The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform
Walter C Willett - One of the best experts on this subject based on the ideXlab platform.
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dietary acrylamide intake and risk of premenopausal breast cancer
American Journal of Epidemiology, 2009Co-Authors: Kathryn M Wilson, Wendy Y Chen, David J Hunter, Lorelei A Mucci, Walter C WillettAbstract:Acrylamide, a probable human carcinogen, is formed during high-temperature cooking of many commonly consumed foods. It is widespread; approximately 30% of calories consumed in the United States are from foods containing acrylamide. In animal studies, acrylamide causes mammary tumors, but it is unknown whether the level of acrylamide in foods affects human breast cancer risk. The authors studied the association between acrylamide intake and breast cancer risk among 90,628 premenopausal women in the Nurses' Health Study II. They calculated acrylamide intake from food frequency questionnaires in 1991, 1995, 1999, and 2003. From 1991 through 2005, they documented 1,179 cases of invasive breast cancer. They used Cox proportional hazards models to assess the association between acrylamide and breast cancer risk. The multivariable-adjusted relative risk of premenopausal breast cancer was 0.92 (95% confidence interval: 0.76, 1.11) for the highest versus the lowest quintile of acrylamide intake (Ptrend = 0.61). Results were similar regardless of smoking status or estrogen and progesterone receptor status of the tumors. The authors found no associations between intakes of foods high in acrylamide, including French fries, coffee, cereal, potato chips, potatoes, and baked goods, and breast cancer risk. They found no evidence that acrylamide intake, within the range of US diets, is associated with increased risk of premenopausal breast cancer.
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Validation of a food frequency questionnaire measurement of dietary acrylamide intake using hemoglobin adducts of acrylamide and glycidamide
Cancer Causes & Control, 2009Co-Authors: Kathryn M Wilson, Paula Tocco, Karl-erik Hellenäs, Johan Rosen, Laura Sampson, Walter C WillettAbstract:Objective Acrylamide, a probable human carcinogen, is formed during high-heat cooking of many common foods. The validity of food frequency questionnaire (FFQ) measures of acrylamide intake has not been established. We assessed the validity of acrylamide intake calculated from an FFQ using a biomarker of acrylamide exposure. Methods We calculated acrylamide intake from an FFQ in the Nurses’ Health Study II. We measured hemoglobin adducts of acrylamide and its metabolite, glycidamide, in a random sample of 342 women. Correlation and regression analyses were used to assess the relationship between acrylamide intakes and adducts. Results The correlation between acrylamide intake and the sum of acrylamide and glycidamide adducts was 0.31 (95% CI: 0.20–0.41), adjusted for laboratory batch, energy intake, and age. Further adjustment for BMI, alcohol intake, and correction for random within-person measurement error in adducts gave a correlation of 0.34 (CI: 0.23–0.45). The intraclass correlation coefficient for the sum of adducts was 0.77 in blood samples collected 1–3 years apart in a subset of 45 women. Intake of several foods significantly predicted adducts in multiple regression. Conclusions Acrylamide intake and hemoglobin adducts of acrylamide and glycidamide were moderately correlated. Within-person consistency in adducts was high over time.
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validation of a food frequency questionnaire measurement of dietary acrylamide intake using hemoglobin adducts of acrylamide and glycidamide
Cancer Causes & Control, 2009Co-Authors: Kathryn M Wilson, Paula Tocco, Karl-erik Hellenäs, Margareta Törnqvist, Johan Rosen, Laura Sampson, Walter C Willett, Hubert W. VesperAbstract:Objective Acrylamide, a probable human carcinogen, is formed during high-heat cooking of many common foods. The validity of food frequency questionnaire (FFQ) measures of acrylamide intake has not been established. We assessed the validity of acrylamide intake calculated from an FFQ using a biomarker of acrylamide exposure.
Vojislava Pophristic - One of the best experts on this subject based on the ideXlab platform.
