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It is predicted that pancreatic ductal adenocarcinoma (PDAC) will become the second most lethal cancer in the US by 2030. PDAC includes a fibrous-like stroma, desmoplasia, encompassing most of the tumor mass, which is produced by cancer-associated fibroblasts (CAFs) and includes their cell-derived extracellular matrices (CDMs). Since elimination of desmoplasia has proven detrimental to patients, CDM reprogramming, as opposed to stromal ablation, is therapeutically desirable. Hence, efforts are being made to harness desmoplasia's anti-tumor functions. We conducted biomechanical manipulations, using variations of pathological and physiological substrates in vitro, to culture patient-harvested CAFs and generate CDMs that restrict PDAC growth and spread. We posited that extrinsic modulation of the environment, via substrate rigidity, influences CAF's cell-intrinsic forces affecting CDM production. Substrates used were polyacrylamide gels of physiological (~1.5â¯kPa) or pathological (~7â¯kPa) stiffnesses. Results showed that physiological substrates influenced CAFs to generate CDMs similar to normal/control fibroblasts. We found CDMs to be softer than the corresponding underlying substrates, and CDM fiber anisotropy (i.e., alignment) to be biphasic and informed via substrate-imparted morphological CAF aspect ratios. The biphasic nature of CDM fiber anisotropy was mathematically modeled and proposed a correlation between CAF aspect ratios and CDM alignment; regulated by extrinsic and intrinsic forces to conserve minimal free energy. Biomechanical manipulation of CDMs, generated on physiologically soft substrates, leads to reduction in nuclear translocation of pERK1/2 in KRAS mutated pancreatic cells. ERK2 was found essential for CDM-regulated tumor cell spread. In vitro findings correlated with in vivo observations; nuclear pERK1/2 is significantly high in human PDAC samples. The study suggests that altering underlying substrates enable CAFs to remodel CDMs and restrict pancreatic cancer cell spread in an ERK2 dependent manner.
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Fibroblastos Associados a Câncer/citologia , Carcinoma Ductal Pancreático/metabolismo , Matriz Extracelular/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Neoplasias Pancreáticas/metabolismo , Animais , Anisotropia , Fenômenos Biomecânicos , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Núcleo Celular/metabolismo , Proliferação de Células , Técnicas de Cocultura , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Células NIH 3T3 , Microambiente TumoralRESUMO
In this study, we examine how the physical properties of cross-linking molecules affect the bulk response of bio-filament networks, an outstanding question in the study of biological gels and the cytoskeleton. We show that the stress-strain relationship of such networks typically undergoes linear increase - strain hardening - stress serration - total fracture transitions due to the interplay between the bending and stretching of individual filaments and the deformation and breakage of cross-linkers. Interestingly, the apparent network modulus is found to scale with the linear and rotational stiffness of the crosslinks to a power exponent of 0.78 and 0.13, respectively. In addition, the network fracture energy will reach its minimum at intermediate rotational compliance values, reflecting the fact that most of the strain energy will be stored in the distorted filaments with rigid cross-linkers while the imposed deformation will be "evenly" distributed among significantly more crosslinking molecules with high rotational compliance.
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Biopolímeros/química , Fenômenos Mecânicos , Citoesqueleto/química , Análise de Elementos Finitos , Modelos Moleculares , Conformação Molecular , Estresse Mecânico , TemperaturaRESUMO
Nanoindentation has been recently used to measure the mechanical properties of polycrystalline graphene. However, the measured failure loads are found to be scattered widely and vary from lab to lab. We perform molecular dynamics simulations of nanoindentation on polycrystalline graphene at different sites including grain center, grain boundary (GB), GB triple junction, and holes. Depending on the relative position between the indenter tip and defects, significant scattering in failure load is observed. This scattering is found to arise from a combination of the non-uniform stress state, varied and weakened strengths of different defects, and the relative location between the indenter tip and the defects in polycrystalline graphene. Consequently, the failure behavior of polycrystalline graphene by nanoindentation is critically dependent on the indentation site, and is thus distinct from uniaxial tensile loading. Our work highlights the importance of the interaction between the indentation tip and defects, and the need to explicitly consider the defect characteristics at and near the indentation site in polycrystalline graphene during nanoindentation.
