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  • 1.
    Ardabili, Sahar
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Gantelius, Jesper
    KTH, School of Biotechnology (BIO), Nano Biotechnology (closed 20130101).
    Kowalewski, Jacob
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Russom, Aman
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Dean flow-coupled inertial focusing for ultra-high-throughput particle filtration2010In: 14th International Conference on Miniaturized Systems for Chemistry and Life Sciences 2010, MicroTAS 2010: Volume 3, 2010, p. 1586-1588Conference paper (Refereed)
    Abstract [en]

    Particle manipulation represents an important and fundamental step prior to counting, sorting and detecting bio-particles. In this study, we report dean-coupled inertial focusing of particles in flows through a single curve microchannel at extremely high channel Reynold numbers (∼325). We found the lateral particle focusing position, xf to be fixed and largely independent of radius of curvature and whether particles are pre-focused (at equilibrium) entering the curvature or randomly distributed. Finally, using a single inlet, u-shaped, microchannel we demonstrate filtration of 10μm particles from 2 μm particles at throughputs several orders of magnitude higher than previously shown.

  • 2.
    Brismar, Hjalmar
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Scott, Lena
    Malmersjö, Seth
    Kowalewski, Jacob M.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Zettergren Markus, Eivor
    Ulfhake, Brun
    Nairn, Angus C.
    Greengard, Paul
    Aperia, Anita
    Kvinnor och barns hälsa, Karolinska Institutet.
    Laterally diffusing dopamine 1 receptors are recruited to dendrtic spines by interaction with allosterically changed NMDA receptors2005In: Neuroscience 2005, 2005Conference paper (Refereed)
  • 3.
    Fu, Ying
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Kowalewski, Jacob
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Wu, J.
    Yue, Y.
    Dai, N.
    Thylén, Lars
    KTH, School of Information and Communication Technology (ICT), Optics and Photonics. KTH, School of Information and Communication Technology (ICT), Centres, Kista Photonics Research Center, KPRC.
    Radiative and nonradiative recombination of photoexcited excitons in multi-shell-coated CdSe/CdS/ZnS quantum dots2009In: Europhysics letters, ISSN 0295-5075, E-ISSN 1286-4854, Vol. 86, no 3, p. 37003-Article in journal (Refereed)
    Abstract [en]

    Colloidal quantum dots (QDs) have been widely studied for nanophotonics and bioimaging applications for which the lifetime of their fluorescence is of critical importance. We report experimental and theoretical characterizations of dynamic optical properties of multi-shell-coated CdSe/CdS/ZnS QDs. Quantum-mechanical studies of fundamental optical excitations and Monte Carlo simulations of energy relaxation mechanisms indicate that the excitonic states are densely compacted in the QDs and are easily photoexcited by the laser pulse in the presence of nonradiative electron-phonon interactions. For spherical QDs, the decay time of spontaneous radiative emission of individual photoexcited excitonic states with zero angular momenta is found to be only tens of picoseconds. In our multi-shell QDs, high-energy excitonic states of nonzero angular momenta have to go through a number of nonradiative electron-phonon interaction steps in order to relax to zero-angular-momentum excitonic states for radiative emission, resulting in an effective fluorescence peak at about 2 ns in the photoncount-time relationship. This explains the measured long average fluorescence lifetime of 3.6 ns. Such a long lifetime facilitates the applications of colloidal QDs in areas such as QD-based solar cells, bioimaging and metamaterials.

  • 4. Gunnarson, Eli
    et al.
    Song, Yutong
    Kowalewski, Jacob M
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Brines, Michael
    Cerami, Anthony
    Andersson, Ulf
    Zelenina, Marina
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Aperia, Anita
    Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection.2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 1091-6490, Vol. 106, no 5, p. 1602-7Article in journal (Refereed)
    Abstract [en]

    Disturbed brain water homeostasis with swelling of astroglial cells is a common complication in stroke, trauma, and meningitis and is considered to be a major cause of permanent brain damage. Astroglial cells possess the water channel aquaporin 4 (AQP4). Recent studies from our laboratory have shown that glutamate, acting on group I metabotropic glutamate receptors (mGluRs), increases the permeability of astrocyte AQP4, which, in situations of hypoxia-ischemia, will increase astrocyte water uptake. Here we report that erythropoietin (EPO), which in recent years has emerged as a potent neuro-protective agent, antagonizes the effect of a group I mGluR agonist on astrocyte water permeability. Activation of group I mGluRs triggers fast and highly regular intracellular calcium oscillations and we show that EPO interferes with this signaling event by altering the frequency of the oscillations. These effects of EPO are immediate, in contrast to the neuroprotective effects of EPO that are known to depend upon gene activation. Our findings indicate that EPO may directly reduce the risk of astrocyte swelling in stroke and other brain insults. In support of this conclusion we found that EPO reduced the neurological symptoms in a mouse model of primary brain edema known to depend upon AQP4 water transport.

