Publications
102 results found
Bertrand T, Lee CF, 2022, Diversity of phase transitions and phase separations in active fluids, Physical Review Research, ISSN: 2643-1564
Lee CF, 2022, An infinite set of integral formulae for polar, nematic, and higher order structures at the interface of motility-induced phase separation, NEW JOURNAL OF PHYSICS, Vol: 24, ISSN: 1367-2630
Killeen A, Bertrand T, Lee CF, 2022, Polar Fluctuations Lead to Extensile Nematic Behavior in Confluent Tissues, PHYSICAL REVIEW LETTERS, Vol: 128, ISSN: 0031-9007
Pirillo C, Birch F, Tissot FS, et al., 2022, Metalloproteinase inhibition reduces AML growth, prevents stem cell loss, and improves chemotherapy effectiveness., Blood Adv
Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. Its prognosis remains poor, highlighting the need for new therapeutic and precision medicine approaches. AML symptoms often include cytopenias, linked to loss of healthy hematopoietic stem and progenitor cells (HSPCs). The mechanisms behind HSPC decline are complex and still poorly understood. Here, intravital microscopy (IVM) of a well-established experimental model of AML allows direct observation of the interactions between healthy and malignant cells in the bone marrow (BM), suggesting that physical dislodgment of healthy cells by AML through damaged vasculature may play an important role. Multiple matrix metalloproteinases (MMPs), known to remodel extracellular matrix remodeling, are expressed by AML cells and the BM microenvironment. We reason MMPs could be involved in cell displacement and vascular leakiness, therefore we evaluate the therapeutic potential of MMP pharmacological inhibition using the broad-spectrum inhibitor prinomastat. IVM analyses of prinomastat-treated mice reveal reduced vascular permeability and healthy cell clusters in circulation, and lower AML infiltration, proliferation and cell migration. Furthermore, treated mice have increased retention of healthy HSPCs in the BM and increased survival following chemotherapy. Analysis of a human AML transcriptomic database reveals widespread MMP deregulation, and human AML cells show susceptibility to MMP inhibition. Overall, our results suggest that MMP inhibition could be a promising complementary therapy to reduce AML growth and limit the loss of HSPC and BM vascular damage caused by MLL-AF9 and possibly other AML subtypes.
Lee CF, 2022, An infinite set of integral formulae for polar, nematic, and higher order structures at the interface of motility-induced phase separation, New Journal of Physics, ISSN: 1367-2630
Motility-induced phase separation (MIPS) is a purely non-equilibriumphenomenon in which self-propelled particles phase separate without any attractive interactions. One surprising feature of MIPS is the emergence of polar, nematic, and higher order structures at the interfacial region, whose underlying physics remains poorly understood. Starting with a model of MIPS in which all many-body interactions are captured by an effective speed function and an effective pressure function that depend solely on the local particle density, I derive analytically an infinite set of integral formulae for the ordering structures at the interface. I then test these integral formulae by applying them to numerical data from direct particle dynamics simulation and find that they remain valid with a high accuracy.
Killeen A, Bertrand T, Lee CF, 2022, Polar fluctuations lead to extensile nematic behavior in confluent tissues, Physical Review Letters, ISSN: 0031-9007
How can a collection of motile cells, each generating contractile nematic stresses in isolation, become an extensile nematic at the tissue-level? Understanding this seemingly contradictory experimental observation, which occurs irrespective of whether the tissue is in the liquid or solid states, is not only crucial to our understanding of diverse biological processes, but is also of fundamental interest to soft matter and many-body physics. Here, we resolve this cellular to tissue level disconnect in the small fluctuation regime by using analytical theories based on hydrodynamic descriptions of confluent tissues, in both liquid and solid states. Specifically, we show that a collection of microscopic constituents with no inherently nematic extensile forces can exhibit active extensile nematic behavior when subject to polar fluctuating forces. We further support our findings byperforming cell level simulations of minimal models of confluent tissues.
