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Capillary droplets form due to surface tension when two immiscible fluids are mixed. We describe the motion of gravity-driven capillary droplets flowing through narrow constrictions and obstacle arrays in both simulations and experiments. Our new capillary deformable particle model recapitulates the shape and velocity of single oil droplets in water as they pass through narrow constrictions in microfluidic chambers. Using this experimentally validated model, we simulate the flow and clogging of single capillary droplets in narrow channels and obstacle arrays and find several important results. First, the capillary droplet speed profile is nonmonotonic as the droplet exits the narrow orifice, and we can tune the droplet properties so that the speed overshoots the terminal speed far from the constriction. Second, in obstacle arrays, we find that extremely deformable droplets can wrap around obstacles, which leads to decreased average droplet speed in the continuous flow regime and increased probability for clogging in the regime where permanent clogs form. Third, the wrapping mechanism causes the clogging probability in obstacle arrays to become nonmonotonic with surface tension Γ . At large Γ , the droplets are nearly rigid and the clogging probability is large since the droplets can not squeeze through the gaps between obstacles. With decreasing Γ , the clogging probability decreases as the droplets become more deformable. However, in the small- Γ limit, the clogging probability increases since the droplets are extremely deformable and wrap around the obstacles. The results from these studies are important for developing a predictive understanding of capillary droplet flows through complex and confined geometries.

Proteins naturally occur in crowded cellular environments and interact with other proteins, nucleic acids, and organelles. Since most previous experimental protein structure determination techniques require that proteins occur in idealized, non-physiological environments, the effects of realistic cellular environments on protein structure are largely unexplored. Recently, Förster resonance energy transfer (FRET) has been shown to be an effective experimental method for investigating protein structure in vivo . Inter-residue distances measured in vivo can be incorporated as restraints in molecular dynamics (MD) simulations to model protein structural dynamics in vivo . Since most FRET studies only obtain inter-residue separations for a small number of amino acid pairs, it is important to determine the minimum number of restraints in the MD simulations that are required to achieve a given root-mean-square deviation (RMSD) from the experimental structural ensemble. Further, what is the optimal method for selecting these inter-residue restraints? Here, we implement several methods for selecting the most important FRET pairs and determine the number of pairs N r that are needed to induce conformational changes in proteins between two experimentally determined structures. We find that enforcing only a small fraction of restraints, N r / N ≲ 0.08 , where N is the number of amino acids, can induce the conformational changes. These results establish the efficacy of FRET-assisted MD simulations for atomic scale structural modeling of proteins in vivo ., Competing Interests: Conflict of interest statement: The authors declare no conflicts of interests.

Chromatin is a polymer complex of DNA and proteins that regulates gene expression. The three-dimensional (3D) structure and organization of chromatin controls DNA transcription and replication. High-throughput chromatin conformation capture techniques generate Hi-C maps that can provide insight into the 3D structure of chromatin. Hi-C maps can be represented as a symmetric matrix [Formula: see text], where each element represents the average contact probability or number of contacts between chromatin loci i and j. Previous studies have detected topologically associating domains (TADs), or self-interacting regions in [Formula: see text] within which the contact probability is greater than that outside the region. Many algorithms have been developed to identify TADs within Hi-C maps. However, most TAD identification algorithms are unable to identify nested or overlapping TADs and for a given Hi-C map there is significant variation in the location and number of TADs identified by different methods. We develop a novel method to identify TADs, KerTAD, using a kernel-based technique from computer vision and image processing that is able to accurately identify nested and overlapping TADs. We benchmark this method against state-of-the-art TAD identification methods on both synthetic and experimental data sets. We find that the new method consistently has higher true positive rates (TPR) and lower false discovery rates (FDR) than all tested methods for both synthetic and manually annotated experimental Hi-C maps. The TPR for KerTAD is also largely insensitive to increasing noise and sparsity, in contrast to the other methods. We also find that KerTAD is consistent in the number and size of TADs identified across replicate experimental Hi-C maps for several organisms. Thus, KerTAD will improve automated TAD identification and enable researchers to better correlate changes in TADs to biological phenomena, such as enhancer-promoter interactions and disease states., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Maisuradze et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Breast cancer invasion into adipose tissue strongly influences disease progression and metastasis. The degree of cancer cell invasion into adipose tissue depends on both biochemical signaling and the mechanical properties of cancer cells, adipocytes, and other key components of adipose tissue. We model breast cancer invasion into adipose tissue using discrete element method simulations of active, cohesive spherical particles (cancer cells) invading into confluent packings of deformable polyhedra (adipocytes). We quantify the degree of invasion by calculating the interfacial area A t between cancer cells and adipocytes. We determine the long-time value of A t vs the activity and strength of the cohesion between cancer cells, as well as the mechanical properties of the adipocytes and extracellular matrix in which adipocytes are embedded. We show that the degree of invasion collapses onto a master curve as a function of the dimensionless energy scale E c , which grows linearly with the cancer cell velocity persistence time and fluctuations, is inversely proportional to the system pressure, and is offset by the cancer cell cohesive energy. When E c > 1 , cancer cells will invade the adipose tissue, whereas for E c < 1 , cancer cells and adipocytes remain de-mixed. We also show that A t decreases when the adipocytes are constrained by the ECM by an amount that depends on the spatial heterogeneity of the adipose tissue., Competing Interests: The authors have no conflicts to disclose., (© 2024 Author(s).)

Swarming is a macroscopic phenomenon in which surface bacteria organize into a motile population. The flagellar motor that drives swarming in Pseudomonas aeruginosa is powered by stators MotAB and MotCD. Deletion of the MotCD stator eliminates swarming, whereas deletion of the MotAB stator enhances swarming. Interestingly, we measured a strongly asymmetric stator availability in the wild-type (WT) strain, with MotAB stators produced at an approximately 40-fold higher level than MotCD stators. However, utilization of MotCD stators in free swimming cells requires higher liquid viscosities, while MotAB stators are readily utilized at low viscosities. Importantly, we find that cells with MotCD stators are ~10× more likely to have an active motor compared to cells uses the MotAB stators. The spectrum of motility intermittency can either cooperatively shut down or promote flagellum motility in WT populations. In P. aeruginosa , transition from a static solid-like biofilm to a dynamic liquid-like swarm is not achieved at a single critical value of flagellum torque or stator fraction but is collectively controlled by diverse combinations of flagellum activities and motor intermittencies via dynamic stator utilization. Experimental and computational results indicate that the initiation or arrest of flagellum-driven swarming motility does not occur from individual fitness or motility performance but rather related to concepts from the "jamming transition" in active granular matter.IMPORTANCEIt is now known that there exist multifactorial influences on swarming motility for P. aeruginosa , but it is not clear precisely why stator selection in the flagellum motor is so important. We show differential production and utilization of the stators. Moreover, we find the unanticipated result that the two motor configurations have significantly different motor intermittencies: the fraction of flagellum-active cells in a population on average with MotCD is active ~10× more often than with MotAB. What emerges from this complex landscape of stator utilization and resultant motor output is an intrinsically heterogeneous population of motile cells. We show how consequences of stator recruitment led to swarming motility and how the stators potentially relate to surface sensing circuitry., Competing Interests: The authors declare no conflict of interest.

