Query: Monolayer assessment MD aimulation

Candidate papers:

abstract: After an initial assessment of the structural and electronic properties of graphene, monolayer MoS2, and graphene/MoS2 bilayer hetero structure, the temperature dependent thermodynamic properties of graphene/MoS2 bilayer hetero structure are examined by using density functional theory calculations. The structure, bandgap, partial density of states, and thermodynamic properties of graphene, monolayer MoS2 and graphene/MoS2 system are investigated and analyzed. Findings from the present study are in good agreement with the previously reported theoretical and experimental studies. Monolayer MoS2 and graphene form a stable Van der Waals heterostructure owing to their negative binding energy, and the system acts as a zero bandgap semiconductor. Debye temperature and the heat capacity of graphene, MoS2 monolayer, and graphene/MoS2 system are calculated from phonon dispersion relations to be 2100 K, 600 K, and 1400 K, and 0.7 J/g.K, 0.218 J/g.K, and 0.46 J/g.K, respectively. Introduction of graphene into the MoS2 semiconductor is, therefore, found to improve the overall thermodynamic properties of the composite as graphene preserved its superior thermal properties. The findings will be beneficial to calculate thermal conductivity of the graphene/MoS2 heterostructure for minimizing the temperature effect in electronic or optoelectronic devices.
author_names: Md Tanver Hossain

Md Ashiqur Rahman
title: A first principle study of the structural, electronic, and temperature dependent thermodynamic properties of graphene/MoS2 heterostructure
venue: Journal of Molecular Modeling
year: 2020

abstract: s for Journals and Proceedings Kaisani A, Delgado O, Kim S, Richardson JA, Wright WE, Story MD, Minna JD, Shay JW. "Risk Assessment of Radiation Induced Invasive Cancer in Mouse Models of Lung Cancer." 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Poster Presentation. 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Jul 2012 Abstracts for Journals and Proceedings Asaithamby A, Chen DJ. "Mechanism of HZE particles induced chromosome instability." 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Oral Presentation. 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Jul 2012s for Journals and Proceedings Asaithamby A, Chen DJ. "Mechanism of HZE particles induced chromosome instability." 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Oral Presentation. 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Jul 2012 Abstracts for Journals and Proceedings Asaithamby A, Chen DJ. "Biological consequences of unrepaired clustered DNA lesions in response to high atomic number and energy particles in monolayer and organotypic cell cultures." 39th Annual Meeting of the European Radiation Research Society, Vietri sul Mare, Italy, October 15 19, 2012. Oral Presentation. 39th Annual Meeting of the European Radiation Research Society, Vietri sul Mare, Italy, October 15 19, 2012. Abstract Book, p. 72. http:/www.iss.infn.it/ Oct 2012s for Journals and Proceedings Asaithamby A, Chen DJ. "Biological consequences of unrepaired clustered DNA lesions in response to high atomic number and energy particles in monolayer and organotypic cell cultures." 39th Annual Meeting of the European Radiation Research Society, Vietri sul Mare, Italy, October 15 19, 2012. Oral Presentation. 39th Annual Meeting of the European Radiation Research Society, Vietri sul Mare, Italy, October 15 19, 2012. Abstract Book, p. 72. http:/www.iss.infn.it/ Oct 2012 Abstracts for Journals and Proceedings Asaithamby A, Chen DJ. "Unrepaired clustered DNA lesions together with defective G2/M checkpoint induce chromosome instability in human cells." The 10th International Symposium on Chromosomal Aberrations, Amalfi, Italy, October 19 21, 2012. Oral Presentation. The 10th International Symposium on Chromosomal Aberrations, Amalfi, Italy, October 19 21, 2012. http:/www.iss.infn.it/ Oct 2012s for Journals and Proceedings Asaithamby A, Chen DJ. "Unrepaired clustered DNA lesions together with defective G2/M checkpoint induce chromosome instability in human cells." The 10th International Symposium on Chromosomal Aberrations, Amalfi, Italy, October 19 21, 2012. Oral Presentation. The 10th International Symposium on Chromosomal Aberrations, Amalfi, Italy, October 19 21, 2012. http:/www.iss.infn.it/ Oct 2012 Abstracts for Journals and Proceedings Shay JW, Cucinotta FA, Sulzman FM, Coleman CN, Minna JD. "From mice and men to Earth and space: joint NASA NCI workshop on lung cancer risk resulting from space and terrestrial radiation." 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Oral presentation. 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Jul 2012s for Journals and Proceedings Shay JW, Cucinotta FA, Sulzman FM, Coleman CN, Minna JD. "From mice and men to Earth and space: joint NASA NCI workshop on lung cancer risk resulting from space and terrestrial radiation." 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Oral presentation. 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Jul 2012 Abstracts for Journals and Proceedings Minna JD, Story MD, Girard L, Delgado O, Asithamby A, Chen D, Park S, Larsen J, Das A, Gao B, Richardson J, Gazdar AF, Xie Y, Xie X J, Shay JW. "Development of a risk assessment model for lung cancer pathogenesis after exposure of human and mouse lung epithelial cells to HZE particle radiation." 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. (Oral Presentation, NSCOR retreat) 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Jul 2012s for Journals and Proceedings Minna JD, Story MD, Girard L, Delgado O, Asithamby A, Chen D, Park S, Larsen J, Das A, Gao B, Richardson J, Gazdar AF, Xie Y, Xie X J, Shay JW. "Development of a risk assessment model for lung cancer pathogenesis after exposure of human and mouse lung epithelial cells to HZE particle radiation." 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. (Oral Presentation, NSCOR retreat) 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Jul 2012 Abstracts for Journals and Proceedings Park S, Ding LH, Larsen JE, Minna JD, Story MD. "Genomic characterization of transformed human bronchial epithelial cells induced by ionizing radiation." 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Oral presentation. 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Jul 2012s for Journals and Proceedings Park S, Ding LH, Larsen JE, Minna JD, Story MD. "Genomic characterization of transformed human bronchial epithelial cells induced by ionizing radiation." 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Oral presentation. 23rd Annual NASA Space Radiation Investigators' Workshop, Durham, NC, July 8 11, 2012. Jul 2012 Page 10 of 11 Task Book Report Generated on: 07/07/2020
author_names: Rolf A Brekken
title: NSCOR: Risks Estimates and Mechanisms of Lung Cancer Pathogenesis after Space Radiation
year: 2019