Lee CF, 2021, Scaling law and universal drop size distribution of coarsening in conversion-limited phase separation, Physical Review Research, Vol: 3, Pages: 1-6, ISSN: 2643-1564
Phase separation is not only ubiquitous in diverse physical systems, but also plays an important organizational role inside biological cells. However, experimental studies of intracellular condensates (drops with condensed concentrations of specific collections of proteins and nucleic acids) have challenged the standard coarsening theories of phase separation. Specifically, the coarsening rates observed are unexpectedly slow for many intracellular condensates. Recently, Folkmann et al. [Science 373, 1218 (2021)] argued that the slow coarsening rate can be caused by the slow conversion of a condensate constituent between the state in the dilute phase and the condensate state. One implication of this conversion-limited picture is that standard theories of coarsening in phase separation (Lifshitz-Slyozov-Wagner theory of Ostwald ripening and drop coalescence schemes) no longer apply. Surprisingly, I show here that the model equations of conversion-limited phase separation can instead be mapped onto a grain growth model in a single-phase material in three dimensions. I further elucidate the universal coarsening behavior in the late stage using analytical and numerical methods.
Folkmann AW, Putnam A, Lee CF, et al., 2021, Regulation of biomolecular condensates by interfacial protein clusters, SCIENCE, Vol: 373, Pages: 1218-+, ISSN: 0036-8075
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- Citations: 11
Folkmann A, Putnam A, Lee CF, et al., 2021, Pickering stabilization of a dynamic intracellular emulsion, Science, ISSN: 0036-8075
Biomolecular condensates are cellular compartments that can form by phase separation in the absence of limiting membranes. Studying the P granules of C. elegans, we find that condensate dynamics are regulated by protein clusters that adsorb to the condensate interface. Using in vitro reconstitution, live observations and theory, we demonstrate that localized assembly of P granules is controlled by MEG-3, an intrinsically disordered protein that forms low dynamic assemblies on P granules. Following classic Pickering emulsion theory, MEG-3 clusters lower surface tension and slow down coarsening. During zygote polarization, MEG-3 recruits DYRK/MBK-2 kinase to accelerate spatially-regulated growth of the P granule emulsion. By tuning condensate-cytoplasm exchange, interfacial clusters regulate the structural integrity of biomolecular condensates, reminiscent of the role of lipid bilayers in membrane-bound organelles.
Nesbitt D, Pruessner G, Lee CF, 2021, Uncovering novel phase transitions in dense dry polar active fluids using a lattice Boltzmann method, New Journal of Physics, Vol: 23, ISSN: 1367-2630
The dynamics of dry active matter have implications for a diverse collection of biological phenomena spanning a range of length and time scales, such as animal flocking, cell tissue dynamics, and swarming of inserts and bacteria. Uniting these systems are a common set of symmetries and conservation laws, defining dry active fluids as a class of physical system. Many interesting behaviours have been observed at high densities, which remain difficult to simulate due to the computational demand. Here, we show how two-dimensional dry active fluids in a dense regime can be studied using a simple modification of the lattice Boltzmann method. We apply our method on a model that exhibits motility-induced phase separation, and an active model with contact inhibition of locomotion, which has relevance to collective cell migration. For the latter, we uncover multiple novel phase transitions: two first-order and one potentially critical. We further support our simulation results with an analytical treatment of the hydrodynamic equations obtained via the Chapman-Enskog coarse-graining procedure.
Chen L, Lee CF, Toner J, 2020, Universality class for a nonequilibrium state of matter: A d=4−ε expansion study of Malthusian flocks, Physical Review E: Statistical, Nonlinear, and Soft Matter Physics, Vol: 102, Pages: 1-40, ISSN: 1539-3755
We show that “Malthusian flocks” – i.e., coherently moving collections of self-propelled entities(such as living creatures) which are being “born” and “dying” during their motion – belong toa new universality class in spatial dimensionsd >2. We calculate the universal exponents andscaling laws of this new universality class toO( ) in ad= 4− expansion, and find these aredifferent from the “canonical” exponents previously conjectured to hold for “immortal” flocks (i.e.,those without birth and death) and shown to hold for incompressible flocks with spatial dimensionsin the range of 2< d≤4. We also obtain a universal amplitude ratio relating the damping oftransverse and longitudinal velocity and density fluctuations in these systems. Furthermore, wefind a universal separatrix in real (r) space between two regions in which the equal time densitycorrelation〈δρ(r,t)δρ(0,t)〉has opposite signs. Our expansion should be quite accurate ind= 3,allowing precise quantitative comparisons between our theory, simulations, and experiments.