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helical Arylamide foldamers structure prediction by molecular dynamics simulations
New Journal of Chemistry, 2015Co-Authors: Zhiwei Liu, Ara M Abramyan, Vojislava PophristicAbstract:We present a molecular dynamics (MD) study on a series of helical Arylamide oligomers with systematically varying building blocks and linkage types. This study showcases a computational approach for the prediction of secondary structure properties of Arylamide foldamers and their solution dynamics. We demonstrate that the conformational characteristics of foldamers, such as the number of units per turn, helical pitch, and pore diameter, can be predicted by MD simulations of small oligomers significantly shorter than the foldamers in question. Importantly, the curvature angle, the key geometrical parameter in helical Arylamide structures, can be accurately determined by MD simulation of tetramers, entities with often less than one helical turn. The curvature angle is found to be a local property associated with one single residue/unit, which enables highly accurate predictive power for designing oligomers with various scaffolds and sizes. In addition, MD simulations with the improved force field parameters capture solvent effects in terms of both protic solvent competition with intramolecular H-bonds and solvophobic effects. The computational approach can provide useful insight into dynamical, mechanistic and functional properties of the Arylamide oligomer class, which will facilitate rational design of foldamers.
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Conformational preferences of furan- and thiophene-based Arylamides: a combined computational and experimental study
Physical chemistry chemical physics : PCCP, 2013Co-Authors: Jhenny F. Galan, Zhiwei Liu, Chi Ngong Tang, Shubhashis Chakrabarty, Guillermo Moyna, Vojislava PophristicAbstract:We examine the conformational preferences of the furan- and thiophene-based Arylamides, N-methylfuran-2-carboxamide (3) and N-methylthiophene-2-carboxamide (4), using a combination of computational methods and NMR experiments. The compound choice stems from their use as foldamer building blocks. We quantify the differences in the conformational rigidity of the two compounds, which governs corresponding foldamer conformations. Specifically, we demonstrate the effects of intramolecular hydrogen bonding (H-bonding), geometrical patterns and solvent polarity on Arylamide conformations by comparing 3, 4 and previously studied ortho-methoxy N-methylbenzamide (1) and ortho-methylthio N-methylbenzamide (2). The study reveals that compound 3, despite its non-optimal S(5)-type H-bond geometry, retains a large portion of the H-bonded (eclipsed) conformation even in polar protic solvents. This behaviour is consistent with the quantum mechanical (QM) torsional energy profile. The percentages of H-bonded conformers that 3 retains are just slightly smaller than those of 1, which has a stronger S(6)-type H-bond. As for 2 and 4, the replacement of the O atom in 1 by an S atom in 2 results in a 70–90% loss of the H-bonded conformer in solution. However, the equivalent O to S replacement in 3 (leading to 4) causes only 15–30% loss of the eclipsed conformers in 4. Therefore, conformational preferences of 4 are very different from 2, in contrast to the similarity between 3 and 1. This study shows how the interplay of several forces modulates the conformational flexibility of Arylamides. It also attests the strategy we are developing, which leads to accurate prediction of foldamer structure. The vital component of this strategy is the re-parameterization of critical force field parameters based on QM potential energy profiles, as well as validation of these parameters using experimental data in solution.
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An ab initio molecular orbital study of intramolecular hydrogen bonding in ortho-substituted Arylamides: implications for the parameterization of molecular mechanics force fields.
