Monte Carlo simulation of light transport in turbid medium with embedded object-spherical, cylindrical, ellipsoidal, or cuboidal objects embedded within multilayered tissues

Monte Carlo modeling of light transport in multilayered tissue (MCML) is modified to incorporate objects of various shapes (sphere, ellipsoid, cylinder, or cuboid) with a refractive-index mismatched boundary. These geometries would be useful for modeling lymph nodes, tumors, blood vessels, capillaries, bones, the head, and other body parts. Mesh-based Monte Carlo (MMC) has also been used to compare the results from the MCML with embedded objects (MCML-EO). Our simulation assumes a realistic tissue model and can also handle the transmission/reflection at the object-tissue boundary due to the mismatch of the refractive index. Simulation of MCML-EO takes a few seconds, whereas MMC takes nearly an hour for the same geometry and optical properties. Contour plots of fluence distribution from MCML-EO and MMC correlate well. This study assists one to decide on the tool to use for modeling light propagation in biological tissue with objects of regular shapes embedded in it. For irregular inhomogeneity in the model (tissue), MMC has to be used. If the embedded objects (inhomogeneity) are of regular geometry (shapes), then MCML-EO is a better option, as simulations like Raman scattering, fluorescent imaging, and optical coherence tomography are currently possible only with MCML. (C) 2014 Society of Photo-Optical Instrumentation Engineers (SPIE)

Nonlinear viscoelasticity of entangled wormlike micellar fluid under large-amplitude oscillatory shear: Role of elastic Taylor-Couette instability

The role of elastic Taylor-Couette flow instabilities in the dynamic nonlinear viscoelastic response of an entangled wormlike micellar fluid is studied by large-amplitude oscillatory shear (LAOS) rheology and in situ polarized light scattering over a wide range of strain and angular frequency values, both above and below the linear crossover point. Well inside the nonlinear regime, higher harmonic decomposition of the resulting stress signal reveals that the normalized third harmonic I-3/I-1 shows a power-law behavior with strain amplitude. In addition, I-3/I-1 and the elastic component of stress amplitude sigma(E)(0) show a very prominent maximum at the strain value where the number density (n(v)) of the Taylor vortices is maximum. A subsequent increase in applied strain (gamma) results in the distortions of the vortices and a concomitant decrease in n(v), accompanied by a sharp drop in I-3 and sigma(E)(0). The peak position of the spatial correlation function of the scattered intensity along the vorticity direction also captures the crossover. Lissajous plots indicate an intracycle strain hardening for the values of gamma corresponding to the peak of I-3, similar to that observed for hard-sphere glasses.

Boundary perturbations and the Helmholtz equation in three dimensions

We propose an analytic perturbative scheme in the spirit of Lord Rayleigh's work for determining the eigenvalues of the Helmholtz equation in three dimensions inside an arbitrary boundary where the eigenfunction satisfies either the Dirichlet boundary condition or the Neumann boundary condition. Although numerous works are available in the literature for arbitrary boundaries in two dimensions, to the best of our knowledge the formulation in three dimensions is proposed for the first time. In this novel prescription, we have expanded the arbitrary boundary in terms of spherical harmonics about an equivalent sphere and obtained perturbative closed-form solutions at each order for the problem in terms of corrections to the equivalent spherical boundary for both the boundary conditions. This formulation is in parallel with the standard time-independent Rayleigh-Schrodinger perturbation theory. The efficacy of the method is tested by comparing the perturbative values against the numerically calculated eigenvalues for spheroidal, superegg and superquadric shaped boundaries. It is shown that this perturbation works quite well even for wide departure from spherical shape and for higher excited states too. We believe this formulation would find applications in the field of quantum dots and acoustical cavities.

