Science.gov

Sample records for molecular mechanics approach

  1. Ab initio quantum mechanical/molecular mechanical simulation of electron transfer process: Fractional electron approach

    SciTech Connect

    Zeng Xiancheng; Hu Hao; Hu Xiangqian; Cohen, Aron J.; Yang Weitao

    2008-03-28

    Electron transfer (ET) reactions are one of the most important processes in chemistry and biology. Because of the quantum nature of the processes and the complicated roles of the solvent, theoretical study of ET processes is challenging. To simulate ET processes at the electronic level, we have developed an efficient density functional theory (DFT) quantum mechanical (QM)/molecular mechanical (MM) approach that uses the fractional number of electrons as the order parameter to calculate the redox free energy of ET reactions in solution. We applied this method to study the ET reactions of the aqueous metal complexes Fe(H{sub 2}O){sub 6}{sup 2+/3+} and Ru(H{sub 2}O){sub 6}{sup 2+/3+}. The calculated oxidation potentials, 5.82 eV for Fe(II/III) and 5.14 eV for Ru(II/III), agree well with the experimental data, 5.50 and 4.96 eV, for iron and ruthenium, respectively. Furthermore, we have constructed the diabatic free energy surfaces from histogram analysis based on the molecular dynamics trajectories. The resulting reorganization energy and the diabatic activation energy also show good agreement with experimental data. Our calculations show that using the fractional number of electrons (FNE) as the order parameter in the thermodynamic integration process leads to efficient sampling and validate the ab initio QM/MM approach in the calculation of redox free energies.

  2. Quantum mechanics-molecular dynamics approach to the interpretation of x-ray absorption spectra.

    PubMed

    Kuzmin, A; Evarestov, R A

    2009-02-01

    The quantum mechanics-molecular dynamics approach to the simulation of configuration-averaged EXAFS spectra is proposed, and its application is discussed for the example of the Ti K-edge EXAFS spectrum in cubic perovskite SrTiO(3). Proper use of ab initio quantum mechanics allows a number of empirical parameters, used in the molecular dynamics simulation, to be reduced, whereas the molecular dynamics allows us to account for temperature effects. All together, the approach provides a way of accounting for static and dynamic disorder in EXAFS signals from the coordination shells above the first one, where many-atom (multiple-scattering) effects are often important.

  3. Computing pKa Values with a Mixing Hamiltonian Quantum Mechanical/Molecular Mechanical Approach.

    PubMed

    Liu, Yang; Fan, Xiaoli; Jin, Yingdi; Hu, Xiangqian; Hu, Hao

    2013-09-10

    Accurate computation of the pKa value of a compound in solution is important but challenging. Here, a new mixing quantum mechanical/molecular mechanical (QM/MM) Hamiltonian method is developed to simulate the free-energy change associated with the protonation/deprotonation processes in solution. The mixing Hamiltonian method is designed for efficient quantum mechanical free-energy simulations by alchemically varying the nuclear potential, i.e., the nuclear charge of the transforming nucleus. In pKa calculation, the charge on the proton is varied in fraction between 0 and 1, corresponding to the fully deprotonated and protonated states, respectively. Inspired by the mixing potential QM/MM free energy simulation method developed previously [H. Hu and W. T. Yang, J. Chem. Phys. 2005, 123, 041102], this method succeeds many advantages of a large class of λ-coupled free-energy simulation methods and the linear combination of atomic potential approach. Theory and technique details of this method, along with the calculation results of the pKa of methanol and methanethiol molecules in aqueous solution, are reported. The results show satisfactory agreement with the experimental data.

  4. Exploring host-guest complexation mechanisms by a molecular dynamics/quantum mechanics/continuum solvent model approach

    NASA Astrophysics Data System (ADS)

    Ye, Renlong; Nie, Xuemei; Zhou, Yumei; Wong, Chung F.; Gong, Xuedong; Jiang, Wei; Tang, Weihua; Wang, Yan A.; Heine, Thomas; Zhou, Baojing

    2016-03-01

    We introduce a molecular dynamics/quantum mechanics/continuum solvent model (MD/QM/CSM) approach to investigate binding mechanisms of host-guest systems. The representative conformations of host, guest, and their complex generated from MD simulations at the molecular-mechanics level are used for binding free energy calculations based on a QM/CSM model. We use this approach to explore the binding mechanisms of β-cyclodextrin (β-CD) and 2, 6-di-methyl-β-CD (DM-β-CD) with various guest molecules. Our results suggest that solvent effects play a more important role in determining the relative binding affinities of DM-β-CD than those of β-CD mainly because the former is more flexible than the latter.

