences may explain the reported targeting of homologous proteins to different mitochondrial subcompartments. Here we have investigated the targeting capacity of the PreP homologues' presequences. We have produced fusion constructs containing N-terminal portions of AtPreP(1-125), hPreP(1-69), and Cym1(1-40) coupled to green fluorescent protein (GFP) and studied their import into isolated plant, mammalian, and yeast mitochondria, followed by mitochondrial subfractionation. Whereas the AtPreP presequence has the capacity to target GFP into the mitochondrial matrix of all three species, the hPreP presequence only targets GFP to the matrix of mammalian and yeast mitochondria. The Cym1/Mop112 presequence has an overall much weaker targeting capacity and only ensures mitochondrial sorting in its host species yeast. Revisiting the submitochondrial localization of Cym1 revealed that endogenous Cym1/Mop112 is localized to the matrix space, as has been previously reported for the plant and human homologues. Moreover, complementation studies in yeast show that native AtPreP restores the growth phenotype of yeast cells lacking Cym1, demonstrating functional conservation.

  • 22. Alizadehheidari, Mohammadreza
    et al.
    Werner, Erik
    Noble, Charleston
    Nyberg, Lena
    Fritzsche, Joachim
    Mehlig, Bernhard
    Tegenfeldt, Jonas
    Ambjoernsson, Tobias
    Persson, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Westerlund, Fredrik
    Nanoconfined Circular DNA2014In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 2, p. 274A-274AArticle in journal (Other academic)
    Abstract [en]

    Nanofluidic channels have become a versatile tool to manipulate single DNA molecules. They allow investigation of confined single DNA molecules from a fundamental polymer physics perspective as well as for example in DNA barcoding techniques.

  • 23. Allahverdiyeva, Yagut
    et al.
    Mamedov, Fikret
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström.
    Mäenpää, Pirkko
    Vass, Imre
    Aro, Eva-Mari
    Modulation of photosynthetic electron transport in the absence of terminal electron acceptors: characterization of the rbcL deletion mutant of tobacco2005In: Biochimica et Biophysica Acta (BBA) - Bioenergetics, ISSN 0005-2728, Vol. 1709, no 1, p. 69-83Article in journal (Refereed)
  • 24.
    Allard, Peter
    Stockholm University, Faculty of Science.
    Nuclear magnetic resonance studies of nucleotide-protein interactions and of peptide structure-dynamics relations1994Doctoral thesis, comprehensive summary (Other academic)
  • 25.
    Allison, Timothy M.
    et al.
    Biomolecular Interaction Centre, School of Physical and Chemical Sciences, University of Canterbury, Christchurch, New Zealand.
    Degiacomi, Matteo T.
    Department of Physics, Durham University, Durham, UK.
    Marklund, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Jovine, Luca
    Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
    Elofsson, Arne
    Science for Life Laboratory and Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.
    Benesch, Justin L. P.
    Department of Chemistry, University of Oxford, Oxford, UK.
    Landreh, Michael
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet – Biomedicum, Stockholm, Sweden.
    Complementing machine learning‐based structure predictions with native mass spectrometry2022In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 31, no 6, article id e4333Article in journal (Refereed)
    Abstract [en]

    The advent of machine learning-based structure prediction algorithms such as AlphaFold2 (AF2) and RoseTTa Fold have moved the generation of accurate structural models for the entire cellular protein machinery into the reach of the scientific community. However, structure predictions of protein complexes are based on user-provided input and may require experimental validation. Mass spectrometry (MS) is a versatile, time-effective tool that provides information on post-translational modifications, ligand interactions, conformational changes, and higher-order oligomerization. Using three protein systems, we show that native MS experiments can uncover structural features of ligand interactions, homology models, and point mutations that are undetectable by AF2 alone. We conclude that machine learning can be complemented with MS to yield more accurate structural models on a small and large scale.