Chen L, Lee CF, Toner J, 2020, Moving, Reproducing, and Dying Beyond Flatland: Malthusian Flocks in Dimensions d > 2, PHYSICAL REVIEW LETTERS, Vol: 125, ISSN: 0031-9007
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- Citations: 3
Chen L, Lee CF, Toner J, 2020, Moving, reproducing, and dying beyond Flatland: Malthusian flocks in dimensions d>2, Physical Review Letters, ISSN: 0031-9007
We show that “Malthusian flocks” – i.e., coherently moving collections of self-propelled entities (such as living creatures) which are being “born” and “dying” during their motion – belong to a new universality class in spatial dimensions d>2. We calculate the universal exponents and scaling laws of this new universality class to O(ϵ) in an ϵ=4−d expansion, and find these are different from the “canonical” exponents previously conjectured to hold for “immortal” flocks (i.e., those without birth and death) and shown to hold for incompressible flocks in d>2. Our expansion should be quite accurate in d=3, allowing precise quantitative comparisons between our theory, simulations, and experiments.
Pytowski L, Lee CF, Foley AC, et al., 2020, Liquid–liquid phase separation of type II diabetes-associated IAPP initiates hydrogelation and aggregation, Proceedings of the National Academy of Sciences of USA, Vol: 117, Pages: 12050-12061, ISSN: 0027-8424
Amyloidoses (misfolded polypeptide accumulation) are among the most debilitating diseases our aging societies face. Amyloidogenesis can be catalyzed by hydrophobic–hydrophilic interfaces (e.g., air–water interface in vitro [AWI]). We recently demonstrated hydrogelation of the amyloidogenic type II diabetes-associated islet amyloid polypeptide (IAPP), a hydrophobic–hydrophilic interface-dependent process with complex kinetics. We demonstrate that human IAPP undergoes AWI-catalyzed liquid–liquid phase separation (LLPS), which initiates hydrogelation and aggregation. Insulin modulates these processes but does not prevent them. Using nonamyloidogenic rat IAPP, we show that, whereas LLPS does not require the amyloidogenic sequence, hydrogelation and aggregation do. Interestingly, both insulin and rat sequence delayed IAPP LLPS, which may reflect physiology. By developing an experimental setup and analysis tools, we show that, within the whole system (beyond the droplet stage), macroscopic interconnected aggregate clusters form, grow, fuse, and evolve via internal rearrangement, leading to overall hydrogelation. As the AWI-adsorbed gelled layer matures, its microviscosity increases. LLPS-driven aggregation may be a common amyloid feature and integral to pathology.
Lee CF, 2020, Formation of liquid-like cellular organelles depends on their composition, NATURE, Vol: 581, Pages: 144-145, ISSN: 0028-0836
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- Citations: 1
Partridge B, Lee CF, 2019, Critical motility-induced phase separation belongs to the Ising universality class, Physical Review Letters, Vol: 123, Pages: 1-6, ISSN: 0031-9007
A collection of self-propelled particles with volume exclusion interactions can exhibit the phenomenology of a gas-liquid phase separation, known as motility-induced phase separation (MIPS). The nonequilibrium nature of the system is fundamental to the phase transition; however, it is unclear whether MIPS at criticality contributes a novel universality class to nonequilibrium physics. We demonstrate here that this is not the case by showing that a generic critical MIPS belongs to the Ising universality class with conservative dynamics.
Sartori P, Lee CF, 2019, Scaling behaviour of non-equilibrium planar N-atic spin systems under weak fluctuations, New Journal of Physics, Vol: 21, Pages: 1-6, ISSN: 1367-2630
Starting from symmetry considerations, we derive the generic hydrodynamic equation of nonequilibrium XY spin systems with N-atic symmetry under weak fluctuations. Through a systematictreatment we demonstrate that, in two dimensions, these systems exhibit two types of scalingbehaviours. For N = 1, they have long-range order and are described by the flocking phase of drypolar active fluids. For all other values of N, the systems exhibit quasi long-range order, as in theequilibrium XY model at low temperature.
