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Search Results: 1 - 10 of 726 matches for " Fredrik Elinder "
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Oxaliplatin neurotoxicity – no general ion channel surface-charge effect
Amir Broomand, Elin Jerremalm, Jeffrey Yachnin, Hans Ehrsson, Fredrik Elinder
Journal of Negative Results in BioMedicine , 2009, DOI: 10.1186/1477-5751-8-2
Abstract: To our surprise, we did not see any effects on the current amplitudes, on the current time courses, or on the voltage dependence of the Shaker wild-type channel. Oxaliplatin is expected to bind to cysteines. Therefore, we explored if there could be a specific effect on single (E418C) and double-cysteine (R362C/F416C) mutated Shaker channels previously shown to be sensitive to cysteine-specific reagents. Neither of these channels were affected by oxaliplatin. The clear lack of effect on the Shaker K channel suggests that oxaliplatin or its monochloro complex has no general surface-charge effect on the channels, as has been suggested before, but rather a specific effect to the channels previously shown to be affected.The platinum-based chemotherapeutic drug oxaliplatin has been used in the clinic for about ten years. The therapeutic indication is metastatic colorectal cancer. The mechanism of action is not fully understood, but it is assumed that DNA-adduct formation is one route to cell destruction [1]. The dose-limiting side effect of oxaliplatin treatment is neurotoxicity. A unique and unpleasant acute neurosensory toxicity with paresthesias and dysesthesias of the distal extremities and perioral region occurs shortly after infusion in as much as 90% of the patients. These symptoms can be worsened or triggered by cold, but are reversed within hours or days after treatment. After cumulative doses of about 800 mg/m2 another form of neurotoxicity, with paresthesias and dysesthesias persisting between cycles and problems with sensorimotor coordination is seen in about 10–15% of the patients. Most of the patients recover a few months after treatment discontinuation [2,3]. Many patients who receive a clinical benefit from oxaliplatin cannot continue treatment because of worsening neurotoxicity. Our understanding of the mechanism underlying this is limited and research in this area could lead to prolonged treatment with this useful drug.Oxaliplatin has a half-life of abou
A Voltage Dependent Non-Inactivating Na+ Channel Activated during Apoptosis in Xenopus Oocytes
Ulrika H. Englund, Jens Gertow, Katarina K?gedal, Fredrik Elinder
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088381
Abstract: Ion channels in the plasma membrane are important for the apoptotic process. Different types of voltage-gated ion channels are up-regulated early in the apoptotic process and block of these channels prevents or delays apoptosis. In the present investigation we examined whether ion channels are up-regulated in oocytes from the frog Xenopus laevis during apoptosis. The two-electrode voltage-clamp technique was used to record endogenous ion currents in the oocytes. During staurosporine-induced apoptosis a voltage-dependent Na+ current increased three-fold. This current was activated at voltages more positive than 0 mV (midpoint of the open-probability curve was +55 mV) and showed almost no sign of inactivation during a 1-s pulse. The current was resistant to the Na+-channel blockers tetrodotoxin (1 μM) and amiloride (10 μM), while the Ca2+-channel blocker verapamil (50 μM) in the bath solution completely blocked the current. The intracellular Na+ concentration increased in staurosporine-treated oocytes, but could be prevented by replacing extracellular Na+ whith either K+ or Choline+. Prevention of this influx of Na+ also prevented the STS-induced up-regulation of the caspase-3 activity, suggesting that the intracellular Na+ increase is required to induce apoptosis. Taken together, we have found that a voltage dependent Na+ channel is up-regulated during apoptosis and that influx of Na+ is a crucial step in the apoptotic process in Xenopus oocytes.