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  • 26.
    Almaqwashi, Ali A.
    et al.
    Northeastern Univ, Dept Phys, Boston, MA 02115 USA..
    Andersson, Johanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Chalmers, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden..
    Lincoln, Per
    Chalmers, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden..
    Rouzina, Ioulia
    Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA..
    Westerlund, Fredrik
    Chalmers, Dept Biol & Biol Engn, S-41296 Gothenburg, Sweden..
    Williams, Mark C.
    Northeastern Univ, Dept Phys, Boston, MA 02115 USA..
    Dissecting the Dynamic Pathways of Stereoselective DNA Threading Intercalation2016In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, no 6, p. 1255-1263Article in journal (Refereed)
    Abstract [en]

    DNA intercalators that have high affinity and slow kinetics are developed for potential DNA-targeted therapeutics. Although many natural intercalators contain multiple chiral subunits, only intercalators with a single chiral unit have been quantitatively probed. Dumbbell-shaped DNA threading intercalators represent the next order of structural complexity relative to simple intercalators, and can provide significant insights into the stereoselectivity of DNA-ligand intercalation. We investigated DNA threading intercalation by binuclear ruthenium complex [mu-dppzip(phen)(4)Ru-2](4+) (Piz). Four Piz stereoisomers are defined by the chirality of the intercalating subunit (Ru(phen)(2)dppz) and the distal subunit (Ru(phen)(2)ip), respectively, each of which can be either right-handed (Delta) or left-handed (Lambda). We used optical tweezers to measure single DNA molecule elongation due to threading intercalation, revealing force-dependent DNA intercalation rates and equilibrium dissociation constants. The force spectroscopy analysis provided the zero-force DNA binding affinity, the equilibrium DNA-ligand elongation Delta x(eq), and the dynamic DNA structural deformations during ligand association x(on) and dissociation x(off). We found that Piz stereoisomers exhibit over 20-fold differences in DNA binding affinity, from a K-d of 27 +/- 3 nM for (Delta,Lambda)-Piz to a K-d of 622 +/- 55 nM for (Lambda,Delta)-Piz. The striking affinity decrease is correlated with increasing Delta x(eq) from 0.30 +/- 0.02 to 0.48 +/- 0.02 nm and x(on) from 0.25 +/- 0.01 to 0.46 +/- 0.02 nm, but limited x(off) changes. Notably, the affinity and threading kinetics is 10-fold enhanced for right-handed intercalating subunits, and 2- to 5-fold enhanced for left-handed distal subunits. These findings demonstrate sterically dispersed transition pathways and robust DNA structural recognition of chiral intercalators, which are critical for optimizing DNA binding affinity and kinetics.

  • 27.
    Alvarez-Rodriguez, Manuel
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Ntzouni, Maria
    Linköping University, Faculty of Medicine and Health Sciences, Core Facility.
    Wright, Dominic
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Khan, Kabirul Islam
    Chattogram Vet and Anim Sci Univ, Bangladesh.
    Lopez-Bejar, Manel
    Univ Autonoma Barcelona, Spain.
    Martinez-Serrano, Cristina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Chicken seminal fluid lacks CD9-and CD44-bearing extracellular vesicles2020In: Reproduction in domestic animals, ISSN 0936-6768, E-ISSN 1439-0531, Vol. 55, no 3, p. 293-300Article in journal (Refereed)
    Abstract [en]

    The avian seminal fluid (SF) is a protein-rich fluid, derived from the testis, the rudimentary epididymis and, finally, from the cloacal gland. The SF interacts with spermatozoa and the inner cell lining of the female genital tract, to modulate sperm functions and female immune responsiveness. Its complex proteome might either be free or linked to extracellular vesicles (EVs) as it is the case in mammals, where EVs depict the tetraspanin CD9; and where those EVs derived from the epididymis (epididymosomes) also present the receptor CD44. In the present study, sperm-free SF from Red Jungle Fowl, White Leghorn and an advanced intercross (AIL, 12th generation) were studied using flow cytometry of the membrane marker tetraspanin CD9, Western blotting of the membrane receptor CD44 and electron microscopy in non-enriched (whole SF) or enriched fractions obtained by precipitation using a commercial kit (Total Exosome Precipitation Solution). Neither CD9- nor CD44 could be detected, and the ultrastructure confirmed the relative absence of EVs, raising the possibility that avian SF interacts differently with the female genitalia as compared to the seminal plasma of mammals.

  • 28.
    Alvelid, Jonatan
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Automating STED microscopy for functional and structural live-cell imaging2021Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Optical microscopy imaging methods are today invaluable tools for studies in life sciences as they allow visualization of biological systems, tissues, cells, and sub-cellular compartments from millimetres down to nanometres. The invention and development of nanoscopy in the past 20 years has pushed fluorescence microscopy down to the nanoscale, reaching beyond the natural diffraction limit of light that does not allow focusing of visible light below sizes of around 200 nm, and into the realm of what was previously only thought possible with electron microscopy. The superior spatial resolution does however come at a price, including complex sample preparation, prolonged recording times, increased illumination doses, and limited fields of view. Stimulated emission depletion (STED) microscopy is one of the techniques that can deliver nanoscale resolution in a range of biological systems, but with all the above-mentioned costs. However, with the right sample the technique can deliver single nanometre spatial resolution, and with the right considerations live-cell imaging is more than possible.