The generalized Onsager model for a binary gas mixture

The Onsager model for the secondary flow field in a high-speed rotating cylinder is extended to incorporate the difference in mass of the two species in a binary gas mixture. The base flow is an isothermal solid-body rotation in which there is a balance between the radial pressure gradient and the centrifugal force density for each species. Explicit expressions for the radial variation of the pressure, mass/mole fractions, and from these the radial variation of the viscosity, thermal conductivity and diffusion coefficient, are derived, and these are used in the computation of the secondary flow. For the secondary flow, the mass, momentum and energy equations in axisymmetric coordinates are expanded in an asymptotic series in a parameter epsilon = (Delta m/m(av)), where Delta m is the difference in the molecular masses of the two species, and the average molecular mass m(av) is defined as m(av) = (rho(w1)m(1) + rho(w2)m(2))/rho(w), where rho(w1) and rho(w2) are the mass densities of the two species at the wall, and rho(w) = rho(w1) + rho(w2). The equation for the master potential and the boundary conditions are derived correct to O(epsilon(2)). The leading-order equation for the master potential contains a self-adjoint sixth-order operator in the radial direction, which is different from the generalized Onsager model (Pradhan & Kumaran, J. Fluid Mech., vol. 686, 2011, pp. 109-159), since the species mass difference is included in the computation of the density, viscosity and thermal conductivity in the base state. This is solved, subject to boundary conditions, to obtain the leading approximation for the secondary flow, followed by a solution of the diffusion equation for the leading correction to the species mole fractions. The O(epsilon) and O(epsilon(2)) equations contain inhomogeneous terms that depend on the lower-order solutions, and these are solved in a hierarchical manner to obtain the O(epsilon) and O(epsilon(2)) corrections to the master potential. A similar hierarchical procedure is used for the Carrier-Maslen model for the end-cap secondary flow. The results of the Onsager hierarchy, up to O(epsilon(2)), are compared with the results of direct simulation Monte Carlo simulations for a binary hard-sphere gas mixture for secondary flow due to a wall temperature gradient, inflow/outflow of gas along the axis, as well as mass and momentum sources in the flow. There is excellent agreement between the solutions for the secondary flow correct to O(epsilon(2)) and the simulations, to within 15 %, even at a Reynolds number as low as 100, and length/diameter ratio as low as 2, for a low stratification parameter A of 0.707, and when the secondary flow velocity is as high as 0.2 times the maximum base flow velocity, and the ratio 2 Delta m/(m(1) + m(2)) is as high as 0.5. Here, the Reynolds number Re = rho(w)Omega R-2/mu, the stratification parameter A = root m Omega R-2(2)/(2k(B)T), R and Omega are the cylinder radius and angular velocity, m is the molecular mass, rho(w) is the wall density, mu is the viscosity and T is the temperature. The leading-order solutions do capture the qualitative trends, but are not in quantitative agreement.

Bmi1 regulates self-renewal and epithelial to mesenchymal transition in breast cancer cells through Nanog

Background: The Bmi1 polycomb ring finger oncogene, a transcriptional repressor belonging to the Polycomb group of proteins plays an important role in the regulation of stem cell self-renewal and is elevated in several cancers. In the current study, we have explored the role of Bmi1 in regulating the stemness and drug resistance of breast cancer cells. Methods: Using real time PCR and immunohistochemistry primary breast tissues were analyzed. Retro-and lentiviruses were utilized to overexpress and knockdown Bmi1, RT-PCR and Western blot was performed to evaluate mRNA and protein expression. Stemness properties were analyzed by flow cytometry and sphere-formation and tumor formation was determined by mouse xenograft experiments. Dual luciferase assay was employed to assess promoter activity and MTT assay was used to analyze drug response. Results: We found Bmi1 overexpression in 64% of grade III invasive ductal breast adenocarcinomas compared to normal breast tissues. Bmi1 overexpression in immortalized and transformed breast epithelial cells increased their sphere-forming efficiency, induced epithelial to mesenchymal transition ( EMT) with an increase in the expression of stemness-related genes. Knockdown of Bmi1 in tumorigenic breast cells induced epithelial morphology, reduced expression of stemness-related genes, decreased the IC50 values of doxorubicin and abrogated tumor-formation. Bmi1-high tumors showed elevated Nanog expression whereas the tumors with lower Bmi1 showed reduced Nanog levels. Overexpression of Bmi1 increased Nanog levels whereas knockdown of Bmi1 reduced its expression. Dual luciferase promoter-reporter assay revealed Bmi1 positively regulated the Nanog and NF kappa B promoter activity. RT-PCR analysis showed that Bmi1 overexpression activated the NF kappa B pathway whereas Bmi1 knockdown reduced the expression of NF kappa B target genes, suggesting that Bmi1 might regulate Nanog expression through the NF kappa B pathway. Conclusions: Our study showed that Bmi1 is overexpressed in several high-grade, invasive ductal breast adenocarcinomas, thus supporting its role as a prognostic marker. While Bmi1 overexpression increased self-renewal and promoted EMT, its knockdown reversed EMT, reduced stemness, and rendered cells drug sensitive, thus highlighting a crucial role for Bmi1 in regulating the stemness and drug response of breast cancer cells. Bmi1 may control self-renewal through the regulation of Nanog expression via the NF kappa B pathway.