  • 5. Gunnarson, Eli
    et al.
    Zelenina, Marina
    Karolinska Institutet.
    Song, Yutong
    Kowalewski, Jacob M.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Brines, Michael
    Cerami, Antony
    Andersson, Ulf
    Aperia, Anita
    Kvinnor och barns hälsa, Karolinska Institutet.
    Erythropoietin modulation of astrocyte water permeability: a potential component of neuroprotection2008In: Neuroscience 2008, 2008Conference paper (Refereed)
  • 6.
    Kamali-Zare, Padideh
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Kowalewski, Jacob M.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Aperia, Anita
    Kvinnor och barns hälsa, Karolinska Institutet.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Diffusion Limited Space (DLS) and its impact on water and K+ homeostasis in kidney principal cells and astrocytes2008In: 9th International Conference on Systems Biology, 2008Conference paper (Refereed)
  • 7.
    Kamali-Zare, Padideh
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Kowalewski, Jacob M.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Modeling the role of Aquaporin-4 in astrocyte K+ spatial buffering2008In: 9th International Conference on Systems Biology, 2008Conference paper (Refereed)
  • 8.
    Kamali-Zare, Padideh
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Kowalewski, Jacob M
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Zelenina, Marina
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Aperia, Anita
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Role of diffusion limited space on water and salt homeostasisManuscript (preprint) (Other academic)
  • 9.
    Kamali-Zare, Padideh
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Kowalewski, Jacob
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Zelenina, Marina
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Aperia, Anita
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Diffusion limited space contributes to K+ siphoning by regulation of K+ and water homeostasis in astrocytesManuscript (preprint) (Other academic)
    Abstract [en]

    Diffusion Limited Space (DLS) is defined as a region where diffusion is limited by the geometry. Two examples of DLS in the brain are the neuronal synapse, and the narrow region between astrocyte endfeet and blood capillaries. In a series of geometrical models we show that DLS plays a role in regulation of water and K+ homeostasis in the brain by an indirect functional coupling of aquaporins (AQPs) and inward rectifying K+ (Kir) channels in a membrane microdomain.

    1. Simulations in geometrical models of a synapse region show that following a step increase in synaptic [K+], both K+ and water are taken up by astrocytes via AQPs and Kir channels lining the synapse.  This uptake creates a transient depletion of water in the synapse region that, enhanced by the DLS, facilitates K+ uptake and an efficient clearance of excess K+ from the synapse.

    2. Simulations in a geometrical model of astrocytes show that the DLS formed between astrocyte endfeet and blood capillaries, facilitate the siphoning of accumulated K+ into the extracellular space facing the blood capillaries. The DLS geometry creates an efficient coupling between AQPs and Kir channels.

    3. Furthermore, the models show that a local coupling between water and K+ transport is important for the maintenance of membrane potential and the net K+ spatial buffering capacity in the astrocytes.

    4. In the full geometrical model of K+ spatial buffering we show that the geometry of the extracellular space both in the synapse region and in the endfeet is an essential component for the cell volume regulation.

    Our results suggest that for regulation of K+ and water homeostasis in astrocytes, not only the classical aspects of functional couplings between proteins, but also the geometry of the cell and the microdomains are important. Further, our results suggest a central role for AQPs in the astrocyte endfeet and identify their contribution to K+ siphoning.

