Frictionless bead packs have macroscopic friction, but no dilatancy

The statement of the title is shown by numerical simulation of homogeneously sheared packings of frictionless, nearly rigid beads in the quasistatic limit. Results coincide for steady flows at constant shear rate γ in the limit of small γ and static approaches, in which packings are equilibrated under growing deviator stresses. The internal friction angle ϕ, equal to 5.76 $\pm$ 0.22 degrees in simple shear, is independent on the average pressure P in the rigid limit. It is shown to stem from the ability of stable frictionless contact networks to form stress-induced anisotropic fabrics. No enduring strain localization is observed. Dissipation at the macroscopic level results from repeated network rearrangements, like the effective friction of a frictionless slider on a bumpy surface. Solid fraction Φ remains equal to the random close packing value ≃ 0.64 in slowly or statically sheared systems. Fluctuations of stresses and volume are observed to regress in the large system limit, and we conclude that the same friction law for simple shear applies in the large psystem limit if normal stress or density is externally controlled. Defining the inertia number as I = γ m/(aP), with m the grain mass and a its diameter, both internal friction coefficient $\mu$∗ = tan ϕ and volume 1/Φ increase as powers of I in the quasistatic limit of vanishing I, in which all mechanical properties are determined by contact network geometry. The microstructure of the sheared material is characterized with a suitable parametrization of the fabric tensor and measurements of connectivity and coordination numbers associated with contacts and near neighbors.Comment: 19 pages. Additional technical details may be found in v

Generation of a human iPSC-derived cardiomyocyte/fibroblast engineered heart tissue model

Animal models have proven integral to broadening our understanding of complex cardiac diseases but have been hampered by significant species-dependent differences in cellular physiology. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have shown great promise in the modelling of cardiac diseases despite limitations in functional and structural maturity. 3D stem cell-derived cardiac models represent a step towards mimicking the intricate microenvironment present in the heart as an in vitro model. Incorporation of non-myocyte cell types, such as cardiac fibroblasts, into engineered heart tissue models (EHTs) can help better recapitulate the cell-to-cell and cell-to-matrix interactions present in the human myocardium. Integration of human-induced pluripotent stem cell-derived cardiac fibroblasts (hiPSC-CFs) and hiPSC-CM into EHT models enables the generation of a genetically homogeneous modelling system capable of exploring the abstruse structural and electrophysiological interplay present in cardiac pathophysiology. Furthermore, the construction of more physiologically relevant 3D cardiac models offers great potential in the replacement of animals in heart disease research. Here we describe efficient and reproducible protocols for the differentiation of hiPSC-CMs and hiPSC-CFs and their subsequent assimilation into EHTs. The resultant EHT consists of longitudinally arranged iPSC-CMs, incorporated alongside hiPSC-CFs. EHTs with both hiPSC-CMs and hiPSC-CFs exhibit slower beating frequencies and enhanced contractile force compared to those composed of hiPSC-CMs alone. The modified protocol may help better characterise the interplay between different cell types in the myocardium and their contribution to structural remodelling and cardiac fibrosis

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

Internal states of model isotropic granular packings. I. Assembling process, geometry and contact networks

This is the first paper of a series of three, reporting on numerical simulation studies of geometric and mechanical properties of static assemblies of spherical beads under an isotropic pressure. Frictionless systems assemble in the unique random close packing (RCP) state in the low pressure limit if the compression process is fast enough, slower processes inducing traces of crystallization, and exhibit specific properties directly related to isostaticity of the force-carrying structure. The different structures of frictional packings assembled by various methods cannot be classified by the sole density. While lubricated systems approach RCP densities and coordination number z^*~=6 on the backbone in the rigid limit, an idealized "vibration" procedure results in equally dense configurations with z^*~=4.5. Near neighbor correlations on various scales are computed and compared to available laboratory data, although z^* values remain experimentally inaccessible. Low coordination packings have many rattlers (more than 10% of the grains carry no force), which should be accounted for on studying position correlations, and a small proportion of harmless "floppy modes" associated with divalent grains. Frictional packings, however slowly assembled under low pressure, retain a finite level of force indeterminacy, except in the limit of infinite friction.Comment: 29 pages. Published in Physical Review

A commonly occurring genetic variant within the NPLOC4-TSPAN10-PDE6G gene cluster is associated with the risk of strabismus.