The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel
Samira Yazdi?,Matthias Stein?,Fredrik Elinder,Magnus Andersson?,Erik Lindahl
PLOS Computational Biology , 2016, DOI: 10.1371/journal.pcbi.1004704
Abstract: Voltage-gated potassium (KV) channels are membrane proteins that respond to changes in membrane potential by enabling K+ ion flux across the membrane. Polyunsaturated fatty acids (PUFAs) induce channel opening by modulating the voltage-sensitivity, which can provide effective treatment against refractory epilepsy by means of a ketogenic diet. While PUFAs have been reported to influence the gating mechanism by electrostatic interactions to the voltage-sensor domain (VSD), the exact PUFA-protein interactions are still elusive. In this study, we report on the interactions between the Shaker KV channel in open and closed states and a PUFA-enriched lipid bilayer using microsecond molecular dynamics simulations. We determined a putative PUFA binding site in the open state of the channel located at the protein-lipid interface in the vicinity of the extracellular halves of the S3 and S4 helices of the VSD. In particular, the lipophilic PUFA tail covered a wide range of non-specific hydrophobic interactions in the hydrophobic central core of the protein-lipid interface, while the carboxylic head group displayed more specific interactions to polar/charged residues at the extracellular regions of the S3 and S4 helices, encompassing the S3-S4 linker. Moreover, by studying the interactions between saturated fatty acids (SFA) and the Shaker KV channel, our study confirmed an increased conformational flexibility in the polyunsaturated carbon tails compared to saturated carbon chains, which may explain the specificity of PUFA action on channel proteins.
The Free Energy Barrier for Arginine Gating Charge Translation Is Altered by Mutations in the Voltage Sensor Domain
Christine S. Schwaiger, Sara I. B?rjesson, Berk Hess, Bj?rn Wallner, Fredrik Elinder, Erik Lindahl
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0045880
Abstract: The gating of voltage-gated ion channels is controlled by the arginine-rich S4 helix of the voltage-sensor domain moving in response to an external potential. Recent studies have suggested that S4 moves in three to four steps to open the conducting pore, thus visiting several intermediate conformations during gating. However, the exact conformational changes are not known in detail. For instance, it has been suggested that there is a local rotation in the helix corresponding to short segments of a 3-helix moving along S4 during opening and closing. Here, we have explored the energetics of the transition between the fully open state (based on the X-ray structure) and the first intermediate state towards channel closing (C), modeled from experimental constraints. We show that conformations within 3 ? of the X-ray structure are obtained in simulations starting from the C model, and directly observe the previously suggested sliding 3-helix region in S4. Through systematic free energy calculations, we show that the C state is a stable intermediate conformation and determine free energy profiles for moving between the states without constraints. Mutations indicate several residues in a narrow hydrophobic band in the voltage sensor contribute to the barrier between the open and C states, with F233 in the S2 helix having the largest influence. Substitution for smaller amino acids reduces the transition cost, while introduction of a larger ring increases it, largely confirming experimental activation shift results. There is a systematic correlation between the local aromatic ring rotation, the arginine barrier crossing, and the corresponding relative free energy. In particular, it appears to be more advantageous for the F233 side chain to rotate towards the extracellular side when arginines cross the hydrophobic region.
Dampening of Hyperexcitability in CA1 Pyramidal Neurons by Polyunsaturated Fatty Acids Acting on Voltage-Gated Ion Channels
Jenny Tigerholm, Sara I. B?rjesson, Linnea Lundberg, Fredrik Elinder, Erik Fransén
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044388
Abstract: A ketogenic diet is an alternative treatment of epilepsy in infants. The diet, rich in fat and low in carbohydrates, elevates the level of polyunsaturated fatty acids (PUFAs) in plasma. These substances have therefore been suggested to contribute to the anticonvulsive effect of the diet. PUFAs modulate the properties of a range of ion channels, including K and Na channels, and it has been hypothesized that these changes may be part of a mechanistic explanation of the ketogenic diet. Using computational modelling, we here study how experimentally observed PUFA-induced changes of ion channel activity affect neuronal excitability in CA1, in particular responses to synaptic input of high synchronicity. The PUFA effects were studied in two pathological models of cellular hyperexcitability associated with epileptogenesis. We found that experimentally derived PUFA modulation of the A-type K (KA) channel, but not the delayed-rectifier K channel, restored healthy excitability by selectively reducing the response to inputs of high synchronicity. We also found that PUFA modulation of the transient Na channel was effective in this respect if the channel's steady-state inactivation was selectively affected. Furthermore, PUFA-induced hyperpolarization of the resting membrane potential was an effective approach to prevent hyperexcitability. When the combined effect of PUFA on the KA channel, the Na channel, and the resting membrane potential, was simulated, a lower concentration of PUFA was needed to restore healthy excitability. We therefore propose that one explanation of the beneficial effect of PUFAs lies in its simultaneous action on a range of ion-channel targets. Furthermore, this work suggests that a pharmacological cocktail acting on the voltage dependence of the Na-channel inactivation, the voltage dependences of KA channels, and the resting potential can be an effective treatment of epilepsy.
