Art and Science of the Cellular Mesoscale.

Experimental information from microscopy, structural biology, and bioinformatics may be integrated to build structural models of entire cells with molecular detail. This integrative modeling is challenging in several ways: the intrinsic complexity of biology results in models with many closely packed and heterogeneous components; the wealth of available experimental data is scattered among multiple resources and must be gathered, reconciled, and curated; and computational infrastructure is only now gaining the capability of modeling and visualizing systems of this complexity. We present recent efforts to address these challenges, both with artistic approaches to depicting the cellular mesoscale, and development and application of methods to build quantitative models.

Algorithm to implement unsteady jump boundary conditions within the lattice Boltzmann method.

An algorithm is proposed to implement unsteady jump boundary conditions in the lattice Boltzmann method (LBM). This is useful for dealing with problems of mass transfer across membranes that exhibit resistance and discontinuity in concentration. The algorithm is simple to implement into an existing LBM-based code that computes diffusion and advection of a solute. Analytical solutions are recovered in the limiting case of a planar membrane. When combined with the immersed boundary method, the algorithm can handle moving deformable boundaries that adopt arbitrary geometries. Simulations of controlled solute release from stationary rigid and moving deformable particles are given as a proof of concept.

Particle pairs and trains in inertial microfluidics.

Staggered and linear multi-particle trains constitute characteristic structures in inertial microfluidics. Using lattice-Boltzmann simulations, we investigate their properties and stability, when flowing through microfluidic channels. We confirm the stability of cross-streamline pairs by showing how they contract or expand to their equilibrium axial distance. In contrast, same-streamline pairs quickly expand to a characteristic separation but even at long times slowly drift apart. We reproduce the distribution of particle distances with its characteristic peak as measured in experiments. Staggered multi-particle trains initialized with an axial particle spacing larger than the equilibrium distance contract non-uniformly due to collective drag reduction. Linear particle trains, similar to pairs, rapidly expand toward a value about twice the equilibrium distance of staggered trains and then very slowly drift apart non-uniformly. Again, we reproduce the statistics of particle distances and the characteristic peak observed in experiments. Finally, we thoroughly analyze the damped displacement pulse traveling as a microfluidic phonon through a staggered train and show how a defect strongly damps its propagation.

Transport of dynamic biochemical signals in a microfluidic single cell trapping channel with varying cross-sections.

Dynamic biochemical signal control in vitro is important in the study of cellular responses to dynamic biochemical stimuli in microenvironment in vivo. To this end, we designed a microfluidic single cell trapping channel with varying cross-sections. In this work, we analyzed the transport of dynamic biochemical signals in steady and non-reversing pulsatile flows in such a microchannel. By numerically solving the 2D time-dependent Taylor-Aris dispersion equation, we studied the transport mechanism of different signals with varying parameters. The amplitude spectrum in steady flow shows that the trapping microchannel acts as a low-pass filter due to the longitudinal dispersion. The input signal can be modulated nonlinearly by the pulsatile flow. In addition, the nonlinear modulation effects are affected by the pulsatile flow frequency, the pulsatile flow amplitude and the average flow rate. When the flow frequency is much smaller or larger than that of the biochemical signal, the signal can be transmitted more efficiently. Besides, smaller pulsatile flow amplitude and larger average flow rate can decrease the nonlinear modulation and promote the signal transmission. These results demonstrate that in order to accurately load a desired dynamic biochemical signal to the trapped cell to probe the cellular dynamic response to the dynamic biochemical stimulus, the transport mechanism of the signals in the microchannel should be carefully considered.

Friction weakening by mechanical vibrations: A velocity-controlled process.

