Critical-like slowdown in thermal soft-sphere glasses via energy minimization.

Using hybrid molecular dynamics/SWAP Monte Carlo (MD/SMC) simulations, we show that while the terminal relaxation times τ(ϕ) for FIRE energy minimization of soft-sphere glasses can decrease by orders of magnitude as sample equilibration proceeds and the jamming density ϕ_{J} increases, they always scale as τ(ϕ)∼(ϕ_{J}-ϕ)^{-2}∼[Z_{iso}-Z_{ms}(τ)]^{-2}, where Z_{iso}=2d and Z_{ms}(τ) is the average coordination number of particles satisfying a minimal local mechanical stability criterion (Z≥d+1) at the top of the final potential-energy-landscape (PEL) sub-basin the system encounters. This scaling allows us to collapse τ datasets that look very different when plotted as a function of ϕ, and to address a closely related question: how does the character of the PEL basins that dense thermal glasses most typically occupy evolve as the glasses age at constant ϕ and T?

Homogeneous crystallization in four-dimensional Lennard-Jones liquids.

We observe homogeneous crystallization in simulated high-dimensional (d>3) liquids that follow physically realistic dynamics and have system sizes that are large enough to eliminate the possibility that crystallization was induced by the periodic boundary conditions. Supercooled four-dimensional (4D) Lennard-Jones (LJ) liquids maintained at zero pressure and constant temperatures 0.59

Deep Learning-Assisted Identification of Femoroacetabular Impingement (FAI) on Routine Pelvic Radiographs.

To use a novel deep learning system to localize the hip joints and detect findings of cam-type femoroacetabular impingement (FAI). A retrospective search of hip/pelvis radiographs obtained in patients to evaluate for FAI yielded 3050 total studies. Each hip was classified separately by the original interpreting radiologist in the following manner: 724 hips had severe cam-type FAI morphology, 962 moderate cam-type FAI morphology, 846 mild cam-type FAI morphology, and 518 hips were normal. The anteroposterior (AP) view from each study was anonymized and extracted. After localization of the hip joints by a novel convolutional neural network (CNN) based on the focal loss principle, a second CNN classified the images of the hip as cam positive, or no FAI. Accuracy was 74% for diagnosing normal vs. abnormal cam-type FAI morphology, with aggregate sensitivity and specificity of 0.821 and 0.669, respectively, at the chosen operating point. The aggregate AUC was 0.736. A deep learning system can be applied to detect FAI-related changes on single view pelvic radiographs. Deep learning is useful for quickly identifying and categorizing pathology on imaging, which may aid the interpreting radiologist.

Structure of jammed ellipse packings with a wide range of aspect ratios.

Motivated in part by the recent observation of liquid glass in suspensions of ellipsoidal colloids, we examine the structure of jammed two-dimensional ellipse packings over a much wider range of particle aspect ratios (α, the ratio of the major and minor axis lengths) than has been previously attempted. We determine the jamming densities ϕJ(α) to high precision, and find empirical analytic formulae that predict ϕJ(α) to within less than 0.1% for all 1≤α≤10, for three different particle dispersities. Then we explore how these packings' local structural order varies with α. We find that the densest packings possess unusually-well-defined nearest-neighbor shells, including both a higher fraction fZ=6 of particles with exactly six contacts and a previously-unreported short-range order marked by "kinetically suppressed" regions in their positional-orientational pair correlation function g(r,Δθ). We also show that the previously-reported approach to isostaticity (coordination number ZJ → Ziso ≡ 6) with increasing α is interrupted and then reversed as local nematic order increases: ZJ(α) drops towards 4 as ellipses are more often trapped by contacts with a parallel-oriented neighbor on either side and a perpendicularly-oriented neighbor on either end. Finally we show that ϕJ/ϕs (where ϕs is the saturated RSA packing density) is nearly α-independent for systems that do not develop substantial local hexatic or nematic order during compression.

Ultraslow Settling Kinetics of Frictional Cohesive Powders.