Growth and Structure of ZnO Nanorods on a Sub-Micrometer Glass Pipette and Their Application as Intracellular Potentiometric Selective Ion Sensors
Muhammad H. Asif,Omer Nur,Magnus Willander,Peter Str?lfors,Cecilia Br?nnmark,Fredrik Elinder,Ulrika H. Englund,Jun Lu,Lars Hultman
Materials , 2010, DOI: 10.3390/ma3094657
Abstract: This paper presents the growth and structure of ZnO nanorods on a sub-micrometer glass pipette and their application as an intracellular selective ion sensor. Highly oriented, vertical and aligned ZnO nanorods were grown on the tip of a borosilicate glass capillary (0.7 μm in diameter) by the low temperature aqueous chemical growth (ACG) technique. The relatively large surface-to-volume ratio of ZnO nanorods makes them attractive for electrochemical sensing. Transmission electron microscopy studies show that ZnO nanorods are single crystals and grow along the crystal’s c-axis. The ZnO nanorods were functionalized with a polymeric membrane for selective intracellular measurements of Na +. The membrane-coated ZnO nanorods exhibited a Na +-dependent electrochemical potential difference versus an Ag/AgCl reference micro-electrode within a wide concentration range from 0.5 mM to 100 mM. The fabrication of functionalized ZnO nanorods paves the way to sense a wide range of biochemical species at the intracellular level.
The Economics of Power Generation Technology Choice and Investment Timing in the Presence of Policy Uncertainty  [PDF]
Robert Lundmark, Fredrik Pettersson
Low Carbon Economy (LCE) , 2012, DOI: 10.4236/lce.2012.31001
Abstract: The purpose of this study is to analyze how market and policy uncertainties affect the general profitability of new investments in the power sector, and investigate the associated investment timing and technology choices. We develop an economic model for new investments in three competing energy technologies in the Swedish electric power sector. The model takes into account the policy impacts of the EU ETS and the Swedish green certificate scheme. By simulating and modeling policy effects through stochastic prices the results suggest that bio-fuelled power is the most profitable technology choice in the presence of existing policy instruments and under our assumptions. The likelihood of choosing gas power increases over time at the expense of wind power due to the relative capital requirement per unit of output for these technologies. Overall the results indicate that the economic incentives to postpone investments into the future are significant.
Teaching Anatomy in the Multimedia World—Using Digital Tools for Progressive Learning over Time  [PDF]
Marcus Granmo, Fredrik Bengtsson
Creative Education (CE) , 2015, DOI: 10.4236/ce.2015.611117
Abstract: In a cross-faculty project journalism students filmed anatomy briefings on a medical program. The material gave medical students free access to rehearse and repeat over time. The journalism students on their part practiced camera technique, directing and editing: It was an opportunity for students to help students. Following a quality evaluation of undergraduate studies at the Lund University medical faculty in 2011, we explored, developed, and implemented novel educational tools to meet students’ need in the multimedia world in which they operate. Incorporating complementary digital learning resources, in particular integration with mobile applications enabled us to meet students in their own world, thereby enhancing the learning process. We produced short video clips on specific anatomic themes, following the curriculum of the well-established anatomy course, and posted them online, allowing continuous rehearsal and repetition over time at a pace that suits individual students. Also, available to all semesters it provides free opportunities for repetition, reducing the risk of knowledge-loss between basic and clinical parts of the program. Besides the obvious benefits for students, the material gave teachers a clear view of the students’ curriculum. Thus, the material can be used for alternative, more interactive forms of examination. The paper describes the project, and the results from evaluations and integration with mobile technology.
