Computational Generation of Virtual Concrete Mesostructures

Concrete is a heterogeneous material with a disordered material morphology that strongly governs the behaviour of the material. In this contribution, we present a computational tool called the Concrete Mesostructure Generator (CMG) for the generation of ultra-realistic virtual concrete morphologies for mesoscale and multiscale computational modelling and the simulation of concrete. Given an aggregate size distribution, realistic generic concrete aggregates are generated by a sequential reduction of a cuboid to generate a polyhedron with multiple faces. Thereafter, concave depressions are introduced in the polyhedron using Gaussian surfaces. The generated aggregates are assembled into the mesostructure using a hierarchic random sequential adsorption algorithm. The virtual mesostructures are first calibrated using laboratory measurements of aggregate distributions. The model is validated by comparing the elastic properties obtained from laboratory testing of concrete specimens with the elastic properties obtained using computational homogenisation of virtual concrete mesostructures. Finally, a 3D-convolutional neural network is trained to directly generate elastic properties from voxel data.     

Behavior and mechanics of dense microgel suspensions

Suspensions of soft and highly deformable microgels can be concentrated far more than suspensions of hard colloids, leading to their unusual mechanical properties. Microgels can accommodate compression in suspensions in a variety of ways such as interpenetration, deformation, and shrinking. Previous experiments have offered insightful, but somewhat conflicting, accounts of the behavior of individual microgels in compressed suspensions. We develop a mesoscale computational model to probe the behavior of compressed suspensions consisting of microgels with different architectures at a variety of packing fractions and solvent conditions. We find that microgels predominantly change shape and mildly shrink above random close packing. Interpenetration is only appreciable above space filling, remaining small relative to the mean distance between cross-links. At even higher packing fractions, microgels solely shrink. Remarkably, irrespective of the single-microgel properties, and whether the suspension concentration is changed via changing the particle number density or the swelling state of the particles, which can even result in colloidal gelation, the mechanics of the suspension can be quantified in terms of the single-microgel bulk modulus, which thus emerges as the correct mechanical measure for these type of soft-colloidal suspensions. Our results rationalize the many and varied experimental results, providing insights into the relative importance of effects defining the mechanics of suspensions comprising soft particles.

Microgel suspensions have diverse and rich mechanical behavior (1–10). Their unique character results from the soft and responsive nature of the constituent microgel particles, which are cross-linked polymer networks (11–14) with a typical size between 50 nm and 10 μm (14, 15). The high particle deformability ultimately results from the flexibility of the constituent polymer chains (16, 17), although the distribution and concentration of cross-linkers (15), as well as the particle−particle interactions (18, 19), can have considerable impact.Microgels typically have a relatively low degree of cross-linking and exhibit open structures with high porosity in their swollen state (2, 4, 20, 21). Changes in network-solvent miscibility result in an osmotic pressure imbalance between the inside and outside of the particles (22), which can lead to swelling or deswelling, and an associated change in microgel volume (23–25); variables like temperature, pH, and salt concentration often enable controlling the swelling state of the particles (22, 26–29). Importantly, the resultant changes in volume and internal structure can yield discernable changes in the microgel mechanical properties, which can, in turn, drastically affect the mechanical properties of the suspension. Furthermore, variations in the solvency induce attractive interactions not only between the chains within the microgel but also between the microgel particles themselves (3).Either at sufficiently high particle densities or in the presence of interparticle attraction, microgels in contact can experience different phenomena. One possibility is that the shape of the microgels deviates from the initial spherical shape, due to compression of peripheral polymer chains (5, 30). Alternatively, microgel particles could interpenetrate with their neighbors (10, 31), and/or shrink, particularly at high particle densities (10, 30, 32). However, the instances where each of these effects dominates and effectively controls the suspension behavior, and/or whether they act with comparable importance, remains elusive, in part due to the difficulties associated with experimentally determining the degree of interpenetration and deformation of individual microgels in a given suspension at high particle number densities. There have been, however, attempts at this. For example, atomic force microscopy measurements seem to suggest that microgels experience important shape changes for sufficiently concentrated suspensions, faceting in ways that are reminiscent of droplet deformation in compressed emulsions (5, 7). Meanwhile, recent advances in high-resolution microscopy enable experiments with dyed microgels indicating that microgels first shrink, then interpenetrate/deform, to finally shrink again (31). Additionally, there are studies indicating that microgels mainly shrink with only mild deformation/interpenetration (30, 32).In this paper, we shed light on these widespread behaviors, using computational modeling. We thus scrutinize the behavior of individual microgels at different particle number densities, solvent conditions, and cross-link distributions and concentrations. We further probe how these factors affect the macroscopic mechanical properties of the suspension.     

