Heparan sulfate deficiency leads to hypertrophic chondrocytes by increasing bone morphogenetic protein signaling.

OBJECTIVE: Exostosin-1 (EXT1) and EXT2 are the major genetic etiologies of multiple hereditary exostoses and are essential for heparan sulfate (HS) biosynthesis. Previous studies investigating HS in several mouse models of multiple hereditary exostoses have reported that aberrant bone morphogenetic protein (BMP) signaling promotes osteochondroma formation in Ext1-deficient mice. This study examined the mechanism underlying the effects of HS deficiency on BMP/Smad signaling in articular cartilage in a cartilage-specific Ext-/- mouse model. METHOD: We generated mice with a conditional Ext1 knockout in cartilage tissue (Ext1-cKO mice) using Prg4-Cre transgenic mice. Structural cartilage alterations were histologically evaluated and phospho-Smad1/5/9 (pSmad1/5/9) expression in mouse chondrocytes was analyzed. The effect of pharmacological intervention of BMP signaling using a specific inhibitor was assessed in the articular cartilage of Ext1-cKO mice. RESULTS: Hypertrophic chondrocytes were significantly more abundant (P = 0.021) and cartilage thickness was greater in Ext1-cKO mice at 3 months postnatal than in control littermates (P = 0.036 for femur; and P < 0.001 for tibia). However, osteoarthritis did not spontaneously occur before the 1-year follow-up. matrix metalloproteinase (MMP)-13 and adamalysin-like metalloproteinases with thrombospondin motifs(ADAMTS)-5 were upregulated in hypertrophic chondrocytes of transgenic mice. Immunostaining and western blotting revealed that pSmad1/5/9-positive chondrocytes were more abundant in the articular cartilage of Ext1-cKO mice than in control littermates. Furthermore, the BMP inhibitor significantly decreased the number of hypertrophic chondrocytes in Ext1-cKO mice (P = 0.007). CONCLUSIONS: HS deficiency in articular chondrocytes causes chondrocyte hypertrophy, wherein upregulated BMP/Smad signaling partially contributes to this phenotype. HS might play an important role in maintaining the cartilaginous matrix by regulating BMP signaling.

Elasticity of smectic liquid crystals with focal conic domains.

We study the elastic properties of thermotropic smectic liquid crystals with focal conic domains (FCDs). After the application of the controlled preshear at different temperatures, we independently measure the shear modulus G' and the FCD size L. We find out that these quantities are related by the scaling relation G' ≈ γ(eff)/L, where γ(eff) is the effective surface tension of the FCDs. The experimentally obtained value of γ(eff) shows the same scaling as the effective surface tension of the layered systems √(KB), where K and B are the bending modulus and the layer compression modulus, respectively. The similarity of this scaling relation to that of the surfactant onion phase suggests an universal rheological behavior of the layered systems with defects.

Dynamics of a polymer chain confined in a membrane.

We present a Brownian dynamics theory with full hydrodynamics (Stokesian dynamics) for a Gaussian polymer chain embedded in a liquid membrane which is surrounded by bulk solvent and walls. The mobility tensors are derived in Fourier space for the two geometries, namely, a free membrane embedded in a bulk fluid, and a membrane sandwiched by the two walls. Within the preaveraging approximation, a new expression for the diffusion coefficient of the polymer is obtained for the free-membrane geometry. We also carry out a Rouse normal mode analysis to obtain the relaxation time and the dynamical structure factor. For large polymer size, both quantities show Zimm-like behavior in the free-membrane case, whereas they are Rouse-like for the sandwiched membrane geometry. We use the scaling argument to discuss the effect of excluded-volume interactions on the polymer relaxation time.

Drag coefficient of a liquid domain in a two-dimensional membrane.

Using a hydrodynamic theory that incorporates a momentum decay mechanism, we calculate the drag coefficient of a circular liquid domain of finite viscosity moving in a two-dimensional membrane. We derive an analytical expression for the drag coefficient which covers the whole range of domain sizes. Several limiting expressions are discussed. The obtained drag coefficient decreases as the domain viscosity becomes smaller with respect to the outer membrane viscosity. This is because the flow induced in the domain acts to transport the fluid in the surrounding matrix more efficiently.

