27 research outputs found
The experiment.
<p>(a) Confocal laser scanning micrograph of a spreading double lipid bilayer membrane(DLBM), top view. (b) Schematic drawing of the DLBM in (a), side view. DLBM consists of a distal (upper, red color) bilayer and the proximal (lower, blue color) bilayer. The spreading edge of the double bilayer performs a 'tank-tread' motion. (c) Micrograph of a ruptured membrane. (d) Schematic drawing showing a rupture in the distal membrane. Upon rupturing, the lipid material migrates towards the edges onto the substrate.</p
The peridynamic model.
<p>(a) A small, randomly selected region in the distal membrane is represented as a collection of particles (small circles). Each particle represents a collection of lipid molecules, and is located at the center of a circular neighborhood (N<sub>x</sub>). The motion of an arbitrary particle x (in yellow) at the center of N<sub>x</sub> is influenced by the motion of every particle in N<sub>x</sub> via bonds. If no forces apply to the membrane, the particles in N<sub>x</sub> are considered to be in an undeformed state. The close-up shows vector ξ, representing the distance between bonded particles x and x’, where T is the force vector state that existed prior to the bond being broken. (b) As tension increases, the particles move apart from each other and the corresponding bonds stretch. At some critical value of stretch, the distance between the center particle (yellow dot) and some number of neighboring particles becomes too large, leading to broken bonds and disconnected particles (x', white dots). This corresponds to the rupture (pore) formation among membrane lipids.</p
Floral and fractal biomembrane ruptures and corresponding peridynamic model simulations.
<p>(a-c) Confocal micrographs of a floral rupture occurring in the distal bilayer of a DLBM. Yellow arrow heads indicate threads of lipids between two layers, which are the pinned regions. (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0165947#pone.0165947.s003" target="_blank">S1 Movie</a>) (d-f) Peridynamic simulations showing floral ruptures (G = 0 MPa). The ruptures nucleate at the pre-determined locations of pinned (fixed) particles, and then merge into one large floral pore. The pinning points (n = 6) are marked with red circles in (d). Black arrow heads show threads of points remain between two layers which correspond to the pinned regions, similar to (c). (g-i) Confocal micrographs showing small circular pores opening and progressing in the distal bilayer. (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0165947#pone.0165947.s004" target="_blank">S2 Movie</a>) (j-l) Peridynamic simulations showing circular pores opening over time. Shear modulus G is 0 MPa as in (a-f), with the number of pinning points increased (n = 17). (m-o) Confocal micrographs of fractal ruptures occurring in the distal bilayer. (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0165947#pone.0165947.s005" target="_blank">S3 Movie</a>) (p-r) Peridynamic simulations showing fractal ruptures (G = 5 MPa). The number and location of pinning points are the same as in (g-l). The color bar in f applies to all simulations in Fig 3 and shows the amount of material point damage (%) where 100% damage corresponds to a complete breaking of all bonds associated with the material point. The scale bar in (e) applies to all simulations in Fig 3. The ratio of the diameter of the expanded membrane to the initial diameter (D/D<sub>0</sub>) is shown below each snapshot of the simulations.</p
Fractal dimension analysis of ruptures in actual membranes and simulations.
<p>(a-c) Binary images showing the contour of the fractal ruptures in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0165947#pone.0165947.g003" target="_blank">Fig 3O and 3R</a> (G = 5) and 4l (G = 7.5). (c) Plots showing the fractal dimension (D) of rupture patterns in (a),(b) and (c). The slope of the red line shows the fractal dimension of the pattern in panel a, D = 1.63, the pattern in panel (b), D = 1.70, and the pattern in c, D = 1.56. The circular rim forming around the expanding membrane in the simulations has been removed manually with image processing software. All fractal dimensions have been calculated by using the reticular cell counting (box counting) method. The plots show the relation between the number of occupied boxes (y-axes) and the box size. The fractals in biological membranes (not shown) feature D values around 1.7[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0165947#pone.0165947.ref001" target="_blank">1</a>]). The analysis from the simulations show that both slope and D are similar to the experimental values.</p
Transition in rupture morphology with increasing shear moduli.
<p>(a-l) The peridynamic simulations of the lipid membrane which is shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0165947#pone.0165947.g003" target="_blank">Fig 3</a> (j-l), but with gradually increased shear modulus. (a-d) The ruptures become rugged where G = 1 MPa. (e-h) The straight edges of the ruptures become more pronounced where G = 2.5 MPa and branches start to appear. (i-l) The ruptures appear as elongated finely branched structures where G = 7.5 MPa. These structures typically evolve into fractals(l). The color bar in (d) applies to all simulations shown in Fig 4, and is identical to the one in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0165947#pone.0165947.g003" target="_blank">Fig 3</a>. The number of pinning points in all simulations in this figure is 16, and the positions of the pinning sites are identical to the ones in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0165947#pone.0165947.g003" target="_blank">Fig 3J</a> and p (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0165947#pone.0165947.s004" target="_blank">S2 Movie</a>). The ratio of the diameter of the expanded membrane to the initial diameter (D/D<sub>0</sub>) is shown below each snapshot of the simulations.</p
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Gold(III) Macrocycles: Nucleotide-Specific Unconventional Catalytic Inhibitors of Human Topoisomerase I
Topoisomerase
IB (Top1) is a key eukaryotic nuclear enzyme that
regulates the topology of DNA during replication and gene transcription.
