Publications

Loss of normal tissue architecture is a hallmark of oncogenic transformation1. In developing organisms, tissues architectures are sculpted by mechanical forces during morphogenesis2. However, the origins and consequences of tissue architecture during tumorigenesis remain elusive. In skin, premalignant basal cell carcinomas form ‘buds’, while invasive squamous cell carcinomas initiate as ‘folds’. Here, using computational modelling, genetic manipulations and biophysical measurements, we identify the biophysical underpinnings and biological consequences of these tumour architectures. Cell proliferation and actomyosin contractility dominate tissue architectures in monolayer, but not multilayer, epithelia. In stratified epidermis, meanwhile, softening and enhanced remodelling of the basement membrane promote tumour budding, while stiffening of the basement membrane promotes folding. Additional key forces stem from the stratification and differentiation of progenitor cells. Tumour-specific suprabasal stiffness gradients are generated as oncogenic lesions progress towards malignancy, which we computationally predict will alter extensile tensions on the tumour basement membrane. The pathophysiologic ramifications of this prediction are profound. Genetically decreasing the stiffness of basement membranes increases membrane tensions in silico and potentiates the progression of invasive squamous cell carcinomas in vivo. Our findings suggest that mechanical forces—exerted from above and below progenitors of multilayered epithelia—function to shape premalignant tumour architectures and influence tumour progression.

In the present paper we describe a class of algorithms for the solution of Laplace's equation on polygonal domains with Neumann boundary conditions. It is well known that in such cases the solutions have singularities near the corners which poses a challenge for many existing methods. If the boundary data is smooth on each edge of the polygon, then in the vicinity of each corner the solution to the corresponding boundary integral equation has an expansion in terms of certain (analytically available) singular powers. Using the known behavior of the solution, universal discretizations have been constructed for the solution of the Dirichlet problem. However, the leading order behavior of solutions to the Neumann problem is $O(t^{\mu})$ for $\mu \in (-1/2,0)$ depending on the angle at the corner (compared to $O(C+t^{\mu})$ with $\mu>1/2$ for the Dirichlet problem); this presents a significant challenge in the design of universal discretizations. Our approach is based on using the discretization for the Dirichlet problem in order to compute a solution in the "weak sense" by solving an adjoint linear system; namely, it can be used to compute inner products with smooth functions accurately, but it cannot be interpolated. Furthermore we present a procedure to obtain accurate solutions arbitrarily close to the corner, by solving a sequence of small local subproblems in the vicinity of that corner. The results are illustrated with several numerical examples.

One of the most powerful approaches to imaging at the nanometer or subnanometer length scale is coherent diffraction imaging using X-ray sources. For amorphous (non-crystalline) samples, the raw data can be interpreted as the modulus of the continuous Fourier transform of the unknown object. Making use of prior information about the sample (such as its support), a natural goal is to recover the phase through computational means, after which the unknown object can be visualized at high resolution. While many algorithms have been proposed for this phase retrieval problem, careful analysis of its well-posedness has received relatively little attention. In this paper, we show that the problem is, in general, not well-posed and describe some of the underlying issues that are responsible for the ill-posedness. We then show how this analysis can be used to develop experimental protocols that lead to better conditioned inverse problems.

We describe a computational framework for simulating suspensions of rigid particles in Newtonian Stokes flow. One central building block is a collision-resolution algorithm that overcomes the numerical constraints arising from particle collisions. This algorithm extends the well-known complementarity method for non-smooth multi-body dynamics to resolve collisions in dense rigid body suspensions. This approach formulates the collision resolution problem as a linear complementarity problem with geometric `non-overlapping' constraints imposed at each timestep. It is then reformulated as a constrained quadratic programming problem and the Barzilai-Borwein projected gradient descent method is applied for its solution. This framework is designed to be applicable for any convex particle shape, e.g., spheres and spherocylinders, and applicable to any Stokes mobility solver, including the Rotne-Prager-Yamakawa approximation, Stokesian Dynamics, and PDE solvers (e.g., boundary integral and immersed boundary methods). In particular, this method imposes Newton's Third Law and records the entire contact network. Further, we describe a fast, parallel, and spectrally-accurate boundary integral method tailored for spherical particles, capable of resolving lubrication effects. We show weak and strong parallel scalings up to 8×104 particles with approximately 4×107 degrees of freedom on 1792 cores. We demonstrate the versatility of this framework with several examples, including sedimentation of particle clusters, and active matter systems composed of ensembles of particles driven to rotate.