Frictional weakening by vibrations was first invoked in the 70s to explain unusual fault slips and earthquakes, low viscosity during the collapse of impact craters or the extraordinary mobility of sturzstroms, peculiar rock avalanches which travels large horizontal distances. This mechanism was further invoked to explain the remote triggering of earthquakes or the abnormally large runout of landslides or pyroclastic flows. Recent experimental and theoretical works pointed out that the key parameter which governs frictional weakening in sheared granular media is the characteristic velocity of the vibrations. Here we show that the mobility of the grains is not mandatory and that the vibration velocity governs the weakening of both granular and solid friction. The critical velocity leading to the transition from stick-slip motion to continuous sliding is in both cases of the same order of magnitude, namely a hundred microns per second. It is linked to the roughness of the surfaces in contact.

Creeping motion of a solid particle inside a spherical elastic cavity: II. Asymmetric motion.

An analytical method is proposed for computing the low-Reynolds-number hydrodynamic mobility function of a small colloidal particle asymmetrically moving inside a large spherical elastic cavity, the membrane of which is endowed with resistance toward shear and bending. In conjunction with the results obtained in the first part (A. Daddi-Moussa-Ider, H. Löwen, S. Gekle, Eur. Phys. J. E 41, 104 (2018)), in which the axisymmetric motion normal to the surface of an elastic cavity is investigated, the general motion for an arbitrary force direction can now be addressed. The elastohydrodynamic problem is formulated and solved using the classic method of images through expressing the hydrodynamic flow fields as a multipole expansion involving higher-order derivatives of the free-space Green's function. In the quasi-steady limit, we demonstrate that the particle self-mobility function of a particle moving tangent to the surface of the cavity is larger than that predicted inside a rigid stationary cavity of equal size. This difference is justified by the fact that a stationary rigid cavity introduces additional hindrance to the translational motion of the encapsulated particle, resulting in a reduction of its hydrodynamic mobility. Furthermore, the motion of the cavity is investigated, revealing that the translational pair (composite) mobility, which linearly couples the velocity of the elastic cavity to the force exerted on the solid particle, is solely determined by membrane shear properties. Our analytical predictions are favorably compared with fully-resolved computer simulations based on a completed-double-layer boundary integral method.

Non-Markovian barrier crossing with two-time-scale memory is dominated by the faster memory component.

We investigate non-Markovian barrier-crossing kinetics of a massive particle in one dimension in the presence of a memory function that is the sum of two exponentials with different memory times, [Formula: see text] and [Formula: see text] . Our Langevin simulations for the special case where both exponentials contribute equally to the total friction show that the barrier-crossing time becomes independent of the longer memory time if at least one of the two memory times is larger than the intrinsic diffusion time. When we associate memory effects with coupled degrees of freedom that are orthogonal to a one-dimensional reaction coordinate, this counterintuitive result shows that the faster orthogonal degrees of freedom dominate barrier-crossing kinetics in the non-Markovian limit and that the slower orthogonal degrees become negligible, quite contrary to the standard time-scale separation assumption and with important consequences for the proper setup of coarse-graining procedures in the non-Markovian case. By asymptotic matching and symmetry arguments, we construct a crossover formula for the barrier crossing time that is valid for general multi-exponential memory kernels. This formula can be used to estimate barrier-crossing times for general memory functions for high friction, i.e. in the overdamped regime, as well as for low friction, i.e. in the inertial regime. Typical examples where our results are important include protein folding in the high-friction limit and chemical reactions such as proton-transfer reactions in the low-friction limit.

Experiments and modeling of nonlinear frequency response of oscillations of a sessile droplet subjected to horizontal vibrations.