  • 10.
    Khorshidi, Mohammad Ali
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Vanherberghen, Bruno
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Kowalewski, Jacob M.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Garrod, Kym R.
    Lindström, Sara
    KTH, School of Biotechnology (BIO), Nano Biotechnology.
    Andersson-Svahn, Helene
    KTH, School of Biotechnology (BIO), Nano Biotechnology.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Cahalan, Michael D.
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Analysis of transient migration behavior of natural killer cells imaged in situ and in vitro2011In: Integrative Biology, ISSN 1757-9694, E-ISSN 1757-9708, Vol. 3, no 7, p. 770-778Article in journal (Refereed)
    Abstract [en]

    We present a simple method for rapid and automatic characterization of lymphocyte migration from time-lapse fluorescence microscopy data. Time-lapse imaging of natural killer (NK) cells in vitro and in situ, both showed that individual cells transiently alter their migration behavior. Typically, NK cells showed periods of high motility, interrupted by transient periods of slow migration or almost complete arrests. Analysis of in vitro data showed that these periods frequently coincided with contacts with target cells, sometimes leading to target cell lysis. However, NK cells were also commonly observed to stop independently of contact with other cells. In order to objectively characterize the migration of NK cells, we implemented a simple method to discriminate when NK cells stop or have low motilities, have periods of directed migration or undergo random movement. This was achieved using a sliding window approach and evaluating the mean squared displacement (MSD) to assess the migration coefficient and MSD curvature along trajectories from individual NK cells over time. The method presented here can be used to quickly and quantitatively assess the dynamics of individual cells as well as heterogeneity within ensembles. Furthermore, it may also be used as a tool to automatically detect transient stops due to the formation of immune synapses, cell division or cell death. We show that this could be particularly useful for analysis of in situ time-lapse fluorescence imaging data where most cells, as well as the extracellular matrix, are usually unlabelled and thus invisible.

  • 11.
    Kowalewski, Jacob
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Mathematical Models in Cellular Biophysics2007Licentiate thesis, comprehensive summary (Other scientific)
    Abstract [en]

    Cellular biophysics deals with, among other things, transport processes within cells. This thesis presents two studies where mathematical models have been used to explain how two of these processes occur.

    Cellular membranes separate cells from their exterior environment and also divide a cell into several subcellular regions. Since the 1970s lateral diffusion in these membranes has been studied, one the most important experimental techniques in these studies is fluorescence recovery after photobleach (FRAP). A mathematical model developed in this thesis describes how dopamine 1 receptors (D1R) diffuse in a neuronal dendritic membrane. Analytical and numerical methods have been used to solve the partial differential equations that are expressed in the model. The choice of method depends mostly on the complexity of the geometry in the model.

    Calcium ions (Ca2+) are known to be involved in several intracellular signaling mechanisms. One interesting concept within this field is a signaling microdomain where the inositol 1,4,5-triphosphate receptor (IP3R) in the endoplasmic reticulum (ER) membrane physically interacts with plasma membrane proteins. This microdomain has been shown to cause the intracellular Ca2+ level to oscillate. The second model in this thesis describes a signaling network involving both ER membrane bound and plasma membrane Ca2+ channels and pumps, among them store-operated Ca2+ (SOC) channels. A MATLAB® toolbox was developed to implement the signaling networks and simulate its properties. This model was also implemented using Virtual cell.

    The results show a high resemblance between the mathematical model and FRAP data in the D1R study. The model shows a distinct difference in recovery characteristics of simulated FRAP experiments on whole dendrites and dendritic spines, due to differences in geometry. The model can also explain trapping of D1R in dendritic spines.

    The results of the Ca2+ signaling model show that stimulation of IP3R can cause Ca2+ oscillations in the same frequency range as has been seen in experiments. The removing of SOC channels from the model can alter the characteristics as well as qualitative appearance of Ca2+ oscillations.

  • 12.
    Kowalewski, Jacob
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Modeling and Data Analysis in Cellular Biophysics2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cellular biophysics deals with the physical aspects of cell biology. This thesis presents a number of studies where mathematical models and data analysis can increase our understanding of this field.

    During recent years development in experimental methods and mathematical modeling have driven the amount of data and complexity in our understanding of cellular biology to a new level. This development has made it possible to describe cellular systems quantitatively where only qualitative descriptions were previously possible. To deal with the complex data and models that arise in this kind of research a combination of tools from physics and cell biology has to be applied; this constitutes a field we call cellular biophysics. The aim of this doctoral thesis is to develop novel approaches in this field. I present eight studies where quantitative modeling and analysis are involved.