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 physical packaging of megabase pairs of genomic DNA stored as the chromatin fiber in eukaryotic cell nuclei has been one of the great challenges in biology (1). The limited resolution and disparate levels that can be studied by both experimental and modeling studies of chromatin, which exhibits multiple spatial and temporal scales par excellence, make it challenging to present an integrated structural view, from nucleosomes to chromosomes (2). Because all fundamental template-directed processes of DNA depend on chromatin architecture, advances in our understanding of chromatin higher-order organization are needed to help interpret numerous regulatory events from DNA damage repair to epigenetic control.At the primary structural level, the DNA makes ∼1.7 left-superhelical turns around eight core histones to form a nucleosome core. The nucleosome cores are connected by linker DNA to form nucleosome arrays. An X-ray crystal structure of the nucleosome core has been solved at atomic resolution (3), and a short, four-nucleosome array has also been solved (4). Next, at the secondary structural level, the nucleosome arrays, aided by linker histones (H1 or H5), form a compact chromatin fiber with a diameter of ∼30 nm and longitudinal compaction of 5–7 nucleosomes per 11 nm (5–8). However, evidence for 30-nm fibers in interphase nuclei of living cells has been controversial (reviewed in refs. 9 and 10). For example, whereas a distinct 30-nm fiber architecture is observed in terminally differentiated cells (11, 12), neither continuous nor periodic 30-nm fibers are observed in the nuclei of proliferating cells (13–15). However, zigzag features of the chromatin fibers are well supported by nucleosome interaction mapping in vitro (16) and in vivo (15).For chromatin architecture within metaphase chromosomes, fluorescence studies of mitotic chromosome condensation in vivo (17), cryo-EM observations of unfixed and unstained chromosomes in situ (18), and small-angle X-ray scattering (19) show no structures resembling folded 30-nm fibers and instead suggest random folding of soft polymers. Evidence is also accumulating that during chromosome condensation in mitosis, chromatin higher-order structure is dramatically altered at the global level (20) by significant increase in looping (21). A random type of looping, however, cannot explain sharp chromosomal boundaries separating the translocated genomic regions in metaphase chromosomes (22) as well as formation of highly localized fibers of transgenic DNA, up to 250 nm in diameter, detected by fluorescence imaging in vivo (17). In contrast, a hierarchical or layered looping could explain the above aspects of chromosome organization; in addition, it could help reconcile the experiments in living cells with in vitro data and determine which aspects of the secondary structure are retained in the metaphase chromosome and how these features correlate with the polymer melt model (18, 23).Here we apply the EM-assisted nucleosome interaction capture (EMANIC) technique, which captures nearest-neighbor interactions in combination with mesoscale modeling of chromatin fibers (16) to deduce chromatin architecture in interphase nuclei and metaphase chromosomes. Our results reveal persistence of the zigzag geometry as a dominant architectural motif in these types of chromatin. For metaphase chromosomes, we report a dramatic increase in longer-range interactions, consistent with intrafiber looping, quite different from that seen in compact chromatin fibers in vitro and interphase chromatin in vivo. Modeling also shows hierarchical looping for long fibers, with the loop occurrence strongly modulated by the density of linker histones. Such looping of loosely folded zigzag arrays appears to be an efficient mechanism for both condensing and unraveling the genomic material. Our hierarchical looping mechanism can also explain how distant regulatory DNA sites can be brought together naturally for genic interactions and how linker histone levels and epigenetic histone modifications can further modulate global and local chromatin architecture.     