In this paper, we experimentally studied the response frequency of oscillations of a sessile water droplet, subjected to horizontal vibrations at varying excitation frequency (5-250 Hz and 40 kHz) and amplitude (0.015 mm to 0.5 mm for low frequencies and 600nm for ultrasonic frequency), as well as static contact angle of the glass substrate ([Formula: see text], [Formula: see text] , [Formula: see text], [Formula: see text]). The droplets were pinned during the experiments and non-axisymmetric oscillation modes were excited due to the horizontal vibrations. For the first time, we observed that at a sufficiently high vibration amplitude, when the excitation frequency is lower than the smallest natural frequency of the sessile droplet, the droplet oscillates at a response frequency multiple of the excitation frequency. At higher excitation frequencies up to several hundreds of Hz, the droplet oscillates nearly at the excitation frequency. At ultrasonic excitation frequency, however, the droplet cannot follow the excitations, since there is a physical limitation for forming infinite modes (infinite wavenumber) on the surface of a small droplet. We have modeled these behaviors with a nonlinear mass-spring-damper system by combining two established models: the Duffing and Van der Pol equations, in order to simulate both nonlinear damping and stiffness.

Dynamics of sedimenting active Brownian particles.

We investigate the stochastic dynamics of one sedimenting active Brownian particle in three dimensions under the influence of gravity and passive fluctuations in the translational and rotational motion. We present an analytical solution of the Fokker-Planck equation for the stochastic process which allows us to describe the dynamics of one active Brownian particle in three dimensions. We address the time evolution of the density, the polarization, and the steady-state solution. We also perform Brownian dynamics simulations and study the effect of the activity of the particles on their collective motion. These results qualitatively agree with our model. Finally, we compare our results with experiments (J. Palacci et al., Phys. Rev. Lett. 105, 088304 (2010)) and find very good agreement.

Thermalization of plastic flow versus stationarity of thermomechanical equilibrium in SGR theory.

We discuss issues related to thermalization of plastic flow in the context of soft glassy rheology (SGR) theory. An apparent problem with the theory in its current form is that the stationarity of thermomechanical equilibrium obtained by requiring that its flow rule satisfy detailed balance in the absence of applied deformation requires plastic flow to be athermal. This prevents proper application of SGR to small-molecule and polymer glasses where plastic flow is often well thermalized. Clearly, one would like to have a SGR-like theory of thermalized plastic flow that satisfies stationarity. We discuss reasons why such a theory could prove very useful and clarify obstacles that must be overcome in order to develop it.

Hierarchical looping of zigzag nucleosome chains in metaphase chromosomes.

The architecture of higher-order chromatin in eukaryotic cell nuclei is largely unknown. Here, we use electron microscopy-assisted nucleosome interaction capture (EMANIC) cross-linking experiments in combination with mesoscale chromatin modeling of 96-nucleosome arrays to investigate the internal organization of condensed chromatin in interphase cell nuclei and metaphase chromosomes at nucleosomal resolution. The combined data suggest a novel hierarchical looping model for chromatin higher-order folding, similar to rope flaking used in mountain climbing and rappelling. Not only does such packing help to avoid tangling and self-crossing, it also facilitates rope unraveling. Hierarchical looping is characterized by an increased frequency of higher-order internucleosome contacts for metaphase chromosomes compared with chromatin fibers in vitro and interphase chromatin, with preservation of a dominant two-start zigzag organization associated with the 30-nm fiber. Moreover, the strong dependence of looping on linker histone concentration suggests a hierarchical self-association mechanism of relaxed nucleosome zigzag chains rather than longitudinal compaction as seen in 30-nm fibers. Specifically, concentrations lower than one linker histone per nucleosome promote self-associations and formation of these looped networks of zigzag fibers. The combined experimental and modeling evidence for condensed metaphase chromatin as hierarchical loops and bundles of relaxed zigzag nucleosomal chains rather than randomly coiled threads or straight and stiff helical fibers reconciles aspects of other models for higher-order chromatin structure; it constitutes not only an efficient storage form for the genomic material, consistent with other genome-wide chromosome conformation studies that emphasize looping, but also a convenient organization for local DNA unraveling and genome access.

The role of vegetation-microclimate feedback in promoting shrub encroachment in the northern Chihuahuan desert.