Identification of a novel AMPK-PEA15 axis in the anoikis-resistant growth of mammary cells

Introduction: Matrix detachment triggers anoikis, a form of apoptosis, in most normal epithelial cells, while acquisition of anoikis resistance is a prime requisite for solid tumor growth. Of note, recent studies have revealed that a small population of normal human mammary epithelial cells (HMECs) survive in suspension and generate multicellular spheroids termed `mammospheres'. Therefore, understanding how normal HMECs overcome anoikis may provide insights into breast cancer initiation and progression. Methods: Primary breast tissue-derived normal HMECs were grown as adherent monolayers or mammospheres. The status of AMP-activated protein kinase (AMPK) and PEA15 signaling was investigated by immunoblotting. Pharmacological agents and an RNA interference (RNAi) approach were employed to gauge their roles in mammosphere formation. Immunoprecipitation and in vitro kinase assays were undertaken to evaluate interactions between AMPK and PEA15. In vitro sphere formation and tumor xenograft assays were performed to understand their roles in tumorigenicity. Results: In this study, we show that mammosphere formation by normal HMECs is accompanied with an increase in AMPK activity. Inhibition or knockdown of AMPK impaired mammosphere formation. Concomitant with AMPK activation, we detected increased Ser(116) phosphorylation of PEA15, which promotes its anti-apoptotic functions. Inhibition or knockdown of AMPK impaired PEA15 Ser(116) phosphorylation and increased apoptosis. Knockdown of PEA15, or overexpression of the nonphosphorylatable S116A mutant of PEA15, also abrogated mammosphere formation. We further demonstrate that AMPK directly interacts with and phosphorylates PEA15 at Ser(116) residue, thus identifying PEA15 as a novel AMPK substrate. Together, these data revealed that AMPK activation facilitates mammosphere formation by inhibition of apoptosis, at least in part, through Ser(116) phosphorylation of PEA15. Since anoikis resistance plays a critical role in solid tumor growth, we investigated the relevance of these findings in the context of breast cancer. Significantly, we show that the AMPK-PEA15 axis plays an important role in the anchorage-independent growth of breast cancer cells both in vitro and in vivo. Conclusions: Our study identifies a novel AMPK-PEA15 signaling axis in the anchorage-independent growth of both normal and cancerous mammary epithelial cells, suggesting that breast cancer cells may employ mechanisms of anoikis resistance already inherent within a subset of normal HMECs. Thus, targeting the AMPK-PEA15 axis might prevent breast cancer dissemination and metastasis.

Dynamics of intermittent force fluctuations in vesicular nanotubulation

Irregular force fluctuations are seen in most nanotubulation experiments. The dynamics behind their presence has, however, been neither commented upon nor modeled. A simple estimate of the mean energy dissipated in force drops turns out to be several times the thermal energy. This coupled with the rate dependent nature of the deformation reported in several experiments point to a dynamical origin of the serrations. We simplify the whole process of tether formation through a three-stage model of successive deformations of sphere to ellipsoid, neck-formation, and tubule birth and extension. Based on this, we envisage a rate-softening frictional force at the neck that must be overcome before a nanotube can be pulled out. Our minimal model includes elastic and visco-elastic deformation of the vesicle, and has built-in dependence on pull velocity, vesicle radius, and other material parameters, enabling us to capture various kinds of serrated force-extension curves for different parameter choices. Serrations are predicted in the nanotubulation region. Other features of force-extension plots reported in the literature such as a plateauing serrated region beyond a force drop, serrated flow region with a small positive slope, an increase in the elastic threshold with pull velocity, force-extension curves for vesicles with larger radius lying lower than those for smaller radius, are all also predicted by the model. A toy model is introduced to demonstrate that the role of the friction law is limited to inducing stick-slip oscillations in the force, and all other qualitative and quantitative features emerging from the model can only be attributed to other physical mechanisms included in the deformation dynamics of the vesicle. (C) 2014 AIP Publishing LLC.

