Metastatic model of HPV+ oropharyngeal squamous cell carcinoma demonstrates heterogeneity in tumor metastasis

Human papillomavirus induced (HPV+) cancer incidence is rapidly rising, comprising 60–80% of oropharyngeal squamous cell carcinomas (OPSCCs); while rare, recurrent/metastatic disease accounts for nearly all related deaths. An in vivo pre-clinical model for these invasive cancers is necessary for testing new therapies. We characterize an immune competent recurrent/metastatic HPV+ murine model of OPSSC which consists of four lung metastatic (MLM) cell lines isolated from an animal with HPV+ OPSCC that failed cisplatin/radiation treatment. These individual metastatic clonal cell lines were tested to verify their origin (parental transgene expression and define their physiological properties: proliferation, metastatic potential, heterogeneity and sensitivity/resistance to cisplatin and radiation. All MLMs retain expression of parental HPV16 E6 and E7 and degrade P53 yet are heterogeneous from one another and from the parental cell line as defined by Illumina expression microarray. Consistent with this, reverse phase protein array defines differences in protein expression/activation between MLMs as well as the parental line. While in vitro growth rates of MLMs are slower than the parental line, in vivo growth of MLM clones is greatly enhanced. Moreover, in vivo resistance to standard therapies is dramatically increased in 3 of the 4 MLMs. Lymphatic and/or lung metastasis occurs 100% of the time in one MLM line. This recurrent/metastatic model of HPV+ OPSCC retains the characteristics evident in refractory human disease (heterogeneity, resistance to therapy, metastasis in lymph nodes/lungs) thus serving as an ideal translational system to test novel therapeutics. Moreover, this system may provide insights into the molecular mechanisms of metastasis

Stress-strain behavior and geometrical properties of packings of elongated particles

We present a numerical analysis of the effect of particle elongation on the quasistatic behavior of sheared granular media by means of the Contact Dynamics method. The particle shapes are rounded-cap rectangles characterized by their elongation. The macroscopic and microstructural properties of several packings subjected to biaxial compression are analyzed as a function of particle elongation. We find that the shear strength is an increasing linear function of elongation. Performing an additive decomposition of the stress tensor based on a harmonic approximation of the angular dependence of branch vectors, contact normals and forces, we show that the increasing mobilization of friction force and the associated anisotropy are key effects of particle elongation. These effects are correlated with partial nematic ordering of the particles which tend to be oriented perpendicular to the major principal stress direction and form side-to-side contacts. However, the force transmission is found to be mainly guided by cap-to-side contacts, which represent the largest fraction of contacts for the most elongated particles. Another interesting finding is that, in contrast to shear strength, the solid fraction first increases with particle elongation, but declines as the particles become more elongated. It is also remarkable that the coordination number does not follow this trend so that the packings of more elongated particles are looser but more strongly connected.Comment: Submited to Physical Review

DNA unzipped under a constant force exhibits multiple metastable intermediates

Single molecule studies, at constant force, of the separation of double-stranded DNA into two separated single strands may provide information relevant to the dynamics of DNA replication. At constant applied force, theory predicts that the unzipped length as a function of time is characterized by jumps during which the strands separate rapidly, followed by long pauses where the number of separated base pairs remains constant. Here, we report previously uncharacterized observations of this striking behavior carried out on a number of identical single molecules simultaneously. When several single lphage molecules are subject to the same applied force, the pause positions are reproducible in each. This reproducibility shows that the positions and durations of the pauses in unzipping provide a sequence-dependent molecular fingerprint. For small forces, the DNA remains in a partially unzipped state for at least several hours. For larger forces, the separation is still characterized by jumps and pauses, but the double-stranded DNA will completely unzip in less than 30 min

The anisotropy of granular materials

The effect of the anisotropy on the elastoplastic response of two dimensional packed samples of polygons is investigated here, using molecular dynamics simulation. We show a correlation between fabric coefficients, characterizing the anisotropy of the granular skeleton, and the anisotropy of the elastic response. We also study the anisotropy induced by shearing on the subnetwork of the sliding contacts. This anisotropy provides an explanation to some features of the plastic deformation of granular media.Comment: Submitted to PR

Towards a framework to evaluate the ‘total’ performance of buildings

Internationally, buildings are a major contributor to carbon emissions. Despite significant advances in the technology and construction of energy-efficient buildings, in many cases a performance gap between designed and actual performance exists. While much research has investigated the drivers of the building energy performance gap – both static and transient– there has been considerably less research into the total performance gap, defined here as performance gaps in building energy use, occupant satisfaction and Indoor Environmental Quality parameters such as thermal comfort and air quality which may impact on occupant health and wellbeing. This paper presents a meta-analysis of building performance data from buildings in the UK and China – selected due to their contrasting development environments – which illustrate the presence of and complexities of evaluating total performance gaps in both countries. The data demonstrate the need for (1) high end-use, spatial granularity and temporal resolution data for both energy and Indoor Environmental Quality, and (2) developing methodologies that allow meaningful comparisons between buildings internationally to facilitate learning from successful building design, construction methodologies and policy environments internationally. Using performance data from a UK building, a potential forward path is illustrated with the objective of developing a framework to evaluate total building performance. Practical application: While much research has examined building energy performance gaps, Indoor Environmental Quality and occupant satisfaction gaps are rarely included despite their relationship to energy. We use a meta-analysis of energy, indoor environmental quality, and occupant satisfaction data from buildings in the UK and China to illustrating the presence of and complexities of evaluating total performance gaps for buildings in the two countries, and the need for high resolution dynamic buildings data and novel methodologies for comparison between buildings across different contexts. Illustrative case studies are used to demonstrate potential future directions for evaluating ‘total’ building performance