Random Material Property Fields of 3D Concrete Microstructures Based on CT Image Reconstruction

The purpose of this paper is to determine the random spatially varying elastic properties of concrete at various scales taking into account its highly heterogeneous microstructure. The reconstruction of concrete microstructure is based on computed tomography (CT) images of a cubic concrete specimen. The variability of the local volume fraction of the constituents (pores, cement paste and aggregates) is quantified and mesoscale random fields of the elasticity tensor are computed from a number of statistical volume elements obtained by applying the moving window method on the specimen along with computational homogenization. Based on the statistical characteristics of the mesoscale random fields, it is possible to assess the effect of randomness in microstructure on the mechanical behavior of concrete.     

Mesoscale Process Modeling of a Thick Pultruded Composite with Variability in Fiber Volume Fraction

Pultruded fiber-reinforced polymer composites are susceptible to microstructural nonuniformity such as variability in fiber volume fraction (Vf), which can have a profound effect on process-induced residual stress. Until now, this effect of non-uniform Vf distribution has been hardly addressed in the process models. In the present study, we characterized the Vf distribution and accompanying nonuniformity in a unidirectional fiber-reinforced pultruded profile using optical light microscopy. The identified nonuniformity in Vf was subsequently implemented in a mesoscale thermal–chemical–mechanical process model, developed explicitly for the pultrusion process. In our process model, the constitutive material behavior was defined locally with respect to the corresponding fiber volume fraction value in different-sized representative volume elements. The effect of nonuniformity on the temperature and cure degree evolution, and residual stress was analyzed in depth. The results show that the nonuniformity in fiber volume fraction across the cross-section increased the absolute magnitude of the predicted residual stress, leading to a more scattered residual stress distribution. The observed Vf gradient promotes tensile residual stress at the core and compressive residual stress at the outer regions. Consequently, it is concluded that it is essential to take the effects of nonuniformity in fiber distribution into account for residual stress estimations, and the proposed numerical framework was found to be an efficient tool to study this aspect.     

A phase 1 antigen dose escalation trial to evaluate safety,tolerability and immunogenicity of the leprosy vaccine candidate LepVax (LEP-F1 + GLA–SE) in healthy adults

Healthy United States-based adult volunteers with no history of travel to leprosy-endemic countries were enrolled for the first-in-human evaluation of LepVax (LEP-F1 + GLA-SE). In total 24 volunteers participated in an open-label clinical trial, with 21 receiving three injections of LepVax consisting of either 2 µg or 10 µg recombinant polyprotein LEP-F1 mixed with 5 µg of the GLA-SE adjuvant formulation. LepVax doses were provided by intramuscular injection on Days 0, 28, and 56, and safety was evaluated for one year following the final injection. LepVax was safe and well tolerated at both antigen doses. Immunological analyses indicated that similar LEP-F1-specific antibody and Th1 cytokine secretion (IFN-γ, IL-2, TNF) were induced by each of the antigen doses evaluated within LepVax. This clinical trial of the first defined vaccine candidate for leprosy demonstrates that LepVax is safe and immunogenic in healthy subjects and supports its advancement to testing in leprosy-endemic regions.     

Chasing the Dreams of Early Connectionists

Mapping and examining the wiring pattern of neural systems is a fundamental pillar of neuroscience. In this Viewpoint, we review a recently described mesoscale connectome map of the mouse brain. We underscore the map’s high spatial resolution and discuss key organizational network attributes of the presented connectome, its potential impact on neuroscience, and the general importance of connectome maps to obtain insight in the workings of the brain at a system’s level.     