Previous studies have shown that the interiors of proteins are densely packed, reaching packing fractions that are as large as those found for static packings of individual amino-acid-shaped particles. How can the interiors of proteins take on such high packing fractions given that amino acids are connected by peptide bonds and many amino acids are hydrophobic with attractive interactions? We investigate this question by comparing the structural and mechanical properties of collapsed attractive disk-shaped bead-spring polymers to those of three reference systems: static packings of repulsive disks, of attractive disks, and of repulsive disk-shaped bead-spring polymers. We show that the attractive systems quenched to temperatures below the glass transition T≪T&#95;{g} and static packings of both repulsive disks and bead-spring polymers possess similar interior packing fractions. Previous studies have shown that static packings of repulsive disks are isostatic at jamming onset, i.e., the number of interparticle contacts N&#95;{c} matches the number of degrees of freedom, which strongly influences their mechanical properties. We find that repulsive polymer packings are hypostatic at jamming onset (i.e., with fewer contacts than degrees of freedom) but are effectively isostatic when including stabilizing quartic modes, which give rise to quartic scaling of the potential energy with displacements along these modes. While attractive disk and polymer packings are often considered hyperstatic with excess contacts over the isostatic number, we identify a definition for interparticle contacts for which they can also be considered as effectively isostatic. As a result, we show that the mechanical properties (e.g., scaling of the potential energy with excess contact number and low-frequency contribution to the density of vibrational modes) of weakly attractive disk and polymer packings are similar to those of isostatic repulsive disk and polymer packings. Our results demonstrate that static packings generated via attractive collapse or compression of repulsive particles possess similar structural and mechanical properties.

The mechanical properties of CuTi alloys have been characterized extensively through experimental studies. However, a detailed understanding of why the strength of Cu increases after a small fraction of Ti atoms are added to the alloy is still missing. In this work, we address this question using density functional theory (DFT) and molecular dynamics (MD) simulations with the modified embedded atom method (MEAM) interatomic potentials. First, we performed calculations of the uniaxial tension deformations of small bicrystalline Cu cells using DFT static simulations. We then carried out uniaxial tension deformations on much larger bicrystalline and polycrystalline Cu cells by using MEAM MD simulations. In bicrystalline Cu, the inclusion of Ti increases the grain boundary separation energy and the maximum tensile stress. The DFT calculations demonstrate that the increase in the tensile stress can be attributed to an increase in the local charge density arising from Ti. MEAM simulations in larger bicrystalline systems have shown that increasing the Ti concentration decreases the density of the stacking faults. This observation is enhanced in polycrystalline Cu, where the addition of Ti atoms, even at concentrations as low as 1.5 atomic (at.) %, increases the yield strength and elastic modulus of the material compared to pure Cu. Under uniaxial tensile loading, the addition of small amounts of Ti hinders the formation of partial Shockley dislocations in the grain boundaries of Cu, leading to a reduced level of local deformation. These results shed light on the role of Ti in determining the mechanical properties of polycrystalline Cu and enable the engineering of grain boundaries and the inclusion of Ti to improve degradation resistance., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Jammed packings of granular materials display complex mechanical response. For example, the ensemble-averaged shear modulus 〈G〉 increases as a power law in pressure p for static packings of soft spherical particles that can rearrange during compression. We seek to design granular materials with shear moduli that can either increase or decrease with pressure without particle rearrangements even in the large-system limit. To do this, we construct tessellated granular metamaterials by joining multiple particle-filled cells together. We focus on cells that contain a small number of bidisperse disks in two dimensions. We first study the mechanical properties of individual disk-filled cells with three types of boundaries: periodic boundary conditions (PBC), fixed-length walls (FXW), and flexible walls (FLW). Hypostatic jammed packings are found for cells with FLW, but not in cells with PBC and FXW, and they are stabilized by quartic modes of the dynamical matrix. The shear modulus of a single cell depends linearly on p. We find that the slope of the shear modulus with pressure λ&#95;{c}<0 for all packings in single cells with PBC where the number of particles per cell N≥6. In contrast, single cells with FXW and FLW can possess λ&#95;{c}>0, as well as λ&#95;{c}<0, for N≤16. We show that we can force the mechanical properties of multicell granular metamaterials to possess those of single cells by constraining the end points of the outer walls and enforcing an affine shear response. These studies demonstrate that tessellated granular metamaterials provide a platform for the design of soft materials with specified mechanical properties.

Strain-controlled isotropic compression gives rise to jammed packings of repulsive, frictionless disks with either positive or negative global shear moduli. We carry out computational studies to understand the contributions of the negative shear moduli to the mechanical response of jammed disk packings. We first decompose the ensemble-averaged, global shear modulus as 〈G〉=(1-F&#95;{-})〈G&#95;{+}〉+F&#95;{-}〈G&#95;{-}〉, where F&#95;{-} is the fraction of jammed packings with negative shear moduli and 〈G&#95;{+}〉 and 〈G&#95;{-}〉 are the average values from packings with positive and negative moduli, respectively. We show that 〈G&#95;{+}〉 and 〈|G&#95;{-}|〉 obey different power-law scaling relations above and below pN^{2}∼1. For pN^{2}>1, both 〈G&#95;{+}〉N and 〈|G&#95;{-}|〉N∼(pN^{2})^{β}, where β∼0.5 for repulsive linear spring interactions. Despite this, 〈G〉N∼(pN^{2})^{β^{'}} with β^{'}≳0.5 due to the contributions from packings with negative shear moduli. We show further that the probability distribution of global shear moduli P(G) collapses at fixed pN^{2} and different values of p and N. We calculate analytically that P(G) is a Γ distribution in the pN^{2}≪1 limit. As pN^{2} increases, the skewness of P(G) decreases and P(G) becomes a skew-normal distribution with negative skewness in the pN^{2}≫1 limit. We also partition jammed disk packings into subsystems using Delaunay triangulation of the disk centers to calculate local shear moduli. We show that the local shear moduli defined from groups of adjacent triangles can be negative even when G>0. The spatial correlation function of local shear moduli C(r[over ⃗]) displays weak correlations for pn&#95;{sub}^{2}<10^{-2}, where n&#95;{sub} is the number of particles within each subsystem. However, C(r[over ⃗]) begins to develop long-ranged spatial correlations with fourfold angular symmetry for pn&#95;{sub}^{2}≳10^{-2}.