Overby DR, Spenlehauer A, Cairoli A, et al., 2019, Actomyosin contractility and the vimentin cytoskeleton influence giant vacuole life-cycle in Schlemm's canal endothelial cells, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Weber C, Zwicker D, Juelicher F, et al., 2019, Physics of active emulsions, Reports on Progress in Physics, Vol: 82, Pages: 1-40, ISSN: 0034-4885
Phase separating systems that are maintained away from thermodynamic equilibrium via molecular processes represent a class of active systems, which we call \textit{ active emulsions}. These systems are driven by external energy input for example provided by an external fuel reservoir. The external energy input gives rise to novel phenomena that are not present in passive systems. For instance, concentration gradients can spatially organise emulsions and cause novel droplet size distributions. Another example are active droplets that are subject to chemical reactions such that their nucleation and size can be controlled and they can spontaneously divide. In this review we discuss the physics of phase separation and emulsions and show how the concepts that governs such phenomena can be extended to capture the physics of active emulsions. This physics is relevant to the spatial organisation of the biochemistry in living cells, for the development novel applications in chemical engineering and models for the origin of life.
Chen L, Lee CF, Toner J, 2018, Incompressible polar active fluids in the moving phase in dimensions d>2, New Journal of Physics, Vol: 20, ISSN: 1367-2630
We study universal behavior in the moving (polar ordered) phase of a generic system of motile particles with alignment interactions in the incompressible limit for spatial dimensions d > 2. Using a dynamical renormalization group analysis, we obtain the exact dynamic, roughness, and anisotropy exponents that describe the scaling behavior of such incompressible systems. This is the first time a compelling argument has been given for the exact values of the anomalous scaling exponents of a flock moving through an isotropic medium in d > 2.
Lee C, Wurtz JD, 2018, Novel physics arising from phase transitions in biology, Journal of Physics D: Applied Physics, Vol: 52, ISSN: 0022-3727
Phase transitions, such as the freezing of water and the magnetisation of a ferromagnet upon lowering the ambient temperature, are familiar physical phenomena. Interestingly, such a collective change of behaviour at a phase transition is also of importance to living systems. From cytoplasmic organisation inside a cell to the collective migration of cell tissue during organismal development and wound healing, phase transitions have emerged as key mechanisms underlying many crucial biological processes. However, a living system is fundamentally different from a thermal system, with driven chemical reactions (e.g. metabolism) and motility being two hallmarks of its non-equilibrium nature. In this review, we will discuss how driven chemical reactions can arrest universal coarsening kinetics expected from thermal phase separation, and how motility leads to the emergence of a novel universality class when the rotational symmetry is spontaneously broken in an incompressible fluid.
Leiming C, Lee CF, John T, 2018, Squeezed in three dimensions, moving in two: hydrodynamic theory of three-dimensional incompressible easy-plane polar active fluids, Physical Review E, Vol: 98, ISSN: 1539-3755
We study the hydrodynamic behavior of three-dimensional (3D) incompressible collections of self-propelled entities in contact with a momentum sink in a state with nonzero average velocity, hereafter called 3D easy-plane incompressible polar active fluids. We show that the hydrodynamic model for this system belongs to the same universality class as that of an equilibrium system, namely, a special 3D anisotropic magnet. The latter can be further mapped onto yet another equilibrium system, a DNA-lipid mixture in the sliding columnar phase. Through these connections we find a divergent renormalization of the damping coefficients in 3D easy-plane incompressible polar active fluids, and obtain their equal-time velocity correlation functions.
Lee C, 2018, Equilibrium kinetics of self-assembling, semi-flexible polymers, Journal of Physics: Condensed Matter, Vol: 30, ISSN: 0953-8984
Self-assembling, semi-flexible polymers are ubiquitous in biology and technology. However, conflicting accounts of the equilibrium kinetics remain for such an important system. Here, by focusing on a dynamical description of a minimal model in an overdamped environment, I identify the correct kinetic scheme that describes the system at equilibrium in the limits of high bonding energy and dilute concentration.