    The first two studies concern cells interacting with their surrounding environment in the kidney. These cells sense fluid flow and respond with calcium (Ca2+) signals. The interaction between fluid and cells in renal tubular epithelium can be described by biomechanical models. This thesis describes a mathematical model of flow sensing by cilia with focus on the flow frequency response and time delay between the mechanical stress and the Ca2+ signaling response.

    Intracellular Ca2+ is kept at a very low level compared to the extracellular environment, while several intracellular compartments have higher Ca2+ concentration than the cytoplasm. This makes Ca2+ an efficient messenger for intra­cellular signaling, the process whereby signals are transduced from an extracellular stimulus to an intracellular activity such as gene expression. An important type of Ca2+ signaling is oscillations in intracellular Ca2+ concentration which occur due to the concerted interplay between different transport mechanisms within a cell. A study in this thesis examines ways to explain these mechanisms in terms of a mathematical model. Another study in the thesis reports that erythropoietin can regulate the water permeability of astrocytes and that it alters the pattern of Ca2+ oscillations in astrocytes. In this thesis the analysis of this Ca2+ signaling is described.

    Simulations described in one of the studies show how different geometries can affect the fluorescence recovery and that geometrically constrained reactions can trap diffusing receptors in dendritic spines. When separate time scales are present in a fluorescence revovery after photobleaching (FRAP) experiment the reaction and diffusion components can be studied separately.

    Applying single particle tracking methods to the migration trajectories of natural killer cells shows that there is a correlation between the formation of conjugates and transient confinement zones (TCZs) in these trajectories in vitro. TCZs are also present in in vivo experiments where they show strong similarities with the in vitro situation. This approach is a novel concept in data analysis methods for tracking immune cells.

  • 13.
    Kowalewski, Jacob M
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Uhlén, Per
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Modeling the impact of store-operated Ca2+ entry on intracellular Ca2+ oscillations2006In: Mathematical biosciences, ISSN 0025-5564, Vol. 204, no 2, p. 232-249Article in journal (Refereed)
    Abstract [en]

    Calcium (Ca2+) oscillations play fundamental roles in various cell signaling processes and have been the subject of numerous modeling studies. Here we have implemented a general mathematical model to simulate the impact of store-operated Ca2+ entry on intracellular Ca2+ oscillations. In addition, we have compared two different models of the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) and their influences on intracellular Ca2+ oscillations. Store-operated Ca2+ entry following Ca2+ depletion of endoplasmic reticulum (ER) is an important component of Ca2+ signaling. We have developed a phenomenological model of store-operated Ca2+ entry via store-operated Ca2+ (SOC) channels, which are activated upon ER Ca2+ depletion. The depletion evokes a bi-phasic Ca2+ signal, which is also produced in our mathematical model. The IP3R is an important regulator of intracellular Ca2+ signals. This IP3 sensitive Ca2+ channel is also regulated by Ca2+. We apply two IP3R models, the Mak-McBride-Foskett model and the De Young and Keizer model, with significantly different channel characteristics. Our results show that the two separate IP3R models evoke intracellular Ca2+ oscillations with different frequencies and amplitudes. Store-operated Ca2+ entry affects the oscillatory behavior of these intracellular Ca2+ oscillations. The IP3 threshold is altered when store-operated Ca2+ entry is excluded from the model. Frequencies and amplitudes of intracellular Ca2+ oscillations are also altered without store-operated Ca2+ entry. Under certain conditions, when intracellular Ca2+ oscillations are absent, excluding store-operated Ca2+ entry induces an oscillatory response. These findings increase knowledge concerning store-operated Ca2+ entry and its impact on intracellular Ca2+ oscillations.

  • 14.
    Kowalewski, Jacob M.
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Uhlén, Per
    Kitano, Hiroaki
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Generation of Slow Calcium oscillations in Spatial Cell Models Driven by Store Operated Calcium Entry2004Conference paper (Refereed)
    Abstract [en]