Coordinate Hyperactivation of Notch1 and Ras/MAPK Pathways Correlates with Poor Patient Survival: Novel Therapeutic Strategy for Aggressive Breast Cancers

Aberrant activation of Notch and Ras pathways has been detected in breast cancers. A synergy between these two pathways has also been shown in breast cell transformation in culture. Yet, the clinical relevance of Notch-Ras cooperation in breast cancer progression remains unexplored. In this study, we show that coordinate hyperactivation of Notch1 and Ras/MAPK pathways in breast cancer patient specimens, as assessed by IHC for cleaved Notch1 and pErk1/2, respectively, correlated with early relapse to vital organs and poor overall survival. Interestingly, majority of such Notch1 (high)Erk(high) cases encompassed the highly aggressive triple-negative breast cancers (TNBC), and were enriched in stem cell markers. We further show that combinatorial inhibition of Notch1 and Ras/MAPK pathways, using a novel mAb against Notch1 and a MEK inhibitor, respectively, led to a significant reduction in proliferation and survival of breast cancer cells compared with individual inhibition. Combined inhibition also abrogated sphere-forming potential, and depleted the putative cancer stem-like cell subpopulation. Most importantly, combinatorial inhibition of Notch1 and Ras/MAPK pathways completely blocked tumor growth in a panel of breast cancer xenografts, including the TNBCs. Thus, our study identifies coordinate hyperactivation of Notch1 and Ras/MAPK pathways as novel biomarkers for poor breast cancer outcome. Furthermore, based on our preclinical data, we propose combinatorial targeting of these two pathways as a treatment strategy for highly aggressive breast cancers, particularly the TNBCs that currently lack any targeted therapeutic module. (C) 2014 AACR.

Efficient Solid-State Light-Emitting CuCdS Nanocrystals Synthesized in Air

Semiconductor nanocrystals (NCs) possess high photoluminescence (PL) typically in the solution phase. In contrary, PL rapidly quenches in the solid state. Efficient solid state luminescence can be achieved by inducing a large Stokes shift. Here we report on a novel synthesis of compositionally controlled CuCdS NCs in air avoiding the usual complexity of using inert atmosphere. These NCs show long-range color tunability over the entire visible range with a remarkable Stokes shift up to about 1.25eV. Overcoating the NCs leads to a high solid-state PL quantum yield (QY) of ca. 55% measured by using an integrating sphere. Unique charge carrier recombination mechanisms have been recognized from the NCs, which are correlated to the internal NC structure probed by using extended X-ray absorption fine structure (EXAFS) spectroscopy. EXAFS measurements show a Cu-rich surface and Cd-rich interior with 46% Cu-I being randomly distributed within 84% of the NC volume creating additional transition states for PL. Color-tunable solid-state luminescence remains stable in air enabling fabrication of light-emitting diodes (LEDs).

On the impact of a concave nosed axisymmetric body on a free surface

We report on an experimental study of the vertical impact of a concave nosed axisymmetric body on a free surface. Previous studies have shown that bodies with a convex nose, like a sphere, produce a well defined splash with a relatively large cavity behind the model. In contrast, we find that with a concave nose, there is hardly a splash and the cavity extent is greatly reduced. This may be explained by the fact that in the concave nosed case, the initial impact is between a confined air pocket and the free surface unlike in the convex nosed case. From measurements of the unsteady pressure in the concave nose portion, we show that in this case, the maximum pressures are significantly lower than the classically expected ``water hammer'' pressures and also lower than those generally measured on other geometries. Thus, the presence of an air pocket in the case of a concave nosed body adds an interesting dimension to the classical problem of impact of solid bodies on to a free surface. (C) 2015 AIP Publishing LLC.

Fermionic edge states and new physics

We investigate the properties of the Dirac operator on manifolds with boundaries in the presence of the Atiyah-Patodi-Singer boundary condition. An exact counting of the number of edge states for boundaries with isometry of a sphere is given. We show that the problem with the above boundary condition can be mapped to one where the manifold is extended beyond the boundary and the boundary condition is replaced by a delta function potential of suitable strength. We also briefly highlight how the problem of the self-adjointness of the operators in the presence of moving boundaries can be simplified by suitable transformations which render the boundary fixed and modify the Hamiltonian and the boundary condition to reflect the effect of moving boundary.

Separation index of graphs and stacked 2-spheres

In 1987, Kalai proved that stacked spheres of dimension d >= 3 are characterised by the fact that they attain equality in Barnette's celebrated Lower Bound Theorem. This result does not extend to dimension d = 2. In this article, we give a characterisation of stacked 2-spheres using what we call the separation index. Namely, we show that the separation index of a triangulated 2-sphere is maximal if and only if it is stacked. In addition, we prove that, amongst all n-vertex triangulated 2-spheres, the separation index is minimised by some n-vertex flag sphere for n >= 6. Furthermore, we apply this characterisation of stacked 2-spheres to settle the outstanding 3-dimensional case of the Lutz-Sulanke-Swartz conjecture that ``tight-neighbourly triangulated manifolds are tight''. For dimension d >= 4, the conjecture has already been proved by Effenberger following a result of Novik and Swartz. (C) 2015 Elsevier Inc. All rights reserved.