    In this thesis I present the development of a flexible STED microscope with methodological advancements in a range of directions that aim at facilitating the use of STED microscopy in life sciences and optimising the information extraction from the image data. The developments firstly focused on automation of the data acquisition, to allow the recording of imaging data both with a higher throughput and correlated with fast dynamic processes. I also implemented improved image analysis, both in terms of high throughput and precision as well as in connection with the data acquisition. Furthermore, I worked on control software development, with novel strategies to unify the control software of microscopes and to allow development and implementation of novel acquisition schemes. I also utilized novel fluorophores, to improve live-cell and multicolour possibilities and allow a wider range of applications in STED microscopy. Lastly, I developed a novel concept that takes advantage of STED. Additionally, I present applications of the microscope and image analysis in diverse biological samples such as mammalian cells, tissue sections, and bacteria. Altogether, this work aims at presenting new tools for an imaging technique that is already well-established, to contribute to further development, facilitation of novel experiments, and expansion of the range of applications.

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    kappa
  • 29.
    Alvelid, Jonatan
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bucci, Andrea
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Testa, Ilaria
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Far Red‐Shifted CdTe Quantum Dots for Multicolour Stimulated Emission Depletion Nanoscopy2022In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 24, no 3Article in journal (Refereed)
    Abstract [en]

    Stimulated emission depletion (STED) nanoscopy is a widely used nanoscopy technique. Two-colour STED imaging in fixed and living cells is standardised today utilising both fluorescent dyes and fluorescent proteins. Solutions to image additional colours have been demonstrated using spectral unmixing, photobleaching steps, or long-Stokes-shift dyes. However, these approaches often compromise speed, spatial resolution, and image quality, and increase complexity. Here, we present multicolour STED nanoscopy with far red-shifted semiconductor CdTe quantum dots (QDs). STED imaging of the QDs is optimized to minimize blinking effects and maximize the number of detected photons. The far-red and compact emission spectra of the investigated QDs free spectral space for the simultaneous use of fluorescent dyes, enabling straightforward three-colour STED imaging with a single depletion beam. We use our method to study the internalization of QDs in cells, opening up the way for future super-resolution studies of particle uptake and internalization.

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  • 30.
    Alvelid, Jonatan
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bucci, Andrea
    Testa, Ilaria
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Far red-shifted quantum dots extend the multicolour possibilities in STED nanoscopyManuscript (preprint) (Other academic)
  • 31.
    Alvelid, Jonatan
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Damenti, Martina
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sgattoni, Chiara
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Testa, Ilaria
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Event-triggered STED imaging2022In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 19, no 10, p. 1268-1275Article in journal (Refereed)
    Abstract [en]

    Monitoring the proteins and lipids that mediate all cellular processes requires imaging methods with increased spatial and temporal resolution. STED (stimulated emission depletion) nanoscopy enables fast imaging of nanoscale structures in living cells but is limited by photobleaching. Here, we present event-triggered STED, an automated multiscale method capable of rapidly initiating two-dimensional (2D) and 3D STED imaging after detecting cellular events such as protein recruitment, vesicle trafficking and second messengers activity using biosensors. STED is applied in the vicinity of detected events to maximize the temporal resolution. We imaged synaptic vesicle dynamics at up to 24 Hz, 40 ms after local calcium activity; endocytosis and exocytosis events at up to 11 Hz, 40 ms after local protein recruitment or pH changes; and the interaction between endosomal vesicles at up to 3 Hz, 70 ms after approaching one another. Event-triggered STED extends the capabilities of live nanoscale imaging, enabling novel biological observations in real time.

  • 32.
    Alvelid, Jonatan
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Damenti, Martina
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Testa, Ilaria
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Event-triggered STED imagingManuscript (preprint) (Other academic)
    Abstract [en]

    The observation of protein organization during cellular signalling calls for imaging methods with increased spatial and temporal resolution. STED nanoscopy can access dynamics of nanoscale structures in living cells. However, the available number of recordable frames is often limited by photo-bleaching. Here, we present an automated method, event-triggered STED, which instantly (< 40 ms) images synaptic proteins with high spatial and temporal resolution (~30 nm, 2.5 Hz) in small regions upon and at the site of local calcium sensing.