Uncovering pathways in DNA oligonucleotide hybridization via transition state analysis

DNA hybridization plays a central role in biology and, increasingly, in materials science. Yet, there is no precedent for examining the pathways by which specific single-stranded DNA sequences interact to assemble into a double helix. A detailed model of DNA is adopted in this work to examine such pathways and to determine the role of sequence, if any, on DNA hybridization. Transition path sampling simulations reveal that DNA rehybridization is prompted by a distinct nucleation event involving molecular sites with approximately four bases pairing with partners slightly offset from those involved in ideal duplexation. Nucleation is promoted in regions with repetitive base pair sequence motifs, which yield multiple possibilities for finding complementary base partners. Repetitive sequences follow a nonspecific pathway to renaturation consistent with a molecular “slithering” mechanism, whereas random sequences favor a restrictive pathway involving the formation of key base pairs before renaturation fully ensues.     

Mesoscale texture of cement hydrates

Strength and other mechanical properties of cement and concrete rely upon the formation of calcium–silicate–hydrates (C–S–H) during cement hydration. Controlling structure and properties of the C–S–H phase is a challenge, due to the complexity of this hydration product and of the mechanisms that drive its precipitation from the ionic solution upon dissolution of cement grains in water. Departing from traditional models mostly focused on length scales above the micrometer, recent research addressed the molecular structure of C–S–H. However, small-angle neutron scattering, electron-microscopy imaging, and nanoindentation experiments suggest that its mesoscale organization, extending over hundreds of nanometers, may be more important. Here we unveil the C–S–H mesoscale texture, a crucial step to connect the fundamental scales to the macroscale of engineering properties. We use simulations that combine information of the nanoscale building units of C–S–H and their effective interactions, obtained from atomistic simulations and experiments, into a statistical physics framework for aggregating nanoparticles. We compute small-angle scattering intensities, pore size distributions, specific surface area, local densities, indentation modulus, and hardness of the material, providing quantitative understanding of different experimental investigations. Our results provide insight into how the heterogeneities developed during the early stages of hydration persist in the structure of C–S–H and impact the mechanical performance of the hardened cement paste. Unraveling such links in cement hydrates can be groundbreaking and controlling them can be the key to smarter mix designs of cementitious materials.Upon dissolution of cement powder in water, calcium–silicate–hydrates (C–S–H) precipitate and assemble into a cohesive gel that fills the pore space in the cement paste over hundreds of nanometers and binds the different components of concrete together (1). The mechanics and microstructure are key to concrete performance and durability, but the level of understanding needed to design new, more performant cements and have an impact on the CO₂ footprint of the material is far from being reached (2).Most of the experimental characterization and models used to predict and design cement performance have been developed at a macroscopic level and hardly include any material heterogeneity over length scales smaller than micrometers (3). However, EM imaging, nanoindentation tests, X-rays and neutron scattering, and NMR analysis as well as atomistic simulations have now elucidated several structural and mechanical features concentrated within a few nanometers (4–8). The hygrothermal behavior of cement suggests a hierarchical and complex pore structure that develops during hydration and continues to evolve (1, 9–11). NMR and small-angle neutron scattering (SANS) studies of hardened C–S–H identified distinctive features of the complex pore network and detected significant structural heterogeneities spanning length scales between tens and hundreds of nanometers (12–14). Nanoindentation experiments have highlighted structural and mechanical heterogeneities over the same length scales (15). Their findings suggested that the internal stresses developed over those length scales during setting may be responsible for delayed nonlinear deformations, such as creep, that ultimately lead to major obstacles when designing the material properties and controlling the durability. Despite these advancements, the link between the nanoscale observations and the macroscale models currently used to predict and design cement performance is missing. Hence, to match the experimental observations, those models use ad hoc assumptions that cannot be independently tested or validated. Providing new quantitative information on the mesoscale texture of cement hydrates and how it may impact the material properties is the conundrum.Here, we use a statistical physics approach to gain insight into the C–S–H at the scale of hundreds of nanometers based on the knowledge developed at the nanoscale. In our model, the complex pore network and the structural heterogeneities naturally emerge from the short-range cohesive interactions typical of nanoscale cement hydrates and the nonequilibrium conditions under which C–S–H densifies during cement setting. The scattering intensity, pore size distribution (PSD), surface area, local volume fractions, indentation modulus, and hardness measured in the simulations are compared with experiments and provide a first, to our knowledge, consistent characterization of the elusive mesoscale structure of C–S–H.