  5. [Modern evolutional developmental biology: mechanical and molecular genetic or phenotypic approaches?].

    PubMed

    Vorob'eva, É I

    2010-01-01

    Heightened interest in the evolutionary problems of developmental biology in the 1980s was due to the success of molecular genetics and disappointment in the synthetic theory of evolution, where the chapters of embryology and developmental biology seem to have been left out. Modern evo-devo, which turned out to be antipodean to the methodology of the synthetic theory of evolution, propagandized in the development of evolutionary problems only the mechanical and molecular genetic approach to the evolution of ontogenesis, based on cellular and intercellular interactions. The phonotypical approach to the evaluation of evolutionary occurrences in ontogenesis, which aids in the joining of the genetic and epigenetic levels of research, the theory of natural selection, the nomogenetic conception, and the problem of the wholeness of the organism in onto- and phylogenesis may be against this. The phenotypic approach to ontogenesis is methodologically the most perspective for evolutionary developmental biology.

  6. A Systems Biology Approach Reveals Converging Molecular Mechanisms that Link Different POPs to Common Metabolic Diseases

    PubMed Central

    Ruiz, Patricia; Perlina, Ally; Mumtaz, Moiz; Fowler, Bruce A.

    2015-01-01

    Background: A number of epidemiological studies have identified statistical associations between persistent organic pollutants (POPs) and metabolic diseases, but testable hypotheses regarding underlying molecular mechanisms to explain these linkages have not been published. Objectives: We assessed the underlying mechanisms of POPs that have been associated with metabolic diseases; three well-known POPs [2,3,7,8-tetrachlorodibenzodioxin (TCDD), 2,2´,4,4´,5,5´-hexachlorobiphenyl (PCB 153), and 4,4´-dichlorodiphenyldichloroethylene (p,p´-DDE)] were studied. We used advanced database search tools to delineate testable hypotheses and to guide laboratory-based research studies into underlying mechanisms by which this POP mixture could produce or exacerbate metabolic diseases. Methods: For our searches, we used proprietary systems biology software (MetaCore™/MetaDrug™) to conduct advanced search queries for the underlying interactions database, followed by directional network construction to identify common mechanisms for these POPs within two or fewer interaction steps downstream of their primary targets. These common downstream pathways belong to various cytokine and chemokine families with experimentally well-documented causal associations with type 2 diabetes. Conclusions: Our systems biology approach allowed identification of converging pathways leading to activation of common downstream targets. To our knowledge, this is the first study to propose an integrated global set of step-by-step molecular mechanisms for a combination of three common POPs using a systems biology approach, which may link POP exposure to diseases. Experimental evaluation of the proposed pathways may lead to development of predictive biomarkers of the effects of POPs, which could translate into disease prevention and effective clinical treatment strategies. Citation: Ruiz P, Perlina A, Mumtaz M, Fowler BA. 2016. A systems biology approach reveals converging molecular mechanisms that

  7. Elucidating the catalytic mechanism of β-secretase (BACE1): a quantum mechanics/molecular mechanics (QM/MM) approach.

    PubMed

    Barman, Arghya; Prabhakar, Rajeev

    2013-03-01

    In this quantum mechanics/molecular mechanics (QM/MM) study, the mechanisms of the hydrolytic cleavage of the Met2-Asp3 and Leu2-Asp3 peptide bonds of the amyloid precursor protein (WT-substrate) and its Swedish mutant (SW) respectively catalyzed by β-secretase (BACE1) have been investigated by explicitly including the electrostatic and steric effects of the protein environment in the calculations. BACE1 catalyzes the rate-determining step in the generation of Alzheimer amyloid beta peptides and is widely acknowledged as a promising therapeutic target. The general acid-base mechanism followed by the enzyme proceeds through the following two steps: (1) formation of the gem-diol intermediate and (2) cleavage of the peptide bond. The formation of the gem-diol intermediate occurs with the barriers of 19.6 and 16.1 kcal/mol for the WT- and SW-substrate respectively. The QM/MM energetics predict that with the barriers of 21.9 and 17.2 kcal/mol for the WT- and SW-substrate respectively the cleavage of the peptide bond occurs in the rate-determining step. The computed barriers are in excellent agreement with the measured barrier of ∼18.0 kcal/mol for the SW-substrate and in line with the experimental observation that the cleavage of this substrate is sixty times more efficient than the WT-substrate.