Using discrete element method simulations, we show that the settling of frictional cohesive grains under ramped-pressure compression exhibits strong history dependence and slow dynamics that are not present for grains that lack either cohesion or friction. Systems prepared by beginning with a dilute state and then ramping the pressure to a small positive value P_{final} over a time τ_{ramp} settle at packing fractions given by an inverse-logarithmic rate law, ϕ_{settled}(τ_{ramp})=ϕ_{settled}(∞)+A/[1+Bln(1+τ_{ramp}/τ_{slow})]. This law is analogous to the one obtained from classical tapping experiments on noncohesive grains, but crucially different in that τ_{slow} is set by the slow dynamics of structural void stabilization rather than the faster dynamics of bulk densification. We formulate a kinetic free-void-volume theory that predicts this ϕ_{settled}(τ_{ramp}), with ϕ_{settled}(∞)=ϕ_{ALP} and A=ϕ_{settled}(0)-ϕ_{ALP}, where ϕ_{ALP}≡.135 is the "adhesive loose packing" fraction found by Liu et al. [Equation of state for random sphere packings with arbitrary adhesion and friction, Soft Matter 13, 421 (2017)SMOABF1744-683X10.1039/C6SM02216B].

RNA-Binding Protein LIN28a Regulates New Myocyte Formation in the Heart Through Long Noncoding RNA-H19.

BACKGROUND: Developmental cardiac tissue holds remarkable capacity to regenerate after injury and consists of regenerative mononuclear diploid cardiomyocytes. On maturation, mononuclear diploid cardiomyocytes become binucleated or polyploid and exit the cell cycle. Cardiomyocyte metabolism undergoes a profound shift that coincides with cessation of regeneration in the postnatal heart. However, whether reprogramming metabolism promotes persistence of regenerative mononuclear diploid cardiomyocytes enhancing cardiac function and repair after injury is unknown. Here, we identify a novel role for RNA-binding protein LIN28a, a master regulator of cellular metabolism in cardiac repair after injury. METHODS: LIN28a overexpression was tested using mouse transgenesis on postnatal cardiomyocyte numbers, cell cycle, and response to apical resection injury. With the use of neonatal and adult cell culture systems and adult and Mosaic Analysis with Double Markers myocardial injury models in mice, the effect of LIN28a overexpression on cardiomyocyte cell cycle and metabolism was tested. Last, isolated adult cardiomyocytes from LIN28a and wild-type mice 4 days after myocardial injury were used for RNA-immunoprecipitation sequencing. RESULTS: LIN28a was found to be active primarily during cardiac development and rapidly decreases after birth. LIN28a reintroduction at postnatal day (P) 1, P3, P5, and P7 decreased maturation-associated polyploidization, nucleation, and cell size, enhancing cardiomyocyte cell cycle activity in LIN28a transgenic pups compared with wild-type littermates. Moreover, LIN28a overexpression extended cardiomyocyte cell cycle activity beyond P7 concurrent with increased cardiac function 30 days after apical resection. In the adult heart, LIN28a overexpression attenuated cardiomyocyte apoptosis, enhanced cell cycle activity, cardiac function, and survival in mice 12 weeks after myocardial infarction compared with wild-type littermate controls. Instead, LIN28a small molecule inhibitor attenuated the proreparative effects of LIN28a on the heart. Neonatal rat ventricular myocytes overexpressing LIN28a mechanistically showed increased glycolysis, ATP production, and levels of metabolic enzymes compared with control. LIN28a immunoprecipitation followed by RNA-immunoprecipitation sequencing in cardiomyocytes isolated from LIN28a-overexpressing hearts after injury identified long noncoding RNA-H19 as its most significantly altered target. Ablation of long noncoding RNA-H19 blunted LIN28a-induced enhancement on cardiomyocyte metabolism and cell cycle activity. CONCLUSIONS: Collectively, LIN28a reprograms cardiomyocyte metabolism and promotes persistence of mononuclear diploid cardiomyocytes in the injured heart, enhancing proreparative processes, thereby linking cardiomyocyte metabolism to regulation of ploidy/nucleation and repair in the heart.

Structure of saturated random-sequential-adsorption ellipse packings.