Morphological transition and emulsification failure in globular microemulsions.

We consider the condensation transition of microemulsion droplets of oil which are dispersed in water in the presence of surfactant. Since a macroscopic oil phase is formed due to this transition, it is called "emulsification failure." Based on the free energy approach, we determine the transition lines between the spherical and the cylindrical droplet phases as well as the phase boundary lines of the emulsification failure. The phase diagrams are calculated by changing the physical properties of the surfactant monolayer such as the saddle-splay modulus and the spontaneous curvature. For a negative saddle-splay modulus, the spherical droplet phase coexists with the excess oil phase. In some cases, a re-entrant transition (sphere-->cylinder-->sphere) is expected to take place. For a positive saddle-splay modulus, the system undergoes a direct transition from the cylindrical droplet phase to the macroscopically phase separated state. The sphere-to-cylinder transition line approaches the emulsification failure boundary as the saddle-splay modulus becomes larger.

Adhesion of binary giant vesicles containing negative spontaneous curvature lipids induced by phase separation.

We report the adhesion of binary giant vesicles composed of two types of phospholipids, one has negative spontaneous curvature which tends to bend toward the head group and the other has zero spontaneous curvature. In a homogeneous one-phase region, the giant vesicles do not adhere to each other, whereas in a coexisting two-phase region, the giant vesicles show adhesion. A fluorescence microscope observation reveals that the adhesion takes place through the domains rich in phospholipids having negative spontaneous curvature. We propose a phase separation induced hemifusion model where two apposed monolayers of adjacent vesicles are hemifused in order to reduce the bending energy of monolayers with negative spontaneous curvature and the boundary energy between the domains and matrix. We provide a strong evidence for the hemifusion model by lipid transfer experiments.

Non-linear rheology of lamellar liquid crystals.

We measure the non-linear relation between the shear stress and shear rate in the lyotropic lamellar phase of C12E5/water system. The measured shear thinning exponent changes with the surfactant concentration. A simple rheology theory of a lamellar or smectic phase is proposed with a prediction gamma approximately sigma3/2, where gamma is the shear rate and sigma is the shear stress. We consider that the shear flow passed through the defect structure causes the main dissipation. As the defect line density varies with the shear rate, the shear thinning arises. The defect density is estimated by the dynamic balance between the production and annihilation processes. The defect production is caused by the shear-induced layer undulation instability. The annihilation occurs through the shear-induced defect collision process. Further flow visualization experiment shows that the defect texture correlates strongly with the shear thinning exponent.

The phase behavior of mixed lipid membranes in the presence of the rippled phase.

We propose a model describing liquid-solid phase coexistence in mixed lipid membranes by including explicitly the occurrence of a rippled phase. For a single component membrane, we employ a previous model in which the membrane thickness is used as an order parameter. As function of temperature, this model properly accounts for the phase behavior of the three possible membrane phases: solid, liquid and the rippled phase. Our primary aim is to explore extensions of this model to binary lipid mixtures by considering the composition dependence of important model parameters. The obtained phase diagrams show various liquid, solid and rippled phase coexistence regions, and are in quantitative agreement with the experimental ones for some specific lipid mixtures.

Conus medullaris spinal arteriovenous malformation in a patient with klippel-trenaunay-weber syndrome. A case report and review of the literature.

SUMMARY: We describe a 24-year-old woman who presented with twice previously unverified subarachnoid hemorrhages from the conus medullaris spinal arteriovenous malformation with Parkes-Weber-syndrome. Spinal MRI examination is considered to be necessary for the diagnosis of Klippel-Trenaunay-Weber syndrome. For diagnosis of the spinal cord arteriovenous malformation, it is indispensable to search carefully for the presence of accompanying lesions. Transarterial glue embolizationis effective for the management of the spinal vascular lesion.