Many arid and semi-arid landscapes around the world are affected by a shift from grassland to shrubland vegetation, presumably induced by climate warming, increasing atmospheric CO2 concentrations, and/or changing land use. This major change in vegetation cover is likely sustained by positive feedbacks with the physical environment. Recent research has focused on a feedback with microclimate, whereby cold intolerant shrubs increase the minimum nocturnal temperatures in their surroundings. Despite the rich literature on the impact of land cover change on local climate conditions, changes in microclimate resulting from shrub expansion into desert grasslands have remained poorly investigated. It is unclear to what extent such a feedback can affect the maximum extent of shrub expansion and the configuration of a stable encroachment front. Here, we focus on the case of the northern Chihuahuan desert, where creosotebush (Larrea tridentata) has been replacing grasslands over the past 100-150 years. We use a process-based coupled atmosphere-vegetation model to investigate the role of this feedback in sustaining shrub encroachment in the region. Simulations indicate that the feedback allows juvenile shrubs to establish in the grassland during average years and, once established, reduce their vulnerability to freeze-induced mortality by creating a warmer microclimate. Such a feedback is crucial in extreme cold winters as it may reduce shrub mortality. We identify the existence of a critical zone in the surroundings of the encroachment front, in which vegetation dynamics are bistable: in this zone, vegetation can be stable both as grassland and as shrubland. The existence of these alternative stable states explains why in most cases the shift from grass to shrub cover is found to be abrupt and often difficult to revert.

Regulation of chromatin architecture by transcription factor binding.

Transcription factors (TF) bind to chromatin and regulate the expression of genes. The pair Myc:Max binds to E-box regulatory DNA elements throughout the genome to control the transcription of a large group of specific genes. We introduce an implicit modeling protocol for Myc:Max binding to mesoscale chromatin fibers at nucleosome resolution to determine TF effect on chromatin architecture and shed light into its mechanism of gene regulation. We first bind Myc:Max to different chromatin locations and show how it can direct fiber folding and formation of microdomains, and how this depends on the linker DNA length. Second, by simulating increasing concentrations of Myc:Max binding to fibers that differ in the DNA linker length, linker histone density, and acetylation levels, we assess the interplay between Myc:Max and other chromatin internal parameters. Third, we study the mechanism of gene silencing by Myc:Max binding to the Eed gene loci. Overall, our results show how chromatin architecture can be regulated by TF binding. The position of TF binding dictates the formation of microdomains that appear visible only at the ensemble level. At the same time, the level of linker histone and tail acetylation, or different linker DNA lengths, regulates the concentration-dependent effect of TF binding. Furthermore, we show how TF binding can repress gene expression by increasing fiber folding motifs that help compact and occlude the promoter region. Importantly, this effect can be reversed by increasing linker histone density. Overall, these results shed light on the epigenetic control of the genome dictated by TF binding.

In Situ Insights into Cathode Calcination for Predictive Synthesis: Kinetic Crystallization of LiNiO2 from Hydroxides.

Calcination is a solid-state synthesis process widely deployed in battery cathode manufacturing. However, its inherent complexity associated with elusive intermediates hinders the predictive synthesis of high-performance cathode materials. Here, correlative in situ X-ray absorption/scattering spectroscopy is used to investigate the calcination of nickel-based cathodes, focusing specifically on the archetypal LiNiO2 from Ni(OH)2. Combining in situ observation with data-driven analysis reveals concurrent lithiation and dehydration of Ni(OH)2 and consequently, the low-temperature crystallization of layered LiNiO2 alongside lithiated rocksalts. Following early nucleation, LiNiO2 undergoes sluggish crystallization and structural ordering while depleting rocksalts; ultimately, it turns into a structurally-ordered layered phase upon full lithiation but remains small in size. Subsequent high-temperature sintering induces rapid crystal growth, accompanied by undesired delithiation and structural degradation. These observations are further corroborated by mesoscale modeling, emphasizing that, even though calcination is thermally driven and favors transformation towards thermodynamically equilibrium phases, the actual phase propagation and crystallization can be kinetically tuned via lithiation, providing freedom for structural and morphological control during cathode calcination.

