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Publications (10 of 179) Show all publications
Johansson, H. J., Socciarelli, F., Vacanti, N. M., Haugen, M. H., Zhu, Y., Siavelis, I., . . . Lehtio, J. (2019). Breast cancer quantitative proteome and proteogenomic landscape. Nature Communications, 10, Article ID 1600.
Open this publication in new window or tab >>Breast cancer quantitative proteome and proteogenomic landscape
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 1600Article in journal (Refereed) Published
Abstract [en]

In the preceding decades, molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches. Presented herein, an unbiased analysis of breast tumor proteomes, inclusive of 9995 proteins quantified across all tumors, for the first time recapitulates BC subtypes. Additionally, poor-prognosis basal-like and luminal B tumors are further subdivided by immune component infiltration, suggesting the current classification is incomplete. Proteome-based networks distinguish functional protein modules for breast tumor groups, with co-expression of EGFR and MET marking ductal carcinoma in situ regions of normal-like tumors and lending to a more accurate classification of this poorly defined subtype. Genes included within prognostic mRNA panels have significantly higher than average mRNA-protein correlations, and gene copy number alterations are dampened at the protein-level; underscoring the value of proteome quantification for prognostication and phenotypic classification. Furthermore, protein products mapping to non-coding genomic regions are identified; highlighting a potential new class of tumor-specific immunotherapeutic targets.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Clinical Medicine
Identifiers
urn:nbn:se:kth:diva-249785 (URN)10.1038/s41467-019-09018-y (DOI)000463695400015 ()30962452 (PubMedID)2-s2.0-85064079271 (Scopus ID)
Note

QC 20190429

Available from: 2019-04-29 Created: 2019-04-29 Last updated: 2019-04-29Bibliographically approved
Fu, Y., Jussi, J., Qin, W., Brismar, H., Liu, Y., Yang, X. & Chen, Y. (2019). Endocytic pathway of vascular cell adhesion molecule 1 in human umbilical vein endothelial cell identified in vitro by using functionalized nontoxic fluorescent quantum dots. Sensors and actuators. B, Chemical, 297, Article ID 126702.
Open this publication in new window or tab >>Endocytic pathway of vascular cell adhesion molecule 1 in human umbilical vein endothelial cell identified in vitro by using functionalized nontoxic fluorescent quantum dots
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2019 (English)In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 297, article id 126702Article in journal (Refereed) Published
Abstract [en]

Studies about vascular cell adhesion molecule 1 (VCAM1) in tumor growth, metastasis, and angiogenesis suggest that targeting VCAM1 expression is an attractive strategy for diagnosis and anti-tumor therapy. However, the endocytic pathway of VCAM1 in vascular cells has not been well characterized. In this study we visualize the endocytic pathway of tumor necrosis factor α (TNFα) induced VCAM1 in human umbilical vein endothelial cell (HUVEC) in vitro using 5-carboxyfluorescein labeled VCAM1 binding peptides and fluorescent water-dispersible 3-mercaptopropionic acid (3MPA)-coated CdSe-CdS/Cd0.5Zn0.5S/ZnS core–multishell nontoxic quantum dots (3MPA-QDs) functionalized with VCAM1 binding peptides. Clear key in vitro observations are as follows: (a) 3MPA-QDs functionalized with VCAM1 binding peptides, denoted as VQDs, adhered and aggregated cumulatively to cell membrane around 2 h after VQD deposition to cell culture medium and were found in lysosomes in TNFα-treated HUVECs approximately 24 h after VQD deposition; (b) VQDs remained in TNFα-treated HUVECs for the whole 16 days of the experimental observation period; (c) quite differently, 3MPA-QDs were endocytosed then exocytosed by HUVECs via endosomes in about 24–48 h after 3MPA-QD deposition. Our study suggests that VCAM1 molecules, initially expressed on cell membrane induced by TNFα treatment, are internalized into lysosomes. This provides a novel means to deliver materials to lysosomes such as enzyme replacement therapy. Moreover, our meticulous sensing methodology of devising fluorescent nontoxic QDs advances biosensing technique for studying cellular activities in vitro and in vivo.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Bionanosensors, Colloidal fluorescent quantum dot, Endosome, Human umbilical vein endothelial cell, Lysosome, Vascular cell adhesion molecule 1 (VCAM1)
National Category
Industrial Biotechnology
Research subject
Physics, Biological and Biomedical Physics
Identifiers
urn:nbn:se:kth:diva-262749 (URN)10.1016/j.snb.2019.126702 (DOI)000478562700041 ()2-s2.0-85067809943 (Scopus ID)
Note