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Understanding the grain size-dependent failure behavior of polycrystalline graphene is important for its applications both structurally and functionally. Here we perform molecular dynamics simulations to study the failure behavior of polycrystalline graphene by varying both grain size and distribution. We show that polycrystalline graphene fails in a brittle mode and grain boundary junctions serve as the crack nucleation sites. We also show that its breaking strength and average grain size follow an inverse pseudo Hall-Petch relation, in agreement with experimental measurements. Further, we find that this inverse pseudo Hall-Petch relation can be naturally rationalized by the weakest-link model, which describes the failure behavior of brittle materials. Our present work reveals insights into controlling the mechanical properties of polycrystalline graphene and provides guidelines for the applications of polycrystalline graphene in flexible electronics and nano-electronic-mechanical devices.
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Precise positioning and packing of nanoscale building blocks is essential for the fabrication of many nanoelectro-mechanical devices. Carrying out such manipulations at the nanoscale still remains a challenge. Here we propose the use of graphone domain arrays embedded in a graphene sheet as a template to precisely position and pack molecules. Our atomistic simulations show that a graphone domain is able to adopt well-defined three-dimensional geometries, which in turn create 'energy wells' to trap molecules by means of physisorption. Using the C60 molecule as a model block, the stable trapping conditions are identified. The present work presents a novel route to position and pack molecules for nanoengineering applications.
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Fulerenos/química , Grafite/química , Modelos Químicos , Modelos Moleculares , Impressão Molecular/métodos , Nanopartículas/química , Nanopartículas/ultraestrutura , Simulação por Computador , Conformação MolecularRESUMO
Using a generalized Brownian ratchet model that accounts for the interactions of actin filaments with the surface of Listeria mediated by proteins like ActA and Arp2/3, we have developed a microscopic model for the movement of Listeria. Specifically, we show that a net torque can be generated within the comet tail, causing the bacteria to spin about its long axis, which in conjunction with spatially varying polymerization at the surface leads to motions of bacteria in curved paths that include circles, sinusoidal-like curves, translating figure eights, and serpentine shapes, as observed in recent experiments. A key ingredient in our formulation is the coupling between the motion of Listeria and the force-dependent rate of filament growth. For this reason, a numerical scheme was developed to determine the kinematic parameters of motion and stress distribution among filaments in a self-consistent manner. We find that a 5-15% variation in polymerization rates can lead to radii of curvatures of the order of 4-20 microm, measured in experiments. In a similar way, our results also show that most of the observed trajectories can be produced by a very low degree of correlation, <10%, among filament orientations. Since small fluctuations in polymerization rate, as well as filament orientation, can easily be induced by various factors, our findings here provide a reasonable explanation for why Listeria can travel along totally different paths under seemingly identical experimental conditions. Besides trajectories, stress distributions corresponding to different polymerization profiles are also presented. We have found that although some actin filaments generate propelling forces that push the bacteria forward, others can exert forces opposing the movement of Listeria, consistent with recent experimental observations.
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Actinas/metabolismo , Listeria/fisiologia , Microscopia/métodos , Modelos Biológicos , Fenômenos Biomecânicos , Movimento/fisiologiaRESUMO
Strain and nanoscale variations in composition can significantly alter the electronic and optical properties of self-assembled alloy quantum systems. Using a combination of finite element and first-principles methods, we have developed an efficient and accurate technique to study the influence of strain and composition on the quantum confinement behavior in alloy quantum dots. Interestingly, we find that a nonuniform distribution of alloy components can lead to an enhanced confinement potential that allows a large quantum dot to behave electronically in a manner similar to a much smaller dot. The approach presented here provides a general means to quantitatively predict the influence of strain and composition variations on the performance characteristics of various small-scale alloy systems.
