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  • 1.
    Abelein, Axel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Modulation of Alzheimer's amyloid β peptide self-assembly: Insights into molecular mechanisms of peptide aggregation associated with Alzheimer's disease2015Doktoravhandling, med artikler (Annet vitenskapelig)
    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
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Modulation of amyloid β peptide self-assembly: Aggregation mechanisms associated with Alzheimer's disease2013Licentiatavhandling, med artikler (Annet vitenskapelig)
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  • 3.
    Abelein, Axel
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The zinc ion – a minimal chaperone mimicking agent forretardation of amyloid β peptide fibril formationManuskript (preprint) (Annet vitenskapelig)
  • 4.
    Abelein, Axel
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Lang, Lisa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Lendel, Christofer
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Corrigendum to “Transient small molecule interactions kinetically modulate amyloid β peptide self-assembly” [FEBS Lett. 586 (2012) 3991–3995]2013Inngår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 587, nr 9, s. 1452-1452Artikkel i tidsskrift (Annet vitenskapelig)
  • 5. Abelein, Axel
    et al.
    Lang, Lisa
    Lendel, Christofer
    Gräslund, Astrid
    Danielsson, Jens
    Transient small molecule interactions kinetically modulate amyloid β peptide self-assembly.2012Inngår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 586, nr 22, s. 3991-3995, artikkel-id S0014-5793(12)00757-0Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Liu, Lifeng
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Wallén, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    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 universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Cellular Chondroitin Sulfate and the Mucin-like Domain of Viral Glycoprotein C Promote Diffusion of Herpes Simplex Virus 1 While Heparan Sulfate Restricts Mobility2022Inngår i: Viruses, E-ISSN 1999-4915, Vol. 14, nr 8, artikkel-id 1836Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity2017Inngår i: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 188, nr 6, s. 597-604Artikkel i tidsskrift (Fagfellevurdert)
    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.
    Abubeker, Ismail
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär biofysik.
    Visualizing fusion between liposomes and influenza virus through trEM2024Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
    Abstract [en]

    Time-resolved cryogenic electron microscopy (cryo-EM) is a powerful technique for capturingtransient molecular and viral structures during conformational changes. This method providesunique and potentially critical insights into the transient states of biomolecules, which can beinvaluable for drug development. Additionally, it offers glimpses into the pathology of viruses asthey interact with their immediate environment. In this project, a plunge freezer initially designedfor a spray-and-plunge approach in time-resolved cryo-EM [24] was modified to implement aflash-and-freeze system [3]. This modified system was tested on two different viruses: influenzaH3N2 type A and Chaetoceros tenuissimus DNA virus type II. The primary objective was tovisualize an intermediate state during the membrane fusion process between influenza A andliposomes with endosomal characteristics. Although no intermediate state was captured forinfluenza, the activation and pH reduction were successfully achieved. The study on Chaetocerostenuissimus DNA virus type II focused on potential conformational changes due to a drop in pH,rather than capturing intermediate states in a time-resolved manner. Future experiments withmore precise control over blotting, delivered intensity, and the concentration of the cagedcompound are expected to facilitate the capture and analysis of intermediate states.

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  • 9.
    Adhikari, Deepak
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Flohr, Gilian
    Hogeschool Leiden, Zernikedreef 11,2333 CK Leiden, The Netherlands.
    Gorre, Nagaraju
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Shen, Yan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Yang, Hairu
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lan, Zijian
    University of Louisville Health Sciences Center, Louisville, Kentucky, USA.
    Liu, Kui
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles2009Inngår i: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 15, nr 12, s. 765-770Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 10.
    Adler, Jeremy
    et al.
    Univ Gothenburg, Inst Biomed, Sahlgrenska Acad, Dept Med Biochem & Cell Biol, Gothenburg, Sweden.
    Bernhem, Kristoffer
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Parmryd, Ingela
    Univ Gothenburg, Inst Biomed, Sahlgrenska Acad, Dept Med Biochem & Cell Biol, Gothenburg, Sweden..
    Membrane topography and the overestimation of protein clustering in single molecule localisation microscopy - identification and correction2024Inngår i: Communications Biology, E-ISSN 2399-3642, Vol. 7, nr 1, artikkel-id 791Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    According to single-molecule localisation microscopy almost all plasma membrane proteins are clustered. We demonstrate that clusters can arise from variations in membrane topography where the local density of a randomly distributed membrane molecule to a degree matches the variations in the local amount of membrane. Further, we demonstrate that this false clustering can be differentiated from genuine clustering by using a membrane marker to report on local variations in the amount of membrane. In dual colour live cell single molecule localisation microscopy using the membrane probe DiI alongside either the transferrin receptor or the GPI-anchored protein CD59, we found that pair correlation analysis reported both proteins and DiI as being clustered, as did its derivative pair correlation-photoactivation localisation microscopy and nearest neighbour analyses. After converting the localisations into images and using the DiI image to factor out topography variations, no CD59 clusters were visible, suggesting that the clustering reported by the other methods is an artefact. However, the TfR clusters persisted after topography variations were factored out. We demonstrate that membrane topography variations can make membrane molecules appear clustered and present a straightforward remedy suitable as the first step in the cluster analysis pipeline. Variations in membrane topography can lead to the overestimation of protein clustering which can be avoided using a second image of a membrane marker, demonstrated with simulations and live cell SMLM.