abstract: Ischemia/reperfusion (I/R) injury is a broad area of medical significance, and includes gut ischemia consequent to such diverse causes as endurance sports activity and congestive heart failure. Few studies have focused on assessment of the direct effects of ischemia on intestinal epithelial integrity. Furthermore, clinical efforts at mitigating the effect of hypoperfusion on gut permeability have focused on restoring gut vascular function. Here we report that, in the Caco 2 cell model of transepithelial transport, calcium glycerophosphate (CGP) an inhibitor of intestinal alkaline phosphatase F3, has a significant effect to preserve transepithelial electrical resistance and to attenuate increases in mannitol flux rates during hypoxia or cytokine stimulation. The effect was observable even at concentrations as low as 1mM. As celiac disease is also marked by a loss of gut epithelial integrity, the effect of CGP to attenuate the effect of the gliadin peptide 31 55 was also examined. In this instance, CGP exerted little effect of preservation of TEER, but significantly attenuated peptide induced increase in mannitol flux. In conclusion, it appears that CGP treatment might synergise with other therapies to preserve gut epithelial integrity. Calcium glycerophosphate and intestinal epithelial permeability. Introduction: Ischemia/reperfusion (I/R) injury is a broad area of medical significance. Stroke and coronary artery disease (CAD) are the most obvious examples of I/R injury. However, the fundamental problem is much broader, and includes gut ischemia consequent to splanchnic hypoperfusion. Chronic gut ischemia is not so dramatic as stroke or CAD, but may be more insidious. Splanchnic hypoperfusion is a consequence of endurance sports activity [Peters et al. 1999; Van Wijck e al. 2012a] and a significant element in the pathophysiology of congestive heart failure [Sandek et al, 2010; Celik et al, 2010;Sandek et al, 2007; Kruger et al, 2007] shock [Arvidsson et al, 1991] cardiac surgery [Jakob, 2002] and hemodialysis [Jakob et al, 2001] Although the ultimate causes of hypoperfusion are different in each of these clinical situations, they share similar clinical consequences. During simulated gut ischemia, there is extensive neutrophil recruitment to the post capillary venule, a process that is dependent, at least in part, on long chain fatty acyl CoA synthetase [Blakeman et al. 2012; Prior et al, 2014] likely acting by inhibiting cell adhesion protein palmitoylation [Sardjono et al. 2006; Sim et al. 2007] The subsequent immune system activation increases synthesis of an array of cytokines, including TNF, IL and IFN. While these have been studied extensively in various pathologies involving splanchnic hypopoperfusion [Esposito et al. 2007; Cavriani et al. 2007] few studies have focused on assessment of the direct effects of either hypoxia or cytokine liberation on intestinal epithelial integrity [Xu et al. 1999; Qiu et al. 2014] Furthermore, clinical efforts at mitigating the effect of hypoperfusion on gut permeability have focused on restoring gut vascular function. Gut epithelial integrity is dependent, at least in part, on sphingosine 1 phosphate (S1P) generation [Greenspon et al. 2011] Earlier studies revealed that beta calcium glycerophosphate (CGP) is an inhibitor of intestinal F3 alkaline phosphatase [Tardivel et al. 1988] As alkaline phosphatase catalyzes the conversion of S1P to sphingosine and inorganic phosphate [Edsall and Spiegel, 1999] here we test the hypothesis that, by inhibiting intestinal alkaline phosphatase, CGP might raise the S1P concentrations, thus helping to preserve intestinal integrity during ischemic insult. Calcium glycerophosphate and intestinal epithelial permeability. Methods: All experiments were conducted on Caco 2 cells, a line of cells derived from a colorectal carcinoma, and obtained from American Type Culture Collection (Rockville MD) Upon prolonged culture, these cells express the characteristics of small intestinal enterocytes [Jumarie and Malo, 