  8. The mechanism of M.HhaI DNA C5 cytosine methyltransferase enzyme: A quantum mechanics/molecular mechanics approach

    PubMed Central

    Zhang, Xiaodong; Bruice, Thomas C.

    2006-01-01

    The mechanism of DNA cytosine-5-methylation catalyzed by the bacterial M.HhaI enzyme has been considered as a stepwise nucleophilic addition of Cys-81-S− to cytosine C6 followed by C5 nucleophilic replacement of the methyl of S-adenosyl-l-methionine to produce 5-methyl-6-Cys-81-S-5,6-dihydrocytosine. In this study, we show that the reaction is concerted from a series of energy calculations by using the quantum mechanical/molecular mechanical hybrid method. Deprotonation of 5-methyl-6-Cys-81-S-5,6-dihydrocytosine and expulsion of Cys-81-S− provides the product DNA 5-methylcytosine. A required base catalyst for this deprotonation is not available as a member of the active site structure. A water channel between the active site and bulk water allows entrance of solvent to the active site. Hydroxide at 10−7 mole fraction (pH = 7) is shown to be sufficient for the required catalysis. We also show that Glu-119-CO2H can divert the reaction by protonating cytosine N3 when Cys-81-S− attacks cytosine, to form the 6-Cys-81-S-3-hydrocytosine. The reactants and 6-Cys-81-S-3-hydrocytosine product are in rapid equilibrium, and this explains the observed hydrogen exchange of cytosine with solvent. PMID:16606828

  9. Medication-Related Osteonecrosis of the Jaw: New Insights into Molecular Mechanisms and Cellular Therapeutic Approaches

    PubMed Central

    Lombard, Thomas; Neirinckx, Virginie; Gilon, Yves

    2016-01-01

    In recent years, medication-related osteonecrosis of the jaw (MRONJ) became an arising disease due to the important antiresorptive drug prescriptions to treat oncologic and osteoporotic patients, as well as the use of new antiangiogenic drugs such as VEGF antagonist. So far, MRONJ physiopathogenesis still remains unclear. Aiming to better understand MRONJ physiopathology, the first objective of this review would be to highlight major molecular mechanisms that are known to be involved in bone formation and remodeling. Recent development in MRONJ pharmacological treatments showed good results; however, those treatments are not curative and could have major side effects. In parallel to pharmacological treatments, MSC grafts appeared to be beneficial in the treatment of MRONJ, in multiple aspects: (1) recruitment and stimulation of local or regional endogenous cells to differentiate into osteoblasts and thus bone formation, (2) beneficial impact on bone remodeling, and (3) immune-modulatory properties that decrease inflammation. In this context, the second objective of this manuscript would be to summarize the molecular regulatory events controlling osteogenic differentiation, bone remodeling, and osteoimmunology and potential beneficial effects of MSC related to those aspects, in order to apprehend MRONJ and to develop new therapeutic approaches. PMID:27721837

  10. Photodesorption of Interstellar Ices: a Wavelength-dependent Approach to Unveil Molecular Mechanisms

    NASA Astrophysics Data System (ADS)

    Fayolle, Edith; Bertin, Mathieu; Romanzin, Claire; Michaut, Xavier; Philippe, Laurent; Oberg, Karin I.; Linnartz, Harold; Fillion, Jean-Hugues