  • 11.
    Adler, Jeremy
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Parmryd, Ingela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Quantification of Colocalisation; Co-Occurrence, Correlation, Empty Voxels, Regions of Interest and Thresholding2014Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, nr 2, s. 602A-602AArtikkel i tidsskrift (Annet vitenskapelig)
    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.

  • 12.
    Adler, Jeremy
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sintorn, Ida-Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Strand, Robin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Parmryd, Ingela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Conventional analysis of movement on non-flat surfaces like the plasma membrane makes Brownian motion appear anomalous2019Inngår i: Communications Biology, E-ISSN 2399-3642, Vol. 2, artikkel-id 12Artikkel i tidsskrift (Fagfellevurdert)
  • 13. Ahn, Young O.
    et al.
    Mahinthichaichan, Paween
    Lee, Hyun Ju
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ouyang, Hanlin
    Kaluka, Daniel
    Yeh, Syun-Ru
    Arjona, Davinia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Rousseau, Denis L.
    Tajkhorshid, Emad
    Ädelroth, Pia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    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 reductase2014Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, nr 42, s. E4419-E4428Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 14.
    Aho, Noora
    et al.
    Nanoscience Center and Department of Chemistry, University of Jyväskylä, 40014Jyväskylä, Finland.
    Buslaev, Pavel
    Nanoscience Center and Department of Chemistry, University of Jyväskylä, 40014Jyväskylä, Finland.
    Jansen, Anton
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bauer, Paul
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Centra, SeRC - Swedish e-Science Research Centre.
    Groenhof, Gerrit
    Nanoscience Center and Department of Chemistry, University of Jyväskylä, 40014Jyväskylä, Finland.
    Hess, Berk
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, SeRC - Swedish e-Science Research Centre. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Scalable Constant pH Molecular Dynamics in GROMACS2022Inngår i: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 18, nr 10, s. 6148-6160Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Molecular dynamics (MD) computer simulations are used routinely to compute atomistic trajectories of complex systems. Systems are simulated in various ensembles, depending on the experimental conditions one aims to mimic. While constant energy, temperature, volume, and pressure are rather straightforward to model, pH, which is an equally important parameter in experiments, is more difficult to account for in simulations. Although a constant pH algorithm based on the λ-dynamics approach by Brooks and co-workers [Kong, X.; Brooks III, C. L. J. Chem. Phys.1996, 105, 2414–2423] was implemented in a fork of the GROMACS molecular dynamics program, uptake has been rather limited, presumably due to the poor scaling of that code with respect to the number of titratable sites. To overcome this limitation, we implemented an alternative scheme for interpolating the Hamiltonians of the protonation states that makes the constant pH molecular dynamics simulations almost as fast as a normal MD simulation with GROMACS. In addition, we implemented a simpler scheme, called multisite representation, for modeling side chains with multiple titratable sites, such as imidazole rings. This scheme, which is based on constraining the sum of the λ-coordinates, not only reduces the complexity associated with parametrizing the intramolecular interactions between the sites but also is easily extendable to other molecules with multiple titratable sites. With the combination of a more efficient interpolation scheme and multisite representation of titratable groups, we anticipate a rapid uptake of constant pH molecular dynamics simulations within the GROMACS user community.

