Extended ensemble molecular dynamics method for constant strain rate uniaxial deformation of polymer systems

We describe a novel molecular dynamics (MD) method to simulate the uniaxial deformation of an amorphous polymer. This method is based on a rigorously defined statistical mechanics ensemble appropriate for describing an isothermal, displacement controlled, uniaxial stress mechanical test. The total number of particles is fixed and the normal stresses in the direction normal to the applied strain are constant, i.e., an NTLxσyyσzzNTLxσyyσzz ensemble. By using the Lagrangian of the extended system (i.e., including additional variables corresponding to the temperature and cross-sectional area fluctuations), we derive a set of equations of motion for the atomic coordinates and the additional variables appropriate to this ensemble. In order to avoid the short MD time step appropriate for the stiff covalent bonds along the polymer chains, we introduce bond length constraints. This is achieved using a variation of the commonly used SHAKE [J. P. Ryckaert, G. Ciccotti, and H. J. C. Berendsen, J. Comp. Phys. 23, 327 (1977)] algorithm. A numerical method for integrating the equations of motion with constraints via a modification of the velocity Verlet [W. C. Swope, H. C. Andersen, P. H. Berens, and K. R. Wilson, J. Chem. Phys. 76, 637 (1982)] algorithm is presented. We apply this new algorithm to the constant strain rate deformation of an amorphous polyethylene in a model containing several distinct polymer chains. To our knowledge, this is the first time that bond length constraints were applied to a macromolecular system together with an extended ensemble in which the simulation cell shape is allowed to fluctuate. © 1997 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71203/2/JCPSA6-107-11-4396-1.pd

Molecular dynamics study of isobaric and isochoric glass transitions in a model amorphous polymer

We perform molecular dynamics simulations of the glass transition through isobaric and isochoric cooling of a model polymeric material. In general, excellent agreement between the simulation results and the existing experimental trends is observed. The glass transition temperature (Tg)(Tg) is found to be a function of pressure under isobaric conditions and specific volume under isochoric conditions. Under both isobaric and isochoric conditions, the trans-state fraction and the torsional contributions to the energy undergo abrupt changes at the glass transition temperature. We analyze these data to show that the glass transition is primarily associated with the freezing of the torsional degrees of the polymer chains which is strongly coupled to the degree of freedom associated with the nonbonded Lennard-Jones potential. We attribute the greater strength of the glass transition under constant pressure conditions to the fact that the nonbonded Lennard-Jones potential is sensitive to the specific volume, which does not change during cooling under isochoric conditions. Comparison of the isochoric and isobaric data demonstrate that the thermodynamic state is independent of cooling path above Tg,Tg, while path-dependent below Tg.Tg. The simulation data show that the free volume at the isobaric glass transition temperature is pressure dependent. We also find that a glass transition occurs under isochoric conditions, even though the free volume actually increases with decreasing temperature. © 1999 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/70861/2/JCPSA6-110-14-7058-1.pd

Toughening of epoxies through thermoplastic crack bridging

The fracture toughness and toughening mechanism of two epoxy matrices containing varying concentrations of pre-formed polyamide-12 particles was investigated. The pre-formed thermoplastic modifier was used to keep the physical and morphological characteristics of the second phase constant while varying the matrix intrinsic toughness to simplify the interpretation of toughening results. We observed that these particles toughened the epoxies through a crack bridging mechanism involving large plastic deformation of the second phase.This mechanism was found to be effective independent of the potential of the matrix for plastic deformation since the increasing fracture toughness was accomplished without significant amounts of plastic deformation in the epoxy matrix. A quantitative model was adapted to account for the increase in toughness due to the crack bridging mechanism. From this model, it was possible to determine the factors which are most important when attempting to toughen a material through thermoplastic crack bridging. A better understanding of the specific factors which influence the efficiency of the crack bridging mechanism enables the fracture properties of brittle materials to be further improved with thermoplastic addition. This was shown to be very important when attempting to enhance the toughness of materials which are believed to be “un-toughenable” by conventional rubber modification, or materials whose other mechanical properties suffer from the addition of elastomeric materials.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44753/1/10853_2004_Article_202802.pd

Rate and temperature effects on the fracture toughness of a rubber-modified epoxy