  • 33.
    Alvelid, Jonatan
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Testa, Ilaria
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Stable stimulated emission depletion imaging of extended sample regions2020In: Journal of Physics D: Applied Physics, ISSN 0022-3727, E-ISSN 1361-6463, Vol. 53, no 2, article id 024001Article in journal (Refereed)
    Abstract [en]

    Stimulated emission depletion (STED) nanoscopy has become one of the most used nanoscopy techniques over the last decade. However, most recordings are done in specimen regions no larger than 10–30  ×  10–30 μm2 due to aberrations, instability and manual mechanical stages. Here, we demonstrate automated 2D and 3D STED nanoscopy of extended sample regions up to 0.5  ×  0.5 mm2 by using a scanning system that maintains stationary beams in the back focal plane. The setup allows up to 80–100  ×  80–100 μm2 field of view (FOV) with uniform spatial resolution, a mechanical stage allowing sequential tiling to record larger sample areas, and a feedback system keeping the sample in focus at all times. Taken together, this allows automated recording of theoretically unlimited-sized sample areas and volumes, without compromising the achievable spatial resolution and image quality.

  • 34.
    Amselem, Elias
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Marklund, Emil
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Kipper, Kalle
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Johansson, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Deindl, Sebastian
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Real- Time Single Protein Tracking with Polarization Readout using a Confocal Microscope2017In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 112, no 3, p. 295A-295AArticle in journal (Other academic)
  • 35.
    Andersson, Alma E. V.
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kasimova, Marina A.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Delemotte, Lucie
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Exploring the Viral Channel Kcv(PBCV-1) Function via Computation2018In: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 251, no 3, p. 419-430Article in journal (Refereed)
    Abstract [en]

    Viral potassium channels (Kcv) are homologous to the pore module of complex -selective ion channels of cellular organisms. Due to their relative simplicity, they have attracted interest towards understanding the principles of conduction and channel gating. In this work, we construct a homology model of the open state, which we validate by studying the binding of known blockers and by monitoring ion conduction through the channel. Molecular dynamics simulations of this model reveal that the re-orientation of selectivity filter carbonyl groups coincides with the transport of potassium ions, suggesting a possible mechanism for fast gating. In addition, we show that the voltage sensitivity of this mechanism can originate from the relocation of potassium ions inside the selectivity filter. We also explore the interaction of with the surrounding bilayer and observe the binding of lipids in the area between two adjacent subunits. The model is available to the scientific community to further explore the structure/function relationship of Kcv channels.

  • 36.
    Andersson, August
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The Application of isotropic bicelles as model membranes2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Isotropic bicelles are disc-shaped aggregates of lipids and detergents, and are suitable model systems for high-resolution NMR studies of membrane-interacting peptides. In this thesis the structures for the two peptides motilin and transportan were determined by homonuclear 1H methods in the presence of bicelles, and the structure of the bovine prion protein peptide (bPrPp) was solved in the presence of DHPC micelles. All of these peptides were found to be largely a-helical when bound to the model membranes. In subsequent experiments both motilin and transportan were shown to reside on the surface of the bicelles, whereas bPrPp is more likely to have a transmembrane configuration.

    NMR translational diffusion experiments revealed that the isotropic bicelles studied here are very large objects compared to what is regularly indicated by high-resolution NMR spectroscopy. Furthermore, these studies showed that all three peptides examined interact strongly with bicelles. Investigation of the NMR-relaxation of labeled sites in the peptides motilin and penetratin demonstrated that the overall rotational correlation times for these peptides do not reflect the bicellar size. Such decoupling of NMR relaxation from the dependence of overall size is also seen for the dynamics of the lipid molecules in the bicelles. It is therefore concluded that the overall size is not the sole determinant of the linewidths in NMR spectra, but that extensive motions within the bicelles also exert significant effects.

    Another interesting observation is that the membrane-bound structures of the peptides motilin, transportan, penetratin and bPrPp are very similar, even though these peptides have very different biological functions. In contrast, considerably more variation is observed in the membrane-positioning and molecular dynamics of these peptides. Since the bicelles have been found to induce differences in membrane positioning and molecular dynamics compared to micelles, these model membranes are likely to be important in order to enhance our understanding of the biological function of membrane interacting peptides.