Motivated by the recent observation of liquid glass in suspensions of ellipsoidal colloids, we examine the structure of (asymptotically) saturated RSA ellipse packings. We determine the packing fractions ϕ_{s}(α) to high precision, finding an empirical analytic formula that predicts ϕ_{s}(α) to within less than 0.1% for all α≤10. Then we explore how these packings' positional-orientational order varies with α. We find a transition from tip/side- to side/side-contact-dominated structure at α=α_{TS}≃2.4. At this aspect ratio, the peak value g_{max} of packings' positional-orientational pair correlation functions is minimal, and systems can be considered maximally locally disordered. For smaller (larger) α, g_{max} increases exponentially with deceasing (increasing) α. Local nematic order and structures comparable to the precursor domains observed in experiments gradually emerge as α increases beyond three. For α≳5, single-layer lamellae become more prominent and long-wavelength density fluctuations increase with α as packings gradually approach the rodlike limit.

Unexpected Ductility in Semiflexible Polymer Glasses with Entanglement Length Equal to Their Kuhn Length.

Semiflexible polymer glasses (SPGs), including those formed by the recently synthesized semiflexible conjugated polymers, are expected to be brittle because classical formulas for their craze extension ratio λ_{craze} and fracture stretch λ_{frac} predict that systems with N_{e}=C_{∞} have λ_{craze}=λ_{frac}=1 and hence cannot be deformed to large strains. Using molecular dynamics simulations, we show that in fact such glasses can form stable crazes with λ_{craze}≃N_{e}^{1/4}≃C_{∞}^{1/4}, and that they fracture at λ_{frac}=(3N_{e}^{1/2}-2)^{1/2}≃(3C_{∞}^{1/2}-2)^{1/2}. We argue that the classical formulas for λ_{craze} and λ_{frac} fail to describe SPGs' mechanical response because they do not account for Kuhn segments' ability to stretch during deformation.

Efficient d-dimensional molecular dynamics simulations for studies of the glass-jamming transition.

We develop an algorithm suitable for parallel molecular dynamics simulations in d spatial dimensions and describe its implementation in C++. All routines work in arbitrary d; the maximum simulated d is limited only by available computing resources. These routines include several that are particularly useful for studies of the glass-jamming transition, such as SWAP Monte Carlo and FIRE energy minimization. The scalings of simulation runtimes with the number of particles N and number of simulation threads n_{threads} are comparable to popular molecular dynamics codes such as LAMMPS. The efficient parallel implementation allows simulation of systems that are much larger than those employed in previous high-dimensional glass-transition studies. As a demonstration of the code's capabilities, we show that supercooled d=6 liquids can possess dynamics that are substantially more heterogeneous and experience a breakdown of the Stokes-Einstein relation that is substantially stronger than previously reported, owing at least in part to the much smaller system sizes employed in earlier simulations.

Validation and Refinement of Unified Analytic Model for Flexible and Semiflexible Polymer Melt Entanglement.

We combine molecular dynamics simulations and topological analyses (TA) to validate and refine a recently proposed unified analytic model [Hoy, R. S.; Kröger, M. Phys. Rev. Lett. 2020, 124, 147801] for the reduced entanglement length, tube diameter, and plateau modulus of polymer melts. While the functional forms of the previously published expressions are insensitive to the choice of the TA method and N e -estimator, obtaining better statistics and eliminating all known sources of systematic error in the N e -estimation alters their numerical coefficients. Our revised expressions quantitatively match bead-spring simulation data over the entire range of chain stiffnesses for which systems remain isotropic, semiquantitatively match all available experimental data for flexible, semiflexible, and stiff polymer melts (including new data for conjugated polymers that lie in a previously unpopulated stiffness regime), and outperform previously developed unified scaling theories.

Facile equilibration of well-entangled semiflexible bead-spring polymer melts.

The widely used double-bridging hybrid (DBH) method for equilibrating simulated entangled polymer melts [Auhl et al., J. Chem. Phys. 119, 12718-12728 (2003)] loses its effectiveness as chain stiffness increases into the semiflexible regime because the energy barriers associated with double-bridging Monte Carlo moves become prohibitively high. Here we overcome this issue by combining DBH with the use of core-softened pair potentials. This reduces the energy barriers substantially, allowing us to equilibrate melts with N ≃ 40Ne and chain stiffnesses all the way up to the isotropic-nematic transition using simulations of no more than 100 × 106 time steps. For semiflexible chains, our method is several times faster than the standard DBH; we exploit this speedup to develop improved expressions for Kremer-Grest melts' chain-stiffness-dependent Kuhn length ℓK and entanglement length Ne.