A healthy school start - Parental support to promote healthy dietary habits and physical activity in children: Design and evaluation of a cluster-randomised intervention
Gisela Nyberg, Elinor Sundblom, ?sa Norman, Liselotte Elinder
BMC Public Health , 2011, DOI: 10.1186/1471-2458-11-185
Abstract: This paper describes the rationale and design of a parental support programme to promote healthy dietary habits and physical activity in six-year-old children starting school. The study is performed in close collaboration with the school health care and is designed as a cluster-randomised controlled trial with a mixed methods approach. In total, 14 pre-school classes are included from a municipality in Stockholm county where there is large variation in socio-economic status between the families. The school classes are randomised to intervention (n = 7) and control (n = 7) groups including a total of 242 children. The intervention is based on social cognitive theory and consists of three main components: 1) a health information brochure; 2) two motivational interviewing sessions with the parents; and 3) teacher-led classroom activities with the children. The primary outcomes are physical activity in the children measured objectively by accelerometry, children's dietary and physical activity habits measured with a parent-proxy questionnaire and parents' self-efficacy measured by a questionnaire. Secondary outcomes are height, weight and waist circumference in the children. The duration of the intervention is six months and includes baseline, post intervention and six months follow-up measurements. Linear and logistic regression models will be used to analyse differences between intervention and control groups in the outcome variables. Mediator and moderator analysis will be performed. Participants will be interviewed.The results from this study will show if it is possible to promote a healthy lifestyle and a normal weight development among children from low-income districts with relatively limited efforts involving parents. Hopefully the study will provide new insights to the further development of effective programmes to prevent overweight and obesity in children.ISRCTN: ISRCTN32750699Childhood obesity is multi-factorial and determined to a large extent by dietary ha
Adapting research to the 21st century – the Swedish Biobank Register
L. Norlin,M. Fransson,S. Eaker,G. Elinder
Norsk Epidemiologi , 2012,
Abstract: In Sweden, there are currently nearly 600 biobanks. The Swedish Biobank Register (SBR) is an on-going national investment by the county councils working to capture information in one database about all biobank samples collected from patients attending the Swedish medical health care. The aim of the SBR is to gather enough information about biobank samples to be able to physically trace the samples. The BioBanking and Molecular Resource Infrastructure of Sweden (BBMRI.se) has been given the task of extending the SBR Information System (IS) with functionality useful for research in connection to health care, quality registers and large patient cohorts. The research extension is called BBMRI catalogue over sample collections for research. To achieve this, the SBR-IS will be extended with attributes useful for both epidemiological and clinical research enabling authorized researchers to search for samples stored at non-clinical biobanks nationwide. The Swedish Biobank Register, together with the BBMRI research catalogue, will be a unique resource for research. SBR-IS will contain information about biobank samples collected by both clinical and population-based biobanks specifically established for research purposes but BBMRI.se researchers will only be granted access to data related to population-based biobanks. As BBMRI.se is the Swedish hub of the pan-European biobank project BBMRI, whose goal is to promote excellence and efficacy in European life science research, the BBMRI research catalogue will also be made compatible with the European register by applying its minimum data set describing biobanks and their objects. In this paper we describe the implementation. Our belief is that it will pave the way for connecting biobanks on an international level as well as stimulate collaborations and optimize usage of biobank samples. In the long run, patients and sample donors will benefit as new results with high statistical power emerge from large scale studies.
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