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  • 37.
    Andersson, Charlotta S.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Berthold, Catrine L.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Högbom, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    A dynamic c terminal segment in the mycobacterium tuberculosis mn/fe r2lox protein can adopt a helical structure with possible functional consequences2012In: Chemistry and Biodiversity, ISSN 1612-1872, E-ISSN 1612-1880, Vol. 9, no 9, p. 1981-1988Article in journal (Refereed)
    Abstract [en]

    Mycobacterium tuberculosis R2-like ligand-binding oxidase (MtR2lox) belongs to a recently discovered group of proteins that are homologous to the ribonucleotide reductase R2 proteins. MtR2lox carries a heterodinuclear Mn/Fe cofactor and, unlike R2 proteins, a large ligand-binding cavity. A unique tyrosine-valine cross link is also found in the vicinity of the active site. To date, all known structures of R2 and R2lox proteins show a disordered C-terminal segment. Here, we present two new crystal forms of MtR2lox, revealing an ordered helical C-terminal. The ability of alternating between an ordered and disordered state agrees well with bioinformatic analysis of the protein sequence. Interestingly, ordering of the C-terminal helix shields a large positively charged patch on the protein surface, potentially used for interaction with other cellular components. We hypothesize that the dynamic C-terminal segment may be involved in control of protein function in vivo.

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  • 38.
    Andersson, Magnus
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics.
    Lindahl, Erik
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden..
    White, Stephen H.
    Univ Calif Irvine, Irvine, CA USA..
    Kaback, Ronald H.
    Univ Calif Los Angeles, Los Angeles, CA USA..
    The Molecular Basis for Substrate Specificity in Lactose Permease2015In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, no 2, p. 309A-309AArticle in journal (Other academic)
  • 39.
    Andersson, Magnus
    et al.
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mattle, Daniel
    Sitsel, Oleg
    Nielsen, Anna Marie
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    White, Stephen H.
    Nissen, Poul
    Gourdon, Pontus
    Transport Pathway in Cu+ P-Type ATPases2014In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 2, p. 427A-427AArticle in journal (Other academic)
  • 40.
    Andersson, Sara B. E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Frenning, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alderborn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gråsjö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Effect of fluid velocity and particle size on the hydrodynamic diffusion layer thickness2022In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 180, p. 1-10Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to determine the thickness of the hydrodynamic diffusion layer (h(HDL)) of three poor water-soluble compounds under laminar fluid flow using a single particle dissolution technique. The single particle dissolution experiments were performed in a flowing aqueous medium using four different fluid velocities (v), ranging from 46 to 103 mm/s. The particles used had an initial radius (r) of 18.8 to 52.3 mu m. The determined h(HDL) values were calculated from both dissolution experiments and computational fluid dynamics (CFD) simulation. In this study, single particle dissolution experiments gave, with one exception, h(HDL) values in the range of 2.09 to 8.85 mu m and corresponding simulations gave h(HDL) values in the range of 2.53 to 4.38 mu m. Hence, we found a semi-quantitative concordance between experimental and simulated determined h(HDL) values. Also, a theoretical relation between the dependence of hHDL on particle radius and flow velocity of the medium was established by a series of CFD simulations in a fluid velocity range of 10-100 mm/s and particle size (radius) range of 5-40 mu m. The outcome suggests a power law relation of the form h(HDL)alpha r(3/5)v(-2/5). In addition, the h(HDL) seems to be independent of the solubility, while it has a diffusion coefficient dependence. In conclusion, the hHDL values were determined under well-defined conditions; hence, this approach can be used to estimate the h(HDL) under different conditions to increase the understanding of the mass transfer mechanisms during the dissolution process.

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  • 41.
    Andronico, Luca
    et al.
    Karolinska Inst, Solna, Sweden..
    Jang, Yidan
    EMBL Heidelberg, Heidelberg, Germany..
    Iskrak, Sofia
    Karolinska Inst, Solna, Sweden..
    Ragaller, Franziska
    Karolinska Inst, Solna, Sweden..
    Sandoz, Patrick
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Buggert, Marcus
    Karolinska Inst, Solna, Sweden..
    Brodin, Petter
    Karolinska Inst, Solna, Sweden..
    Sezgin, Erdinc
    Karolinska Inst, Solna, Sweden..
    Cell biophysical properties unlock a new dimension in defining functional state of cells in health and diseases.2023In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 52, no SUPPL 1, p. S169-S169Article in journal (Other academic)
  • 42.
    Angelopoulos, Angelos
    et al.
    -.
    Aslanides, E.
    -.
    Backenstoss, G.
    -.
    Bargassa, P.
    -.
    Behnke, O.
    -.
    Benelli, A.
    -.
    Bertin, V.
    -.
    Blanc, F.
    -.
    Bloch, P.
    -.
    Carlson, P.
    -.
    Danielsson, Mats
    KTH, Superseded Departments (pre-2005), Physics.
    K0⇋ K̄0 transitions monitored by strong interactions: a new determination of the K L–K S mass difference2001In: Physics Letters B, ISSN 0370-2693, E-ISSN 1873-2445, Vol. 503, no 1, p. 49-57Article in journal (Refereed)
    Abstract [en]