  • 15.
    Akkuratov, Evgeny E.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    The Biophysics of Na+,K+-ATPase in neuronal health and disease2020Doktoravhandling, med artikler (Annet vitenskapelig)
    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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  • 16.
    Akkuratov, Evgeny E.
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Sorrell, Frankie
    Souza, Vasco
    Paukar, Martin
    Picton, Laurence
    Jans, Daniel
    Andersson, Magnus
    Fritz, Nicolas
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Zhang, Xiaoqun
    Liebmann, Thomas
    KTH.
    Lindskog, Maria
    KTH.
    Svenningsson, Per
    Miles, Gareth
    Brismar, Hjalmar
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    Aperia, Anita
    KTH.
    Mechanisms by which the T613M mutation causes mobility and gait disturbances in Rapid-Onset Dystonia-ParkinsonismManuskript (preprint) (Annet vitenskapelig)
  • 17.
    Akkuratov, Evgeny E.
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, 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, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lindskog, Maria
    Brismar, Hjalmar
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Aperia, Anita
    Ouabain Modulates the Functional Interaction Between Na,K-ATPase and NMDA Receptor.2020Inngår i: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 57, nr 10, s. 4018-4030Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 18.
    Akpe, Victor
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Cellens fysik.
    Photophysical and Chemical Approaches to Cellular Biophysics2008Licentiatavhandling, med artikler (Annet vitenskapelig)
    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.

    Fulltekst (pdf)
    FULLTEXT01
  • 19.
    Akpe, Victor
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Cellens fysik.
    Nyokong, Tebello
    Brismar, Hjalmar
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Cellens fysik.
    Photophysics and photochemistry of zinc, aluminium and tin octakis (benzylthio) phthalocyanines2008Rapport (Annet vitenskapelig)
  • 20.
    Akpe, Victor
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Cellens fysik.
    Vernet, Erik
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    Gräslund, Torbjörn
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    Brismar, Hjalmar
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Cellens fysik.
    Characterization studies of aluminum phthalocyanine binding to antibodies from SKBR 3 cell line2008Rapport (Annet vitenskapelig)
  • 21.
    Alam, Md Khorshed
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Vinklarek, Ivo
    Gröbner, Gerhard
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Johansson, Lennart B-Å
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sachl, Radek
    Fluorescence Studies of Lipid Distribution in Bilayers under Oxidative Stress2019Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 116, nr 3, s. 508A-508AArtikkel i tidsskrift (Annet vitenskapelig)
  • 22.
    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 adsorption2010Inngår i: Soft Matter, ISSN 1744-683X, E-ISSN 1744-6848, Vol. 6, nr 14, s. 3211-3219Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 23.
    Albet-Torres, Nuria
    et al.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Månsson, Alf
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Long-Term Storage of Surface-Adsorbed Protein Machines2011Inngår i: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 27, nr 11, s. 7108-7112Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 24.
    Alikhani, Nyosha
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Berglund, Anna-Karin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Engmann, Tanja
    Spånning, Erika
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Voegtle, F. -Nora
    Pavlov, Pavel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Meisinger, Chris
    Langer, Thomas
    Glaser, Elzbieta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Targeting Capacity and Conservation of PreP Homologues Localization in Mitochondria of Different Species2011Inngår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 410, nr 3, s. 400-410Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 25. Alizadehheidari, Mohammadreza
    et al.
    Werner, Erik
    Noble, Charleston
    Nyberg, Lena
    Fritzsche, Joachim
    Mehlig, Bernhard
    Tegenfeldt, Jonas
    Ambjoernsson, Tobias
    Persson, Fredrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
    Westerlund, Fredrik
    Nanoconfined Circular DNA2014Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, nr 2, s. 274A-274AArtikkel i tidsskrift (Annet vitenskapelig)
    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.

  • 26. Allahverdiyeva, Yagut
    et al.
    Mamedov, Fikret
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - 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 tobacco2005Inngår i: Biochimica et Biophysica Acta (BBA) - Bioenergetics, ISSN 0005-2728, Vol. 1709, nr 1, s. 69-83Artikkel i tidsskrift (Fagfellevurdert)
  • 27.
    Allard, Peter
    Stockholms universitet, Naturvetenskapliga fakulteten.
    Nuclear magnetic resonance studies of nucleotide-protein interactions and of peptide structure-dynamics relations1994Doktoravhandling, med artikler (Annet vitenskapelig)
  • 28.
    Allerbo, Oskar
    et al.
    Chalmers university.
    Lundström, Anders
    Chalmers university.
    Dimitrievski, Kristian
    Simulations of Lipid Vesicle Rupture Induced by an Adjacent Supported Lipid Bilayer Patch2011Inngår i: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 82, s. 632-636Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Using a simple phenomenological model of a lipid bilayer and a surface, simulations were performed to study the bilayer-induced vesicle rupture probability as a vesicle adsorbs adjacently to a bilayer patch already adsorbed on the surface. The vesicle rupture probability was studied as a function of temperature, vesicle size, and surface-bilayer interaction strength. From the simulation data, estimates of the apparent activation energy for bilayer-induced vesicle rupture were calculated, both for different vesicle sizes and for different surface-bilayer interaction strengths.