1991] They are widely used as a model of transepithelial transport in the small intestine, and are considered a model for celiac disease [Iacomino et al, 2013; Caputo et al, 2012; Rauhavirta et al, 2013] Cells were grown on a transwell inserts (6 well, 12 well or 24well, 0.4 micron pore size, PET Polyester, Corning) a permeable barrier system, in minimal essential media (MEM) supplemented with 20% fetal calf serum. Cells were seeded at a density of 3.9 X 10/cm, and media was changed at 2 day intervals. The media volumes in the apical and basolateral chambers were 1.5ml and 1 ml (6 well plates) 0.5 ml and 1 ml (12 well plates) and 0.1 ml and 0l5 ml (24 well plates) respectively. Measurement of transepithelial electrical resistance: The tightness of the tight junctions in a transporting epithelium was evaluated by measuring the transepithelial electrical resistance (TEER) TEER measures the movement of ions across the cell (transcellular) and between cells (paracellular) In a very tight monolayer, transport is nearly all transcellular, hence the electrical resistance is high; the electrical resistance across the membrane was measured using the EVOM2 epithelial voltohmmeter (World Precision Instruments, Sarasota FL, USA) At 3 to 4 weeks in culture, TEER was in the range of 600 700 /cm. Mannitol flux: The TEER results were complemented by measuring mannitol flux. Cells were seeded into 6 well plates, and [C] labeled mannitol (10 mM) was added to the apical media; 10ml samples were removed from the basolateral media at intervals throughout the experiment. The rate of mannitol flux was determined by calculating the slope of dpm in the basolateral chamber as a function of time. E cadherin expression: E cadherin is the principle protein of tight junctions. The levels of Ecadherin was measured in cells by western blot analysis (primary antibody from BD biosciences) Sphingosine 1 Phosphate: Calcium glycerophosphate has activity as a phosphatase inhibitor, inviting our hypothesis that CGP elevates S1P concentrations by inhibiting dephosphorylation. S1P concentrations were measured in the media of Caco 2 cells using a commercially available ELISA kit (Echelon Catalog K 1900) Baseline values of mannitol flux, TEER and S1P were obtained in unstimulated cells, in the presence and absence of increasing concentrations of CGP. The effect of hypoxia was measured for TEER and mannitol flux, in the presence and absence of CGP. Cells were grown to confluence on transwells, 0.4 micron pore size. Experiments in hypoxic conditions were conducted in a hypoxia chamber (Coy Laboratory Products, Grass Lake MI, USA) as detailed elsewhere [Yang et al. 2006] Briefly, confluent cultures were placed in the chamber under a 95% N2/5% CO2 atmosphere and fed with serum and glucose free MEM, and bubbled with 95% N2/5% CO2. Under these conditions, the PO2 in the media is below 25 mm Hg (6% Normoxic conditions were the standard CO2 incubator and media containing glucose. The effect of exogenous cytokines were measured for each parameter, in the presence and absence of CGP. Both hypoxia/ischemia and celiac disease are characterized by cytokine release, which increase monolayer permeability [5] A mixture of the cytokines TNF, ILand Calcium glycerophosphate and intestinal epithelial permeability. IF (final concentrations: 10 ng/ml; 1 ng/ml; 100 ng/ml, respectively) then TEER, mannitol flux, E Cadherin expression and media concentrations of S1P were measured. The effect of gliadin 31 55 peptide was measured for each parameter. Gliadin is the offending protein initiating the symptoms of celiac disease in susceptible patients. Gastric and pancreatic proteases cleave gliadin to peptides, which are likely the direct cause of the enteropathy. The literature [Iacomino et al, 2013] suggests that the peptide comprised of gliadin amino acids 31 55 is a likely candidate. The peptide (Thermo Scientific, Custom synthesis) and added to the media at 100mg/ml. Calcium glycerophosphate and intestinal epithelial permeability.
author_names: P Datta