Hydrovenous disorder in vein of galen aneurysmal dilatation: special focus on tonsilar prolapse.

We analyzed five cases of vein of Galen aneurysmal dilatation (VGAD) and 12 cases of vein of Galen aneurysmal malformation (VGAM) using sagittal T1-weighted images. Tonsilar prolapse (TP) was confirmed in three cases, which were all VGAD. Two of these cases were treated by endovascular procedures. In one of these two cases, elevation of TP was observed after intervention. There were no signs of TP in the control group of 12 VGAMs. Venous hypertension interferes with cerebrospinal fluid (CSF) resorption resulting in increased brain fluid. TP frequently develops in high flow AVFs and is reversible if therapeutic intervention is performed by an experienced clinical team when appropriately indicated. We consider that TP in VGAD is mainly the result of cerebellar swelling due to chronic venous hypertension.

Adsorption of Janus particles to curved interfaces.

We investigate the adsorption of a spherical Janus particle to a spherically curved liquid-liquid interface. We show that the equilibrium contact angle is determined by the geometry of the particle, its wettability, and also the interfacial curvature. In contrast with a homogeneous particle, there is a preferred interfacial curvature (spontaneous curvature) due to the Janus particle when the particle satisfies certain conditions.

Concentration fluctuations in binary fluid membranes.

We investigate the dynamics of critical fluctuations in binary fluid membranes using a two-dimensional hydrodynamic model with momentum decay to the surrounding water. In particular, the decay rate of concentration fluctuations is obtained analytically. In the limit of small wavenumber q with respect to the correlation length, the decay rate is proportional to q², as usual. In the large-q limit, however, the effective diffusion coefficient increases only logarithmically with q.

Tension-induced morphological transition in mixed lipid bilayers.

Recently, Rozovsky et al. reported on the morphology and dynamics of superstructures in three-component lipid bilayers containing saturated lipid, unsaturated lipid, and cholesterol (Rozovsky, S.; Kaizuka, Y.; Groves, J. T. J. Am. Chem. Soc. 2005, 127, 36). We suggest that the observed sequence of the striped-to-hexagonal morphological transition in mixed bilayers can be attributed to an enhanced membrane surface tension that is induced by the vesicle adhesion onto the solid surface.

Adsorption of colloidal particles to curved interfaces.

As a simple model for a Pickering emulsion droplet, we consider the adsorption of spherical particles to a spherical liquid-liquid interface in order to investigate the curvature effect on the particle adsorption. By taking into account both the surface and the volume energies due to the presence of a particle, we show that the equilibrium contact angle is determined by the classical Young's equation although the adsorption energy depends on the curvature. We also calculate the partitioning of the colloidal particles among the two liquids and the interface. The distribution of colloidal particles is expressed in terms of the interfacial curvature as well as the relative wettability of the particle.

Unbinding and preunbinding in surfactant solutions.

We propose models for the first-order unbinding transition of lyotropic lamellae in surfactant solutions. The coupling between the surfactant volume fraction and the elastic degree of freedom is considered so that the net attractive interaction between the surfactant molecules is enhanced. The elastic degree of freedom can be either (i) a membrane elastic degree of freedom or (ii) a bulk elastic degree of freedom. The phase behaviors of these two models are analyzed. For both cases, the unbinding transition becomes first order when the coupling is strong enough. We determine the associated preunbinding line which separates two lamellar phases having different repeat distances.

Buckling of spherical shells adhering onto a rigid substrate.