Journal of computational chemistry, 2011Co-Authors: Zhiwei Liu, Alexey Teslja, Vojislava PophristicAbstract:The aromatic oligoamide (Arylamide) foldamer class, characterized by the repetitive aromatic-amide pattern, is one of the most intensively studied foldamer families. In this article, the potential energy profiles with regard to torsional motions around the two types of aromatic-amide bonds (CaCp and CaN) are obtained at the B3LYP/6-311G(d,p) level of theory. The effect of ortho substituents with different hydrogen bonding abilities (OCH3 vs. SCH3) on the torsional potential profiles is analyzed in detail. There are several findings that have implications in foldamer design. The ortho-SCH3 substituent on the benzene ring produces a much more flexible Arylamide backbone with respect to the OCH3 substituent, as it restricts the CaCp torsion to a lesser extent. Interestingly, the rigidifying effect of the ortho-SCH3 substituent on the CaN torsion is very similar to that of the OCH3 substituent on the same linkage type. In addition, the SCH3 substituent prefers a perpendicular orientation with respect to the benzene ring to the in-plane one. It is also found that reparameterization of the corresponding torsional parameters, sometimes specific to the ortho substituent type, in the general amber force field is necessary for an accurate description of the backbone torsions in Arylamides. Six sets of partial charge/torsional parameters for each linkage (CaCp or CaN)/substituent (OCH3 or SCH3) combination are obtained based on the ab initio torsional profiles. Initial assessments of these parameters show good agreement with the ab initio results. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011
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Controlling the shape and flexibility of Arylamides: A combined ab initio, ab initio molecular dynamics, and classical molecular dynamics study
Journal of Physical Chemistry B, 2006Co-Authors: Vojislava Pophristic, Satyavani Vemparala, Michael L. Klein, Ivaylo Ivanov, Zhiwei Liu, William F. DegradoAbstract:Using quantum chemistry plus ab initio molecular dynamics and classical molecular dynamics methods, we address the relationship between molecular conformation and the biomedical function of Arylamide polymers. Specifically, we have developed new torsional parameters for a class of these polymers and applied them in a study of the interaction between a representative Arylamide and one of its biomedical targets, the anticoagulant drug heparin. Our main finding is that the torsional barrier of a C(aromatic)-C(carbonyl) bond increases significantly upon addition of an o-OCH2CH2NH3+ substituent on the benzene ring. Our molecular dynamics studies that are based on the original general AMBER force field (GAFF) and GAFF modified to include our newly developed torsional parameters show that the binding mechanism between the Arylamide and heparin is very sensitive to the choice of torsional potentials. Ab initio molecular dynamics simulation of the Arylamide independently confirms the degree of flexibility we obtain by classical molecular dynamics when newly developed torsional potentials are used.
Ingming Chiu - One of the best experts on this subject based on the ideXlab platform.
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inhibition of neurosphere formation in neural stem progenitor cells by acrylamide
Cell Transplantation, 2015Co-Authors: Jonghang Chen, Meishu Chen, Yingchin Ko, Ingming ChiuAbstract:Abstract Previous studies showed that transplantation of cultured neural stem/progenitor cells (NSPCs) could improve functional recovery for various neurological diseases. This study aims to develop a stem cell-based model for predictive toxicology of development in the neurological system after acrylamide exposure. Treatment of mouse (KT98/F1B-GFP) and human (U-1240 MG/F1B-GFP) NSPCs with 0.5 mM acrylamide resulted in the inhibition of neurosphere formation (definition of self-renewal ability in NSPCs), but not inhibition of cell proliferation. Apoptosis and differentiation of KT98 (a precursor of KT98/F1B-GFP) and KT98/F1B-GFP are not observed in acrylamide-treated neurospheres. Analysis of secondary neurosphere formation and differentiation of neurons and glia illustrated that acrylamide-treated KT98 and KT98/F1B-GFP neurospheres retain the NSPC properties, such as self-renewal and differentiation capacity. Correlation of acrylamide-inhibited neurosphere formation with cell-cell adhesion was observed in mouse NSPCs by live cell image analysis and the presence of acrylamide. Protein expression levels of cell adhesion molecules [neural cell adhesion molecule (NCAM) and N-cadherin] and extracellular signal-regulated kinases (ERK) in acrylamide-treated KT98/F1B-GFP and U-1240 MG/F1B-GFP neurospheres demonstrated that NCAM decreased and phospho-ERK (pERK) increased, whereas expression of N-cadherin remained unchanged. Analysis of AKT (protein kinase B, PKB)/β-catenin pathway showed decrease in phospho-AKT (p-AKT) and cyclin D1 expression in acrylamide-treated neurospheres of KT98/F1B-GFP. Furthermore, PD98059, an ERK phosphorylation inhibitor, attenuated acrylamide-induced ERK phosphorylation, indicating that pERK contributed to the cell proliferation, but not in neurosphere formation in mouse NSPCs. Coimmunoprecipitation results of KT98/F1B-GFP cell lysates showed that the complex of NCAM and fibroblast growth factor receptor 1 (FGFR1) is present in the neurosphere, and the amount of this complex decreases after acrylamide treatment. Our results reveal that acrylamide inhibits neurosphere formation through the disruption of the neurosphere architecture in NSPCs. The downregulation of cell-cell adhesion resulted from decreasing the levels of NCAM as well as the formation of NCAM/FGFR complex.