Margaret T Weis
title: CALCIUM GLYCEROPHOSPHATE ATTENUATES HYPOXIA AND CYTOKINE INDUCED INCREASES IN EPITHELIAL PERMEABILITY IN THE CACO 2 MODEL OF INTESTINAL TRANSPORT
year: 2019

abstract: The secreted hexameric form of the dengue virus non structural protein 1 (NS1) has recently been shown to elicit inflammatory cytokine release and disrupt endothelial cell monolayer integrity. This suggests that circulating NS1 contributes to the vascular leak that plays a major role in the pathology of dengue haemorrhagic fever and shock. Pathways activated by NS1 are thus of great interest as potential therapeutic targets. Recent works have separately implicated both Toll like receptor 4 (TLR4) and the TLR2/6 heterodimer in immune cell activation by NS1. Here we have used mouse gene knockout macrophages and antibodies blocking TLR function in human peripheral blood mononuclear cells to show that recombinant NS1, expressed and purified from eukaryotic cells, induces cytokine production via TLR4 but not TLR2/6. Furthermore, the commercial E. coli derived recombinant NS1 preparation used in other work to implicate TLR2/6 in the response is not correctly folded and appears to be contaminated by several microbial TLR ligands. Thus TLR4 remains a therapeutic target for dengue virus infections, with TLR4 antagonists holding promise for the treatment of dengue disease. INTRODUCTION The dengue virus (DENV) NS1 protein functions intracellularly to promote viral replication, but is also secreted from infected mammalian cells as a 300 kDa hexameric glycoprotein. This hexameric species is found circulating in the blood of infected individuals and its presence is used for the rapid diagnosis of DENV infection. Recent results suggest a critical role for NS1 in the vascular leak that characterises severe infection. We demonstrated that NS1 activates both immune and endothelial cells via engagement with TLR4, leading to cytokine secretion and endothelial cell monolayer disruption. Furthermore, we found that TLR2 was not involved in the response to NS1. The best studied ligand for the TLR4/MD 2 complex is bacterial lipopolysaccharide (LPS) although a number of viral proteins including Ebola virus glycoprotein, respiratory syncytial virus F protein, and human immunodeficiency virus Tat protein, have also been shown to be TLR4 agonists. In contrast, Chen and colleagues reported that NS1 activates human and murine immune cells via TLR2 and TLR6, which otherwise act as a heterodimer in the recognition of diacylated lipoproteins from some Gram positive bacteria and Mycoplasma. To resolve these apparently contradictory reports on innate immune recognition of NS1, we assessed the roles of TLR2, TLR4 and TLR6 in response to the different sources of NS1 used in the two papers. RESULTS AND DISCUSSION Chen et al. used commercially available recombinant E. coli derived NS1 (Abcam Cat. 64456) in experiments implicating TLR2/6 in recognition of NS1. The Abcam product is Cterminally His tagged NS1 from DENV 1, supplied in 1.5 M urea and recommended for use in ELISA and western blot applications. We first compared the oligomeric state of E. coliderived NS1 to DENV 2 NS1 immunoaffinity purified from the supernatant of stablytransfected S2 cells "insect NS1" or from the medium of DENV 2 infected Vero cells cultured without serum "native NS1" The secreted form of NS1 has a barrel like hexameric structure formed by a trimer of stable NS1 dimers. The formation of this oligomeric structure is dependent on both glycosylation and correct disulphide bonding of the 12 cysteines in NS1. Immunoaffinity purified preparations of NS1 used routinely in our laboratory are hexameric, based on both size exclusion chromatography and electron microscopic (EM) analysis (Modhiran et al. Figure S1) Chemical cross linking confirms the hexameric nature of the particles seen on EM. Insect cell expressed NS1 hexamers dissociate to dimers upon SDS PAGE analysis of unboiled samples, and to monomers after boiling, regardless of the presence or absence of reducing agent (Figure 1) In contrast, the commercially available E. coli derived NS1 was monomeric under all conditions, with an unknown low molecular weight product also noted. Thus the E. coli derived NS1 is not in its native conformation and is likely denatured given that it is supplied in 1.5 M urea. Such a misfolded protein may be suitable as an antigen substrate for western blot and qualitative ELISA analyses using antibodies recognising linear epitopes, but are less likely to be functional in receptor activation studies, that generally rely on protein structure based interactions. Antibodies specific for human TLR2 and TLR6 were used by Chen et al. to demonstrate inhibition of IL 6 production by human PBMC in response to E. coli derived NS1. Using these antibodies, we found no effect of TLR2 or TLR6 blockade on the response to insect NS1 (Figure 2a) As expected for PBMC from four different donors, the absolute level of response to stimuli was variable, but in all cases the activity of insect derived NS1 was completely