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| 2. |
- Edwards, Katarina, et al.
(författare)
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Effect of polyethyleneglycol-phospholipids on aggregate structure in preparations of small unilamellar liposomes
- 1997
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Ingår i: Biophysical Journal. - 0006-3495 .- 1542-0086. ; 73:1, s. 258-266
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Phospholipids with covalently attached poly(ethylene glycol) (PEG lipids) are commonly used for the preparation of long circulating liposomes. Although it is well known that lipid/PEG-lipid mixed micelles may form above a certain critical concentration of PEG-lipid, little is known about the effects of PEG-lipids on liposome structure and leakage at submicellar concentrations. In this study we have used cryogenic transmission electron microscopy to investigate the effect of PEG(2000)-PE on aggregate structure in preparations of liposomes with different membrane compositions. The results reveal a number of important aggregate structures not documented before. The micrographs show that enclosure of PEG-PE induces the formation of open bilayer discs at concentrations well below those where mixed micelles begin to form. The maximum concentration of PEG-lipid that may be incorporated without alteration of the liposome structure depends on the phospholipid chain length, whereas phospholipid saturation or the presence of cholesterol has little or no effect. The presence of cholesterol does, however, affect the shape of the mixed micelles formed at high concentrations of PEG-lipid. Threadlike micelles form in the absence of cholesterol but adapt a globular shape when cholesterol is present.
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| 3. |
- Fridberger, Anders, 1966-, et al.
(författare)
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Measuring hearing organ vibration patterns with confocal microscopy and optical flow
- 2004
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Ingår i: Biophysical Journal. - : Cell Press. - 0006-3495 .- 1542-0086. ; 86:1, s. 535-543
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Tidskriftsartikel (refereegranskat)abstract
- A new method for visualizing vibrating structures is described. The system provides a means to capture very fast repeating events by relatively minor modi. cations to a standard confocal microscope. An acousto-optic modulator was inserted in the beam path, generating brief pulses of laser light. Images were formed by summing consecutive frames until every pixel of the resulting image had been exposed to a laser pulse. Images were analyzed using a new method for optical flow computation; it was validated through introducing artificial displacements in confocal images. Displacements in the range of 0.8 to 4 pixels were measured with 5% error or better. The lower limit for reliable motion detection was 20% of the pixel size. These methods were used for investigating the motion pattern of the vibrating hearing organ. In contrast to standard theory, we show that the organ of Corti possesses several degrees of freedom during sound-evoked vibration. Outer hair cells showed motion indicative of deformation. After acoustic overstimulation, supporting cells contracted. This slowly developing structural change was visualized during simultaneous intense sound stimulation and its speed measured with the optical flow technique.
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| 4. |
- Jabak, Adam A., et al.
(författare)
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Left versus right: Exploring the effects of chiral threading intercalators using optical tweezers
- 2022
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Ingår i: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 121:19, s. 3745-3752
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Tidskriftsartikel (refereegranskat)abstract
- Small-molecule DNA-binding drugs have shown promising results in clinical use against many types of cancer. Understanding the molecular mechanisms of DNA binding for such small molecules can be critical in advancing future drug designs. We have been exploring the interactions of ruthenium-based small molecules and their DNA-binding properties that are highly relevant in the development of novel metal-based drugs. Previously we have studied the effects of the right-handed binuclear ruthenium threading intercalator ΔΔ-[μ-bidppz(phen)4Ru2]4+, or ΔΔ-P for short, which showed extremely slow kinetics and high-affinity binding to DNA. Here we investigate the left-handed enantiomer ΛΛ-[μ-bidppz(phen)4Ru2]4+, or ΛΛ-P for short, to study the effects of chirality on DNA threading intercalation. We employ single-molecule optical trapping experiments to understand the molecular mechanisms and nanoscale structural changes that occur during DNA binding and unbinding as well as the association and dissociation rates. Despite the similar threading intercalation binding mode of the two enantiomers, our data show that the left-handed ΛΛ-P complex requires increased lengthening of the DNA to thread, and it extends the DNA more than double the length at equilibrium compared with the right-handed ΔΔ-P. We also observed that the left-handed ΛΛ-P complex unthreads three times faster than ΔΔ-P. These results, along with a weaker binding affinity estimated for ΛΛ-P, suggest a preference in DNA binding to the chiral enantiomer having the same right-handed chirality as the DNA molecule, regardless of their common intercalating moiety. This comparison provides a better understanding of how chirality affects binding to DNA and may contribute to the development of enhanced potential cancer treatment drug designs.