Mesoscale Modeling of Polymer Concrete Dynamic Properties.

There is a constant need to predict the dynamic properties of composite materials already at the design stage. A particularly attractive tool for achieving this goal is mesoscale finite element modeling. This paper presents the mesoscale modeling of the dynamic properties of polymer concrete. The method is based on finite element modeling and substructural identification. Substructural identification is a model updating technique based on frequency response functions. It enables the identification of model dynamic properties considering damping. The presented method is used to model the dynamic properties of a polymer concrete beam. In the first step, the mesoscale finite element model is built and then it is decoupled into substructures: a polymer matrix, aggregates, and an interfacial transition zone (ITZ). Next, the dynamic properties of the polymer matrix substructure are updated, and the model is reassembled. Then, second-stage updating takes place, which consists of determining the parameters of the aggregates and the ITZ. The use of substructural identification made it possible to determine the parameters of substructures that do not exist in an independent, isolated form like the ITZ. Moreover, it allows for determining the amount of damping that ITZ brings to the structure.

Macro-Mesoscale Modeling of the Evolution of the Surface Roughness of the Al Metallization Layer of an IGBT Module during Power Cycling.

One of the main failure modes of an insulated-gate bipolar transistor (IGBT) module is the reconstruction of an aluminum (Al) metallization layer on the surface of the IGBT chip. In this study, experimental observations and numerical simulations were used to investigate the evolution of the surface morphology of this Al metallization layer during power cycling, and both internal and external factors affecting the surface roughness of the layer were analyzed. The results indicate that the microstructure of the Al metallization layer evolves during power cycling, where the initially flat surface gradually becomes uneven, such that the roughness varies significantly across the IGBT chip surface. The surface roughness depends on several factors, including the grain size, grain orientation, temperature, and stress. With regard to the internal factors, reducing the grain size or orientation differences between neighboring grains can effectively decrease the surface roughness. With regard to the external factors, the reasonable design of the process parameters, a reduction in the stress concentration and temperature hotspots, and preventing large local deformation can also reduce the surface roughness.

Feasibility of Stress Wave-Based Debond Defect Detection for RCFSTs Considering the Influence of Randomly Distributed Circular Aggregates with Mesoscale Homogenization Methodology.

In order to efficiently investigate the effect of the mesoscale heterogeneity of a concrete core and the randomness of circular coarse aggregate distribution on the stress wave propagation procedure and the response of PZT sensors in traditional coupling mesoscale finite element models (CMFEMs), firstly, a mesoscale homogenization approach is introduced to establish coupling homogenization finite element models (CHFEMs) with circular coarse aggregates. CHFEMs of rectangular concrete-filled steel tube (RCFST) members include a surface-mounted piezoelectric lead zirconate titanate (PZT) actuator, PZT sensors at different measurement distances, a concrete core with mesoscale homogeneity. Secondly, the computation efficiency and accuracy of the proposed CHFEMs and the size effect of representative area elements (RAEs) on the stress wave field simulation results are investigated. The stress wave field simulation results indicate that the size of an RAE limitedly affects the stress wave fields. Thirdly, the responses of PZT sensors at different measurement distances of the CHFEMs under both sinusoidal and modulated signals are studied and compared with those of the corresponding CMFEMs. Finally, the effect of the mesoscale heterogeneity of a concrete core and the randomness of circular coarse aggregate distribution on the responses of PZT sensors in the time domain of the CHFEMs with and without debond defects is further investigated. The results show that the mesoscale heterogeneity of a concrete core and randomness of circular coarse aggregate distribution only have a certain influence on the response of PZT sensors that are close to the PZT actuator. Instead, the interface debond defects dominantly affect the response of each PZT sensor regardless of the measurement distance. This finding supports the feasibility of stress wave-based debond detection for RCFSTs where the concrete core is a heterogeneous material.