    The CPLEAR set-up (modified) has been used to determine the KL–KS mass difference by a method where neutral-kaon strangeness oscillations are monitored through kaon strong interactions, rather than semileptonic decays, thus requiring no assumptions on CPT invariance for the decay amplitudes. The result, Δm=(0.5343±0.0063stat±0.0025syst)×1010ℏ/s, provides a valuable input for CPT tests.

  • 43. Ans, Muhammad
    et al.
    Iqbal, Javed
    Eliasson, Bertil
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Saif, Muhammad Jawwad
    Javed, Hafiz Muhammad Asif
    Ayub, Khurshid
    Designing of non-fullerene 3D star-shaped acceptors for organic solar cells2019In: Journal of Molecular Modeling, ISSN 1610-2940, E-ISSN 0948-5023, Vol. 25, no 5, article id 129Article in journal (Refereed)
    Abstract [en]

    The design and fabrication of solar cells have recently witnessed the exploration of non-fullerene-based acceptor molecules for higher efficiency. In this study, the optical and electronic properties of four new three-dimensional (3D) star-shaped acceptor molecules (M1, M2, M3, and M4) are evaluated for use as acceptor molecules in organic solar cells. These molecules contain a triphenylamine donor core with diketopyrrolopyrrole acceptor arms linked via a thiophene bridge unit. Molecules M1–M4 are characterized by different end-capped acceptor moieties, including 2-(5-methylene-6-oxo-5,6-dihydrocyclopenta-b-thiophen-4-ylidene)malononitrile (M1), 2-(2-methylene-3-oxo-2,3-dihydroinden-1-ylidene)malononitrile (M2), 2-(5-methyl-2-methylene-3-oxo-2,3-dihydroinden-1-ylidene)malononitrile (M3), and 3-methyl-5-methylnene-thioxothiazolidin-4-one (M4). The properties of the newly designed molecules were compared with a well-known reference compound R, which was recently reported as an excellent acceptor molecule for organic solar cells. Molecules M1–M4 exhibit suitable frontier molecular orbital patterns for charge mobility. M2 shows maximum absorption (λmax) at 846.8 nm in dichloromethane solvent, which is ideal for the design of transparent solar cells. A strong electron withdrawing end-capped acceptor causes a red shift in absorption spectra. All molecules are excellent for hole mobility due to a lower value of λh compared to the reference R.

  • 44.
    Ansell, Ricky
    et al.
    Swedish National Forensic Centre, Linköping, Sweden.
    Allen, Marie
    Molekylär patologi och rättsgenetik, Uppsala universitet.
    DNA-analyser inom brottsbekämpningen2016In: Skurk, sjuk eller släkt?: vem ska ha ditt DNA? / [ed] Eva Regårdh, Sofie Pehrssoon, Stockholm: Stiftelsen för strategisk forskning , 2016, p. 18-27Chapter in book (Other academic)
    Abstract [sv]

    Idag räcker det med DNA från enstaka celler för att kunna få fram en DNA-profil som kan jämföras med per-soner eller andra DNA-spår. En DNA-träff mot ett biologiskt spår kan utgöra en mycket stark bevisning och vara avgörande för en fällande dom. DNA-teknik gör det möjligt att analysera och ta fram en DNA-profil för de allra flesta typer av humana biologiska spår som avsatts i samband med brott, såsom blod, sperma, vaginalsekret, saliv, hår och ”kontaktspår”. Teknikerna har med åren utvecklats och förfinats. På senare år har också det internationella utbytet av DNA-profiler ökat samtidigt som fortsatt teknik- och metodutveckling banar väg för fördjupade analy-ser som kan bidra till att klara upp brott. Det kan handla om att utifrån DNA-spår ringa in ungefärlig ålder, ursprung, hårfärg, ögonfärg och kroppsstorlek på en misstänkt gärningsman