QC 20191022

Available from: 2019-10-20 Created: 2019-10-20 Last updated: 2019-11-26Bibliographically approved
Fu, Y., Jussi, J. I., Elmlund, L., Dunne, S., Wang, Q. & Brismar, H. (2019). Intrinsic blinking characteristics of single colloidal CdSe-CdS/ZnS core-multishell quantum dots. Physical Review B, 99(3), Article ID 035404.
Open this publication in new window or tab >>Intrinsic blinking characteristics of single colloidal CdSe-CdS/ZnS core-multishell quantum dots
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2019 (English)In: Physical Review B, ISSN 2469-9950, E-ISSN 2469-9969, Vol. 99, no 3, article id 035404Article in journal (Refereed) Published
Abstract [en]

Fluorescence blinking of single colloidal semiconductor quantum dots (QDs) has been extensively studied, and several sophisticated models have been proposed. In this work, we derive Heisenberg equations of motion to carefully study principal transition processes, i.e., photoexcitation, energy relaxation, impact ionization and Auger recombination, radiative and nonradiative recombinations, and tunneling between core states and surface states, of the electron-hole pair in single CdSe-CdS/ZnS core-multishell QDs and show that the on-state probability density distribution of the QD fluorescence obeys the random telegraph signal theory because of the random radiative recombination of the photoexcited electron-hole pair in the QD core, while the off-state probability density distribution obeys the inverse power law distribution due to the series of random walks of the photoexcited electron in the two-dimensional surface-state network after the electron tunnels from the QD core to the QD surface. These two different blinking characteristics of the single QD are resolved experimentally by properly adjusting the optical excitation power and the bin time.

Place, publisher, year, edition, pages
AMER PHYSICAL SOC, 2019
National Category
Physical Sciences
Identifiers
urn:nbn:se:kth:diva-241317 (URN)10.1103/PhysRevB.99.035404 (DOI)000454766400012 ()2-s2.0-85059881217 (Scopus ID)
Note

QC 20190125

Available from: 2019-01-25 Created: 2019-01-25 Last updated: 2019-10-20Bibliographically approved
Siadat, M., Aghazadeh, N., Akbarifard, F., Brismar, H. & Öktem, O. (2019). Joint Image Deconvolution and Separation Using Mixed Dictionaries. IEEE Transactions on Image Processing, 28(8), 3936-3945
Open this publication in new window or tab >>Joint Image Deconvolution and Separation Using Mixed Dictionaries
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2019 (English)In: IEEE Transactions on Image Processing, ISSN 1057-7149, E-ISSN 1941-0042, Vol. 28, no 8, p. 3936-3945Article in journal (Refereed) Published
Abstract [en]

The task of separating an image into distinct components that represent different features plays an important role in many applications. Traditionally, such separation techniques are applied once the image in question has been reconstructed from measured data. We propose an efficient iterative algorithm, where reconstruction is performed jointly with the task of separation. A key assumption is that the image components have different sparse representations. The algorithm is based on a scheme that minimizes a functional composed of a data discrepancy term and the l(1)-norm of the coefficients of the different components with respect to their corresponding dictionaries. The performance is demonstrated for joint 2D deconvolution and separation into curve- and point-like components, and tests are performed on synthetic data as well as experimental stimulated emission depletion and confocal microscopy data. Experiments show that such a joint approach outperforms a sequential approach, where one first deconvolves data and then applies image separation.