prevented by anti TLR4 antibody as well as the TLR4 antagonist, Rhodobacter sphaeroides LPS (LPS RS) (Figure 2a) in agreement with our previous work. Responses to the control TLR2/6 stimulus Pam2CSK4 and TLR4 stimulus LPS were sensitive to the respective anti TLR antibodies, as expected. However, none of these TLR inhibitory agents affected the response to E. coli NS1 (Figure 2a) suggesting that it may be contaminated with a variety of TLR ligands acting redundantly. The dominant contaminants from E. coli are likely to be LPS and a number of TLR2/1 agonists including triacylated lipopeptides. Despite using the same sources of E. coli derived NS1 and blocking antibodies we were unable to replicate the results of Chen et al. One possible explanation for their results is that the TLR targeting antibodies bound to cells may lead to cell death if used in combination with serum that has not been adequately heat inactivated to destroy complement function, whilst isotype control antibodies that do not bind cells would have no effect. It is notable that in one experiment shown by Chen et al. anti TLR2 and TLR6 blocking antibodies inhibited the PBMC response to LPS to the same extent as they inhibited the response to a TLR2/6 ligand. In contrast, a supplementary figure showed LPS response unaffected by the same antibodies, but this data does not appear to have been generated in parallel with the relevant experiments. A further assessment of TLR dependence was performed with bone marrow derived macrophages (BMMs) from Tlr knockout mice. Activity of the insect derived NS1 was lost in Tlr4 cells, but was unaffected by knockout of Tlr1 or Tlr6 (Figure 2b) Our prior work using Tlr2 BMM similarly showed no role for TLR2 in the stimulatory activity of purified insectderived NS1. Similar to results with PBMC cultures, E. coli derived NS1 at 10 mg/ml was strongly active, with this activity not abolished by any individual Tlr knockout. However at 1 mg/ml, its induction of IL 6 was TLR4 dependent. This was distinct from the human cell response, where TLR4 responses did not clearly dominate at this concentration of E. coli NS1 (Figure 2a) This may reflect greater sensitivity of the human cells to possible contaminants within the preparation. Overall, these results cannot be reconciled with those of Chen et al. who reported that the response to E. coli derived NS1 was completely lost in Tlr6 mouse macrophages. Any study proposing a new ligand for TLR activation must exclude microbial contaminants. Chen and co workers used a synthetic 6X His tag peptide (Abcam Cat. 14943) as a control for NS1, however this preparation is unlikely to provide an adequate experimental control for possible bacterial contaminants present in a recombinant protein purified from E. coli. We used a Limulus amoebocyte lysate (LAL) assay to estimate the LPS content in 1 mg/ml of the commercially sourced E. coli derived NS1 to be 0.55 EU/ml, whilst 10 mg/ml insect derived NS1 was below the limit of detection <0.1 EU/ml) The E. coli derived NS1 preparation was active in induction of IL 6 by PBMC at concentrations as low as 0.64 ng/ml NS1, which was approximately 1000 fold more potent than insect cell derived NS1 (Figures 3a and 3b) The LPS binding antibiotic polymyxin B had no effect on the response to insect cell derived NS1 (Figure 3a) showing a lack of any accessible LPS as being responsible for its activity. In contrast, E. coli derived NS1 activity was reproducibly inhibited by polymyxin B, but only at low concentrations of NS1 (Figure 3b) suggesting the presence of a number of immunostimulatory agents including LPS. LPS and Pam2CSK4 treatments were used as positive and negative controls for TLR4 and TLR2/6 activation and polymyxin B sensitivity (Figures 3c and 3d) The broad dose response curve seen with E. coli derived NS1 is also consistent with it containing a number of stimulatory contaminants. In contrast, purified insect cell derived NS1, ultrapure LPS and Pam2CSK4 showed saturation of responses within 1 2 log units (Figures 3a d) The molar concentrations required for response to insect NS1 were approximately 10 fold higher than for LPS (Figures 3a and 3c) Whilst NS1 is a somewhat less potent agonist, concentrations of circulating NS1 seen in dengue virus infected patients are higher than levels of circulating LPS in bacterial sepsis. The median LPS reported in sepsis is 300 pg/ml (0.03 nM assuming molecular weight of 10 kDa) ranging up to 5 ng/ml (0.5 nM) NS1 is detected in serum at ng/ml to mg/ml levels (1 mg/ml is 3.3 nM) Consequently, active concentrations of NS1 are within its physiological range. In addition, NS1 may be sequestered in vivo, for example by binding to endothelial cells, or masked by antibody, and its functional concentration may be higher than that measurable in serum. The results presented here clearly show the inadequacy of commercial bacterial expressed NS1 for studies of innate immune responses, due to protein misfolding and likely immunostimulatory contaminants. Although Chen et al. use
author_names: Naphak Modhiran