Lee C, Leanne M, Liu L-N, et al., 2018, Insights into the origin of distinct medin fibril morphologies induced by incubation conditions and seeding., International Journal of Molecular Sciences, Vol: 19, ISSN: 1661-6596
Incubation conditions are an important factor to consider when studying protein aggregation in vitro. Here, we employed biophysical methods and atomic force microscopy to show that agitation dramatically alters the morphology of medin, an amyloid protein deposited in the aorta. Agitation reduces the lag time for fibrillation by ~18-fold, suggesting that the rate of fibril formation plays a key role in directing the protein packing arrangement within fibrils. Utilising preformed sonicated fibrils as seeds, we probed the role of seeding on medin fibrillation and revealed three distinct fibril morphologies, with biophysical modelling explaining the salient features of experimental observations. We showed that nucleation pathways to distinct fibril morphologies may be switched on and off depending on the properties of the seeding fibrils and growth conditions. These findings may impact on the development of amyloid-based biomaterials and enhance understanding of seeding as a pathological mechanism.
Wurtz J, Lee C, 2018, Stress granule formation via ATP depletion-triggered phase separation, New Journal of Physics, Vol: 20, Pages: 1-20, ISSN: 1367-2630
Stress granules (SG) are droplets of proteins and RNA that formin the cell cytoplasm during stress conditions. We consider minimal models ofstress granule formation based on the mechanism of phase separation regulatedby ATP-driven chemical reactions. Motivated by experimental observations, weidentify a minimal model of SG formation triggered by ATP depletion. Ouranalysis indicates that ATP is continuously hydrolysed to deter SG formationunder normal conditions, and we provide specific predictions that can be testedexperimentally.
Wurtz JD, Lee C, 2018, Chemical reaction-controlled phase separated drops: Formation, size selection, and coarsening, Physical Review Letters, Vol: 120, Pages: 1-5, ISSN: 0031-9007
Phase separation under nonequilibrium conditions is exploited by biological cells to organize their cytoplasm but remains poorly understood as a physical phenomenon. Here, we study a ternary fluid model in which phase-separating molecules can be converted into soluble molecules, and vice versa, via chemical reactions. We elucidate using analytical and simulation methods how drop size, formation, and coarsening can be controlled by the chemical reaction rates, and categorize the qualitative behavior of the system into distinct regimes. Ostwald ripening arrest occurs above critical reaction rates, demonstrating that this transition belongs entirely to the nonequilibrium regime. Our model is a minimal representation of the cell cytoplasm.
Nesbitt D, Pruessner G, Lee C, 2017, Edge instability in incompressible planar active fluids, Physical Review E, Vol: 96, ISSN: 1539-3755
Interfacial instability is highly relevant to many important biological processes. A key example arises in wound healing experiments, which observe that an epithelial layer with an initially straight edge does not heal uniformly. We consider the phenomenon in the context of active fluids. Improving upon the approximation used by Zimmermann, Basan, and Levine [Eur. Phys. J.: Spec. Top. 223, 1259 (2014)], we perform a linear stability analysis on a two-dimensional incompressible hydrodynamic model of an active fluid with an open interface. We categorize the stability of the model and find that for experimentally relevant parameters, fingering instability is always absent in this minimal model. Our results point to the crucial role of density variation in the fingering instability in tissue regeneration.
Hong L, Lee CF, Huang YJ, 2017, Statistical Mechanics and Kinetics of Amyloid Fibrillation, Pages: 113-186, ISSN: 1793-1363
Wurtz JD, Lee CF, 2017, Chemically-driven kinetics of phase separated membrane-free organelles, 19th IUPAB Congress / 11th EBSA Congress, Publisher: SPRINGER, Pages: S63-S63, ISSN: 0175-7571
Chen L, Toner J, Lee CF, 2017, Universality in Incompressible Active Fluids, 19th IUPAB Congress / 11th EBSA Congress, Publisher: SPRINGER, Pages: S281-S281, ISSN: 0175-7571
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