Use of polydispersity index as control parameter to study melting/freezing of Lennard-Jones system: Comparison among predictions of bifurcation theory with Lindemann criterion, inherent structure analysis and Hansen-Verlet rule

Using polydispersity index as an additional order parameter we investigate freezing/melting transition of Lennard-Jones polydisperse systems (with Gaussian polydispersity in size), especially to gain insight into the origin of the terminal polydispersity. The average inherent structure (IS) energy and root mean square displacement (RMSD) of the solid before melting both exhibit quite similar polydispersity dependence including a discontinuity at solid-liquid transition point. Lindemann ratio, obtained from RMSD, is found to be dependent on temperature. At a given number density, there exists a value of polydispersity index (delta (P)) above which no crystalline solid is stable. This transition value of polydispersity(termed as transition polydispersity, delta (P) ) is found to depend strongly on temperature, a feature missed in hard sphere model systems. Additionally, for a particular temperature when number density is increased, delta (P) shifts to higher values. This temperature and number density dependent value of delta (P) saturates surprisingly to a value which is found to be nearly the same for all temperatures, known as terminal polydispersity (delta (TP)). This value (delta (TP) similar to 0.11) is in excellent agreement with the experimental value of 0.12, but differs from hard sphere transition where this limiting value is only 0.048. Terminal polydispersity (delta (TP)) thus has a quasiuniversal character. Interestingly, the bifurcation diagram obtained from non-linear integral equation theories of freezing seems to provide an explanation of the existence of unique terminal polydispersity in polydisperse systems. Global bond orientational order parameter is calculated to obtain further insights into mechanism for melting.

Electric field and temperature dependence of the local structural disorder in the lead-free ferroelectric Na0.5Bi0.5TiO3: An EXAFS study

The complex nature of the structural disorder in the lead-free ferroelectric Na1/2Bi1/2TiO3 has a profound impact on the perceived global structure and polar properties. In this paper, we have investigated the effect of electric field and temperature on the local structure around theBi and Ti atoms using extended x-ray absorption fine structure. Detailed analysis revealed that poling brings about a noticeable change in the bond distances associated with the Bi-coordination sphere, whereas the Ti coordination remains unaffected. We also observed discontinuity in the Bi-O bond lengths across the depolarization temperature of the poled specimen. These results establish that the disappearance of the monoclinic-like (Cc) global distortion, along with the drastic suppression of the short-ranged in-phase octahedral tilt after poling B. N. Rao et al., Phys. Rev. B 88, 224103 (2013)] is a result of the readjustment of theA-O bonds by the electric field, so as to be in conformity with the rhombohedral R3c structure.

Enhanced Metastatic Potential in a 3D Tissue Scaffold toward a Comprehensive in Vitro Model for Breast Cancer Metastasis

Metastasis is clinically the most challenging and lethal aspect of breast cancer. While animal-based xenograft models are expensive and time-consuming, conventional two-dimensional (2D) cell culture systems fail to mimic in vivo signaling. In this study we have developed a three-dimensional (3D) scaffold system that better mimics the topography and mechanical properties of the breast tumor, thus recreating the tumor microenvironment in vitro to study breast cancer metastasis. Porous poly(e-caprolactone) (PCL) scaffolds of modulus 7.0 +/- 0.5 kPa, comparable to that of breast tumor tissue were fabricated, on which MDA-MB-231 cells proliferated forming tumoroids. A comparative gene expression analysis revealed that cells growing in the scaffolds expressed increased levels of genes implicated in the three major events of metastasis, viz., initiation, progression, and the site-specific colonization compared to cells grown in conventional 2D tissue culture polystyrene (TCPS) dishes. The cells cultured in scaffolds showed increased invasiveness and sphere efficiency in vitro and increased lung metastasis in vivo. A global gene expression analysis revealed a significant increase in the expression of genes involved in cell cell and cell matrix interactions and tissue remodeling, cancer inflammation, and the PI3K/Akt, Wnt, NF-kappaB, and HIFI signaling pathways all of which are implicated in metastasis. Thus, culturing breast cancer cells in 3D scaffolds that mimic the in vivo tumor-like microenvironment enhances their metastatic potential. This system could serve as a comprehensive in vitro model to investigate the manifold mechanisms of breast cancer metastasis.