A series of three-point bend fracture toughness tests was performed at various loading rates and temperatures on both rubber-modified and unmodified epoxy specimens. The fracture toughness of the modified samples was determined to be rate- and temperature-dependent. Using time-temperature superposition, an apparent activation energy was determined by shifting the fracture toughness data along the rate axis for each temperature tested. Surprisingly, this apparent activation energy calculated for the rubber-modified epoxy was found to be within 2% of the value of the activation energy determined for the [beta] relaxation peak found from small strain d.m.a. measurements of the unmodified epoxy matrix. This was an unexpected yet interesting correlation. Since shear yielding is the primary mechanism by which this epoxy system is toughened, it can be hypothesized the [beta] relaxation may significantly influence the kinetics of yielding and consequently the fracture tougness of the material. Plastic zone geometry and fracture mechanisms were investigated and were found to support this hypothesis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30897/1/0000566.pd

Interfacial adhesion and toughening mechanisms in an alloy of polycarbonate/polyethylene

Interfacial adhesion and toughening mechanisms in an alloy of polycarbonate/polyethylene (PC/PE) are investigated using transmission electron microscopy. In contrast to the general speculation, it is found that the PE particles strongly adhere to the PC matrix. The toughening mechanisms in the PC/PE blend are found to be debonding of the PC/PE interface, which relieves the triaxial tension in front of the crack tip, followed by shear banding of the PC matrix. Possible causes for such an unexpected strong interfacial adhesion between PC and PE are discussed. Also, the importance of the cavitational strength of the toughener phase in toughness optimization is addressed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30378/1/0000780.pd

The quantitative proteomes of human-induced pluripotent stem cells and embryonic stem cells

An in-depth proteomic comparison of human-induced pluripotent stem cells, and their parent fibroblast cells, with embryonic stem cells shows that the reprogramming process comprehensively remodels protein expression levels, creating cells that closely resemble natural stem cells

Versican G3 Domain Modulates Breast Cancer Cell Apoptosis: A Mechanism for Breast Cancer Cell Response to Chemotherapy and EGFR Therapy

Overexpression of EGFR and versican has been reported in association with breast cancers. Considered oncogenic, these molecules may be attractive therapeutic targets. Possessing anti-apoptotic and drug resistant properties, overexpression of these molecules is accompanied by selective sensitization to the process of apoptosis. In this study, we exogenously expressed a versican G3 construct in breast cancer cell lines and analyzed the effects of G3 on cell viability in fetal bovine serum free conditioned media and evaluated the effects of apoptotic agent C2-ceramide, and chemotherapeutic agents including Docetaxel, Doxorubicin, and Epirubicin. Versican G3 domain enhanced tumor cell resistance to apoptosis when cultured in serum free medium, Doxorubicin, or Epirubicin by up-regulating pERK and GSK-3β (S9P). However, it could be prevented by selective EGFR inhibitor AG 1478 and selective MEK inhibitor PD 98059. Both AG 1478 and PD 98059 enhanced expression of pSAPK/JNK, while selective JNK inhibitor SP 600125 enhanced expression of GSK-3β (S9P). Versican G3 promoted cell apoptosis induced by C2-ceramide or Docetaxel by enhancing expression of pSAPK/JNK and decreasing expression of GSK-3β (S9P), an observation blocked by AG 1478 or SP 6000125. Inhibition of endogenous versican expression by siRNA or reduction of versican G3's expression by linking G3 with 3′UTR prevented G3 modulated cell apoptosis. The dual roles of G3 in modulating breast cancer cell resistance to chemotherapeutic agents may in part explain a potential mechanism for breast cancer cell resistance to chemotherapy and EGFR therapy. The apoptotic effects of chemotherapeutics depend upon the activation and balance of down stream signals in the EGFR pathway. GSK-3β (S9P) appears to function as a key checkpoint in this balance of apoptosis and anti-apoptosis. Investigation and potential consideration of targeting GSK-3β (S9P) merits further study

Multilocus Sequence Typing Methods for the Emerging Campylobacter Species C. hyointestinalis, C. lanienae, C. sputorum, C. concisus, and C. curvus