Mesoscale cycling of organophosphorus flame retardants (OPFRs) in the Bohai Sea and Yellow Sea biotic and abiotic environment: A WRF-CMAQ modeling.

Rapid urbanization and industrialization in the eastern seaboard region of China enhance the widespread use of organophosphorus flame retardants (OPFRs). The present study set up a coupled WRF-CMAQ-SMOKE and multi-compartment exchange modeling framework to assess the environmental fate and cycling of OPFRs and their contamination in the Bohai and Yellow Seas' marine food web. The framework predicts meteorological conditions, optimized air emissions, and concentrations of OPFRs in air, seawaters, marine sediment, and the food web. The model was implemented to simulate the temporal and spatial fluctuations of Tris (2-chloroisopropyl) phosphate (TCPP), the most dominant congener of OPFRs in China, in the Bohai and the Yellow Sea ecosystems on a spatial resolution of 10 km. Results revealed the effects of source proximity, atmospheric transport and deposition, and the changes in meteorology on TCPP's temporal-spatial distribution across different areas of coastal waters. The model also captures TCPP levels in commercial fish species in the Bohai Sea. The detailed temporal-spatial characteristics of TCPP with the mesoscale resolution provide useful information and a new tool for the environmental and health consequences of mariculture, urban and industrial emission mitigation in coastal regions for emerging chemicals, and fishery industry development.

Mesoscale Modeling and Single-Nucleosome Tracking Reveal Remodeling of Clutch Folding and Dynamics in Stem Cell Differentiation.

Nucleosomes form heterogeneous groups in vivo, named clutches. Clutches are smaller and less dense in mouse embryonic stem cells (ESCs) compared to neural progenitor cells (NPCs). Using coarse-grained modeling of the pluripotency Pou5f1 gene, we show that the genome-wide clutch differences between ESCs and NPCs can be reproduced at a single gene locus. Larger clutch formation in NPCs is associated with changes in the compaction and internucleosome contact probability of the Pou5f1 fiber. Using single-molecule tracking (SMT), we further show that the core histone protein H2B is dynamic, and its local mobility relates to the structural features of the chromatin fiber. H2B is less stable and explores larger areas in ESCs compared to NPCs. The amount of linker histone H1 critically affects local H2B dynamics. Our results have important implications for how nucleosome organization and H2B dynamics contribute to regulate gene activity and cell identity.

Nucleosome Clutches are Regulated by Chromatin Internal Parameters.

Nucleosomes cluster together when chromatin folds in the cell to form heterogeneous groups termed "clutches". These structural units add another level of chromatin regulation, for example during cell differentiation. Yet, the mechanisms that regulate their size and compaction remain obscure. Here, using our chromatin mesoscale model, we dissect clutch patterns in fibers with different combinations of nucleosome positions, linker histone density, and acetylation levels to investigate their role in clutch regulation. First, we isolate the effect of each chromatin parameter by studying systems with regular nucleosome spacing; second, we design systems with naturally-occurring linker lengths that fold onto specific clutch patterns; third, we model gene-encoding fibers to understand how these combined factors contribute to gene structure. Our results show how these chromatin parameters act together to produce different-sized nucleosome clutches. The length of nucleosome free regions (NFRs) profoundly affects clutch size, while the length of linker DNA has a moderate effect. In general, higher linker histone densities produce larger clutches by a chromatin compaction mechanism, while higher acetylation levels produce smaller clutches by a chromatin unfolding mechanism. We also show that it is possible to design fibers with naturally-occurring DNA linkers and NFRs that fold onto specific clutch patterns. Finally, in gene-encoding systems, a complex combination of variables dictates a gene-specific clutch pattern. Together, these results shed light into the mechanisms that regulate nucleosome clutches and suggest a new epigenetic mechanism by which chromatin parameters regulate transcriptional activity via the three-dimensional folded state of the genome at a nucleosome level.