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Magnetism in graphene is of fundamental as well as technological interest, with potential applications in molecular magnets and spintronic devices. While defects and/or adsorbates in freestanding graphene nanoribbons and graphene sheets have been shown to cause itinerant magnetism, controlling the density and distribution of defects and adsorbates is in general difficult. We show from first principles calculations that graphene buffer layers on SiC(0001) can also show intrinsic magnetism. The formation of graphene-substrate chemical bonds disrupts the graphene pi-bonds and causes localization of graphene states near the Fermi level. Exchange interactions between these states lead to itinerant magnetism in the graphene buffer layer. We demonstrate the occurrence of magnetism in graphene buffer layers on both bulk-terminated as well as more realistic adatom-terminated SiC(0001) surfaces. Our calculations show that adatom density has a profound effect on the spin distribution in the graphene buffer layer, thereby providing a means of engineering magnetism in epitaxial graphene.
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Using in situ electron microscopy, we have measured the structure of SiC(0001)-4H during annealing in vacuum. Above 1000 degrees C, an additional SiC bilayer forms on the surface that changes the polytype from hexagonal (4H) to cubic (3C). The interaction with surface steps prevents the cubic layer from growing thicker: the new phase does not wet the steps of the underlying 4H substrate. Instead, the cubic layer expands laterally, accelerating step bunching in the surrounding hexagonal regions. During SiC homoepitaxy, this lack of step edge wetting leads to the growth of 3C twins separated by deep grooves.
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Ion-induced surface patterns (sputter ripples) are observed to grow more rapidly than predicted by current models, suggesting that additional sources of roughening may be involved. Using a linear stability analysis, we consider the contribution of ion-induced stress in the near surface region to the formation rate of ripples. This leads to a simple model that combines the effects of stress-induced roughening with the curvature-dependent erosion model of Bradley and Harper. The enhanced growth rate observed on Cu surfaces appears to be consistent with the magnitude of stress measured from wafer curvature measurements.
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We show that edge stresses introduce intrinsic ripples in freestanding graphene sheets even in the absence of any thermal effects. Compressive edge stresses along zigzag and armchair edges of the sheet cause out-of-plane warping to attain several degenerate mode shapes. Based on elastic plate theory, we identify scaling laws for the amplitude and penetration depth of edge ripples as a function of wavelength. We also demonstrate that edge stresses can lead to twisting and scrolling of nanoribbons as seen in experiments. Our results underscore the importance of accounting for edge stresses in thermal theories and electronic structure calculations for freestanding graphene sheets.
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Nanoscale variations in composition arising from the competition between chemical mixing effects and elastic relaxation can substantially influence the electronic and optical properties of self-assembled alloy quantum dots. Using a combination of finite element and quadratic programming optimization methods, we have developed an efficient technique to compute the equilibrium composition profiles in strained quantum dots. We find that the composition profiles depend strongly on the morphological features such as the slopes and curvatures of their surfaces and the presence of corners and edges as well as the ratio of the strain and chemical mixing energy densities. More generally, our approach provides a means to quantitatively model the interplay among the composition variations, the temperature, the strain, and the shapes of small-scale lattice-mismatched structures.
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We show that 2D self-assembled domains can remain trapped in a large variety of long-lived and metastable shapes that arise from an interplay of crystalline anisotropy and relaxation of elastic strain. On commonly used cubic (111) substrates, these shapes include extended or stacked structures made up of triangular domains connected at their corners, compact shapes with both convex and concave curvatures and others with narrow and elongated arms. We show that all of these distinct experimentally observed shapes can be explained within a unified framework and present a phase diagram that systematically classifies the metastable shapes as a function of their size.
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Sputtering of an amorphous or crystalline material by an ion beam often results in the formation of periodic nanoscale ripple patterns on the surface. In this Letter, we show that, in the case of alloy surfaces, the differences in the sputter yields and surface diffusivities of the alloy components will also lead to spontaneous modulations in composition that can be in or out of phase with the ripple topography. The degree of this kinetic alloy decomposition can be altered by varying the flux of the ion beam. In the high-temperature and low-flux regime, the degree of decomposition scales linearly with the ion flux, but it scales inversely with the ion flux in the low-temperature, high-flux regime.