High fat diet causes inferior vertebral structure and function without disc degeneration in RAGE-KO mice.

Back pain and spinal pathologies are associated with obesity in juveniles and adults, yet studies identifying causal relationships are lacking and none investigate sex differences. This study determined if high fat (HF) diet causes structural and functional changes to vertebrae and intervertebral discs (IVDs); if these changes are modulated in mice with systematic ablation for the receptor for advanced glycation endproducts (RAGE-KO); and if these changes are sex-dependent. Wild-type (WT) and RAGE-KO mice were fed a low fat (LF) or HF diet for 12 weeks starting at 6 weeks, representing the juvenile population. HF diet led to weight/fat gain, glucose intolerance, and increased cytokine levels (IL-5, MIG, and RANTES); with less fat gain in RAGE-KO females. Most importantly, HF diet reduced vertebral trabecular bone volume fraction and compressive and shear moduli, without a modifying effect of RAGE-KO, but with a more pronounced effect in females. HF diet caused reduced cortical area fraction only in WT males. Neither HF diet nor RAGE-KO affected IVD degeneration grade. Biomechanical properties of coccygeal motion segments were affected by RAGE-KO but not diet, with some interactions identified. In conclusion, HF diet resulted in inferior vertebral structure and function with some sex differences, no IVD degeneration, and few modifying effects of RAGE-KO. These structural and functional deficiencies with HF diet provide further evidence that diet can affect spinal structures and may increase the risk for spinal injury and degeneration with aging and additional stressors. Back pain and spinal pathologies are associated with obesity in juveniles and adults, yet studies identifying causal relationships are lacking and none investigate sex differences.

Hierarchy and Reliability of the Preschool Language Scales-Fifth Edition: Mokken Scale Analysis.

Purpose This study examined the psychometric properties of the Preschool Language Scales-Fifth Edition (PLS-5 English) among preschool children from low-socioeconomic status (SES) families. Method The PLS-5 was administered individually to 169 3- to 4-year-old children enrolled in Head Start programs. We carried out a Mokken scale analysis (MSA), which is a nonparametric item response theory analysis, to examine the hierarchy among items and the reliability of test scores of the PLS-5 Auditory Comprehension (AC) and Expressive Communication (EC) scales. Results The PLS-5 EC items retained a moderate Mokken scale with the inclusion of all the items. On the other hand, the PLS-5 AC items formed a moderate Mokken scale only with the exclusion of five unscalable items. The latent class reliability coefficients for the AC and the EC scale scores were both above .90. Several items that violated the invariant item ordering assumption were found for both scales. Conclusions MSA can be used to examine the relationship between the latent language ability and the probability of passing an item with ordinal responses. Results indicate that for preschool children from low-SES families, it is appropriate to use the PLS-5 EC scale scores for comparing individuals' expressive language abilities; however, researchers and speech-language pathologists should be cautious when using the PLS-5 AC scale scores to evaluate individuals' receptive language abilities. Other implications of the MSA results are further discussed.

Thermodynamic stability of hard sphere crystals in dimensions 3 through 10.

Although much is known about the metastable liquid branch of hard spheres-from low dimension d up to [Formula: see text]-its crystal counterpart remains largely unexplored for [Formula: see text]. In particular, it is unclear whether the crystal phase is thermodynamically stable in high dimensions and thus whether a mean-field theory of crystals can ever be exact. In order to determine the stability range of hard sphere crystals, their equation of state is here estimated from numerical simulations, and fluid-crystal coexistence conditions are determined using a generalized Frenkel-Ladd scheme to compute absolute crystal free energies. The results show that the crystal phase is stable at least up to [Formula: see text], and the dimensional trends suggest that crystal stability likely persists well beyond that point.

Stem Cell Metabolism: Powering Cell-Based Therapeutics.