The spongy mesophyll is a complex, porous tissue found in plant leaves that enables carbon capture and provides mechanical stability. Unlike many other biological tissues, which remain confluent throughout development, the spongy mesophyll must develop from an initially confluent tissue into a tortuous network of cells with a large proportion of intercellular airspace. How the airspace in the spongy mesophyll develops while the tissue remains mechanically stable is unknown. Here, we use computer simulations of deformable polygons to develop a purely mechanical model for the development of the spongy mesophyll tissue. By stipulating that cell wall growth and remodelling occurs only near void space, our computational model is able to recapitulate spongy mesophyll development observed in Arabidopsis thaliana leaves. We find that robust generation of pore space in the spongy mesophyll requires a balance of cell growth, adhesion, stiffness and tissue pressure to ensure cell networks become porous yet maintain mechanical stability. The success of this mechanical model of morphogenesis suggests that simple physical principles can coordinate and drive the development of complex plant tissues like the spongy mesophyll.

Numerous experimental and computational studies show that continuous hopper flows of granular materials obey the Beverloo equation that relates the volume flow rate Q and the orifice width w : Q ∼ ( w / σ avg - k ) β , where σ avg is the average particle diameter, kσ avg is an offset where Q ∼ 0, the power-law scaling exponent β = d - 1/2, and d is the spatial dimension. Recent studies of hopper flows of deformable particles in different background fluids suggest that the particle stiffness and dissipation mechanism can also strongly affect the power-law scaling exponent β . We carry out computational studies of hopper flows of deformable particles with both kinetic friction and background fluid dissipation in two and three dimensions. We show that the exponent β varies continuously with the ratio of the viscous drag to the kinetic friction coefficient, λ = ζ / μ . β = d - 1/2 in the λ → 0 limit and d - 3/2 in the λ → ∞ limit, with a midpoint λ c that depends on the hopper opening angle θ w . We also characterize the spatial structure of the flows and associate changes in spatial structure of the hopper flows to changes in the exponent β . The offset k increases with particle stiffness until k ∼ k max in the hard-particle limit, where k max ∼ 3.5 is larger for λ → ∞ compared to that for λ → 0. Finally, we show that the simulations of hopper flows of deformable particles in the λ → ∞ limit recapitulate the experimental results for quasi-2D hopper flows of oil droplets in water.

The Integrated Graduate Program in Physical and Engineering Biology (IGPPEB) at Yale University brings together Ph.D. students from the physical, engineering, and biological sciences. The main goals of this program are for students to become comfortable working in an interdisciplinary and collaborative research environment and adept at communicating with scientists and nonscientists. To fill a student-identified learning gap in engaging in inclusive discussions, IGPPEB students developed a communication workshop to improve skills in visual engagement, citing specific content, constructive conversation entrances, and encouragement of peers. Based on short- and long-term assessment of the workshop, 100% of students reported that it should be offered to future cohorts and 63% of students perceived it to be personally helpful. Additionally, 92% of participants reported using one or more of the core skills beyond the course, with skills in "Encouraging peers" and "Constructive conversation entrances" rated the highest in perceived improvement. Based on the highest average rating of 76 ± 24 (on a scale of 0-100), students agreed that the workshop made them feel more welcome in the IGPPEB community. With a rating of 68 ± 13, they also agreed that the workshop had a positive impact on their graduate school experience. Participants provided suggestions for future improvements, such as increasing student involvement in leading discussions of course material. This study demonstrates that a student-led workshop can improve perceived discussion skills and build community across an interdisciplinary program in the sciences., Competing Interests: The authors have stated explicitly that there are no conflicts of interest in connection with this article., (©2022 The Authors FASEB BioAdvances published by The Federation of American Societies for Experimental Biology.)

Numerous studies have investigated the differences and similarities between protein structures determined by solution NMR spectroscopy and those determined by X-ray crystallography. A fundamental question is whether any observed differences are due to differing methodologies or to differences in the behavior of proteins in solution versus in the crystalline state. Here, we compare the properties of the hydrophobic cores of high-resolution protein crystal structures and those in NMR structures, determined using increasing numbers and types of restraints. Prior studies have reported that many NMR structures have denser cores compared with those of high-resolution X-ray crystal structures. Our current work investigates this result in more detail and finds that these NMR structures tend to violate basic features of protein stereochemistry, such as small non-bonded atomic overlaps and few Ramachandran and sidechain dihedral angle outliers. We find that NMR structures solved with more restraints, and which do not significantly violate stereochemistry, have hydrophobic cores that have a similar size and packing fraction as their counterparts determined by X-ray crystallography at high resolution. These results lead us to conclude that, at least regarding the core packing properties, high-quality structures determined by NMR and X-ray crystallography are the same, and the differences reported earlier are most likely a consequence of methodology, rather than fundamental differences between the protein in the two different environments., (© 2022 The Protein Society.)

We investigate the structural, vibrational, and mechanical properties of jammed packings of deformable particles with shape degrees of freedom in three dimensions (3D). Each 3D deformable particle is modeled as a surface-triangulated polyhedron, with spherical vertices whose positions are determined by a shape-energy function with terms that constrain the particle surface area, volume, and curvature, and prevent interparticle overlap. We show that jammed packings of deformable particles without bending energy possess low-frequency, quartic vibrational modes, whose number decreases with increasing asphericity and matches the number of missing contacts relative to the isostatic value. In contrast, jammed packings of deformable particles with non-zero bending energy are isostatic in 3D, with no quartic modes. We find that the contributions to the eigenmodes of the dynamical matrix from the shape degrees of freedom are significant over the full range of frequency and shape parameters for particles with zero bending energy. We further show that the ensemble-averaged shear modulus 〈 G 〉 scales with pressure P as 〈 G 〉 ∼ P β , with β ≈ 0.75 for jammed packings of deformable particles with zero bending energy. In contrast, β ≈ 0.5 for packings of deformable particles with non-zero bending energy, which matches the value for jammed packings of soft, spherical particles with fixed shape. These studies underscore the importance of incorporating particle deformability and shape change when modeling the properties of jammed soft materials.

We investigate the non-affine displacement fields that occur in two-dimensional Lennard-Jones models of metallic glasses subjected to athermal, quasistatic simple shear (AQS). During AQS, the shear stress versus strain displays continuous quasi-elastic segments punctuated by rapid drops in shear stress, which correspond to atomic rearrangement events. We capture all information concerning the atomic motion during the quasi-elastic segments and shear stress drops by performing Delaunay triangularizations and tracking the deformation gradient tensor F α associated with each triangle α . To understand the spatio-temporal evolution of the displacement fields during shear stress drops, we calculate F α along minimal energy paths from the mechanically stable configuration immediately before to that after the stress drop. We find that quadrupolar displacement fields form and dissipate both during the quasi-elastic segments and shear stress drops. We then perform local perturbations (rotation, dilation, simple and pure shear) to single triangles and measure the resulting displacement fields. We find that local pure shear deformations of single triangles give rise to mostly quadrupolar displacement fields, and thus pure shear strain is the primary type of local strain that is activated by bulk, athermal quasistatic simple shear. Other local perturbations, e.g. rotations, dilations, and simple shear of single triangles, give rise to vortex-like and dipolar displacement fields that are not frequently activated by bulk AQS. These results provide fundamental insights into the non-affine atomic motion that occurs in driven, glassy materials.