    Calcium signaling is involved in many cellular processes ranging from fertilization to apoptosis. We have created two general mathematical models to simulate calcium transport between the endoplasmic reticulum (ER), the cytosol and the extracellular environment. Active in this process is inositol-1,4,5-trisphosphate (InsP3). The behavior of the changes in calcium concentration was studied. The first model is compartmental and uses ordinary differential equations. The second one is a spatial model, which uses partial differential equations. The tools used in constructing these models were MATLAB and Virtual Cell. Store operated calcium entry can be observed in experiments with living cells when the sarco(endo)plasmic reticulum calcium-ATPase (SERCA) pumps are blocked by cyclopiazonic acid (CPA) or thapsigargin. We have developed a phenomenological model of store operated calcium channels (SOC). This model involves a diffusible messenger that leaves the ER and binds to a channel in the plasma membrane. Many parameters in the models are not fully known. A basic assumption is that the parameters can be estimated from the fact that a cell at rest has an almost constant level of calcium. Results from both the compartmental and the spatial simulations show that InsP3 can cause the cytosolic calcium level to oscillate at frequencies between 1 and 5 mHz. Experimental studies have shown than calcium oscillations in this frequency range are present in renal cells. The SERCA blocking simulations show good similarity with experimental results. The results also show that the high surface-to-volume ratio of the ER is important for causing oscillations.

  • 15.
    Li, Zhilun
    et al.
    Department of Biosciences and Nutrition, Karolinska Institutet.
    Lock, John
    Department of Biosciences and Nutrition, Karolinska Institutet.
    Olofsson, Helene
    Department of Biosciences and Nutrition, Karolinska Institutet.
    Kowalewski, Jacob
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Teller, Steffen
    Department of Laboratory Medicine, Karolinska Institutet.
    Liu, Yajuan
    Department of Laboratory Medicine, Karolinska Institutet.
    Zhang, Hongquan
    Department of Biosciences and Nutrition, Karolinska Institutet.
    Strömblad, Staffan
    Department of Biosciences and Nutrition, Karolinska Institutet.
    Integrin-mediated cell attachment induces a PAK4-dependent feedback loop regulating cell adhesion through modified integrin alpha v beta 5 clustering and turnover2010In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 21, no 19, p. 3317-3329Article in journal (Refereed)
    Abstract [en]

    Cell-to-extracellular matrix adhesion is regulated by a multitude of pathways initiated distally to the core cell-matrix adhesion machinery, such as via growth factor signaling. In contrast to these extrinsically sourced pathways, we now identify a regulatory pathway that is intrinsic to the core adhesion machinery, providing an internal regulatory feedback loop to fine tune adhesion levels. This autoinhibitory negative feedback loop is initiated by cell adhesion to vitronectin, leading to PAK4 activation, which in turn limits total cell-vitronectin adhesion strength. Specifically, we show that PAK4 is activated by cell attachment to vitronectin as mediated by PAK4 binding partner integrin alpha v beta 5, and that active PAK4 induces accelerated integrin alpha v beta 5 turnover within adhesion complexes. Accelerated integrin turnover is associated with additional PAK4-mediated effects, including inhibited integrin alpha v beta 5 clustering, reduced integrin to F-actin connectivity and perturbed adhesion complex maturation. These specific outcomes are ultimately associated with reduced cell adhesion strength and increased cell motility. We thus demonstrate a novel mechanism deployed by cells to tune cell adhesion levels through the autoinhibitory regulation of integrin adhesion.

  • 16.
    Rydholm, Susanna
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Frisk, Thomas
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Kowalewski, Jacob
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Andersson Svahn, Helene
    KTH, School of Biotechnology (BIO), Nano Biotechnology.
    Stemme, Göran
    KTH, School of Electrical Engineering (EES), Microsystem Technology.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Controlled stimuli of primary cilia in microfabricated device2008Conference paper (Refereed)
  • 17.
    Rydholm, Susanna
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Frisk, Thomas
    KTH, School of Electrical Engineering (EES), Microsystem Technology.
    Kowalewski, Jacob M
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Andersson Svahn, Helene
    KTH, School of Biotechnology (BIO), Nano Biotechnology.
    Stemme, Göran
    KTH, School of Electrical Engineering (EES), Microsystem Technology.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Microfluidic devices for studies of primary cilium mediated cellular response to dynamic flow conditions2008In: Biomedical microdevices (Print), ISSN 1387-2176, E-ISSN 1572-8781, Vol. 10, no 4, p. 555-560Article in journal (Refereed)
    Abstract [en]

    We present the first microfabricated microfluidic devices designed specifically for studies of primary cilium mediated cellular response to dynamic flow. The primary cilium functions as a mechano-sensor in renal tubular epithelium, sensing the extracellular fluid flow. Malfunction of cilia has been implicated in e.g. polycystic kidney disease and other pathological conditions. Bending of the primary cilium by fluid flow has been shown to give rise to an intracellular calcium signal, however little is known about the sensitivity to flow duration, magnitude and direction. This paper presents a novel method for studying cilia forming cells in asymmetric microfluidic environments. The microfluidic devices presented here were designed for a dynamic control of the local fluid flow on a cellular level, and thus, enables studies of cellular responses to an amplitude, frequency and direction controlled cilium movement.