    2014-06-01

    In the cold and dense regions of the interstellar medium, non-thermal desorption of interstellar ices drives the ice-to-gas ratio of most molecules. More specifically, non-thermal desorption induced by UV photons has been proposed as the dominating mechanism responsible for the observation of cold molecular gas in various star-forming environments. In protoplanetary disks mid-planes, for example, UV photons from the pre-main sequence star can penetrate deep into the disk, reach the ice region and induce ice sublimation. In prestellar cores and in the outer parts of protostellar envelopes, it is the Lyman-alpha-dominated UV field generated locally by the interaction of cosmic rays with H2 that can potentially interact with ice mantles and result in observable cold molecular gas.To constrain the photodesorption mechanism of interstellar ices and predict its efficiency for various UV fields, we have developed a novel wavelength-dependent approach using the vacuum UV beamline DESIRS at the French synchrotron facility SOLEIL. Monochromatic tunable UV light in the 7 - 14 eV window is used to irradiate interstellar ice analogues and the rates at which molecules photodesorb are simultaneously measured using mass-spectrometry. The frequency resolved photodesorption spectra of pure CO and N2 ices show a clear UV-wavelength dependency, directly scaled to the absorption spectra of the condensed molecules, which hints for a Desorption Induced by Electronic Transition (DIET) process.The application of this technique to isotopically labeled layered ices and binary ice mixtures has further revealed that CO and N2 ice photodesorption is an indirect process where it is the electronic excitation of sub-surface species that leads to the desorption of surface molecules. The photodesorption efficiency of a species is thus linked to its molecular environment and photodesorption rates are different for pure and mixed ices. This has strong implications for astrochemical modeling and could

  11. Hybrid Quantum Mechanics/Molecular Mechanics/Coarse Grained Modeling: A Triple-Resolution Approach for Biomolecular Systems.

    PubMed

    Sokkar, Pandian; Boulanger, Eliot; Thiel, Walter; Sanchez-Garcia, Elsa

    2015-04-14

    We present a hybrid quantum mechanics/molecular mechanics/coarse-grained (QM/MM/CG) multiresolution approach for solvated biomolecular systems. The chemically important active-site region is treated at the QM level. The biomolecular environment is described by an atomistic MM force field, and the solvent is modeled with the CG Martini force field using standard or polarizable (pol-CG) water. Interactions within the QM, MM, and CG regions, and between the QM and MM regions, are treated in the usual manner, whereas the CG-MM and CG-QM interactions are evaluated using the virtual sites approach. The accuracy and efficiency of our implementation is tested for two enzymes, chorismate mutase (CM) and p-hydroxybenzoate hydroxylase (PHBH). In CM, the QM/MM/CG potential energy scans along the reaction coordinate yield reaction energies that are too large, both for the standard and polarizable Martini CG water models, which can be attributed to adverse effects of using large CG water beads. The inclusion of an atomistic MM water layer (10 Å for uncharged CG water and 5 Å for polarizable CG water) around the QM region improves the energy profiles compared to the reference QM/MM calculations. In analogous QM/MM/CG calculations on PHBH, the use of the pol-CG description for the outer water does not affect the stabilization of the highly charged FADHOOH-pOHB transition state compared to the fully atomistic QM/MM calculations. Detailed performance analysis in a glycine-water model system indicates that computation times for QM energy and gradient evaluations at the density functional level are typically reduced by 40-70% for QM/MM/CG relative to fully atomistic QM/MM calculations.

  12. Molecular mechanisms of tungstate-induced pancreatic plasticity: a transcriptomics approach

    PubMed Central

    Altirriba, Jordi; Barbera, Albert; Del Zotto, Héctor; Nadal, Belen; Piquer, Sandra; Sánchez-Pla, Alex; Gagliardino, Juan J; Gomis, Ramon

    2009-01-01

    Background Sodium tungstate is known to be an effective anti-diabetic agent, able to increase beta cell mass in animal models of diabetes, although the molecular mechanisms of this treatment and the genes that control pancreas plasticity are yet to be identified. Using a transcriptomics approach, the aim of the study is to unravel the molecular mechanisms which participate in the recovery of exocrine and endocrine function of streptozotocin (STZ) diabetic rats treated with tungstate, determining the hyperglycemia contribution and the direct effect of tungstate. Results Streptozotocin (STZ)-diabetic rats were treated orally with tungstate for five weeks. Treated (STZ)-diabetic rats showed a partial recovery of exocrine and endocrine function, with lower glycemia, increased insulinemia and amylasemia, and increased beta cell mass achieved by reducing beta cell apoptosis and raising beta cell proliferation. The microarray analysis of the pancreases led to the identification of three groups of differentially expressed genes: genes altered due to diabetes, genes restored by the treatment, and genes specifically induced by tungstate in the diabetic animals. The results were corroborated by quantitative PCR. A detailed description of the pathways involved in the pancreatic effects of tungstate is provided in this paper. Hyperglycemia contribution was studied in STZ-diabetic rats treated with phloridzin, and the direct effect of tungstate was determined in INS-1E cells treated with tungstate or serum from untreated or treated STZ-rats, observing that tungstate action in the pancreas takes places via hyperglycemia-independent pathways and via a combination of tungstate direct and indirect (through the serum profile modification) effects. Finally, the MAPK pathway was evaluated, observing that it has a key role in the tungstate-induced increase of beta cell proliferation as tungstate activates the mitogen-activated protein kinase (MAPK) pathway directly by increasing p42/p44