We investigate the mechanical response of jammed packings of circulo-lines in two spatial dimensions, interacting via purely repulsive, linear spring forces, as a function of pressure P during athermal, quasistatic isotropic compression. The surface of a circulo-line is defined as the collection of points that is equidistant to a line; circulo-lines are composed of a rectangular central shaft with two semicircular end caps. Prior work has shown that the ensemble-averaged shear modulus for jammed disk packings scales as a power law, 〈G(P)〉∼P^{β}, with β∼0.5, over a wide range of pressure. For packings of circulo-lines, we also find robust power-law scaling of 〈G(P)〉 over the same range of pressure for aspect ratios R≳1.2. However, the power-law scaling exponent β∼0.8-0.9 is much larger than that for jammed disk packings. To understand the origin of this behavior, we decompose 〈G〉 into separate contributions from geometrical families, G&#95;{f}, and from changes in the interparticle contact network, G&#95;{r}, such that 〈G〉=〈G&#95;{f}〉+〈G&#95;{r}〉. We show that the shear modulus for low-pressure geometrical families for jammed packings of circulo-lines can both increase and decrease with pressure, whereas the shear modulus for low-pressure geometrical families for jammed disk packings only decreases with pressure. For this reason, the geometrical family contribution 〈G&#95;{f}〉 is much larger for jammed packings of circulo-lines than for jammed disk packings at finite pressure, causing the increase in the power-law scaling exponent for 〈G(P)〉.

Functional particles that respond to external stimuli are spurring technological evolution across various disciplines. While large-scale production of functional particles is needed for their use in real-life applications, precise control over particle shapes and directional properties has remained elusive for high-throughput processes. We developed a high-throughput emulsion-based process that exploits rapid vitrification of a thixotropic medium to manufacture diverse functional particles in large quantities. The vitrified medium renders stationary emulsion droplets that preserve their shape and size during solidification, and energetic fields can be applied to build programmed anisotropy into the particles. We showcase mass-production of several functional particles, including low-melting point metallic particles, self-propelling Janus particles, and unidirectionally-magnetized robotic particles, via this static-state particle fabrication process.

We investigate the mechanical response of jammed packings of repulsive, frictionless spherical particles undergoing isotropic compression. Prior simulations of the soft-particle model, where the repulsive interactions scale as a power law in the interparticle overlap with exponent α, have found that the ensemble-averaged shear modulus 〈G(P)〉 increases with pressure P as ∼P^{(α-3/2)/(α-1)} at large pressures. 〈G〉 has two key contributions: (1) continuous variations as a function of pressure along geometrical families, for which the interparticle contact network does not change, and (2) discontinuous jumps during compression that arise from changes in the contact network. Using numerical simulations, we show that the form of the shear modulus G^{f} for jammed packings within near-isostatic geometrical families is largely determined by the affine response G^{f}∼G&#95;{a}^{f}, where G&#95;{a}^{f}/G&#95;{a0}=(P/P&#95;{0})^{(α-2)/(α-1)}-P/P&#95;{0}, P&#95;{0}∼N^{-2(α-1)} is the characteristic pressure at which G&#95;{a}^{f}=0, G&#95;{a0} is a constant that sets the scale of the shear modulus, and N is the number of particles. For near-isostatic geometrical families that persist to large pressures, deviations from this form are caused by significant nonaffine particle motion. We further show that the ensemble-averaged shear modulus 〈G(P)〉 is not simply a sum of two power laws, but 〈G(P)〉∼(P/P&#95;{c})^{a}, where a≈(α-2)/(α-1) in the P→0 limit and 〈G(P)〉∼(P/P&#95;{c})^{b}, where b≳(α-3/2)/(α-1), above a characteristic pressure that scales as P&#95;{c}∼N^{-2(α-1)}.

Many experiments over the past half century have shown that, for a range of protocols, granular materials compact under pressure and repeated small disturbances. A recent experiment on cyclically sheared spherical grains showed significant compaction via homogeneous crystallization (Rietz et al., 2018). Here we present numerical simulations of frictionless, purely repulsive spheres undergoing cyclic simple shear via Newtonian dynamics with linear viscous drag at fixed vertical load. We show that for sufficiently small strain amplitudes, cyclic shear gives rise to homogeneous crystallization at a volume fraction ϕ=0.646±0.001. This result indicates that neither friction nor gravity is essential for homogeneous crystallization in driven granular media. Understanding how crystal formation is initiated within a homogeneous disordered state gives key insights into the old open problem of glass formation in fluids.

We investigate the mechanical response of packings of purely repulsive, frictionless disks to quasistatic deformations. The deformations include simple shear strain at constant packing fraction and at constant pressure, "polydispersity" strain (in which we change the particle size distribution) at constant packing fraction and at constant pressure, and isotropic compression. For each deformation, we show that there are two classes of changes in the interparticle contact networks: jump changes and point changes. Jump changes occur when a contact network becomes mechanically unstable, particles "rearrange", and the potential energy (when the strain is applied at constant packing fraction) or enthalpy (when the strain is applied at constant pressure) and all derivatives are discontinuous. During point changes, a single contact is either added to or removed from the contact network. For repulsive linear spring interactions, second- and higher-order derivatives of the potential energy/enthalpy are discontinuous at a point change, while for Hertzian interactions, third- and higher-order derivatives of the potential energy/enthalpy are discontinuous. We illustrate the importance of point changes by studying the transition from a hexagonal crystal to a disordered crystal induced by applying polydispersity strain. During this transition, the system only undergoes point changes, with no jump changes. We emphasize that one must understand point changes, as well as jump changes, to predict the mechanical properties of jammed packings.

There have been several studies suggesting that protein structures solved by NMR spectroscopy and X-ray crystallography show significant differences. To understand the origin of these differences, we assembled a database of high-quality protein structures solved by both methods. We also find significant differences between NMR and crystal structures-in the root-mean-square deviations of the C α atomic positions, identities of core amino acids, backbone, and side-chain dihedral angles, and packing fraction of core residues. In contrast to prior studies, we identify the physical basis for these differences by modeling protein cores as jammed packings of amino acid-shaped particles. We find that we can tune the jammed packing fraction by varying the degree of thermalization used to generate the packings. For an athermal protocol, we find that the average jammed packing fraction is identical to that observed in the cores of protein structures solved by X-ray crystallography. In contrast, highly thermalized packing-generation protocols yield jammed packing fractions that are even higher than those observed in NMR structures. These results indicate that thermalized systems can pack more densely than athermal systems, which suggests a physical basis for the structural differences between protein structures solved by NMR and X-ray crystallography., (© 2020 Wiley Periodicals, Inc.)