Cell-based therapeutics for cardiac repair have been extensively used during the last decade. Preclinical studies have demonstrated the effectiveness of adoptively transferred stem cells for enhancement of cardiac function. Nevertheless, several cell-based clinical trials have provided largely underwhelming outcomes. A major limitation is the lack of survival in the harsh cardiac milieu as only less than 1% donated cells survive. Recent efforts have focused on enhancing cell-based therapeutics and understanding the biology of stem cells and their response to environmental changes. Stem cell metabolism has recently emerged as a critical determinant of cellular processes and is uniquely adapted to support proliferation, stemness, and commitment. Metabolic signaling pathways are remarkably sensitive to different environmental signals with a profound effect on cell survival after adoptive transfer. Stem cells mainly generate energy through glycolysis while maintaining low oxidative phosphorylation (OxPhos), providing metabolites for biosynthesis of macromolecules. During commitment, there is a shift in cellular metabolism, which alters cell function. Reprogramming stem cell metabolism may represent an attractive strategy to enhance stem cell therapy for cardiac repair. This review summarizes the current literature on how metabolism drives stem cell function and how this knowledge can be applied to improve cell-based therapeutics for cardiac repair.

Does the Sastry transition control cavitation in simple liquids?

We examine the Sastry (athermal cavitation) transitions for model monatomic liquids interacting via Lennard-Jones as well as shorter- and longer-ranged pair potentials. Low-temperature thermodynamically stable liquids have ρ < ρS except when the attractive forces are long-ranged. For moderate- and short-ranged attractions, stable liquids with ρ > ρS exist at higher temperatures; the pressures in these liquids are high, but the Sastry transition may strongly influence their cavitation under dynamic hydrostatic expansion. The temperature T* at which stable ρ > ρS liquids emerge is ∼0.84ϵ/kB for Lennard-Jones liquids; T* decreases (increases) rapidly with increasing (decreasing) pair-interaction range. In particular, for short-ranged potentials, T* is above the critical temperature. All liquids' inherent structures are isostructural (isomorphic) for densities below (above) the Sastry density ρS. Overall, our results suggest that the barriers to cavitation in most simple liquids under ambient conditions for which significant cavitation is likely to occur are primarily vibrational-energetic and entropic rather than configurational-energetic. The most likely exceptions to this rule are liquids with long-ranged pair interactions, such as alkali metals.

Cortical Bone Derived Stem Cells Modulate Cardiac Fibroblast Response via miR-18a in the Heart After Injury.

The adult heart following injury such as a myocardial infarction forms a fibrotic scar associated with transformation of resident cardiac fibroblasts into myofibroblast, accelerating cardiac remodeling and dysfunction. Cell therapies provide a novel direction for the enhancement of cardiac structure and function but remain poorly described in terms of the effect on resident cardiac fibroblasts. We have shown cortical bone derived stem cells (CBSCs) exhibit an ability to repair the heart after myocardial injury together with reduced scar formation. Nevertheless, whether CBSCs possess ability to modulate resident fibroblast response after myocardial injury remains untested. OBJECTIVE: To determine the effect of secreted factors from CSBCs to attenuate myofibroblast formation in the heart after injury. METHODS AND RESULTS: CBSCs were injected in mice after myocardial infarction which demonstrated reduced fibrosis as determined by Masson's trichrome and Picro-Sirius red staining. In parallel, decreased expression of myofibroblast markers such as Acta2 was observed compared to PBS injected mice. To determine the effect of CBSCs on cardiac fibrosis, adult mouse cardiac fibroblasts were isolated from C57BL/6 mice, primed with CBSC pre-conditioned media for 12 h, and treated with 10ng TGF-ß for 48 h to mimic cardiac injury. Decreased expression of Acta2, periostin and CTGF was observed in adult cardiac fibroblasts cultured in CBSC medium compared to control cells. Additionally, analysis of myofibroblast markers such as vimentin and pSMAD/SMAD was also decreased compared to control cells. To determine the mechanism, we looked for enriched miRNA in CBSCs that can mediate anti fibrotic response after injury. Results showed significantly increased expression of miR-18a in CBSCs. The upregulation of miR-18a was also validated in adult fibroblasts treated with CBSCs compared to control cells. Adult fibroblasts treated with mimic for miR-18a followed by TGF-ß showed significant decrease in myofibroblast formation while miR-18a inhibitor completely inhibited the effect of CBSC medium. CONCLUSION: CBSCs reduce fibroblast to myofibroblast transition and differentiation in adult cardiac fibroblasts via miR-18a-5p. This finding reveals a new avenue for cell therapies to target myocardial scar modulation and provides a resolution for the cardiac repair response after injury in the adult myocardium.