  • 29.
    Allgöwer, Friederike
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mechanistic Insight Into Photosystem II: From Light-Capture to Protonation Dynamics Explored by Multi-Scale Simulations2024Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Oxygen powers aerobic life. Its production on Earth relies on the cellular process of photosynthesis, in which the energy of sunlight is converted into an electrochemical proton gradient, driving the synthesis of biomass and plant growth. At the heart of photosynthesis lies photosystem II, an enzyme which catalyzes the oxidation of water to molecular oxygen. Following photon absorption, chlorophylls funnel light energy to the reaction center, initiating charge separation. This triggers rapid electron transfers, ultimately resulting in the reduction of quinone and the oxidation of water to molecular oxygen. The molecular principles of photosystem II are investigated in this thesis by combining atomistic molecular dynamics with hybrid quantum/classical simulations. We identify a regulatory role of bicarbonate in preventing the formation of harmful singlet oxygen, elucidate proton transfer pathways and their dependency on S state dynamics, and characterize water networks essential for efficient proton translocation. Additionally, our work on far-red light-adapted photosystem II highlights how specific chlorophyll substitutions expand the spectral range of photosynthesis, facilitating efficient light absorption and energy transfer under scarce light conditions.

    Fulltekst (pdf)
    Mechanistic Insight Into Photosystem II: From Light-Capture to Protonation Dynamics Explored by Multi-Scale Simulations
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  • 30.
    Allgöwer, Friederike
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Pöverlein, Maximilian C.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Rutherford, A. William
    Imperial College London, United Kingdom.
    Kaila, Ville R. I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mechanism of Proton Release during Water Oxidation in Photosystem IIInngår i: Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Photosystem II (PSII) catalyzes the light-driven water oxidation that releases dioxygen into our atmosphere and provides the electrons needed for the synthesis of biomass. The catalysis occurs in the oxygen-evolving oxo-manganese-calcium (Mn4O5Ca) cluster that drives the stepwise oxidation and deprotonation of substrate water molecules leading to the O2 formation. However, despite recent advances, the mechanism of these reactions remains unclear and much debated. Here we show that the light-driven Tyr161D1 (Yz) oxidation adjacent to the Mn4O5Ca cluster, significantly decreases the barrier for proton transfer from the putative substrate water molecule (W3/Wx) to Glu310D2, which is accessible to the luminal bulk. By combining hybrid quantum/classical (QM/MM) free energy calculations with atomistic molecular dynamics (MD) simulations, we probe the energetics of the proton transfer along the Cl1 pathway. We demonstrate that the proton transfer occurs via water molecules and a cluster of conserved carboxylates, driven by redox-triggered electric fields directed along the pathway. Glu65D1 establishes a local molecular gate that controls the proton transfer to the luminal bulk, whilst Glu312D2 acts as a local proton storage site. The identified gating region could be important in preventing back-flow of protons to the Mn4O5Ca cluster. The structural changes, derived here based on the dark-state PSII structure, strongly support recent time-resolved XFEL data of the S3→S4 transition (Nature 617, 629, 2023), and reveal the mechanistic basis underlying deprotonation of the substrate water molecules. Our combined findings provide insight into the water oxidation mechanism of PSII and show how the interplay between redox-triggered electric fields, ion-pairs, and hydration effects control proton transport reactions.