  13. A synthetic approach to a molecular crank mechanism: toward intramolecular motion transformation between rotation and translation.

    PubMed

    Okuno, Erika; Hiraoka, Shuichi; Shionoya, Mitsuhiko

    2010-05-01

    A molecular crank mechanism that enables transformation between rotational and translational motions was designed and synthesized. This molecule consists of a molecular ball bearing as the rotational part in which two disk-shaped rotors can rotate relative to each other through ligand exchange and flipping motion, and a [2]rotaxane as a translational part in which an axle molecule can move back-and-forth through the cavity of a crown ether-based macrocycle. (1)H NMR analysis revealed that these two motions influence each other.

  14. Interpretation of nuclear resonant vibrational spectra of rubredoxin using a combined quantum mechanics and molecular mechanics approach.

    PubMed

    Paulsen, Hauke; Trautwein, Alfred X; Wegner, Patrick; Schmidt, Christian; Chumakov, Aleksandr I; Schünemann, Volker

    2011-12-01

    Nuclear resonant vibrational spectra of the reduced and oxidized form of a mutant of rubredoxin from Pyrococcus abyssii were measured and are compared with simulated spectra that were calculated by a combined quantum mechanics (QM) and molecular mechanics (MM) method. Density functional theory was used for the QM level. Calculations were performed for different models of rubredoxin. Realistic spectra were simulated with reduced models that include at least the iron center, the four cysteins coordinating it, and the residues connected to the cysteins together with a QM layer that comprises the first two coordination shells of the iron center. Larger QM layers did not lead to significant changes of the simulated spectra.

  15. Molecular mechanisms of ionic liquid cytotoxicity probed by an integrated experimental and computational approach

    DOE PAGES

    Yoo, Brian; Jing, Benxin; Jones, Stuart E.; Lamberti, Gary A.; Zhu, Yingxi; Shah, Jindal K.; Maginn, Edward J.

    2016-02-02

    Ionic liquids (ILs) are salts that remain liquid down to low temperatures, and sometimes well below room temperature. ILs have been called “green solvents” because of their extraordinarily low vapor pressure and excellent solvation power, but ecotoxicology studies have shown that some ILs exhibit greater toxicity than traditional solvents. A fundamental understanding of the molecular mechanisms responsible for IL toxicity remains elusive. Here we show that one mode of IL toxicity on unicellular organisms is driven by swelling of the cell membrane. Cytotoxicity assays, confocal laser scanning microscopy, and molecular simulations reveal that IL cations nucleate morphological defects in themore » microbial cell membrane at concentrations near the half maximal effective concentration (EC50) of several microorganisms. Lastly, cytotoxicity increases with increasing alkyl chain length of the cation due to the ability of the longer alkyl chain to more easily embed in, and ultimately disrupt, the cell membrane.« less

  16. Molecular mechanisms of ionic liquid cytotoxicity probed by an integrated experimental and computational approach

    PubMed Central

    Yoo, Brian; Jing, Benxin; Jones, Stuart E.; Lamberti, Gary A.; Zhu, Yingxi; Shah, Jindal K.; Maginn, Edward J.