We present a theoretical formulation of the frequency domain multidimensional pump-probe analog spectroscopy, which utilizes the spectral– temporal entanglement features of the biphoton sources. It has been shown, via a compact multi-time, convolutional Green’s function expression and the accompanying numerical simulations, that utilizing the correlation properties of non-classical sources offers a viable scheme for the exploration of dissipative kinetics of the cavity confined quantum aggregates. The cooperative and competitive modifications brought in by the photonic cavity mode and the auxiliary vibrational modes into the scattering and dephasing properties of the exciton– polaritons have been explored via their signatures in the multidimensional correlation maps. The study offers a new parameter window for the investigation of the dynamical polariton characteristics and warrants the usage of multi-mode entanglement properties of the external photonic sources in future studies.

Elucidating the carrier density at which strongly bound excitons dissociate into a plasma of uncorrelated electron-hole pairs is a central topic in the many-body physics of semiconductors. However, there is a lack of information on the high-density response of excitons absorbing in the near-to-mid ultraviolet, due to the absence of suitable experimental probes in this elusive spectral range. Here, we present a unique combination of many-body perturbation theory and state-of-the-art ultrafast broadband ultraviolet spectroscopy to unveil the interplay between the ultraviolet-absorbing two-dimensional excitons of anatase TiO2 and a sea of electron-hole pairs. We discover that the critical density for the exciton Mott transition in this material is the highest ever reported in semiconductors. These results deepen our knowledge of the exciton Mott transition and pave the route toward the investigation of the exciton phase diagram in a variety of wide-gap insulators.

The translational power of human microbiome studies is limited by high interindividual variation. We describe a dimensionality reduction tool, compositional tensor factorization (CTF), that incorporates information from the same host across multiple samples to reveal patterns driving differences in microbial composition across phenotypes. CTF identifies robust patterns in sparse compositional datasets, allowing for the detection of microbial changes associated with specific phenotypes that are reproducible across datasets.

Fibrin is the three-dimensional mechanical scaffold of protective blood clots that stop bleeding and pathological thrombi that obstruct blood vessels. Fibrin must be mechanically tough to withstand rupture, after which life-threatening pieces (thrombotic emboli) are carried downstream by blood flow. Despite multiple studies on fibrin viscoelasticity, mechanisms of fibrin rupture remain unknown. Here, we examined mechanically and structurally the strain-driven rupture of human blood plasma–derived fibrin clots where clotting was triggered with tissue factor. Toughness, i.e., resistance to rupture, quantified by the critical energy release rate (a measure of the propensity for clot embolization) of physiologically relevant fibrin gels was determined to be 7.6 ± 0.45 J/m2. Finite element (FE) simulations using fibrin material models that account for forced protein unfolding independently supported this measured toughness and showed that breaking of fibers ahead the crack at a critical stretch is the mechanism of rupture of blood clots, including thrombotic embolization.

The high-field regime of the spin-s XXZ antiferromagnet on the kagome lattice gives rise to macroscopically degenerate ground states thanks to a completely flat lowest single-magnon band. The corresponding excitations can be localized on loops in real space and have been coined "localized magnons". The description of the many-body ground states amounts thus to characterizing the allowed classical loop configurations and eliminating the quantum mechanical linear relations between them. Here we investigate this loop-gas description on finite kagome lattices with open boundary conditions and compare the results with exact diagonalization for the spin-1/2 XY model on the same lattice. We find that the loop gas provides an exact account of the degenerate ground-state manifold while a hard-hexagon description misses contributions from nested loop configuration. The densest packing of the loops corresponds to a magnon crystal that according to the zero-temperature magnetization curve is the stable ground state of the spin-1/2 XY model in a window of magnetic fields of about 4% of the saturation field just below this saturation field. We also present numerical results for the specific heat obtained by the related methods of thermal pure quantum (TPQ) states and the finite-temperature Lanczos method (FTLM). For a field in the stability range of the magnon crystal, one finds a low-temperature maximum of the specific heat that corresponds to a finite-temperature phase transition into the magnon crystal at low temperatures.

Microglial cells play a key role in brain homeostasis from development to adulthood. Here we show the involvement of a site-specific phosphorylation of Presenilin 1 (PS1) in microglial development. Profiles of microglia-specific transcripts in different temporal stages of development, combined with multiple systematic transcriptomic analysis and quantitative determination of microglia progenitors, indicate that the phosphorylation of PS1 at serine 367 is involved in the temporal dynamics of microglial development, specifically in the developing brain rudiment during embryonic microgliogenesis. We constructed a developing brain-specific microglial network to identify transcription factors linked to PS1 during development. Our data showed that PS1 functional connections appear through interaction hubs at Pu.1, Irf8 and Rela-p65 transcription factors. Finally, we showed that the total number of microglia progenitors was markedly reduced in the developing brain rudiment of embryos lacking PS1 phosphorylation compared to WT. Our work identifies a novel role for PS1 in microglial development.