The ability to consistently distinguish real protein structures from computationally generated model decoys is not yet a solved problem. One route to distinguish real protein structures from decoys is to delineate the important physical features that specify a real protein. For example, it has long been appreciated that the hydrophobic cores of proteins contribute significantly to their stability. We used two sources to obtain datasets of decoys to compare with real protein structures: submissions to the biennial Critical Assessment of protein Structure Prediction competition, in which researchers attempt to predict the structure of a protein only knowing its amino acid sequence, and also decoys generated by 3DRobot, which have user-specified global root-mean-squared deviations from experimentally determined structures. Our analysis revealed that both sets of decoys possess cores that do not recapitulate the key features that define real protein cores. In particular, the model structures appear more densely packed (because of energetically unfavorable atomic overlaps), contain too few residues in the core, and have improper distributions of hydrophobic residues throughout the structure. Based on these observations, we developed a feed-forward neural network, which incorporates key physical features of protein cores, to predict how well a computational model recapitulates the real protein structure without knowledge of the structure of the target sequence. By identifying the important features of protein structure, our method is able to rank decoy structures with similar accuracy to that obtained by state-of-the-art methods that incorporate many additional features. The small number of physical features makes our model interpretable, emphasizing the importance of protein packing and hydrophobicity in protein structure prediction., (© 2020 The Protein Society.)

The mechanical response of packings of purely repulsive, spherical particles to athermal, quasistatic simple shear near jamming onset is highly nonlinear. Previous studies have shown that, at small pressure p, the ensemble-averaged static shear modulus ⟨G-G&#95;{0}⟩ scales with p^{α}, where α≈1, but above a characteristic pressure p^{**}, ⟨G-G&#95;{0}⟩∼p^{β}, where β≈0.5. However, we find that the shear modulus G^{i} for an individual packing typically decreases linearly with p along a geometrical family where the contact network does not change. We resolve this discrepancy by showing that, while the shear modulus does decrease linearly within geometrical families, ⟨G⟩ also depends on a contribution from discontinuous jumps in ⟨G⟩ that occur at the transitions between geometrical families. For p>p^{**}, geometrical-family and rearrangement contributions to ⟨G⟩ are of opposite signs and remain comparable for all system sizes. ⟨G⟩ can be described by a scaling function that smoothly transitions between two power-law exponents α and β. We also demonstrate the phenomenon of compression unjamming, where a jammed packing unjams via isotropic compression.

We carry out numerical studies of static packings of frictionless superellipsoidal particles in three spatial dimensions. We consider more than 200 different particle shapes by varying the three shape parameters that define superellipsoids. We characterize the structural and mechanical properties of both disordered and ordered packings using two packing-generation protocols. We perform athermal quasi-static compression simulations starting from either random, dilute configurations (Protocol 1) or thermalized, dense configurations (Protocol 2), which allows us to tune the orientational order of the packings. In general, we find that superellipsoid packings are hypostatic, with coordination number zJ < ziso, where ziso = 2df and df = 5 or 6 depending on whether the particles are axi-symmetric or not. Over the full range of orientational order, we find that the number of quartic modes of the dynamical matrix for the packings always matches the number of missing contacts relative to the isostatic value. This result suggests that there are no mechanically redundant contacts for ordered, yet hypostatic packings of superellipsoidal particles. Additionally, we find that the packing fraction at jamming onset for disordered packings of superellipsoidal depends on at least two particle shape parameters, e.g. the asphericity A and reduced aspect ratio β of the particles.

Micro- and nanoresonators have important applications including sensing, navigation, and biochemical detection. Their performance is quantified using the quality factor Q, which gives the ratio of the energy stored to the energy dissipated per cycle. Metallic glasses are a promising material class for micro- and nanoscale resonators since they are amorphous and can be fabricated precisely into complex shapes on these length scales. To understand the intrinsic dissipation mechanisms that ultimately limit large Q-values in metallic glasses, we perform molecular dynamics simulations to model metallic glass resonators subjected to bending vibrations at low temperatures. We calculate the power spectrum of the kinetic energy, redistribution of energy from the fundamental mode of vibration, and Q vs the kinetic energy per atom K of the excitation. In the harmonic and anharmonic response regimes where there are no atomic rearrangements, we find that Q → ∞ over the time periods we consider (since we do not consider coupling to the environment). We identify a characteristic K r above which atomic rearrangements occur, and there is significant energy leakage from the fundamental mode to higher frequencies, causing finite Q. Thus, K r is a critical parameter determining resonator performance. We show that K r decreases as a power-law, K r ∼ N -k , with increasing system size N, where k ≈ 1.3. We estimate the critical strain ⟨γ r ⟩∼ 10 -8 for micrometer-sized resonators below which atomic rearrangements do not occur in the millikelvin temperature range, and thus, large Q-values can be obtained when they are operated below γ r . We also find that K r for amorphous resonators is comparable to that for resonators with crystalline order.

We perform computational studies of jammed particle packings in two dimensions undergoing isotropic compression using the well-characterized soft particle (SP) model and deformable particle (DP) model that we developed for bubbles and emulsions. In the SP model, circular particles are allowed to overlap, generating purely repulsive forces. In the DP model, particles minimize their perimeter, while deforming at fixed area to avoid overlap during compression. We compare the structural and mechanical properties of jammed packings generated using the SP and DP models as a function of the packing fraction ρ, instead of the reduced number density φ. We show that near jamming onset the excess contact number Δz = z - zJ and shear modulus G scale as Δρ0.5 in the large system limit for both models, where Δρ = ρ - ρJ and zJ ≈ 4 and ρJ ≈ 0.842 are the values at jamming onset. Δz and G for the SP and DP models begin to differ for ρ ⪆ 0.88. In this regime, Δz ∼ G can be described by a sum of two power-laws in Δρ, i.e. Δz ∼ G ∼ C0Δρ0.5 + C1Δρ1.0 to lowest order. We show that the ratio C1/C0 is much larger for the DP model compared to that for the SP model. We also characterize the void space in jammed packings as a function of ρ. We find that the DP model can describe the formation of Plateau borders as ρ → 1. We further show that the results for z and the shape factor A versus ρ for the DP model agree with recent experimental studies of foams and emulsions.

Embryonic organizers establish gradients of diffusible signaling molecules to pattern the surrounding cells. Here, we elucidate an additional mechanism of embryonic organizers that is a secondary consequence of morphogen signaling. Using pharmacological and localized transgenic perturbations, 4D imaging of the zebrafish embryo, systematic analysis of cell motion, and computational modeling, we find that the vertebrate tail organizer orchestrates morphogenesis over distances beyond the range of morphogen signaling. The organizer regulates the rate and coherence of cell motion in the elongating embryo using mechanical information that is transmitted via relay between neighboring cells. This mechanism is similar to a pressure front in granular media and other jammed systems, but in the embryo the mechanical information emerges from self-propelled cell movement and not force transfer between cells. The propagation likely relies upon local biochemical signaling that affects cell contractility, cell adhesion, and/or cell polarity but is independent of transcription and translation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We employ numerical simulations to study active transistor-like switches made from two-dimensional (2D) granular crystals containing two types of grains with the same size but different masses. We tune the mass contrast and arrangement of the grains to maximize the width of the frequency band gap in the device. The input signal is applied to a single grain on one side of the device, and the output signal is measured from another grain on the other side of the device. Changing the size of one or many grains tunes the pressure, which controls the vibrational response of the device. Switching between the on and off states is achieved using two mechanisms: (1) pressure-induced switching where the interparticle contact network is the same in the on and off states and (2) switching through contact breaking. In general, the performance of the acoustic switch, as captured by the gain ratio and switching time between the on and off states, is better for pressure-induced switching. We show that in these acoustic switches the gain ratio between the on and off states can be larger than 10^{4} and the switching time (multiplied by the driving frequency) is comparable to that obtained recently for sonic crystals and less than that for photonic transistor-like switches. Since the self-assembly of grains with different masses into 2D granular crystals is challenging, we describe simulations of circular grains with small circular knobs placed symmetrically around the perimeter mixed with circular grains without knobs. Using umbrella sampling techniques, we show that grains with six knobs most efficiently form the hexagonal crystals that yield the largest frequency band gap. Using the simulation results, we estimate the time required for vibration experiments to generate granular crystals of millimeter-sized steel beads with maximal band gaps.