Deformation of a spherical shell adhering onto a rigid substrate due to van der Waals attractive interaction is investigated by means of numerical minimization (conjugate gradient method) of the sum of the elastic and adhesion energies. The conformation of the deformed shell is governed by two dimensionless parameters, i.e., Cs/epsilon and Cb/epsilon where Cs and Cb are respectively the stretching and the bending constants, and epsilon is the depth of the van der Waals potential between the shell and substrate. Four different regimes of deformation are characterized as these parameters are systematically varied: (i) small deformation regime, (ii) disk formation regime, (iii) isotropic buckling regime, and (iv) anisotropic buckling regime. By measuring the various quantities of the deformed shells, we find that both discontinuous and continuous bucking transitions occur for large and small Cs/epsilon, respectively. This behavior of the buckling transition is analogous to van der Waals liquids or gels, and we have numerically determined the associated critical point. Scaling arguments are employed to explain the adhesion induced buckling transition, i.e., from the disk formation regime to the isotropic buckling regime. We show that the buckling transition takes place when the indentation length exceeds the effective shell thickness which is determined from the elastic constants. This prediction is in good agreement with our numerical results. Moreover, the ratio between the indentation length and its thickness at the transition point provides a constant number (2-3) independent of the shell size. This universal number is observed in various experimental systems ranging from nanoscale to macroscale. In particular, our results agree well with the recent compression experiment using microcapsules.

Inter-lamellar interactions modulated by addition of guest components.

We have investigated the effects of a guest component (polymer or spherical colloidal particle) confined between flexible lamellar slits on the inter-lamellar interaction by means of a small-angle X-ray scattering technique and a neutron spin echo technique. The dominant interaction between flexible lamellar membranes without guest components is the Helfrich mechanism. The addition of a neutral polymer into the lamellar phase induces an attractive inter-lamellar interaction and finally destabilizes the lamellar phase. On the other hand, spherical colloidal particles confined between flexible lamellar membranes reduce the undulational fluctuations of lamellae and bring a repulsive inter-lamellar interaction. The behavior of the layer compression modulus of the lamellar membrane containing colloidal particles is well described by the entropical repulsive inter-lamellar interaction driven by steric hindrance.

Temperature and pressure effects on the bending modulus of monolayers in a ternary microemulsion.

We performed small-angle neutron scattering and neutron spin echo experiments on a ternary microemulsion composed of ionic surfactant AOT, water, and decane. Thermal fluctuations of monolayers have been investigated as a function of temperature and pressure. The amphiphilic monolayers become more flexible with increasing temperature and more rigid with increasing pressure. These results are consistent with the microscopic picture that the head-head repulsion of the AOT molecules is enhanced at high temperature while an attractive interaction between the hydrophobic tails of the AOT molecules increases at high pressure.

Deformation of adhering elastic tubes.

Deformation of an elastic tube adhering onto a substrate due to van der Waals attractive force is investigated by means of numerical minimization and scaling theory. The onset of the deformation is determined by the critical value of Cb/Epsilon N2, where Cb is the bending constant, epsilon is the depth of the van der Waals potential, and N is the size of the tube. For a significantly deformed tube, we found a scaling behavior of the bending energy, which is explained within the shell theory.

Possible dominant-negative mutation of the SHIP gene in acute myeloid leukemia.

The SH2 domain-containing inositol 5'-phosphatase (SHIP) is crucial in hematopoietic development. To evaluate the possible tumor suppressor role of the SHIP gene in myeloid leukemogenesis, we examined primary leukemia cells from 30 acute myeloid leukemia (AML) patients, together with eight myeloid leukemia cell lines. A somatic mutation at codon 684, replacing Val with Glu, was detected in one patient, lying within the signature motif 2, which is the phosphatase active site. The results of an in vitro inositol 5'-phosphatase assay revealed that the mutation reduced catalytic activity of SHIP. Leukemia cells with the mutation showed enhanced Akt phosphorylation following IL-3 stimulation. K562 cells transfected with the mutated SHIP-V684E cDNA showed a growth advantage even at lower serum concentrations and resistance to apoptosis induced by serum deprivation and exposure to etoposide. These results suggest a possible role of the mutated SHIP gene in the development of acute leukemia and chemotherapy resistance through the deregulation of the phosphatidylinositol-3,4,5-triphosphate (PI(3,4,5)P3)/Akt signaling pathway. This is the first report of a mutation in the SHIP gene in any given human cancer, and indicates the need for more attention to be paid to this gene with respect to cancer pathogenesis.