  • 31.
    Allgöwer, Friederike
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Sirohiwal, Abhishek
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gamiz-Hernandez, Ana P.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Pöverlein, Maximilian C.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Fantuzzi, Andrea
    Imperial College London, United Kingdom.
    Rutherford, A. William
    Imperial College London, United Kingdom.
    Modified Chlorophyll Pigment at ChlD1 Tunes Photosystem II Beyond the Red-Light LimitManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Photosystem II (PSII) is powered by the light-capturing properties of chlorophyll a pigments that define the spectral range of oxygenic photosynthesis. Some photosynthetic cyanobacteria can acclimate to growth in longer wavelength light by replacing five chlorophylls for long wavelength pigments in specific locations, including one in the reaction center (RC). However, the exact location and the nature of this long wavelength pigment still remain uncertain. Here we have addressed the color-tuning mechanism of the far-red light PSII (FRL-PSII) by excited state calculations at both the ab initio correlated (ADC2) and linear-response time-dependent density functional theory (LR-TDDFT) levels in combination with large-scale hybrid quantum/classical (QM/MM) simulations and atomistic molecular dynamics. We show that substitution of a single chlorophyll pigment (ChlD1) at the RC by chlorophyll d leads to a spectral shift beyond the far-red light limit, as a result of the protein electrostatic, polarization and electronic coupling effects that reproduce key structural and spectroscopic observations. Pigment substitution at the ChlD1 site further results in a low site energy within the RC that could function as a sink for the excitation energy and initiate the primary charge separation reaction, driving the water oxidation. Our findings provide a basis for understanding color-tuning mechanisms and bioenergetic principles of oxygenic photosynthesis at the far-red light limit. 

  • 32.
    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 universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    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 spectrometry2022Inngår i: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 31, nr 6, artikkel-id e4333Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 33.
    Almaqwashi, Ali A.
    et al.
    Northeastern Univ, Dept Phys, Boston, MA 02115 USA..
    Andersson, Johanna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - 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 Intercalation2016Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, nr 6, s. 1255-1263Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 34. Altun, Diyar
    et al.
    Larsson, Per
    Bergström, Christel A.S.
    Hossain, Shakhawath
    Molecular dynamics simulations of lipid composition and its impact on structural and dynamic properties of skin membrane2024Inngår i: Chemistry and Physics of Lipids, ISSN 0009-3084, E-ISSN 1873-2941, Vol. 265, s. 105448-105448, artikkel-id 105448Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The stratum corneum (SC) plays the most important role in the absorption of topical and transdermal drugs. In this study, we developed a multi-layered SC model using coarse-grained molecular dynamics (CGMD) simulations of ceramides, cholesterol, and fatty acids in equimolar proportions, starting from two different initial configurations. In the first approach, all ceramide molecules were initially in the hairpin conformation, and the membrane bilayers were pre-formed. In the second approach, ceramide molecules were introduced in either the hairpin or splayed conformation, with the lipid molecules randomly oriented at the start of the simulation. The aim was to evaluate the effects of lipid chain length on the structural and dynamic properties of SC. By incorporating ceramides and fatty acids of different chain lengths, we simulated the SC membrane in healthy and diseased states. We calculated key structural properties including the thickness, normalized lipid area, lipid tail order parameters, and spatial ordering of the lipids from each system. The results showed that systems with higher ordering and structural integrity contained an equimolar ratio of ceramides (chain length of 24 carbon atoms), fatty acids with chain lengths ≥ of 20 carbon atoms, and cholesterol. In these systems, strong apolar interactions between the ceramide and fatty acid long acyl chains restricted the mobility of the lipid molecules, thereby maintaining a compact lipid headgroup region and high order in the lipid tail region. The simulations also revealed distinct flip-flop mechanisms for cholesterol and fatty acid within the multi-layered membrane. Cholesterol is mostly diffused through the tail-tail interface region of the membrane and could flip-flop in the same bilayer. In contrast, fatty acids flip-flopped between adjacent leaflets of two bilayers in which the tails crossed the thinner headgroup region of the membrane. To conclude, our SC model provides mechanistic insights into lipid mobility and is flexible in its design and composition of different lipids, enabling studies of varying skin conditions.Keywords: Coarse-grained molecular dynamics; Lipid flip-flop; Membrane structural properties; Skin membrane; k-means clustering.

  • 35.
    Alvarez-Rodriguez, Manuel
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Ntzouni, Maria
    Linköpings universitet, Medicinska fakulteten, Core Facility.
    Wright, Dominic
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Khan, Kabirul Islam
    Chattogram Vet and Anim Sci Univ, Bangladesh.
    Lopez-Bejar, Manel
    Univ Autonoma Barcelona, Spain.
    Martinez-Serrano, Cristina
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Rodriguez-Martinez, Heriberto
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Chicken seminal fluid lacks CD9-and CD44-bearing extracellular vesicles2020Inngår i: Reproduction in domestic animals, ISSN 0936-6768, E-ISSN 1439-0531, Vol. 55, nr 3, s. 293-300Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 36.
    Alvelid, Jonatan
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Automating STED microscopy for functional and structural live-cell imaging2021Doktoravhandling, med artikler (Annet vitenskapelig)
    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.