While common growth models assume a structure-less liquid composed of atomic flow units, structural ordering has been shown in liquid metals. Here, we conduct in situ transmission electron microscopy crystallization experiments on metallic glass nanorods, and show that structural ordering strongly affects crystal growth and is controlled by nanorod thermal history. Direct visualization reveals structural ordering as densely populated small clusters in a nanorod heated from the glass state, and similar behavior is found in molecular dynamics simulations of model metallic glasses. At the same growth temperature, the asymmetry in growth rate for rods that are heated versus cooled decreases with nanorod diameter and vanishes for very small rods. We hypothesize that structural ordering enhances crystal growth, in contrast to assumptions from common growth models. The asymmetric growth rate is attributed to the difference in the degree of the structural ordering, which is pronounced in the heated glass but sparse in the cooled liquid.

Dense packing of hydrophobic residues in the cores of globular proteins determines their stability. Recently, we have shown that protein cores possess packing fraction ϕ≈0.56, which is the same as dense, random packing of amino-acid-shaped particles. In this article, we compare the structural properties of protein cores and jammed packings of amino-acid-shaped particles in much greater depth by measuring their local and connected void regions. We find that the distributions of surface Voronoi cell volumes and local porosities obey similar statistics in both systems. We also measure the probability that accessible, connected void regions percolate as a function of the size of a spherical probe particle and show that both systems possess the same critical probe size. We measure the critical exponent τ that characterizes the size distribution of connected void clusters at the onset of percolation. We find that the cluster size statistics are similar for void percolation in packings of amino-acid-shaped particles and randomly placed spheres, but different from that for void percolation in jammed sphere packings. We propose that the connected void regions are a defining structural feature of proteins and can be used to differentiate experimentally observed proteins from decoy structures that are generated using computational protein design software. This work emphasizes that jammed packings of amino-acid-shaped particles can serve as structural and mechanical analogs of protein cores, and could therefore be useful in modeling the response of protein cores to cavity-expanding and -reducing mutations.

We introduce the deformable particle (DP) model for cells, foams, emulsions, and other soft particulate materials, which adds to the benefits and eliminates deficiencies of existing models. The DP model combines the ability to model individual soft particles with the shape-energy function of the vertex model, and adds arbitrary particle deformations. We focus on 2D deformable polygons with a shape-energy function that is minimized for area a&#95;{0} and perimeter p&#95;{0} and repulsive interparticle forces. We study the onset of jamming versus particle asphericity, A=p&#95;{0}^{2}/4πa&#95;{0}, and find that the packing fraction grows with A until reaching A^{*}=1.16 of the underlying Voronoi cells at confluence. We find that DP packings above and below A^{*} are solidlike, which helps explain the solid-to-fluid transition at A^{*} in the vertex model as a transition from tension- to compression-dominated regimes.

We present the structure of an engineered protein-protein interface between two beta barrel proteins, which is mediated by interactions between threonine (Thr) residues. This Thr zipper structure suggests that the protein interface is stabilized by close-packing of the Thr residues, with only one intermonomer hydrogen bond (H-bond) between two of the Thr residues. This Thr-rich interface provides a unique opportunity to study the behavior of Thr in the context of many other Thr residues. In previous work, we have shown that the side chain (χ 1 ) dihedral angles of interface and core Thr residues can be predicted with high accuracy using a hard sphere plus stereochemical constraint (HS) model. Here, we demonstrate that in the Thr-rich local environment of the Thr zipper structure, we are able to predict the χ 1 dihedral angles of most of the Thr residues. Some, however, are not well predicted by the HS model. We therefore employed explicitly solvated molecular dynamics (MD) simulations to further investigate the side chain conformations of these residues. The MD simulations illustrate the role that transient H-bonding to water, in combination with steric constraints, plays in determining the behavior of these Thr side chains. Broader Audience Statement: Protein-protein interactions are critical to life and the search for ways to disrupt adverse protein-protein interactions involved in disease is an ongoing area of drug discovery. We must better understand protein-protein interfaces, both to be able to disrupt existing ones and to engineer new ones for a variety of biotechnological applications. We have discovered and characterized an artificial Thr-rich protein-protein interface. This novel interface demonstrates a heretofore unknown property of Thr-rich surfaces: mediating protein-protein interactions., (© 2018 The Protein Society.)

The fracture toughness of glassy materials remains poorly understood. In large part, this is due to the disordered, intrinsically non-equilibrium nature of the glass structure, which challenges its theoretical description and experimental determination. We show that the notch fracture toughness of metallic glasses exhibits an abrupt toughening transition as a function of a well-controlled fictive temperature (T f ), which characterizes the average glass structure. The ordinary temperature, which has been previously associated with a ductile-to-brittle transition, is shown to play a secondary role. The observed transition is interpreted to result from a competition between the T f -dependent plastic relaxation rate and an applied strain rate. Consequently, a similar toughening transition as a function of strain rate is predicted and demonstrated experimentally. The observed mechanical toughening transition bears strong similarities to the ordinary glass transition and explains the previously reported large scatter in fracture toughness data and ductile-to-brittle transitions.

We show that the yielding transition in granular media displays second-order critical-point scaling behavior. We carry out discrete element simulations in the low-inertial-number limit for frictionless, purely repulsive spherical grains undergoing simple shear at fixed nondimensional shear stress Σ in two and three spatial dimensions. To find a mechanically stable (MS) packing that can support the applied Σ, isotropically prepared states with size L must undergo a total strain γ&#95;{ms}(Σ,L). The number density of MS packings (∝γ&#95;{ms}^{-1}) vanishes for Σ>Σ&#95;{c}≈0.11 according to a critical scaling form with a length scale ξ∝|Σ-Σ&#95;{c}|^{-ν}, where ν≈1.7-1.8. Above the yield stress (Σ>Σ&#95;{c}), no MS packings that can support Σ exist in the large-system limit L/ξ≫1. MS packings generated via shear possess anisotropic force and contact networks, suggesting that Σ&#95;{c} is associated with an upper limit in the degree to which these networks can be deformed away from those for isotropic packings.