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The bacterial pathogen Listeria monocytogenes propels itself in the cytoplasm of the infected cells by forming a filamentous comet tail assembled by the polymerization of the cytoskeletal protein actin. Although a great deal is known about the molecular processes that lead to actin-based movement, most macroscale aspects of motion, including the nature of the trajectories traced out by the motile bacteria, are not well understood. Here, we present 2D trajectories of Listeria moving between a glass-slide and coverslip in a Xenopus frog egg extract motility assay. We observe that the bacteria move in a number of fascinating geometrical trajectories, including winding S curves, translating figure eights, small- and large-amplitude sine curves, serpentine shapes, circles, and a variety of spirals. We then develop a dynamic model that provides a unified description of these seemingly unrelated trajectories. A key ingredient of the model is a torque (not included in any microscopic models of which we are aware) that arises from the rotation of the propulsive force about the body axis of the bacterium. We show that a large variety of trajectories with a rich mathematical structure are obtained by varying the rate at which the propulsive force moves about the long axis. The trajectories of bacteria executing both steady and saltatory motion are found to be in excellent agreement with the predictions of our dynamic model. When the constraints that lead to planar motion are removed, our model predicts motion along regular helical trajectories, observed in recent experiments.
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Actinas/metabolismo , Listeria monocytogenes/citologia , Animais , Fenômenos Biomecânicos , Bactérias Gram-Negativas , Modelos Biológicos , XenopusRESUMO
We have used low-energy electron microscopy to measure step motion on Si(111) and Si(001) near dislocations during growth and sublimation. Steps on Si(111) exhibit the classic rotating Archimedean spiral motion, as predicted by Burton, Cabrera, and Frank. Steps on Si(001), however, move in a strikingly different manner. The strain-relieving anomalous behavior can be understood in detail by considering how the local step velocity is affected by the nonuniform strain field arising from the dislocation. We show how the dynamic step-flow pattern is related to the dislocation slip system.
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We examine the process of expansion of a focal adhesion complex by which a biological membrane containing mobile binders adheres to a substrate with complementary binders. Attention is focused on the situation, common among living cells, in which the mean mobile binder density is insufficient to overcome generic resistance to close approach of the membrane to its substrate. For the membrane to adhere, binders must be recruited from adjacent regions to join an adhesion patch of density adequate for adhesion, thereby expanding the size of the patch. The specific configuration examined is the expansion of a circular adhesion zone for which diffusive binder transport driven by a chemical potential gradient is the mechanism of binder recruitment. An aspect of the process of particular interest is the stability of the circular shape of the expanding front. It is found that the adhesion front radius increases as radical(t), where t is the time elapsed since nucleation, and that the circular shape becomes unstable under sinusoidal perturbations for radii large compared with the nucleation size, as observed in recent experiments.
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Adesão Celular , Membrana CelularRESUMO
We show that the decay of sinusoidal ripples on crystal surfaces, where mass transport is limited by the attachment and detachment of atoms at the step edges, is remarkably different from the decay behavior that has been reported until now. Unlike the decreasing or at most constant rate of amplitude decay of sinusoidal profiles observed in earlier work, we find that the decay rate increases with decreasing amplitude in this kinetic regime. The rate of shape invariant amplitude relaxation is shown to be inversely proportional to both the square of the wavelength and the current amplitude. We have also carried out numerical simulations of the relaxation of realistic sputter ripples.
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Glutamine is an important energy source for small intestinal epithelial enterocytes and serves as a key precursor for de novo synthesis of purines and pyrimidines in these rapidly dividing cells. Although glutamine synthetase (GS) is known to be the major enzyme of glutamine biosynthesis, the precise localization of this enzyme in the small intestine is not known. Because glutamine is an important precursor for nucleic acids biosynthesis, we hypothesized that GS is preferentially expressed in the crypt region, which contains the rapidly proliferating cells in the small intestine. Accordingly, immunofluorescence with a specific polyclonal antibody and in situ hybridization using a riboprobe were performed to localize GS protein and mRNA, respectively, in adult rats. Both GS protein and GS mRNA were detected primarily in the crypt region. This finding suggests that GS is located in the region with the highest nucleotide synthesis and cell proliferation. This finding is in support of the use of parenteral glutamine in patients with severe mucosal injury affecting the crypts.