    Fulltekst (pdf)
    kappa
  • 37.
    Alvelid, Jonatan
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bucci, Andrea
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Testa, Ilaria
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Far Red‐Shifted CdTe Quantum Dots for Multicolour Stimulated Emission Depletion Nanoscopy2022Inngår i: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 24, nr 3Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 38.
    Alvelid, Jonatan
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bucci, Andrea
    Testa, Ilaria
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Far red-shifted quantum dots extend the multicolour possibilities in STED nanoscopyManuskript (preprint) (Annet vitenskapelig)
  • 39.
    Alvelid, Jonatan
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Damenti, Martina
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sgattoni, Chiara
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Testa, Ilaria
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Event-triggered STED imaging2022Inngår i: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 19, nr 10, s. 1268-1275Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 40.
    Alvelid, Jonatan
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Damenti, Martina
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Testa, Ilaria
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Event-triggered STED imagingManuskript (preprint) (Annet vitenskapelig)
    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.

  • 41.
    Alvelid, Jonatan
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Testa, Ilaria
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Stable stimulated emission depletion imaging of extended sample regions2020Inngår i: Journal of Physics D: Applied Physics, ISSN 0022-3727, E-ISSN 1361-6463, Vol. 53, nr 2, artikkel-id 024001Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 42.
    Amselem, Elias
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    Marklund, Emil
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    Kipper, Kalle
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Johansson, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    Deindl, Sebastian
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    Elf, Johan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    Real- Time Single Protein Tracking with Polarization Readout using a Confocal Microscope2017Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 112, nr 3, s. 295A-295AArtikkel i tidsskrift (Annet vitenskapelig)
  • 43.
    Andersson, Alma E. V.
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kasimova, Marina A.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Delemotte, Lucie
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Exploring the Viral Channel Kcv(PBCV-1) Function via Computation2018Inngår i: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 251, nr 3, s. 419-430Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 44.
    Andersson, August
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The Application of isotropic bicelles as model membranes2005Doktoravhandling, med artikler (Annet vitenskapelig)
    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.

    Fulltekst (pdf)
    FULLTEXT01
  • 45.
    Andersson, Charlotta S.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Berthold, Catrine L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Högbom, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    A dynamic c terminal segment in the mycobacterium tuberculosis mn/fe r2lox protein can adopt a helical structure with possible functional consequences2012Inngår i: Chemistry and Biodiversity, ISSN 1612-1872, E-ISSN 1612-1880, Vol. 9, nr 9, s. 1981-1988Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 46.
    Andersson, Magnus
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik.
    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 Permease2015Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, nr 2, s. 309A-309AArtikkel i tidsskrift (Annet vitenskapelig)
  • 47.
    Andersson, Magnus
    et al.
    KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mattle, Daniel
    Sitsel, Oleg
    Nielsen, Anna Marie
    Lindahl, Erik
    KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Experimentell biomolekylär fysik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    White, Stephen H.
    Nissen, Poul
    Gourdon, Pontus
    Transport Pathway in Cu+ P-Type ATPases2014Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, nr 2, s. 427A-427AArtikkel i tidsskrift (Annet vitenskapelig)
  • 48.
    Andersson, Sara B. E.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Frenning, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Alderborn, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gråsjö, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Effect of fluid velocity and particle size on the hydrodynamic diffusion layer thickness2022Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 180, s. 1-10Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 49.
    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, Skolan för teknikvetenskap (SCI), Tillämpad fysik, Biofysik.
    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.2023Inngår i: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 52, nr SUPPL 1, s. S169-S169Artikkel i tidsskrift (Annet vitenskapelig)
  • 50.
    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, Tidigare Institutioner (före 2005), Fysik.
    K0⇋ K̄0 transitions monitored by strong interactions: a new determination of the K L–K S mass difference2001Inngår i: Physics Letters B, ISSN 0370-2693, E-ISSN 1873-2445, Vol. 503, nr 1, s. 49-57Artikkel i tidsskrift (Fagfellevurdert)
    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.

1234567 1 - 50 of 1561
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