Daniel Watterson

Antje Blumenthal

Alan G Baxter

Paul R Young

Katryn J Stacey
title: Dengue virus NS 1 protein activates immune cells via TLR 4 but not TLR 2 or TLR 6
year: 2018

abstract: BackgroundExposure to particulate matter (PM) is a significant risk factor for increased cardiopulmonary morbidity and mortality. The mechanism of PM mediated pathophysiology remains unknown. However, PM is proinflammatory to the endothelium and increases vascular permeability in vitro and in vivo via ROS generation.ObjectivesWe explored the role of tight junction proteins as targets for PM induced loss of lung endothelial cell (EC) barrier integrity and enhanced cardiopulmonary dysfunction.MethodsChanges in human lung EC monolayer permeability were assessed by Transendothelial Electrical Resistance (TER) in response to PM challenge (collected from Ft. McHenry Tunnel, Baltimore, MD, particle size >0.1 mm) Biochemical assessment of ROS generation and Ca2+ mobilization were also measured.ResultsPM exposure induced tight junction protein Zona occludens 1 (ZO 1) relocation from the cell periphery, which was accompanied by significant reductions in ZO 1 protein levels but not in adherens junction proteins (VE cadherin and b catenin) N acetyl cysteine (NAC, 5 mM) reduced PM induced ROS generation in ECs, which further prevented TER decreases and atteneuated ZO 1 degradation. PM also mediated intracellular calcium mobilization via the transient receptor potential cation channel M2 (TRPM2) in a ROS dependent manner with subsequent activation of the Ca2+ dependent protease calpain. PM activated calpain is responsible for ZO 1 degradation and EC barrier disruption. Overexpression of ZO 1 attenuated PM induced endothelial barrier disruption and vascular hyperpermeability in vivo and in vitro.ConclusionsThese results demonstrate that PM induces marked increases in vascular permeability via ROS mediated calcium leakage via activated TRPM2, and via ZO 1 degradation by activated calpain. These findings support a novel mechanism for PM induced lung damage and adverse cardiovascular outcomes.
author_names: Ting Wang

Lichun Wang

Liliana Moreno-Vinasco

Gabriel D Lang

Jessica H Siegler

Biji Mathew

Peter V Usatyuk

Jonathan M Samet

Alison Geyh

Patrick N Breysse

Viswanathan Natarajan

Joe G N Garcia
title: Particulate matter air pollution disrupts endothelial cell barrier via calpain mediated tight junction protein degradation
venue: Particle and Fibre Toxicology
year: 2012

abstract: This special issue is a selection of 15 papers reflecting recent advances in the molecular simulation of chemical reactions. The first part of this issue is devoted to new developments and applications of reactive force fields and reactive molecular dynamics (MD) simulation. Yunfeng Shi discusses a minimalist's reactive force field, known as the reactive state summation potential, which can be regarded as a 'reactive Lennard Jones' potential, and its application to the modelling of detonation, of the pyrolysis of activated carbon and of catalytic chemical reactions. Ziqi Tian, Jin Wen and Jing Ma discuss how reactive MD simulations can be used to model the collective switching process in azobenzenebased self assembled monolayers on a Au (111) surface. Xiaoxia Li, Zheng Mo, Jian Liu and Li Guo develop a new methodology by combining graphics processing unit enabled high performance computing with cheminformatics analysis in order to explore coal pyrolysis using reactive MD (ReaxFF MD) The second part of this issue focuses on the development on new simulation strategies and new simulation methods to identify reaction pathways and reaction intermediates. Paul M. Zimmerman discusses an automated simulation strategy for investigating multiple elementary step reaction mechanisms in chemical systems, by starting from a single input structure, seeking out nearby intermediates, optimising the proposed structure and then determining the kinetic viability of each elementary step. Shaohui Zheng and Jim Pfaendtner discuss the application of metadynamics to perform an enhanced sampling of chemical and biochemical reactions and provide detailed summaries of the method applied in various contexts including condensed phase and biological reactions. Styliani Consta and Anatoly Malevanets use different molecular simulation techniques to sample the activated processes of fragmentation and ion escapes and to shed light on the disintegration mechanisms of charged nanodroplets. Sophya Garashchuk, Jacek Jakowski and Vitaly Rassolov propose an approximate quantum trajectory dynamics method, based on a Bohmian formulation of the time dependent Schrodinger equation, and apply this approach to study systems with applications in biochemistry and in materials science. Franz Martinez and Gabriel Hanna discuss the assessment of approximate solutions of the quantum classical Liouville equation for the dynamics simulations of quantum subsystems embedded in classical environments and present results on photo induced electron transfer and on proton transfer. The third part of this issue examines the reactivity and catalytic properties of systems of nanoscopic dimensions. Using representative models of various supported nanoparticle systems, Eric D. Hermes, Glen R. Jenness and J.R. Schmidt perform computational studies based on density functional theory (DFT) to decouple the metal support interaction in terms of electronic and geometric effects, including the role of support oxygen vacancies and the reactivity of perimeter sites at the metal oxide boundary. Qingguo Meng, Jiangchao Chen and Dmitri Kilin use ab initio MD at the DFT level to carry out a systematic study of the sequential H2 dissociation of a Pd13H24 cluster and compare the catalytic activities of Pd nanoparticles for proton reduction. The fourth part focuses on furthering our understanding of electronic processes in solution. Katie W. Corum and Sara E. Mason test the reactivity of cations (Cu2th, Pb2th, Zn2th) and anions (SO4 Cl) to aqueous Al30 by using DFT methods with the aim of developing a molecular level understanding of geochemical model systems. Chun C. Mak and Gilles H. Peslherbe present a comprehensive overview of the development and application of state of the art first principles MD simulations to understand the results of femtosecond photoelectron spectroscopy experiments on [I(Solv)n] relaxation, and unveil the solvent specificity of excited anionic cluster relaxation and electron solvation. The last part of the issue discusses the latest developments on combined quantum classical methods. Building on the widely used combined QM/MM (quantum mechanics/molecular mechanics) methods in multi scale modelling, Soroosh Pezeshki and Hai Lin provide an overview of recently developed QM/MM algorithms towards the ultimate goal of establishing an open boundary between the QM and MM subsystems. Patrik R. Callis highlights selected classical MD in combination with QM (MD th QM) simulations of time dependent wavelength shifts in solvents and proteins, fluorescence quenching rates, dielectric compensation by water, heterogeneity of quenching rates and applications to protein folding. Feng Wang and Marawan Ahmed review applications of computational methods and rational molecule design,
author_names: Jerome Delhommelle
title: Recent advances in the molecular simulation of chemical reactions
year: 2015