  • 18.
    Rydholm, Susanna
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Zwartz, Gordon
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Kowalewski, Jacob
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Kamali-Zare, Padideh
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Frisk, Thomas
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Mechanical Properties of Primary Cilia Regulate the Response to Fluid flow2010In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 298, no 5, p. 1096-1102Article in journal (Refereed)
    Abstract [en]

    The primary cilium is a ubiquitous organelle present on most mammalian cells. Malfunction of the organelle has been associated with various pathological disorders, many of which lead to cystic disorders in liver, pancreas, and kidney. Primary cilia have in kidney epithelial cells been observed to generate intracellular calcium in response to fluid flow, and disruption of proteins involved in this calcium signaling lead to autosomal dominant polycystic kidney disease, implying a direct connection between calcium signaling and cyst formation. It has also been shown that there is a significant lag between the onset of flow and initiation of the calcium signal. The present study focuses on the mechanics of cilium bending and the resulting calcium signal. Visualization of real-time cilium movements in response to different types of applied flow showed that the bending is fast compared with the initiation of calcium increase. Mathematical modeling of cilium and surrounding membrane was performed to deduce the relation between bending and membrane stress. The results showed a delay in stress buildup that was similar to the delay in calcium signal. Our results thus indicate that the delay in calcium response upon cilia bending is caused by mechanical properties of the cell membrane.

  • 19.
    Scott, Lena
    et al.
    Department of Woman and Child Health, Karolinska Institutet.
    Zelenin, Sergey
    Department of Woman and Child Health, Karolinska Institutet.
    Malmersjö, Seth
    Department of Woman and Child Health, Karolinska Institutet.
    Kowalewski, Jacob M
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Zettergren Markus, Eivor
    Department of Woman and Child Health, Karolinska Institutet.
    Nairn, Angus C
    Department of Psychiatry, Yale University School of Medicine, New Haven, CT .
    Greengard, Paul
    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Aperia, Anita
    Department of Woman and Child Health, Karolinska Institutet.
    Allosteric changes of the NMDA receptor trap diffusible dopamine 1 receptors in spines2006In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 3, p. 762-767Article in journal (Refereed)
    Abstract [en]

    The dopaminergic and glutamatergic systems interact to initiate and organize normal behavior, a communication that may be perturbed in many neuropsychiatric diseases, including schizophrenia. We show here that NMDA, by allosterically modifying NMDA receptors, can act as a scaffold to recruit laterally diffusing dopamine D1 receptors (D1R) to neuronal spines. Using organotypic culture from rat striatum transfected with D1R fused to a fluorescent protein, we show that the majority of dendritic D1R are in lateral diffusion and that their mobility is confined by interaction with NMDA receptors. Exposure to NMDA reduces the diffusion coefficient for D1R and causes an increase in the number of D1R-positive spines. Unexpectedly, the action of NMDA in potentiating D1R recruitment was independent of calcium flow via the NMDA receptor channel. Thus, a highly energy-efficient, diffusion-trap mechanism can account for intraneuronal interaction between the glutamatergic and dopaminergic systems and for regulation of the number of D1R-positive spines. This diffusion trap system represents a molecular mechanism for brain plasticity and offers a promising target for development of antipsychotic therapy

  • 20.
    Vanherberghen, Bruno
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Kowalewski, Jacob
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Garrod, Kym
    Lindström, Sara
    KTH, School of Biotechnology (BIO).
    Andersson Svahn, Helene
    KTH, School of Biotechnology (BIO).
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Cahalan, Michael D.
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Single Cell Tracking of Natural Killer CellMigration in vivo and in vitro reveals Transient Migration Arrest PeriodsManuscript (preprint) (Other (popular science, discussion, etc.))
1 - 20 of 20
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