  • 45. Aquila, Andrew
    et al.
    Hunter, Mark S.
    Doak, R. Bruce
    Kirian, Richard A.
    Fromme, Petra
    White, Thomas A.
    Andreasson, Jakob
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Arnlund, David
    Bajt, Saša
    Barends, Thomas R. M.
    Barthelmess, Miriam
    Bogan, Michael J.
    Bostedt, Christoph
    Bottin, Hervé
    Bozek, John D.
    Caleman, Carl
    Coppola, Nicola
    Davidsson, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    DePonte, Daniel P.
    Elser, Veit
    Epp, Sascha W.
    Erk, Benjamin
    Fleckenstein, Holger
    Foucar, Lutz
    Frank, Matthias
    Fromme, Raimund
    Graafsma, Heinz
    Grotjohann, Ingo
    Gumprecht, Lars
    Hajdu, Janos
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Hampton, Christina Y.
    Hartmann, Andreas
    Hartmann, Robert
    Hau-Riege, Stefan
    Hauser, Günter
    Hirsemann, Helmut
    Holl, Peter
    Holton, James M.
    Hömke, André
    Johansson, Linda
    Kimmel, Nils
    Kassemeyer, Stephan
    Krasniqi, Faton
    Kühnel, Kai-Uwe
    Liang, Mengning
    Lomb, Lukas
    Malmerberg, Erik
    Marchesini, Stefano
    Martin, Andrew V.
    Maia, Filipe R.N.C.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Messerschmidt, Marc
    Nass, Karol
    Reich, Christian
    Neutze, Richard
    Rolles, Daniel
    Rudek, Benedikt
    Rudenko, Artem
    Schlichting, Ilme
    Schmidt, Carlo
    Schmidt, Kevin E.
    Schulz, Joachim
    Seibert, M. Marvin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Soltau, Heike
    Shoeman, Robert L.
    Sierra, Raymond
    Starodub, Dmitri
    Stellato, Francesco
    Stern, Stephan
    Strüder, Lothar
    Timneanu, Nicusor
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Ullrich, Joachim
    Wang, Xiaoyu
    Williams, Garth J.
    Weidenspointner, Georg
    Weierstall, Uwe
    Wunderer, Cornelia
    Barty, Anton
    Spence, John C. H.
    Chapman, Henry N.
    Time-resolved protein nanocrystallography using an X-ray free-electron laser2012In: Optics Express, E-ISSN 1094-4087, Vol. 20, no 3, p. 2706-2716Article in journal (Refereed)
    Abstract [en]

    We demonstrate the use of an X-ray free electron laser synchronized with an optical pump laser to obtain X-ray diffraction snapshots from the photoactivated states of large membrane protein complexes in the form of nanocrystals flowing in a liquid jet. Light-induced changes of Photosystem I-Ferredoxin co-crystals were observed at time delays of 5 to 10 µs after excitation. The result correlates with the microsecond kinetics of electron transfer from Photosystem I to ferredoxin. The undocking process that follows the electron transfer leads to large rearrangements in the crystals that will terminally lead to the disintegration of the crystals. We describe the experimental setup and obtain the first time-resolved femtosecond serial X-ray crystallography results from an irreversible photo-chemical reaction at the Linac Coherent Light Source. This technique opens the door to time-resolved structural studies of reaction dynamics in biological systems.

  • 46. Arbeitman, Claudia R.
    et al.
    Rojas, Pablo
    Ojeda-May, Pedro
    Umeå University, Faculty of Science and Technology, High Performance Computing Center North (HPC2N). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Garcia, Martin E.
    The SARS-CoV-2 spike protein is vulnerable to moderate electric fields2021In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 5407Article in journal (Refereed)
    Abstract [en]