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author_names: John Wiley
title: A wiley interscience publication
year: 1972

abstract: 3238 Assessment of Pgp function in leukemic blasts provides useful prognostic information regarding rates and treatment response and may be used for therapy selection in acute myeloid leukemia (AML) patients. Traditional assessment of Pgp function has utilized fluorescent indicators, such as DiOC2(3)or rhodamine 123 (Rh123) as surrogates for drug uptake and efflux. The objectives of this study were 1) to compare the performance of these two commonly used probes and representative therapeutic drugs in bidirectional in vitro permeability models, and 2) to validate the methodology for measuring Pgp+ status in patient cells when exposed to actual drugs susceptible to MDR [eg, daunorubicin (DNR) epirubicin (EPI) etoposide (VP 16) idarubicin (IDA) and mitoxantrone (MIT) versus the surrogate probes and amonafide, a topoisomerase II inhibitor, which is not an MDR substrate (O'Loughlin et al. Blood 2007) Pgp mediated differential transport was assessed in Caco 2 cells (Pgplow) or MDR1 MDCK (Pgphigh) monolayer cells as a bidirectional efflux/influx ratio (BD) calculated from separate apical to basolateral (A B) and basolateral to apical (B A) drug permeability measurements or as a monodirectional efflux/influx ratio (MD) based on the change in B A permeability, both performed before and after co administration of cyclosporin A (CSA) an inhibitor of Pgp. Our results indicated a significant correlation between BD and MD. The two methods afforded the same rank order in extent of efflux for the cohort of test compounds in both Pgplow and Pgphigh. The net efflux of amonafide was
author_names: Mydoanh Chau

Ante Sven Lundberg

Maria R Baer

Harry P Erba

Robert L Capizzi

Alfred M Ajami
title: Multidrug resistance (MDR) in AML: Predicting P glycoprotein (Pgp) function by direct measurement of drug efflux is more effective than use of surrogate efflux indicators
year: 2008

abstract: The mode of action of venom from the endoparasitic wasp, Pimpla turionellae, was studied using in vitro assays and fluorescent microscopy. Crude venom was found to be cytotoxic to an embryonic cell line (BTI TN 5B1 4) derived from the cabbage looper, Trichoplusia ni. Susceptible cells displayed progressive morphological changes, such as retraction of cytoplasmic extensions, followed by Correspondence/Reprint request: Dr. David B. Rivers, Department of Biology, Loyola College in Maryland Baltimore MD, USA. E mail: drivers@loyola.edu Bridget Keenan et al. 2 rounding, swelling, and eventual vacuolization of the cytoplasm, all within 6 h of venom treatment. Cell death, however, did not occur for an additional 6 10 h at 27C. Pre treatment of cell monolayers with the osmotic protectants raffinose and sucrose afforded limited protection from the effects of venom: the presence of either saccharide yielded a time and dose dependent delay in the induction of cell rounding and swelling. The protection was not permanent as all pre treated cells eventually died by 24 36 h following incubation with crude venom. Venom induced changes in cell morphology were preceded by elevations in intracellular Ca as evidenced by labeling of cytosolic Ca with the fluorescent probe fluo 4 AM. Such changes in calcium homeostasis suggested involvement of calcium release channels on the endoplasmic reticulum. However, when array of potent calcium channel modulators (heparin, verapamil, caffeine, and xestospongin c) were tested, none were capable of preventing a rise in intracellular Ca or the venom associated morphological changes. Likewise, inhibitors of calcium channels typical of insect plasma membranes and use of culture media lacking calcium did not prevent increases in [Ca]i following venom exposure. Assessment of mitochondrial membrane potential (Psm) using rhodamine 123 revealed no significant qualitative changes due to wasp venom, and thus arguing that unregulated efflux of calcium into the cytosol did not account for the rise in [Ca]i.
author_names: B S Keenan