Internal states of model isotropic granular packings. III. Elastic properties

In this third and final paper of a series, elastic properties of numerically simulated isotropic packings of spherical beads assembled by different procedures and subjected to a varying confining pressure P are investigated. In addition P, which determines the stiffness of contacts by Hertz's law, elastic moduli are chiefly sensitive to the coordination number, the possible values of which are not necessarily correlated with the density. Comparisons of numerical and experimental results for glass beads in the 10kPa-10MPa range reveal similar differences between dry samples compacted by vibrations and lubricated packings. The greater stiffness of the latter, in spite of their lower density, can hence be attributed to a larger coordination number. Voigt and Reuss bounds bracket bulk modulus B accurately, but simple estimation schemes fail for shear modulus G, especially in poorly coordinated configurations under low P. Tenuous, fragile networks respond differently to changes in load direction, as compared to load intensity. The shear modulus, in poorly coordinated packings, tends to vary proportionally to the degree of force indeterminacy per unit volume. The elastic range extends to small strain intervals, in agreement with experimental observations. The origins of nonelastic response are discussed. We conclude that elastic moduli provide access to mechanically important information about coordination numbers, which escape direct measurement techniques, and indicate further perspectives.Comment: Published in Physical Review E 25 page

Bayesian hierarchical modeling of longitudinal glaucomatous visual fields using a two-stage approach

The Bayesian approach has become increasingly popular because it allows to fit quite complex models to data via Markov chain Monte Carlo sampling. However, it is also recognized nowadays that Markov chain Monte Carlo sampling can become computationally prohibitive when applied to a large data set. We encountered serious computational difficulties when fitting an hierarchical model to longitudinal glaucoma data of patients who participate in an ongoing Dutch study. To overcome this problem, we applied and extended a recently proposed two-stage approach to model these data. Glaucoma is one of the leading causes of blindness in the world. In order to detect deterioration at an early stage, a model for predicting visual fields (VFs) in time is needed. Hence, the true underlying VF progression can be determined, and treatment strategies can then be optimized to prevent further VF loss. Because we were unable to fit these data with the classical one-stage approach upon which the current popular Bayesian software is based, we made use of the two-stage Bayesian approach. The considered hierarchical longitudinal model involves estimating a large number of random effects and deals with censoring and high measurement variability. In addition, we extended the approach with tools for model evaluation. Copyrigh

Rheophysics of dense granular materials : Discrete simulation of plane shear flows

We study the steady plane shear flow of a dense assembly of frictional, inelastic disks using discrete simulation and prescribing the pressure and the shear rate. We show that, in the limit of rigid grains, the shear state is determined by a single dimensionless number, called inertial number I, which describes the ratio of inertial to pressure forces. Small values of I correspond to the quasi-static regime of soil mechanics, while large values of I correspond to the collisional regime of the kinetic theory. Those shear states are homogeneous, and become intermittent in the quasi-static regime. When I increases in the intermediate regime, we measure an approximately linear decrease of the solid fraction from the maximum packing value, and an approximately linear increase of the effective friction coefficient from the static internal friction value. From those dilatancy and friction laws, we deduce the constitutive law for dense granular flows, with a plastic Coulomb term and a viscous Bagnold term. We also show that the relative velocity fluctuations follow a scaling law as a function of I. The mechanical characteristics of the grains (restitution, friction and elasticity) have a very small influence in this intermediate regime. Then, we explain how the friction law is related to the angular distribution of contact forces, and why the local frictional forces have a small contribution to the macroscopic friction. At the end, as an example of heterogeneous stress distribution, we describe the shear localization when gravity is added.Comment: 24 pages, 19 figure

Extended M1 sum rule for excited symmetric and mixed-symmetry states in nuclei

A generalized M1 sum rule for orbital magnetic dipole strength from excited symmetric states to mixed-symmetry states is considered within the proton-neutron interacting boson model of even-even nuclei. Analytic expressions for the dominant terms in the B(M1) transition rates from the first and second $2^+$ states are derived in the U(5) and SO(6) dynamic symmetry limits of the model, and the applicability of a sum rule approach is examined at and in-between these limits. Lastly, the sum rule is applied to the new data on mixed-symmetry states of 94Mo and a quadrupole d-boson ratio $nd(0^+_1)/nd(2^+_2) \approx 0.6$ is obtained in a largely parameter-independent wayComment: 19 pages, 3 figures, Revte