Place, publisher, year, edition, pages
Institute of Electrical and Electronics Engineers (IEEE), 2019
Keywords
Inverse problems, image separation, sparse recovery, curvelets, wavelets
National Category
Computer Vision and Robotics (Autonomous Systems)
Identifiers
urn:nbn:se:kth:diva-255299 (URN)10.1109/TIP.2019.2903316 (DOI)000472609200006 ()30843839 (PubMedID)2-s2.0-85067800119 (Scopus ID)
Note

QC 20190730

Available from: 2019-07-30 Created: 2019-07-30 Last updated: 2019-07-30Bibliographically approved
Panizza, E., Zhang, L., Fontana, J. M., Hamada, K., Svensson, D., Akkuratov, E. E., . . . Aperia, A. (2019). Ouabain-regulated phosphoproteome reveals molecular mechanisms for Na+, K+-ATPase control of cell adhesion, proliferation, and survival. The FASEB Journal, 33(9), 10193-10206
Open this publication in new window or tab >>Ouabain-regulated phosphoproteome reveals molecular mechanisms for Na+, K+-ATPase control of cell adhesion, proliferation, and survival
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2019 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 9, p. 10193-10206Article in journal (Refereed) Published
Abstract [en]

The ion pump Na+, K+-ATPase (NKA) is a receptor for the cardiotonic steroid ouabain. Subsaturating concentration of ouabain triggers intracellular calcium oscillations, stimulates cell proliferation and adhesion, and protects from apoptosis. However, it is controversial whether ouabain-bound NKA is considered a signal transducer. To address this question, we performed a global analysis of protein phosphorylation in COS-7 cells, identifying 2580 regulated phosphorylation events on 1242 proteins upon 10- and 20-min treatment with ouabain. Regulated phosphorylated proteins include the inositol triphosphate receptor and stromal interaction molecule, which are essential for initiating calcium oscillations. Hierarchical clustering revealed that ouabain triggers a structured phosphorylation response that occurs in a well-defined, time-dependent manner and affects specific cellular processes, including cell proliferation and cell-cell junctions. We additionally identify regulation of the phosphorylation of several calcium and calmodulin-dependent protein kinases (CAMKs), including 2 sites of CAMK type II-gamma (CAMK2G), a protein known to regulate apoptosis. To verify the significance of this result, CAMK2G was knocked down in primary kidney cells. CAMK2G knockdown impaired ouabain-dependent protection from apoptosis upon treatment with high glucose or serum deprivation. In conclusion, we establish NKA as the coordinator of a broad, tightly regulated phosphorylation response in cells and define CAMK2G as a downstream effector of NKA.-Panizza, E., Zhang, L., Fontana, J. M., Hamada, K., Svensson, D., Akkuratov, E. E., Scott, L., Mikoshiba, K., Brismar, H., Lehtio, J., Aperia, A. Ouabain-regulated phosphoproteome reveals molecular mechanisms for Na+, K+-ATPase control of cell adhesion, proliferation, and survival.

Place, publisher, year, edition, pages
FEDERATION AMER SOC EXP BIOL, 2019
Keywords
calcium and calmodulin-dependent protein kinase, phosphoproteomics, apoptosis, inositol triphosphate receptor, kidney
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-259434 (URN)10.1096/fj.201900445R (DOI)000482214200038 ()31199885 (PubMedID)2-s2.0-85071786321 (Scopus ID)
Note

QC 20190924

Available from: 2019-09-24 Created: 2019-09-24 Last updated: 2019-09-24Bibliographically approved
Kouznetsova, A., Kitajima, T. S., Brismar, H. & Höög, C. (2019). Post-metaphase correction of aberrant kinetochore-microtubule attachments in mammalian eggs. EMBO Reports, Article ID e47905.
Open this publication in new window or tab >>Post-metaphase correction of aberrant kinetochore-microtubule attachments in mammalian eggs
2019 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, article id e47905Article in journal (Refereed) Epub ahead of print
Abstract [en]

The accuracy of the two sequential meiotic divisions in oocytes is essential for creating a haploid gamete with a normal chromosomal content. Here, we have analysed the 3D dynamics of chromosomes during the second meiotic division in live mouse oocytes. We find that chromosomes form stable kinetochore-microtubule attachments at the end of prometaphase II stage that are retained until anaphase II onset. Remarkably, we observe that more than 20% of the kinetochore-microtubule attachments at the metaphase II stage are merotelic or lateral. However, II are found to lag at the spindle equator and < 10% of the laggards missegregate and give rise to aneuploid gametes. Our results demonstrate that aberrant kinetochore-microtubule attachments are not corrected at the metaphase stage of the second meiotic division. Thus, the accuracy of the chromosome segregation process in mouse oocytes during meiosis II is ensured by an efficient correction process acting at the anaphase stage.