We perform computational studies of static packings of a variety of nonspherical particles including circulo-lines, circulo-polygons, ellipses, asymmetric dimers, dumbbells, and others to determine which shapes form packings with fewer contacts than degrees of freedom (hypostatic packings) and which have equal numbers of contacts and degrees of freedom (isostatic packings), and to understand why hypostatic packings of nonspherical particles can be mechanically stable despite having fewer contacts than that predicted from naive constraint counting. To generate highly accurate force- and torque-balanced packings of circulo-lines and cir-polygons, we developed an interparticle potential that gives continuous forces and torques as a function of the particle coordinates. We show that the packing fraction and coordination number at jamming onset obey a masterlike form for all of the nonspherical particle packings we studied when plotted versus the particle asphericity A, which is proportional to the ratio of the squared perimeter to the area of the particle. Further, the eigenvalue spectra of the dynamical matrix for packings of different particle shapes collapse when plotted at the same A. For hypostatic packings of nonspherical particles, we verify that the number of "quartic" modes along which the potential energy increases as the fourth power of the perturbation amplitude matches the number of missing contacts relative to the isostatic value. We show that the fourth derivatives of the total potential energy in the directions of the quartic modes remain nonzero as the pressure of the packings is decreased to zero. In addition, we calculate the principal curvatures of the inequality constraints for each contact in circulo-line packings and identify specific types of contacts with inequality constraints that possess convex curvature. These contacts can constrain multiple degrees of freedom and allow hypostatic packings of nonspherical particles to be mechanically stable.

We focus on the response of mechanically stable (MS) packings of frictionless, bidisperse disks to thermal fluctuations, with the aim of quantifying how nonlinearities affect system properties at finite temperature. In contrast, numerous prior studies characterized the structural and mechanical properties of MS packings of frictionless spherical particles at zero temperature. Packings of disks with purely repulsive contact interactions possess two main types of nonlinearities, one from the form of the interaction potential (e.g., either linear or Hertzian spring interactions) and one from the breaking (or forming) of interparticle contacts. To identify the temperature regime at which the contact-breaking nonlinearities begin to contribute, we first calculated the minimum temperatures T&#95;{cb} required to break a single contact in the MS packing for both single- and multiple-eigenmode perturbations of the T=0 MS packing. We find that the temperature required to break a single contact for equal velocity-amplitude perturbations involving all eigenmodes approaches the minimum value obtained for a perturbation in the direction connecting disk pairs with the smallest overlap. We then studied deviations in the constant volume specific heat C[over ¯]&#95;{V} and deviations of the average disk positions Δr from their T=0 values in the temperature regime T&#95;{C[over ¯]&#95;{V}}100 for linear spring interactions is independent of system size. This result emphasizes that contact-breaking nonlinearities are dominant over form nonlinearities in the low-temperature range T&#95;{cb}

We present the experimental and numerical studies of a two-dimensional sheared amorphous material composed of bidisperse photoelastic disks. We analyze the statistics of avalanches during shear including the local and global fluctuations in energy and changes in particle positions and orientations. We find scale-free distributions for these global and local avalanches denoted by power laws whose cutoffs vary with interparticle friction and packing fraction. Different exponents are found for these power laws depending on the quantity from which variations are extracted. An asymmetry in time of the avalanche shapes is evidenced along with the fact that avalanches are mainly triggered by the shear bands. A simple relation independent of the intensity is found between the number of local avalanches and the global avalanches they form. We also compare these experimental and numerical results for both local and global fluctuations to predictions from mean-field and depinning theories.

Amorphous materials such as metallic, polymeric, and colloidal glasses exhibit complex preparation-dependent mechanical response to applied shear. In particular, glassy solids yield, with a mechanical response that transitions from elastic to plastic, with increasing shear strain. We perform numerical simulations to investigate the mechanical response of binary Lennard-Jones glasses undergoing athermal, quasistatic pure shear as a function of the cooling rate R used to prepare them. The ensemble-averaged stress versus strain curve 〈σ(γ)〉 resembles the spatial average in the large size limit, which appears smooth and displays a putative elastic regime at small strains, a yielding-related peak in stress at intermediate strain, and a plastic flow regime at large strains. In contrast, for each glass configuration in the ensemble, the stress-strain curve σ(γ) consists of many short nearly linear segments that are punctuated by particle-rearrangement-induced rapid stress drops. To explain the nonlinearity of 〈σ(γ)〉, we quantify the shape of the small stress-strain segments and the frequency and size of the stress drops in each glass configuration. We decompose the stress loss [i.e., the deviation in the slope of 〈σ(γ)〉 from that at 〈σ(0)〉] into the loss from particle rearrangements and the loss from softening [i.e., the reduction of the slopes of the linear segments in σ(γ)], and then compare the two contributions as a function of R and γ. For the current studies, the rearrangement-induced stress loss is larger than the softening-induced stress loss, however, softening stress losses increase with decreasing cooling rate. We also characterize the structure of the potential energy landscape along the strain direction for glasses prepared with different R, and observe a dramatic change of the properties of the landscape near the yielding transition. We then show that the rearrangement-induced energy loss per strain can serve as an order parameter for the yielding transition, which sharpens for slow cooling rates and in large systems.

Amorphous solids, such as metallic, polymeric, and colloidal glasses, display complex spatiotemporal response to applied deformations. In contrast to crystalline solids, during loading, amorphous solids exhibit a smooth crossover from elastic response to plastic flow. In this study, we investigate the mechanical response of binary Lennard-Jones glasses to athermal, quasistatic pure shear as a function of the cooling rate used to prepare them. We find several key results concerning the connection between strain-induced particle rearrangements and mechanical response. We show that the energy loss per strain dU&#95;{loss}/dγ caused by particle rearrangements for more rapidly cooled glasses is larger than that for slowly cooled glasses. We also find that the cumulative energy loss U&#95;{loss} can be used to predict the ductility of glasses even in the putative linear regime of stress versus strain. U&#95;{loss} increases (and the ratio of shear to bulk moduli decreases) with increasing cooling rate, indicating enhanced ductility. In addition, we characterized the degree of reversibility of particle motion during a single shear cycle. We find that irreversible particle motion occurs even in the linear regime of stress versus strain. However, slowly cooled glasses, which undergo smaller rearrangements, are more reversible during a single shear cycle than rapidly cooled glasses. Thus, we show that more ductile glasses are also less reversible.