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| 5. |
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| 6. |
- Jabak, Adam A., et al.
(författare)
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Effect of Chirality on the Elastic Properties of the DNA-Threading Binuclear Ruthenium Complex
- 2020
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Ingår i: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 118:3, Supplement 1, s. 617a-
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Konferensbidrag (refereegranskat)abstract
- Transition metal-based small molecules have been promising candidates for cancer treatments. A certain type of these molecules falls into a category known as threading intercalators, that have a dumbbell shape with a flat intercalating section in between bulky side chains. In order to bind to DNA, they must thread one of their bulky side chains through the DNA base pairs. The ruthenium-based molecule, ΛΛ-[μ-bidppz(phen)4Ru2]4+ (ΛΛ-P for short), is a transition metal-based threading intercalator. We use optical tweezers to study the interactions of ΛΛ-P with DNA to compare it with the previously studied ΔΔ-P, a complex that has the same chemical components but an opposite chirality. In these studies, we use the optical tweezers to trap a single DNA molecule and stretch it in the presence of various concentrations of ΛΛ-P. The DNA stretches obtained at saturated concentrations of ΛΛ-P at various forces allows us to obtain the effective elastic properties of the DNA-ΛΛ-P complex. This allows us to compare these properties to the previously studied ΔΔ-P complex to determine whether chirality has an effect. This type of comparison may lead us towards a better understanding of the role chirality has towards DNA binding.
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| 7. |
- Almqvist, Joachim E, 1980, et al.
(författare)
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Modeling the Effect of Kv1.5 Block on the Canine Action Potential
- 2010
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Ingår i: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 99:9, s. 2726-2736
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Tidskriftsartikel (refereegranskat)abstract
- A wide range of ion channels have been considered as potential targets for pharmacological treatment of atrial fibrillation. The Kv1.5 channel, carrying the IKur current, has received special attention because it contributes to repolarization in the atria but is absent or weakly expressed in ventricular tissue. The dog serves as an important animal model for electrophysiological studies of the heart and mathematical models of the canine atrial action potential (CAAP) have been developed to study the interplay between ionic currents. To enable more-realistic studies on the effects of Kv1.5 blockers on the CAAP in silico, two continuous-time Markov models of the guarded receptor type were formulated for Kv1.5 and subsequently inserted into the Ramirez-Nattel-Courtemanche model of the CAAP. The main findings were: 1), time- and state-dependent Markov models of open-channel Kv1.5 block gave significantly different results compared to a time- and state-independent model with a downscaled conductance; 2), the outcome of Kv1.5 block on the macroscopic system variable APD90 was dependent on the precise mechanism of block; and 3), open-channel block produced a reverse use-dependent prolongation of APD90. This study suggests that more-complex ion-channel models are a prerequisite for quantitative modeling of drug effects.
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| 8. |
- Bano, Fouzia, et al.
(författare)
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Single-molecule unbinding forces between the polysaccharide hyaluronan and its binding proteins
- 2018
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Ingår i: Biophysical Journal. - : Biophysical society. - 0006-3495 .- 1542-0086. ; 114:12, s. 2910-2922
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Tidskriftsartikel (refereegranskat)abstract
- The extracellular polysaccharide hyaluronan (HA) is ubiquitous in all vertebrate tissues, where its various functions are encoded in the supramolecular complexes and matrices that it forms with HA-binding proteins (hyaladherins). In tissues, these supramolecular architectures are frequently subjected to mechanical stress, yet how this affects the intermolecular bonding is largely unknown. Here, we used a recently developed single-molecule force spectroscopy platform to analyze and compare the mechanical strength of bonds between HA and a panel of hyaladherins from the Link module superfamily, namely the complex of the proteoglycan aggrecan and cartilage link protein, the proteoglycan versican, the inflammation-associated protein TSG-6, the HA receptor for endocytosis (stabilin-2/HARE), and the HA receptor CD44. We find that the resistance to tensile stress for these hyaladherins correlates with the size of the HA-binding domain. The lowest mean rupture forces are observed for members of the type A subgroup (i.e., with the shortest HA-binding domains; TSG-6 and HARE). In contrast, the mechanical stability of the bond formed by aggrecan in complex with cartilage link protein (two members of the type C subgroup, i.e., with the longest HA-binding domains) and HA is equal or even superior to the high affinity streptavidin⋅biotin bond. Implications for the molecular mechanism of unbinding of HA⋅hyaladherin bonds under force are discussed, which underpin the mechanical properties of HA⋅hyaladherin complexes and HA-rich extracellular matrices.
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