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.

Erratum: Ultraslow Settling Kinetics of Frictional Cohesive Powders [Phys. Rev. Lett. 130, 166102 (2023)].

This corrects the article DOI: 10.1103/PhysRevLett.130.166102.

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].

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.

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.

Controlled fragmentation of multimaterial fibres and films via polymer cold-drawing.

Polymer cold-drawing is a process in which tensile stress reduces the diameter of a drawn fibre (or thickness of a drawn film) and orients the polymeric chains. Cold-drawing has long been used in industrial applications, including the production of flexible fibres with high tensile strength such as polyester and nylon. However, cold-drawing of a composite structure has been less studied. Here we show that in a multimaterial fibre composed of a brittle core embedded in a ductile polymer cladding, cold-drawing results in a surprising phenomenon: controllable and sequential fragmentation of the core to produce uniformly sized rods along metres of fibre, rather than the expected random or chaotic fragmentation. These embedded structures arise from mechanical-geometric instabilities associated with 'neck' propagation. Embedded, structured multimaterial threads with complex transverse geometry are thus fragmented into a periodic train of rods held stationary in the polymer cladding. These rods can then be easily extracted via selective dissolution of the cladding, or can self-heal by thermal restoration to re-form the brittle thread. Our method is also applicable to composites with flat rather than cylindrical geometries, in which case cold-drawing leads to the break-up of an embedded or coated brittle film into narrow parallel strips that are aligned normally to the drawing axis. A range of materials was explored to establish the universality of this effect, including silicon, germanium, gold, glasses, silk, polystyrene, biodegradable polymers and ice. We observe, and verify through nonlinear finite-element simulations, a linear relationship between the smallest transverse scale and the longitudinal break-up period. These results may lead to the development of dynamical and thermoreversible camouflaging via a nanoscale Venetian-blind effect, and the fabrication of large-area structured surfaces that facilitate high-sensitivity bio-detection.

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.

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.

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.

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.

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.

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

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

Factors influencing thermal solidification of bent-core trimers.

Bent-core trimers are a simple model system for which the competition between crystallization and glass-formation can be tuned by varying a single parameter: the bond angle θ0. Using molecular dynamics simulations, we examine how varying θ0 affects their thermal solidification. By examining trends with θ0, comparing these to the trends in trimers' jamming phenomenology, and then focusing on the six θ0 that are commensurable with close-packed crystalline order, we obtain three key results: (i) the increase in trimers' solidification temperature Ts(θ0) as they straighten (as θ0 → 0°) is driven by the same gradual loss of effective configurational freedom that drives athermal trimers' decreasing ϕJ(θ0) [where ϕJ(θ0) is the packing fraction at jamming]; (ii) θ0 that allow formation of both FCC and HCP order crystallize, while θ0 that only allow formation of HCP order glass-form; and (iii) local cluster-level structure at temperatures slightly above Ts(θ0) is highly predictive of whether trimers will crystallize or glass-form.

Biomechanical Comparison of Transosseous Knotless Rotator Cuff Repair Versus Transosseous Equivalent Repair: Half The Anchors With Equivalent Biomechanics?

PURPOSE: To compare the biomechanics of a transosseous equivalent (TOE) repair using medial and lateral anchors with tape to a transosseous knotless (TOK) tape repair with only laterally placed intraosseous anchors. METHODS: One of 2 different repairs were performed on 8 paired specimens: (1) transosseous equivalent (TOE) tape repair or (2) transosseous knotless (TOK) tape repair. Specimens were mounted on a materials testing machine and loaded in uniaxial tension to measure cyclic construct gap formation, followed by failure testing. Paired t tests were used to compare gapping, ultimate stiffness, and failure loads. Fisher exact test was used to compare modes of failure (soft tissue failure vs construct failure). RESULTS: Peak cyclic gapping, failure stiffness, and ultimate failure loads did not differ between TOE and TOK repairs (P = .140 for gapping, P = .106 for stiffness, and P = .672 for peak failure loads). All TOK repairs failed via soft tissue failure medial to the medial suture line, with no construct failures. TOE repairs failed more often through construct failure (anchor migration or suture-bone interface cut through) than TOK repairs (P = .026). CONCLUSION: TOK repairs only failed through soft tissue whereas TOE repairs failed through both soft tissue and the repair construct. Despite 50% fewer suture anchors in the TOK repairs than the TOE repairs, cyclic gapping and ultimate stiffness and failure loads were not significantly different. CLINICAL RELEVANCE: The transosseous knotless construct presented is a 2-anchor construct that is equivalent in biomechanical function to a traditional 4-anchor construct, reducing anchor load in the tuberosity.

Jamming of Semiflexible Polymers.