    2016-01-01

    Ionic liquids (ILs) are salts that remain liquid down to low temperatures, and sometimes well below room temperature. ILs have been called “green solvents” because of their extraordinarily low vapor pressure and excellent solvation power, but ecotoxicology studies have shown that some ILs exhibit greater toxicity than traditional solvents. A fundamental understanding of the molecular mechanisms responsible for IL toxicity remains elusive. Here we show that one mode of IL toxicity on unicellular organisms is driven by swelling of the cell membrane. Cytotoxicity assays, confocal laser scanning microscopy, and molecular simulations reveal that IL cations nucleate morphological defects in the microbial cell membrane at concentrations near the half maximal effective concentration (EC50) of several microorganisms. Cytotoxicity increases with increasing alkyl chain length of the cation due to the ability of the longer alkyl chain to more easily embed in, and ultimately disrupt, the cell membrane. PMID:26831599

  17. Mechanical Properties of Carbon Nanofiber Reinforced Polymer Composites-Molecular Dynamics Approach

    NASA Astrophysics Data System (ADS)

    Sharma, Sumit; Chandra, Rakesh; Kumar, Pramod; Kumar, Navin

    2016-06-01

    Molecular dynamics simulation has been used to study the effect of carbon nanofiber (CNF) volume fraction ( V f) and aspect ratio ( l/d) on mechanical properties of CNF-reinforced polypropylene (PP) composites. Materials Studio 5.5 has been used as a tool for finding the modulus and damping in composites. CNF composition in PP was varied by volume from 0% to 16%. The aspect ratio of CNF was varied from l/d = 5 to l/d = 100. Results show that, with only 2% addition by volume of CNF in PP, E 11 increases 748%. Increase in E 22 is much less in comparison to the increase in E 11. With the increase in the CNF aspect ratio ( l/d) up to l/d = 60, the longitudinal loss factor ( η 11) decreases rapidly. The results of this study have been compared with those available in the literature.

  18. Molecular mechanics approach for design and conformational studies of macrocyclic ligands

    SciTech Connect

    Rohini,; Akbar, Rifat; Kanungo, B. K.

    2015-08-28

    Computational Chemistry has revolutionized way of viewing molecules at the quantum mechanical scale by allowing simulating various chemical scenarios that are not possible to study in a laboratory. The remarkable applications of computational chemistry have promoted to design and test of the effectiveness of various methods for searching the conformational space of highly flexible molecules. In this context, we conducted a series of optimization and conformational searches on macrocyclic based ligands, 9N3Me5Ox, (1,4,7-tris(5-methyl-8-hydroxyquinoline)-1,4,7-triazacyclononane) and 12N3Me5Ox, (1,5,9-tris(5-methyl-8-hydroxyquinoline)-1,5,9-triazacyclododecane) and studied their selectivity and coordination behavior with some lanthanide metal ions in molecular mechanics and semiempirical methods. The methods include both systematic and random conformational searches for dihedral angles, torsion angles and Cartesian coordinates. Structural studies were carried out by using geometry optimization, coordination scans and electronic properties were evaluated. The results clearly show that chair-boat conformational isomer of 9N3Me5Ox ligand is more stable due to lower eclipsing ethane interaction and form stronger adduct complexes with lanthanide metal ion. This is because of the fact that, in a central unit of 9N3 of the ligand form six endo type bonds out of nine. The rest of bonds have trans conformation. In contrast, for the adduct of 12N3Me5Ox, two C-C bonds have on eclipsed conformation, and others have synclinal and antiperiplanar confirmations. The distortion of the two eclipsed conformations may affect the yields and the stability of the complexes.

  19. Molecular Characterisation of Transport Mechanisms at the Developing Mouse Blood–CSF Interface: A Transcriptome Approach

    PubMed Central

    Liddelow, Shane A.; Temple, Sally; Møllgård, Kjeld; Gehwolf, Renate; Wagner, Andrea; Bauer, Hannelore; Bauer, Hans-Christian; Phoenix, Timothy N.; Dziegielewska, Katarzyna M.; Saunders, Norman R.