Place, publisher, year, edition, pages
Wiley, 2019
Keywords
aneuploidy, meiosis, oocyte, second meiotic division, segregation
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-255756 (URN)10.15252/embr.201947905 (DOI)000477354000001 ()31290587 (PubMedID)2-s2.0-85068754789 (Scopus ID)
Note

QC 20190813

Available from: 2019-08-13 Created: 2019-08-13 Last updated: 2019-10-04Bibliographically approved
Nilsson, L., Zhang, L., Alexander, B., Svensson, D., Wernerson, A., Brismar, H., . . . Aperia, A. (2019). Prompt apoptotic response to high glucose in SGLT expressing cells. American Journal of Physiology - Renal Physiology
Open this publication in new window or tab >>Prompt apoptotic response to high glucose in SGLT expressing cells
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2019 (English)In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466Article in journal (Refereed) Epub ahead of print
Abstract [en]

It is generally believed that cells that are unable to downregulate glucose transport are particularly vulnerable to hyperglycemia. Yet little is known about the relation between expression of glucose transporters and acute toxic effects of high glucose exposure.Here we have, in an ex vivo study on rat renal cells, compared the apoptotic response to a moderate increase in glucose concentration. We have studied the cell types that commonly are targeted in diabetic kidney disease (DKD): proximal tubule cells (PTC) that express SGLT2, mesangial cells (MC) that express SGLT1, and podocytes that lack SGLT and take up glucose via the insulin dependent GLUT4.PTC and MC responded within 4-8 h exposure to 15 mM glucose with translocation of the apoptotic protein Bax to mitochondria and increased apoptotic index. SGLT down-regulation and exposure to SGLT inhibitors abolished the apoptotic response. Onset of overt DKD generally coincides with onset of albuminuria. Albumin had an additive effect on the apoptotic response. Ouabain, which interferes with apoptotic onset, rescued from the apoptotic response. Insulin supplemented podocytes remained resistant to 15 and 30 mM glucose for at least 24 h.Our study points to a previously unappreciated role of SGLT dependent glucose uptake as a risk-factor for diabetic complications and highlights the importance of therapeutic approaches that specifically target the different cell types in DKD.

National Category
Biophysics Cell Biology Biochemistry and Molecular Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-249971 (URN)10.1152/ajprenal.00615.2018 (DOI)000468323700012 ()
Note

QC 20190429

Available from: 2019-04-24 Created: 2019-04-24 Last updated: 2019-10-24Bibliographically approved
Fontana, J. M., Khodus, G. R., Unnersjö Jess, D., Blom, H., Aperia, A. & Brismar, H. (2019). Spontaneous calcium activity in metanephric mesenchymal cells regulates branching morphogenesis in the embryonic kidney. The FASEB Journal, 33(3), 4089-4096
Open this publication in new window or tab >>Spontaneous calcium activity in metanephric mesenchymal cells regulates branching morphogenesis in the embryonic kidney
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2019 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 3, p. 4089-4096Article in journal (Refereed) Published
Abstract [en]

The central role of calcium signaling during development of early vertebrates is well documented, but little is known about its role in mammalian embryogenesis. We have used immunofluorescence and time-lapse calcium imaging of cultured explanted embryonic rat kidneys to study the role of calcium signaling for branching morphogenesis. In mesenchymal cells, we recorded spontaneous calcium activity that was characterized by irregular calcium transients. The calcium signals were dependent on release of calcium from intracellular stores in the endoplasmic reticulum. Down-regulation of the calcium activity, both by blocking the sarco-endoplasmic reticulum Ca2+-ATPase and by chelating cytosolic calcium, resulted in retardation of branching morphogenesis and a reduced formation of primitive nephrons but had no effect on cell proliferation. We propose that spontaneous calcium activity contributes with a stochastic factor to the self-organizing process that controls branching morphogenesis, a major determinant of the ultimate number of nephrons in the kidney.Fontana, J. M., Khodus, G. R., Unnersjo-Jess, D., Blom, H., Aperia, A., Brismar, H. Spontaneous calcium activity in metanephric mesenchymal cells regulates branching morphogenesis in the embryonic kidney.