In 2008, we established the Integrated Graduate Program in Physical and Engineering Biology (IGPPEB) at Yale University. Our goal was to create a comprehensive graduate program to train a new generation of scientists who possess a sophisticated understanding of biology and who are capable of applying physical and quantitative methodologies to solve biological problems. Here we describe the framework of the training program, report on its effectiveness, and also share the insights we gained during its development and implementation. The program features co-teaching by faculty with complementary specializations, student peer learning, and novel hands-on courses that facilitate the seamless blending of interdisciplinary research and teaching. It also incorporates enrichment activities to improve communication skills, engage students in science outreach, and foster a cohesive program cohort, all of which promote the development of transferable skills applicable in a variety of careers. The curriculum of the graduate program is integrated with the curricular requirements of several Ph.D.-granting home programs in the physical, engineering, and biological sciences. Moreover, the wide-ranging recruiting activities of the IGPPEB serve to enhance the quality and diversity of students entering graduate school at Yale. We also discuss some of the challenges we encountered in establishing and optimizing the program, and describe the institution-level changes that were catalyzed by the introduction of the new graduate program. The goal of this article is to serve as both an inspiration and as a practical "how to" manual for those who seek to establish similar programs at their own institutions. © 2016 by The International Union of Biochemistry and Molecular Biology, 44(6):537-549, 2016., (© 2016 The Authors Biochemistry and Molecular Biology Education published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology.)

Clinical diagnosis of acute infectious diseases during the early stages of infection is critical to administering the appropriate treatment to improve the disease outcome. We present a data driven analysis of the human cellular response to respiratory viruses including influenza, respiratory syncytia virus, and human rhinovirus, and compared this with the response to the bacterial endotoxin, Lipopolysaccharides (LPS). Using an anomaly detection framework we identified pathways that clearly distinguish between asymptomatic and symptomatic patients infected with the four different respiratory viruses and that accurately diagnosed patients exposed to a bacterial infection. Connectivity pathway analysis comparing the viral and bacterial diagnostic signatures identified host cellular pathways that were unique to patients exposed to LPS endotoxin indicating this type of analysis could be used to identify host biomarkers that can differentiate clinical etiologies of acute infection. We applied the Multivariate State Estimation Technique (MSET) on two human influenza (H1N1 and H3N2) gene expression data sets to define host networks perturbed in the asymptomatic phase of infection. Our analysis identified pathways in the respiratory virus diagnostic signature as prognostic biomarkers that triggered prior to clinical presentation of acute symptoms. These early warning pathways correctly predicted that almost half of the subjects would become symptomatic in less than forty hours post-infection and that three of the 18 subjects would become symptomatic after only 8 hours. These results provide a proof-of-concept for utility of anomaly detection algorithms to classify host pathway signatures that can identify presymptomatic signatures of acute diseases and differentiate between etiologies of infection. On a global scale, acute respiratory infections cause a significant proportion of human co-morbidities and account for 4.25 million deaths annually. The development of clinical diagnostic tools to distinguish between acute viral and bacterial respiratory infections is critical to improve patient care and limit the overuse of antibiotics in the medical community. The identification of prognostic respiratory virus biomarkers provides an early warning system that is capable of predicting which subjects will become symptomatic to expand our medical diagnostic capabilities and treatment options for acute infectious diseases. The host response to acute infection may be viewed as a deterministic signaling network responsible for maintaining the health of the host organism. We identify pathway signatures that reflect the very earliest perturbations in the host response to acute infection. These pathways provide a monitor the health state of the host using anomaly detection to quantify and predict health outcomes to pathogens.

Methionine (Met) is a structurally versatile amino acid most commonly found in protein cores and at protein-protein interfaces. Thus, a complete description of the structure of Met is important for a fundamental understanding of protein structure and design. In previous work, we showed that the hard-sphere dipeptide model is able to recapitulate the side-chain dihedral angle distributions observed in high-resolution protein crystal structures for the nine amino acids we have studied to date: Val, Thr, Ser, Leu, Ile, Cys, Tyr, Trp, and Phe. Using the same approach, we are also able to predict the observed χ1 and χ2 side-chain dihedral angle distributions for Met. However, the form of the side-chain dihedral angle distribution P(χ3 ) predicted by the hard-sphere model does not match the observed distribution. We investigate the possible origins of the discrepancy and find that specific bond lengths and angles in Met side chains strongly influence P(χ3 ). We then identify minimal additions to the hard-sphere dipeptide model necessary to quantitatively predict P(χ3 ) of Met, and its near isosteres norleucine (Nle) and selenomethionine (Mse). We find that adding weak attractive interactions between hydrogen atoms to the model is sufficient to achieve predictions for P(χ3 ) that closely match the observed P(χ3 ) distributions for Met, Nle, and Mse. We explicitly show that weak attractive interactions between hydrogens do not negatively affect the agreement between the predicted and observed side-chain dihedral angle distribution for Val, Leu, Ile, and Phe, as we expect for other amino acids. Proteins 2016; 84:900-911. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Shortly after the determination of the first protein x-ray crystal structures, researchers analyzed their cores and reported packing fractions ϕ ≈ 0.75, a value that is similar to close packing of equal-sized spheres. A limitation of these analyses was the use of extended atom models, rather than the more physically accurate explicit hydrogen model. The validity of the explicit hydrogen model was proved in our previous studies by its ability to predict the side chain dihedral angle distributions observed in proteins. In contrast, the extended atom model is not able to recapitulate the side chain dihedral angle distributions, and gives rise to large atomic clashes at side chain dihedral angle combinations that are highly probable in protein crystal structures. Here, we employ the explicit hydrogen model to calculate the packing fraction of the cores of over 200 high-resolution protein structures. We find that these protein cores have ϕ ≈ 0.56, which is similar to results obtained from simulations of random packings of individual amino acids. This result provides a deeper understanding of the physical basis of protein structure that will enable predictions of the effects of amino acid mutations to protein cores and interfaces of known structure.

We propose a theoretical framework for predicting the protocol dependence of the jamming transition for frictionless spherical particles that interact via repulsive contact forces. We study isostatic jammed disk packings obtained via two protocols: isotropic compression and simple shear. We show that for frictionless systems, all jammed packings can be obtained via either protocol. However, the probability to obtain a particular jammed packing depends on the packing-generation protocol. We predict the average shear strain required to jam initially unjammed isotropically compressed packings from the density of jammed packings, shape of their basins of attraction, and path traversed in configuration space. We compare our predictions to simulations of shear strain-induced jamming and find quantitative agreement. We also show that the packing fraction range, over which shear strain-induced jamming occurs, tends to zero in the large system limit for frictionless packings with overdamped dynamics.

We examine the role of intrinsic chain susceptibility anisotropy in magnetic field directed self-assembly of a block copolymer using in situ x-ray scattering. Alignment of a lamellar mesophase is observed on cooling across the disorder-order transition with the resulting orientational order inversely proportional to the cooling rate. We discuss the origin of the susceptibility anisotropy, Δχ, that drives alignment and calculate its magnitude using coarse-grained molecular dynamics to sample conformations of surface-tethered chains, finding Δχ≈2×10^{-8}. From field-dependent scattering data, we estimate that grains of ≈1.2  μm are present during alignment. These results demonstrate that intrinsic anisotropy is sufficient to support strong field-induced mesophase alignment and suggest a versatile strategy for field control of orientational order in block copolymers.