    2012-01-01

    Exchange mechanisms across the blood–cerebrospinal fluid (CSF) barrier in the choroid plexuses within the cerebral ventricles control access of molecules to the central nervous system, especially in early development when the brain is poorly vascularised. However, little is known about their molecular or developmental characteristics. We examined the transcriptome of lateral ventricular choroid plexus in embryonic day 15 (E15) and adult mice. Numerous genes identified in the adult were expressed at similar levels at E15, indicating substantial plexus maturity early in development. Some genes coding for key functions (intercellular/tight junctions, influx/efflux transporters) changed expression during development and their expression patterns are discussed in the context of available physiological/permeability results in the developing brain. Three genes: Secreted protein acidic and rich in cysteine (Sparc), Glycophorin A (Gypa) and C (Gypc), were identified as those whose gene products are candidates to target plasma proteins to choroid plexus cells. These were investigated using quantitative- and single-cell-PCR on plexus epithelial cells that were albumin- or total plasma protein-immunopositive. Results showed a significant degree of concordance between plasma protein/albumin immunoreactivity and expression of the putative transporters. Immunohistochemistry identified SPARC and GYPA in choroid plexus epithelial cells in the embryo with a subcellular distribution that was consistent with transport of albumin from blood to cerebrospinal fluid. In adult plexus this pattern of immunostaining was absent. We propose a model of the cellular mechanism in which SPARC and GYPA, together with identified vesicle-associated membrane proteins (VAMPs) may act as receptors/transporters in developmentally regulated transfer of plasma proteins at the blood–CSF interface. PMID:22457777

  20. Multi-omics approach identifies molecular mechanisms of plant-fungus mycorrhizal interaction

    DOE PAGES

    Larsen, Peter E.; Sreedasyam, Avinash; Trivedi, Geetika; Desai, Shalaka D.; Dai, Yang; Cseke, Leland; Collart, Frank R.

    2016-01-19

    In mycorrhizal symbiosis, plant roots form close, mutually beneficial interactions with soil fungi. Before this mycorrhizal interaction can be established however, plant roots must be capable of detecting potential beneficial fungal partners and initiating the gene expression patterns necessary to begin symbiosis. To predict a plant root – mycorrhizal fungi sensor systems, we analyzed in vitro experiments of Populus tremuloides (aspen tree) and Laccaria bicolor (mycorrhizal fungi) interaction and leveraged over 200 previously published transcriptomic experimental data sets, 159 experimentally validated plant transcription factor binding motifs, and more than 120-thousand experimentally validated protein-protein interactions to generate models of pre-mycorrhizal sensormore » systems in aspen root. These sensor mechanisms link extracellular signaling molecules with gene regulation through a network comprised of membrane receptors, signal cascade proteins, transcription factors, and transcription factor biding DNA motifs. Modeling predicted four pre-mycorrhizal sensor complexes in aspen that interact with fifteen transcription factors to regulate the expression of 1184 genes in response to extracellular signals synthesized by Laccaria. Predicted extracellular signaling molecules include common signaling molecules such as phenylpropanoids, salicylate, and, jasmonic acid. Lastly, this multi-omic computational modeling approach for predicting the complex sensory networks yielded specific, testable biological hypotheses for mycorrhizal interaction signaling compounds, sensor complexes, and mechanisms of gene regulation.« less

  1. Multi-Omics Approach Identifies Molecular Mechanisms of Plant-Fungus Mycorrhizal Interaction

    PubMed Central

    Larsen, Peter E.; Sreedasyam, Avinash; Trivedi, Geetika; Desai, Shalaka; Dai, Yang; Cseke, Leland J.; Collart, Frank R.

    2016-01-01

    In mycorrhizal symbiosis, plant roots form close, mutually beneficial interactions with soil fungi. Before this mycorrhizal interaction can be established however, plant roots must be capable of detecting potential beneficial fungal partners and initiating the gene expression patterns necessary to begin symbiosis. To predict a plant root—mycorrhizal fungi sensor systems, we analyzed in vitro experiments of Populus tremuloides (aspen tree) and Laccaria bicolor (mycorrhizal fungi) interaction and leveraged over 200 previously published transcriptomic experimental data sets, 159 experimentally validated plant transcription factor binding motifs, and more than 120-thousand experimentally validated protein-protein interactions to generate models of pre-mycorrhizal sensor systems in aspen root. These sensor mechanisms link extracellular signaling molecules with gene regulation through a network comprised of membrane receptors, signal cascade proteins, transcription factors, and transcription factor biding DNA motifs. Modeling predicted four pre-mycorrhizal sensor complexes in aspen that interact with 15 transcription factors to regulate the expression of 1184 genes in response to extracellular signals synthesized by Laccaria. Predicted extracellular signaling molecules include common signaling molecules such as phenylpropanoids, salicylate, and jasmonic acid. This multi-omic computational modeling approach for predicting the complex sensory networks yielded specific, testable biological hypotheses for mycorrhizal interaction signaling compounds, sensor complexes, and mechanisms of gene regulation. PMID:26834754

  2. Combined transcriptomic and metabolomic approach uncovers molecular mechanisms of cold tolerance in a temperate flesh fly.