Anticancer drugs that block Top1 are either well-characterized interfacial
poisons or lesser-known catalytic inhibitor compounds. Here we describe
a new class of cytotoxic redox-stable cationic Au<sup>3+</sup> macrocycles
which, through hierarchical cluster analysis of cytotoxicity data
for the lead compound, <b>3</b>, were identified as either poisons
or inhibitors of Top1. Two pivotal enzyme inhibition assays prove
that the compounds are true catalytic inhibitors of Top1. Inhibition
of human topoisomerase IIα (Top2α) by <b>3</b> was
2 orders of magnitude weaker than its inhibition of Top1, confirming
that <b>3</b> is a type I-specific catalytic inhibitor. Importantly,
Au<sup>3+</sup> is essential for both DNA intercalation and enzyme
inhibition. Macromolecular simulations show that <b>3</b> intercalates
directly at the 5′-TA-3′ dinucleotide sequence targeted
by Top1 via crucial electrostatic interactions, which include π–π
stacking and an Au···O contact involving a thymine
carbonyl group, resolving the ambiguity of conventional (drug binds
protein) vs unconventional (drug binds substrate) catalytic inhibition
of the enzyme. Surface plasmon resonance studies confirm the molecular
mechanism of action elucidated by the simulations
Gold(III) Macrocycles: Nucleotide-Specific Unconventional Catalytic Inhibitors of Human Topoisomerase I
Topoisomerase
IB (Top1) is a key eukaryotic nuclear enzyme that
regulates the topology of DNA during replication and gene transcription.
Anticancer drugs that block Top1 are either well-characterized interfacial
poisons or lesser-known catalytic inhibitor compounds. Here we describe
a new class of cytotoxic redox-stable cationic Au<sup>3+</sup> macrocycles
which, through hierarchical cluster analysis of cytotoxicity data
for the lead compound, <b>3</b>, were identified as either poisons
or inhibitors of Top1. Two pivotal enzyme inhibition assays prove
that the compounds are true catalytic inhibitors of Top1. Inhibition
of human topoisomerase IIα (Top2α) by <b>3</b> was
2 orders of magnitude weaker than its inhibition of Top1, confirming
that <b>3</b> is a type I-specific catalytic inhibitor. Importantly,
Au<sup>3+</sup> is essential for both DNA intercalation and enzyme
inhibition. Macromolecular simulations show that <b>3</b> intercalates
directly at the 5′-TA-3′ dinucleotide sequence targeted
by Top1 via crucial electrostatic interactions, which include π–π
stacking and an Au···O contact involving a thymine
carbonyl group, resolving the ambiguity of conventional (drug binds
protein) vs unconventional (drug binds substrate) catalytic inhibition
of the enzyme. Surface plasmon resonance studies confirm the molecular
mechanism of action elucidated by the simulations
Gold(III) Macrocycles: Nucleotide-Specific Unconventional Catalytic Inhibitors of Human Topoisomerase I
Topoisomerase
IB (Top1) is a key eukaryotic nuclear enzyme that
regulates the topology of DNA during replication and gene transcription.
Anticancer drugs that block Top1 are either well-characterized interfacial
poisons or lesser-known catalytic inhibitor compounds. Here we describe
a new class of cytotoxic redox-stable cationic Au<sup>3+</sup> macrocycles
which, through hierarchical cluster analysis of cytotoxicity data
for the lead compound, <b>3</b>, were identified as either poisons
or inhibitors of Top1. Two pivotal enzyme inhibition assays prove
that the compounds are true catalytic inhibitors of Top1. Inhibition
of human topoisomerase IIα (Top2α) by <b>3</b> was
2 orders of magnitude weaker than its inhibition of Top1, confirming
that <b>3</b> is a type I-specific catalytic inhibitor. Importantly,
Au<sup>3+</sup> is essential for both DNA intercalation and enzyme
inhibition. Macromolecular simulations show that <b>3</b> intercalates
directly at the 5′-TA-3′ dinucleotide sequence targeted
by Top1 via crucial electrostatic interactions, which include π–π
stacking and an Au···O contact involving a thymine
carbonyl group, resolving the ambiguity of conventional (drug binds
protein) vs unconventional (drug binds substrate) catalytic inhibition
of the enzyme. Surface plasmon resonance studies confirm the molecular
mechanism of action elucidated by the simulations