Multilocus sequence typing (MLST) systems have been reported previously for multiple food- and food animal-associated Campylobacter species (e.g., C. jejuni, C. coli, C. lari, and C. fetus) to both differentiate strains and identify clonal lineages. These MLST methods focused primarily on campylobacters of human clinical (e.g., C. jejuni) or veterinary (e.g., C. fetus) relevance. However, other, emerging, Campylobacter species have been isolated increasingly from environmental, food animal, or human clinical samples. We describe herein four MLST methods for five emerging Campylobacter species: C. hyointestinalis, C. lanienae, C. sputorum, C. concisus, and C. curvus. The concisus/curvus method uses the loci aspA, atpA, glnA, gltA, glyA, ilvD, and pgm, whereas the other methods use the seven loci defined for C. jejuni (i.e., aspA, atpA, glnA, gltA, glyA, pgm, and tkt). Multiple food animal and human clinical C. hyointestinalis (n = 48), C. lanienae (n = 34), and C. sputorum (n = 24) isolates were typed, along with 86 human clinical C. concisus and C. curvus isolates. A large number of sequence types were identified using all four MLST methods. Additionally, these methods speciated unequivocally isolates that had been typed ambiguously using other molecular-based speciation methods, such as 16S rDNA sequencing. Finally, the design of degenerate primer pairs for some methods permitted the typing of related species; for example, the C. hyointestinalis primer pairs could be used to type C. fetus strains. Therefore, these novel Campylobacter MLST methods will prove useful in differentiating strains of multiple, emerging Campylobacter species

The novel mTOR inhibitor RAD001 (Everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells

Background/Aim: Tumors exhibiting constitutively activated PI(3) K/Akt/mTOR signaling are hypersensitive to mTOR inhibitors such as RAD001 (everolimus) which is presently being investigated in clinical phase II trials in various tumor entities, including neuroendocrine tumors (NETs). However, no preclinical data about the effects of RAD001 on NET cells have been published. In this study, we aimed to evaluate the effects of RAD001 on BON cells, a human pancreatic NET cell line that exhibits constitutively activated PI(3) K/Akt/mTOR signaling. Methods: BON cells were treated with different concentrations of RAD001 to analyze its effect on cell growth using proliferation assays. Apoptosis was examined by Western blot analysis of caspase-3/PARP cleavage and by FACS analysis of DNA fragmentation. Results: RAD001 potently inhibited BON cell growth in a dose-dependent manner which was dependent on the serum concentration in the medium. RAD001-induced growth inhibition involved G0/G1-phase arrest as well as induction of apoptosis. Conclusion: In summary, our data demonstrate antiproliferative and apoptotic effects of RAD001 in NET cells in vitro supporting its clinical use in current phase II trials in NET patients. Copyright (c) 2007 S. Karger AG, Basel

Positron Emission Tomography-Computed Tomography Compared with Invasive Mediastinal Staging in Non-small Cell Lung Cancer: Results of Mediastinal Staging in the Early Lung Positron Emission Tomography Trial

IntroductionPatients with non-small cell lung cancer (NSCLC) require careful preoperative staging to define resectability for potential cure. 18Fluorodeoxyglucose positron emission tomography combined with computed tomography (18FDG PET-CT) is widely used to stage NSCLC. If the mediastinum is positive on PET-CT examination, some practitioners conclude that the patient is inoperable and refer the patient for nonsurgical treatment.MethodsIn this analysis of a previously reported trial comparing PET-CT with conventional imaging in the diagnostic work-up of patients with clinical stage I, II, or IIIA NSCLC, we determined the accuracy of PET-CT in mediastinal staging compared with invasive mediastinal staging either by mediastinoscopy alone or by mediastinoscopy combined with thoracotomy.ResultsAll 149 patients had mediastinal nodal staging at mediastinoscopy alone (14), thoracotomy alone (64), or both (71). The sensitivity of PET-CT was 70% (95% confidence interval [CI], 48–85%), and specificity was 94% (95% CI, 88–97%). Of 22 patients with a PET-CT interpreted as positive for mediastinal nodes, 8 did not have tumor. The positive predictive value and negative predictive value were 64% (95% CI, 43–80%) and 95% (95% CI, 90–98%), respectively. Based on PET-CT alone, eight patients would have been denied potentially curative surgery if the mediastinal abnormalities detected by PET-CT had not been evaluated with an invasive mediastinal procedure.ConclusionsPET-CT assessment of the mediastinum is associated with a clinically relevant false-positive result. Our study confirms the need for pathologic confirmation of mediastinal lymph node abnormalities detected by PET-CT