Two-stage athermal solidification of semiflexible polymers and fibers.

We study how solidification of model freely rotating polymers under athermal quasistatic compression varies with their bond angle θ0. All systems undergo two discrete, first-order-like transitions: entanglement at φ = φE(θ0) followed by jamming at φ = φJ(θ0) ≃ (4/3 ± 1/12)φE(θ0). For φ < φE(θ0), systems are in a "gas" phase wherein all chains remain free to translate and reorient. For φE(θ0) ≤ φ ≤ φJ(θ0), systems are in a liquid-like phase wherein chains are entangled. In this phase, chains' rigid-body-like motion is blocked, yet they can still locally relax via dihedral rotations, and hence energy and pressure remain extremely small. The ability of dihedral relaxation mechanisms to accommodate further compression becomes exhausted, and systems rigidify, at φJ(θ0). At and slightly above φJ, the bulk moduli increase linearly with the pressure P rather than jumping discontinuously, indicating these systems solidify via rigidity percolation. The character of the energy and pressure increases above φJ(θ0) can be characterized via chains' effective aspect ratio αeff. Large-αeff (small-θ0) systems' jamming is bending-dominated and is similar to that observed in systems composed of straight fibers. Small-αeff (large-θ0) systems' jamming is dominated by the degree to which individual chains' dihedrals can collapse into compact, tetrahedron-like structures. For intermediate θ0, chains remain in highly disordered globule-like configurations throughout the compression process; jamming occurs when entangled globules can no longer even locally relax away from one another.

Leptin signaling and the intervertebral disc: Sex dependent effects of leptin receptor deficiency and Western diet on the spine in a type 2 diabetes mouse model.

Type 2 diabetes and obesity are associated with back pain in juveniles and adults and are implicated in intervertebral disc (IVD) degeneration. Hypercaloric Western diets are associated with both obesity and type 2 diabetes. The objective of this study was to determine if obesity and type 2 diabetes result in spinal pathology in a sex-specific manner using in vivo diabetic and dietary mouse models. Leptin is an appetite-regulating hormone, and its deficiency leads to polyphagia, resulting in obesity and diabetes. Leptin is also associated with IVD degeneration, and increased expression of its receptor was identified in degenerated IVDs. We used young, leptin receptor deficient (Db/Db) mice to mimic the effect of diet and diabetes on adolescents. Db/Db and Control mice were fed either Western or Control diets, and were sacrificed at 3 months of age. Db/Db mice were obese, while only female mice developed diabetes. Female Db/Db mice displayed altered IVD morphology, with increased intradiscal notochordal band area, suggesting delayed IVD cell proliferation and differentiation, rather than IVD degeneration. Motion segments from Db/Db mice exhibited increased failure risk with decreased torsional failure strength. Db/Db mice also had inferior bone quality, which was most prominent in females. We conclude that obesity and diabetes due to impaired leptin signaling contribute to pathological changes in vertebrae, as well as an immature IVD phenotype, particularly of females, suggesting a sex-dependent role of leptin in the spine.

Unified Analytic Expressions for the Entanglement Length, Tube Diameter, and Plateau Modulus of Polymer Melts.

By combining molecular dynamics simulations and topological analyses with scaling arguments, we obtain analytic expressions that quantitatively predict the entanglement length N_{e}, the plateau modulus G, and the tube diameter a in melts that span the entire range of chain stiffnesses for which systems remain isotropic. Our expressions resolve conflicts between previous scaling predictions for the loosely entangled [Lin-Noolandi, Gℓ_{K}^{3}/k_{B}T∼(ℓ_{K}/p)^{3}], semiflexible [Edwards-de Gennes: Gℓ_{K}^{3}/k_{B}T∼(ℓ_{K}/p)^{2}], and tightly entangled [Morse, Gℓ_{K}^{3}/k_{B}T∼(ℓ_{K}/p)^{1+ϵ}] regimes, where ℓ_{K} and p are, respectively, the Kuhn and packing lengths. We also find that maximal entanglement (minimal N_{e}) coincides with the onset of local nematic order.