Strabismus refers to an abnormal alignment of the eyes leading to the loss of central binocular vision. Concomitant strabismus occurs when the angle of deviation is constant in all positions of gaze and often manifests in early childhood when it is considered to be a neurodevelopmental disorder of the visual system. As such, it is inherited as a complex genetic trait, affecting 2-4% of the population. A genome-wide association study (GWAS) for self-reported strabismus (1345 cases and 65,349 controls from UK Biobank) revealed a single genome-wide significant locus on chromosome 17q25. Approximately 20 variants across the NPLOC4-TSPAN10-PDE6G gene cluster and in almost perfect linkage disequilibrium (LD) were most strongly associated (lead variant: rs75078292, OR = 1.26, p = 2.24E-08). A recessive model provided a better fit to the data than an additive model. Association with strabismus was independent of refractive error, and the degree of association with strabismus was minimally attenuated after adjustment for amblyopia. The association with strabismus was replicated in an independent cohort of clinician-diagnosed children aged 7 years old (116 cases and 5084 controls; OR = 1.85, p = 0.009). The associated variants included 2 strong candidate causal variants predicted to have functional effects: rs6420484, which substitutes tyrosine for a conserved cysteine (C177Y) in the TSPAN10 gene, and a 4-bp deletion variant, rs397693108, predicted to cause a frameshift in TSPAN10. The population-attributable risk for the locus was approximately 8.4%, indicating an important role in conferring susceptibility to strabismus

Modulation control and spectral shaping of optical fiber supercontinuum generation in the picosecond regime

Numerical simulations are used to study how fiber supercontinuum generation seeded by picosecond pulses can be actively controlled through the use of input pulse modulation. By carrying out multiple simulations in the presence of noise, we show how tailored supercontinuum Spectra with increased bandwidth and improved stability can be generated using an input envelope modulation of appropriate frequency and depth. The results are discussed in terms of the non-linear propagation dynamics and pump depletion.Comment: Aspects of this work were presented in Paper ThJ2 at OECC/ACOFT 2008, Sydney Australia 7-10 July (2008). Journal paper submitted for publication 30 July 200

Chronic activation of human cardiac fibroblasts in vitro attenuates the reversibility of the myofibroblast phenotype

Activation of cardiac fibroblasts and differentiation to myofibroblasts underlies development of pathological cardiac fibrosis, leading to arrhythmias and heart failure. Myofibroblasts are characterised by increased α-smooth muscle actin (α-SMA) fibre expression, secretion of collagens and changes in proliferation. Transforming growth factor-beta (TGF-β) and increased mechanical stress can initiate myofibroblast activation. Reversibility of the myofibroblast phenotype has been observed in murine cells but has not been explored in human cardiac fibroblasts. In this study, chronically activated adult primary human ventricular cardiac fibroblasts and human induced pluripotent stem cell derived cFbs (hiPSC-cFbs) were used to investigate the potential for reversal of the myofibroblast phenotype using either subculture on soft substrates or TGF-β receptor inhibition. Culture on softer plates (25 or 2 kPa Young's modulus) did not alter proliferation or reduce expression of α-SMA and collagen 1. Similarly, culture of myofibroblasts in the presence of TGF-β inhibitor did not reverse myofibroblasts back to a quiescent phenotype. Chronically activated hiPSC-cFbs also showed attenuated response to TGF-β receptor inhibition and inability to reverse to quiescent fibroblast phenotype. Our data demonstrate substantial loss of TGF-β signalling plasticity as well as a loss of feedback from the surrounding mechanical environment in chronically activated human myofibroblasts