Fevzi Uckan

Ekrem Ergin

David B Rivers

Jay A Yoder
title: Morphological and biochemical changes in cultured cells induced by venom from the endoparasitoid, Pimpla turionellae.
year: 2007

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Antitumor efficacy of poly(brassylic acid pentadecandioic acid) copolymer. Guo WX, Long ZJ, Zhang Z, Hu LX. 2007. Materials Science Engineering C Biomimetic and Supramolecular Systems 27:51 56. Application of sucrose fatty acid esters in transdermal therapeutic systems. Csoka G, Marton S, Zelko R, Otomo N, Antal I. 2007. European Journal of Pharmaceutics and Biopharmaceutics 65:233 237. Assessment of subconjunctival and intrascleral drug delivery to the posterior segment using dynamic contrast enhanced magnetic resonance imaging. Kim SH, Galban CJ, Lutz RJ, Dedrick RL, Csaky KG, Lizak MJ, Wang NS, Tansey G, Robinson MR. 2007. Investigative Ophthalmology Visual Science 48:808 814. Behavior of temperature sensitive PNIPAM confined in polyelectrolyte capsules. Prevot M, Dejugnat C, Mohwald H, Sukhorukov GB. 2006. Chemphyschem 7:2497 2502. Bifunctional ligands that target cells displaying the alpha(v)beta(3) integrin. Owen RM, Carlson CB, Xu JW, Mowery P, Fasella E, Kiessling LL. 2007. Chembiochem 8:68 82. Bio functional micelles self assembled from a folate conjugated block copolymer for targeted intracellular delivery of anticancer drugs. Liu SQ, Wiradharma N, Gao SJ, Tong YW, Yang YY. 2007. Biomaterials 28:1423 1433. Bioavailability of riboflavin from a gastric retention formulation. Ahmed IS, Ayres JW. 2007. International Journal of Pharmaceutics 330:146 154. Biocompatible polymer vesicles from biamphiphilic triblock copolymers and their interaction with bovine serum albumin. Wittemann A, Azzam T, Eisenberg A. 2007. Langmuir 23:2224 2230. Biodegradable blend films based on two polysaccharide derivatives and their use as ibuprofen releasing matrices. Yi JZ, Zhang LM. 2007. Journal of Applied Polymer Science 103:3553 3559. Biodegradable polymers applied in tissue engineering research: a review. Martina M, Hutmacher DW. 2007. Polymer International 56:145 157. Blood brain barrier delivery. Pardridge WM. 2007. Drug Discovery Today 12:54 61. 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Clinical health information technologies and the role of Medicaid. Alfreds ST, Tutty M, Savageau JA, Young S, Himmelstein J. 2006. Health Care Financing Review 28:11 20. Colloidal stabilization of nanoparticles in concentrated suspensions. Studart AR, Amstad E, Gauckler LJ. 2007. Langmuir 23:1081 1090. Computational modeling to predict effect of treatment schedule on drug delivery to prostate in humans. Hu LJ, Au JLS, Wientjes MG. 2007. Clinical Cancer Research 13:1278 1287. Controlled release of vancomycin from thin sol gel films on titanium alloy fracture plate material. Radin S, Ducheyne P, 2007. Biomaterials 28:1721 1729. Controlled submicro particle formation of ampicillin by supercritical antisolvent precipitation. Tenorio A, Gordillo MD, Pereyra C, de la Ossa EJM. 2007. Journal of Supercritical Fluids 40:308 316. Core shell nanohydrogel structures as tunable delivery systems. Sahiner N, Alb AM, Graves R, Mandal T, McPherson GL, Reed WF, John VT. 2007. Polymer 48:704 711. Coronary stents: A materials perspective. Mani G, Feldman MD, Patel D, Agrawal CM. 2007. Biomaterials 28:1689 1710. Cross linking chitosan nanofibers. Schiffman JD, Schauer CL. 2007. Biomacromolecules 8:594 601. Customized PEG derived copolymers for tissue engineering applications. Tessmar JK, Gopferich AM. 2007. Macromolecular Bioscience 7:23 39. Cyanocobalamin (vitamin B 12) conjugates with enhanced solubility. Wang XY, Wei LH, Kotra LP. 2007. Bioorganic Medicinal Chemistry 15:1780 1787. Cyclodextrins and their pharmaceutical applications. Loftsson T, Duchene D. 2007. International Journal of Pharmaceutics 329:1 11.
title: Literature Alerts
year: 2007