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Inhibition of neurosphere formation in neural stem/progenitor cells by acrylamide.
Cell Transplantation, 2013Co-Authors: Jonghang Chen, Meishu Chen, Yingchin Ko, Ingming ChiuAbstract:Abstract Previous studies showed that transplantation of cultured neural stem/progenitor cells (NSPCs) could improve functional recovery for various neurological diseases. This study aims to develop a stem cell-based model for predictive toxicology of development in the neurological system after acrylamide exposure. Treatment of mouse (KT98/F1B-GFP) and human (U-1240 MG/F1B-GFP) NSPCs with 0.5 mM acrylamide resulted in the inhibition of neurosphere formation (definition of self-renewal ability in NSPCs), but not inhibition of cell proliferation. Apoptosis and differentiation of KT98 (a precursor of KT98/F1B-GFP) and KT98/F1B-GFP are not observed in acrylamide-treated neurospheres. Analysis of secondary neurosphere formation and differentiation of neurons and glia illustrated that acrylamide-treated KT98 and KT98/F1B-GFP neurospheres retain the NSPC properties, such as self-renewal and differentiation capacity. Correlation of acrylamide-inhibited neurosphere formation with cell-cell adhesion was observed in mouse NSPCs by live cell image analysis and the presence of acrylamide. Protein expression levels of cell adhesion molecules [neural cell adhesion molecule (NCAM) and N-cadherin] and extracellular signal-regulated kinases (ERK) in acrylamide-treated KT98/F1B-GFP and U-1240 MG/F1B-GFP neurospheres demonstrated that NCAM decreased and phospho-ERK (pERK) increased, whereas expression of N-cadherin remained unchanged. Analysis of AKT (protein kinase B, PKB)/β-catenin pathway showed decrease in phospho-AKT (p-AKT) and cyclin D1 expression in acrylamide-treated neurospheres of KT98/F1B-GFP. Furthermore, PD98059, an ERK phosphorylation inhibitor, attenuated acrylamide-induced ERK phosphorylation, indicating that pERK contributed to the cell proliferation, but not in neurosphere formation in mouse NSPCs. Coimmunoprecipitation results of KT98/F1B-GFP cell lysates showed that the complex of NCAM and fibroblast growth factor receptor 1 (FGFR1) is present in the neurosphere, and the amount of this complex decreases after acrylamide treatment. Our results reveal that acrylamide inhibits neurosphere formation through the disruption of the neurosphere architecture in NSPCs. The downregulation of cell-cell adhesion resulted from decreasing the levels of NCAM as well as the formation of NCAM/FGFR complex.
William F. Degrado - One of the best experts on this subject based on the ideXlab platform.
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Antibacterial Mechanism of Action of Arylamide Foldamers
Antimicrobial agents and chemotherapy, 2011Co-Authors: Bruk Mensa, Yong Ho Kim, Sungwook Choi, Richard W. Scott, Gregory A. Caputo, William F. DegradoAbstract:Small Arylamide foldamers designed to mimic the amphiphilic nature of antimicrobial peptides (AMPs) have shown potent bactericidal activity against both Gram-negative and Gram-positive strains without many of the drawbacks of natural AMPs. These foldamers were shown to cause large changes in the permeability of the outer membrane of Escherichia coli. They cause more limited permeabilization of the inner membrane which reaches critical levels corresponding with the time required to bring about bacterial cell death. Transcriptional profiling of E. coli treated with sublethal concentrations of the Arylamides showed induction of genes related to membrane and oxidative stresses, with some overlap with the effects observed for polymyxin B. Protein secretion into the periplasm and the outer membrane is also compromised, possibly contributing to the lethality of the Arylamide compounds. The induction of membrane stress response regulons such as rcs coupled with morphological changes at the membrane observed by electron microscopy suggests that the activity of the Arylamides at the membrane represents a significant contribution to their mechanism of action.