Place, publisher, year, edition, pages
FEDERATION AMER SOC EXP BIOL, 2019
Keywords
organogenesis, nephron, calcium imaging
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-246250 (URN)10.1096/fj.201802054R (DOI)000459794800079 ()30496703 (PubMedID)
Note

QC 20190402

Available from: 2019-04-02 Created: 2019-04-02 Last updated: 2019-04-02Bibliographically approved
Jess, D. U., Scott, L., Sevilla, S. Z., Patrakka, J., Blom, H. & Brismar, H. (2018). Confocal super-resolution imaging of the glomerular filtration barrier enabled by tissue expansion. Kidney International, 93(4), 1008-1013
Open this publication in new window or tab >>Confocal super-resolution imaging of the glomerular filtration barrier enabled by tissue expansion
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2018 (English)In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 93, no 4, p. 1008-1013Article in journal (Refereed) Published
Abstract [en]

The glomerular filtration barrier, has historically only been spatially resolved using electron microscopy due to the nanometer-scale dimensions of these structures. Recently, it was shown that the nanoscale distribution of proteins in the slit diaphragm can be resolved by fluorescence based stimulated emission depletion microscopy, in combination with optical clearing. Fluorescence microscopy has advantages over electron microscopy in terms of multiplex imaging of different epitopes, and also the amount of volumetric data that can be extracted from thicker samples. However, stimulated emission depletion microscopy is still a costly technique commonly not available to most life science researchers. An imaging technique with which the glomerular filtration barrier can be visualized using more standard fluorescence imaging techniques is thus desirable. Recent studies have shown that biological tissue samples can be isotropically expanded, revealing nanoscale localizations of multiple epitopes using confocal microscopy. Here we show that kidney samples can be expanded sufficiently to study the finest elements of the filtration barrier using confocal microscopy. Thus, our result opens up the possibility to study protein distributions and foot process morphology on the effective nanometer-scale.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2018
Keywords
glomerulus, imaging, podocyte, renal pathology
National Category
Atom and Molecular Physics and Optics Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:kth:diva-226201 (URN)10.1016/j.kint.2017.09.019 (DOI)000428169200029 ()29241621 (PubMedID)2-s2.0-85037568536 (Scopus ID)
Note

QC 20180518

Available from: 2018-05-18 Created: 2018-05-18 Last updated: 2019-04-10Bibliographically approved
Bernhem, K., Blom, H. & Brismar, H. (2018). Quantification of endogenous and exogenous protein expressions of Na,K-ATPase with super-resolution PALM/STORM imaging. PLoS ONE, 13(4), Article ID e0195825.
Open this publication in new window or tab >>Quantification of endogenous and exogenous protein expressions of Na,K-ATPase with super-resolution PALM/STORM imaging
2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 4, article id e0195825Article in journal (Refereed) Published
Abstract [en]

Transient transfection of fluorescent fusion proteins is a key enabling technology in fluorescent microscopy to spatio-temporally map cellular protein distributions. Transient transfection of proteins may however bypass normal regulation of expression, leading to overexpression artefacts like misallocations and excess amounts. In this study we investigate the use of STORM and PALM microscopy to quantitatively monitor endogenous and exogenous protein expression. Through incorporation of an N-terminal hemagglutinin epitope to a mMaple3 fused Na,K-ATPase (α1 isoform), we analyze the spatial and quantitative changes of plasma membrane Na,K-ATPase localization during competitive transient expression. Quantification of plasma membrane protein density revealed a time dependent increase of Na,K-ATPase, but no increase in size of protein clusters. Results show that after 41h transfection, the total plasma membrane density of Na,K-ATPase increased by 63% while the endogenous contribution was reduced by 16%. © 2018 Bernhem et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Place, publisher, year, edition, pages
Public Library of Science, 2018
National Category
Physical Sciences
Identifiers
urn:nbn:se:kth:diva-227364 (URN)10.1371/journal.pone.0195825 (DOI)000430802400044 ()2-s2.0-85045925649 (Scopus ID)
Note

Export Date: 9 May 2018; Article; CODEN: POLNC; Correspondence Address: Brismar, H.; Science for Life Laboratory, Department of Applied Physics, Royal Institute of TechnologySweden; email: brismar@kth.se. QC 20180604

Available from: 2018-06-04 Created: 2018-06-04 Last updated: 2018-06-04Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-0578-4003

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