We study jamming in model freely rotating polymers as a function of chain length N and bond angle θ_{0}. The volume fraction at jamming ϕ_{J}(θ_{0}) is minimal for rigid-rodlike chains (θ_{0}=0), and increases monotonically with increasing θ_{0}≤π/2. In contrast to flexible polymers, marginally jammed states of freely rotating polymers are highly hypostatic, even when bond and angle constraints are accounted for. Large-aspect-ratio (small θ_{0}) chains behave comparably to stiff fibers: resistance to large-scale bending plays a major role in their jamming phenomenology. Low-aspect-ratio (large θ_{0}) chains behave more like flexible polymers, but still jam at much lower densities due to the presence of frozen-in three-body correlations corresponding to the fixed bond angles. Long-chain systems jam at lower ϕ and are more hypostatic at jamming than short-chain systems. Implications of these findings for polymer solidification are discussed.

Isostaticity and the solidification of semiflexible polymer melts.

Using molecular dynamics simulations of a tangent-soft-sphere bead-spring polymer model, we examine the degree to which semiflexible polymer melts solidify at isostaticity. Flexible and stiff chains crystallize when they are isostatic as defined by appropriate degree-of-freedom-counting arguments. Semiflexible chains also solidify when isostatic if a generalized isostaticity criterion that accounts for the slow freezing out of configurational freedom as chain stiffness increases is employed. The configurational freedom associated with bond angles (θ) can be associated with the characteristic ratio C∞ = (1 + 〈cos(θ)〉)/(1 - 〈cos(θ)〉). We find that the dependence of the average coordination number at solidification [Z(Ts)] on chains' characteristic ratio C∞ has the same functional form [Z ≃ a - b ln(C∞)] as the dependence of the average coordination number at jamming [Z(ϕJ)] on C∞ in athermal systems, suggesting that jamming-related phenomena play a significant role in thermal polymer solidification.

Psychological and neuropsychological assessment of regular hoasca users.

BACKGROUND: Hoasca (also called ayahuasca) is a N,N-dimethyltryptamine (DMT) - containing psychedelic brew originally used for magico-religious purposes by Amerindian populations of the Amazon Basin. Recently, Brazilian syncretic churches have helped spread the ritual use of hoasca to Western societies. The aim of this study was to evaluate substance use, and neuropsychological and psychological functioning of regular hoasca users within a religious setting. METHODS: Assessment of socio-economic status, mood, personality traits, impulsiveness, drug use, quality of life, extrinsic and intrinsic religiosity, and neuropsychological function was performed on 30 volunteers from a U.S. branch of União do Vegetal (UDV), a Brazilian religion which uses hoasca ritually. We also assessed 27 non-hoasca-using control subjects matched by socio-demographic profile and church attendance. Mann-Whitney U, chi-squared and Fisher tests were used to analyze differences between groups. Spearman's association and simple logistic regression tests were used to analyze the impact of frequency of hoasca use on dependent variables. RESULTS: Relative to the control group, the UDV group demonstrated lower scores for depression (p=0.043, r=.27) and confusion (p=0.032, r=.29) as assessed by the Profile of Mood States (POMS); higher scores on the instrument Big Five Inventory (BFI) for the personality traits agreeableness (p=0.028, r=.29) and openness (p=0.037, r=.28); higher scores on the quality life domain role limitations due to physical health as determined by the instrument Medical Outcomes Study Short Form-36 - SF-36 (p=0.035, r=.28); less recent use of alcohol (p<0.001, φc=.57), greater past use of alcohol to intoxication (p=0.007, φc=.36) and past use of cannabis (p=0.001, φc=.45) as measured by the Addiction Severity Index (ASI), 5th edition; better score on a measure of memory vulnerability to proactive interference as measured by the California Verbal Learning Test - CVLT (p=0.040, r=.27). Lifetime use of hoasca was positively correlated with role limitations due to physical health (p=0.032, rs=.39) and negatively associated with lifetime heavy alcohol use (p=0.034, OR=0.979). CONCLUSIONS: The findings indicate that religious use of hoasca does not adversely affect neuropsychological functioning and may have positive effects on substance abuse and mood.

Effect of chain stiffness on the competition between crystallization and glass-formation in model unentangled polymers.

We map out the solid-state morphologies formed by model soft-pearl-necklace polymers as a function of chain stiffness, spanning the range from fully flexible to rodlike chains. The ratio of Kuhn length to bead diameter (lK/r0) increases monotonically with increasing bending stiffness kb and yields a one-parameter model that relates chain shape to bulk morphology. In the flexible limit, monomers occupy the sites of close-packed crystallites while chains retain random-walk-like order. In the rodlike limit, nematic chain ordering typical of lamellar precursors coexists with close-packing. At intermediate values of bending stiffness, the competition between random-walk-like and nematic chain ordering produces glass-formation; the range of kb over which this occurs increases with the thermal cooling rate |T| implemented in our molecular dynamics simulations. Finally, values of kb between the glass-forming and rodlike ranges produce complex ordered phases such as close-packed spirals. Our results should provide a useful initial step in a coarse-grained modeling approach to systematically determining the effect of chain stiffness on the crystallization-vs-glass-formation competition in both synthetic and colloidal polymers.

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

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?