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Orientation, Dynamics, and Lipid Interaction of an Antimicrobial Arylamide Investigated by 19F and 31P Solid-State NMR Spectroscopy
Journal of the American Chemical Society, 2010Co-Authors: William F. Degrado, Mei HongAbstract:A number of Arylamides have been synthesized and found to exhibit potent antimicrobial activities against a broad spectrum of Gram-positive and Gram-negative bacteria while exhibiting low toxicity toward eukaryotic cells. These facially amphiphilic foldamers have a relatively rigid intramolecular hydrogen-bonded Arylamide as a framework, which places trifluormethyl versus positively charged amino and guanidino groups along opposite faces of the elongated molecule, facilitating interactions with lipid membranes. To better understand the mechanism of action of these antimicrobial foldamers, we have investigated the lipid interaction, depth of insertion, orientation, and dynamics of an Arylamide, PMX30016, using 31P and 19F solid-state NMR spectroscopy. Static 31P NMR line shapes of lipid membranes with a range of compositions indicate that PMX30016 does not disrupt the lamellar order of the lipid bilayer but perturbs the lipid headgroup conformation. This headgroup perturbation, manifested as systematic 31P...
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Controlling the shape and flexibility of Arylamides: A combined ab initio, ab initio molecular dynamics, and classical molecular dynamics study
Journal of Physical Chemistry B, 2006Co-Authors: Vojislava Pophristic, Satyavani Vemparala, Michael L. Klein, Ivaylo Ivanov, Zhiwei Liu, William F. DegradoAbstract:Using quantum chemistry plus ab initio molecular dynamics and classical molecular dynamics methods, we address the relationship between molecular conformation and the biomedical function of Arylamide polymers. Specifically, we have developed new torsional parameters for a class of these polymers and applied them in a study of the interaction between a representative Arylamide and one of its biomedical targets, the anticoagulant drug heparin. Our main finding is that the torsional barrier of a C(aromatic)-C(carbonyl) bond increases significantly upon addition of an o-OCH2CH2NH3+ substituent on the benzene ring. Our molecular dynamics studies that are based on the original general AMBER force field (GAFF) and GAFF modified to include our newly developed torsional parameters show that the binding mechanism between the Arylamide and heparin is very sensitive to the choice of torsional potentials. Ab initio molecular dynamics simulation of the Arylamide independently confirms the degree of flexibility we obtain by classical molecular dynamics when newly developed torsional potentials are used.
Holger Stark - One of the best experts on this subject based on the ideXlab platform.
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development of novel 1 2 3 4 tetrahydroisoquinoline derivatives and closely related compounds as potent and selective dopamine d3 receptor ligands
ChemBioChem, 2004Co-Authors: Ulrich R Mach, Anneke E Hackling, Sylvie Perachon, Sandrine Ferry, Camille Georges Wermuth, Jeancharles Schwartz, Pierre Sokoloff, Holger StarkAbstract:: Based on N-alkylated 1,2,3,4-tetrahydroisoquinoline derivatives, which are structurally related to the partial agonist BP 897, a series of novel, selective dopamine D3 receptor antagonists has been synthesised. Derivatisation included changes in the Arylamide moiety and the tetrahydroisoquinoline substructure leading to compounds with markedly improved selectivities and affinities in the low nanomolar concentration range. From the 55 structures presented here, (E)-3-(4-iodophenyl)-N-(4-(1,2,3,4-tetrahydroisoquinolin-2-yl)butyl)acrylamide (51) has high affinity (Ki(hD3)=12 nM) and a 123-fold preference for the D3 receptor relative to the D2 receptor subtype. Its pharmacological profile offers the prospect of a novel radioligand as a tool for various dopamine D3-receptor-related in vitro and in vivo investigations.