    Most of the ongoing projects aimed at the development of specific therapies and vaccines against COVID-19 use the SARS-CoV-2 spike (S) protein as the main target. The binding of the spike protein with the ACE2 receptor (ACE2) of the host cell constitutes the first and key step for virus entry. During this process, the receptor binding domain (RBD) of the S protein plays an essential role, since it contains the receptor binding motif (RBM), responsible for the docking to the receptor. So far, mostly biochemical methods are being tested in order to prevent binding of the virus to ACE2. Here we show, with the help of atomistic simulations, that external electric fields of easily achievable and moderate strengths can dramatically destabilise the S protein, inducing long-lasting structural damage. One striking field-induced conformational change occurs at the level of the recognition loop L3 of the RBD where two parallel beta sheets, believed to be responsible for a high affinity to ACE2, undergo a change into an unstructured coil, which exhibits almost no binding possibilities to the ACE2 receptor. We also show that these severe structural changes upon electric-field application also occur in the mutant RBDs corresponding to the variants of concern (VOC) B.1.1.7 (UK), B.1.351 (South Africa) and P.1 (Brazil). Remarkably, while the structural flexibility of S allows the virus to improve its probability of entering the cell, it is also the origin of the surprising vulnerability of S upon application of electric fields of strengths at least two orders of magnitude smaller than those required for damaging most proteins. Our findings suggest the existence of a clean physical method to weaken the SARS-CoV-2 virus without further biochemical processing. Moreover, the effect could be used for infection prevention purposes and also to develop technologies for in-vitro structural manipulation of S. Since the method is largely unspecific, it can be suitable for application to other mutations in S, to other proteins of SARS-CoV-2 and in general to membrane proteins of other virus types.

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  • 47.
    Arja, Katriann
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Elgland, Mathias
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Synthesis and Characterization of Oligothiophene-Porphyrin-Based Molecules That Can Be Utilized for Optical Assignment of Aggregated Amyloid-beta Morphotypes2018In: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 6, article id 391Article in journal (Refereed)
    Abstract [en]

    Molecular tools for fluorescent imaging of protein aggregates are essential for understanding the significance of these pathological hallmarks in proteopathic neurodegenerative diseases, such as Alzheimers disease. Here, we report the synthesis of a series of oligothiophene porphyrin hybrids, OTPHs, and the evaluation of these dyes for fluorescent imaging of beta-amyloid aggregates in tissue sections from a transgenic mouse model with Alzheimers disease pathology. The OTPHs proved to be successful for spectral and lifetime imaging assessment of protein deposits and our findings confirm that the enhanced spectral range and distinct lifetime diversity of these novel tools allow a more precise assessment of heterogeneous amyloid morphology compared with the corresponding oligothiophene dye. In addition, the chemical identity of the porphyrin moiety, as well as the spacing between the two optical active moieties, influenced the OTPHs performance for fluorescent assignment of the protein deposits. We foresee that our findings will aid in the chemical design of dyes that can be utilized as optical tools for studying the polymorphic nature of protein aggregates associated with proteopathic neurodegenerative diseases.

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    fulltext
  • 48.
    Arndt, Anton
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Laboratory for Biomechanics and Motor Control.
    In vivo, intrinsic kinematics of the foot and ankle2012Conference paper (Other academic)
  • 49.
    Arndt, Anton
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Laboratory for Biomechanics and Motor Control.
    The effects of running in minimalistic shoes on non-uniform displacement in the Achilles tendon2019Conference paper (Refereed)
  • 50.
    Arner, P.
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden.
    Bernard, S.
    Univ Lyon, CNRS, UMR5208, Inst Camille Jordan, Villeurbanne, France.
    Appelsved, L.
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.
    Fu, K. -Y
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Andersson, D. P.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden.
    Salehpour, Mehran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Thorell, A.
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden;Karolinska Inst, Ersta Hosp, Dept Surg, Stockholm, Sweden.
    Ryden, M.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden.
    Spalding, K. L.
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden;Integrated Cardio Metab Ctr, Dept Med, Stockholm, Sweden.
    Adipose lipid turnover and long-term changes in body weight2019In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 25, no 9, p. 1385-1389Article in journal (Refereed)
    Abstract [en]

    The worldwide obesity epidemic(1) makes it important to understand how lipid turnover (the capacity to store and remove lipids) regulates adipose tissue mass. Cross-sectional studies have shown that excess body fat is associated with decreased adipose lipid removal rates(2,3). Whether lipid turnover is constant over the life span or changes during long-term weight increase or loss is unknown. We determined the turnover of fat cell lipids in adults followed for up to 16 years, by measuring the incorporation of nuclear bomb test-derived C-14 in adipose tissue triglycerides. Lipid removal rate decreases during aging, with a failure to reciprocally adjust the rate of lipid uptake resulting in weight gain. Substantial weight loss is not driven by changes in lipid removal but by the rate of lipid uptake in adipose tissue. Furthermore, individuals with a low baseline lipid removal rate are more likely to remain weight-stable after weight loss. Therefore, lipid turnover adaptation might be important for maintaining pronounced weight loss. Together these findings identify adipose lipid turnover as an important factor for the long-term development of overweight/obesity and weight loss maintenance in humans.

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