    PubMed

    Teets, Nicholas M; Peyton, Justin T; Ragland, Gregory J; Colinet, Herve; Renault, David; Hahn, Daniel A; Denlinger, David L

    2012-08-01

    The ability to respond rapidly to changes in temperature is critical for insects and other ectotherms living in variable environments. In a physiological process termed rapid cold-hardening (RCH), exposure to nonlethal low temperature allows many insects to significantly increase their cold tolerance in a matter of minutes to hours. Additionally, there are rapid changes in gene expression and cell physiology during recovery from cold injury, and we hypothesize that RCH may modulate some of these processes during recovery. In this study, we used a combination of transcriptomics and metabolomics to examine the molecular mechanisms of RCH and cold shock recovery in the flesh fly, Sarcophaga bullata. Surprisingly, out of ∼15,000 expressed sequence tags (ESTs) measured, no transcripts were upregulated during RCH, and likewise RCH had a minimal effect on the transcript signature during recovery from cold shock. However, during recovery from cold shock, we observed differential expression of ∼1,400 ESTs, including a number of heat shock proteins, cytoskeletal components, and genes from several cell signaling pathways. In the metabolome, RCH had a slight yet significant effect on several metabolic pathways, while cold shock resulted in dramatic increases in gluconeogenesis, amino acid synthesis, and cryoprotective polyol synthesis. Several biochemical pathways showed congruence at both the transcript and metabolite levels, indicating that coordinated changes in gene expression and metabolism contribute to recovery from cold shock. Thus, while RCH had very minor effects on gene expression, recovery from cold shock elicits sweeping changes in gene expression and metabolism along numerous cell signaling and biochemical pathways.

  3. A Module Analysis Approach to Investigate Molecular Mechanism of TCM Formula: A Trial on Shu-feng-jie-du Formula

    PubMed Central

    Zhang, Fangbo; Tang, Shihuan; Liu, Xi; Gao, Yibo; Wang, Yanping

    2013-01-01

    At the molecular level, it is acknowledged that a TCM formula is often a complex system, which challenges researchers to fully understand its underlying pharmacological action. However, module detection technique developed from complex network provides new insight into systematic investigation of the mode of action of a TCM formula from the molecule perspective. We here proposed a computational approach integrating the module detection technique into a 2-class heterogeneous network (2-HN) which models the complex pharmacological system of a TCM formula. This approach takes three steps: construction of a 2-HN, identification of primary pharmacological units, and pathway analysis. We employed this approach to study Shu-feng-jie-du (SHU) formula, which aimed at discovering its molecular mechanism in defending against influenza infection. Actually, four primary pharmacological units were identified from the 2-HN for SHU formula and further analysis revealed numbers of biological pathways modulated by the four pharmacological units. 24 out of 40 enriched pathways that were ranked in top 10 corresponding to each of the four pharmacological units were found to be involved in the process of influenza infection. Therefore, this approach is capable of uncovering the mode of action underlying a TCM formula via module analysis. PMID:24376467

  4. Toxicogenomic approaches for understanding molecular mechanisms of heavy metal mutagenicity and carcinogenicity.

    PubMed

    Koedrith, Preeyaporn; Kim, Hyelim; Weon, Jong-Il; Seo, Young Rok

    2013-08-01

    Heavy metals that are harmful to humans include arsenic, cadmium, chromium, lead, mercury, and nickel. Some metals or their related compounds may even cause cancer. However, the mechanism underlying heavy metal-induced cancer remains unclear. Increasing data show a link between heavy metal exposure and aberrant changes in both genetic and epigenetic factors via non-targeted multiple toxicogenomic technologies of the transcriptome, proteome, metabolome, and epigenome. These modifications due to heavy metal exposure might provide a better understanding of environmental disorders. Such informative changes following heavy metal exposure might also be useful for screening of biomarker-monitored exposure to environmental pollutants and/or predicting the risk of disease. We summarize advances in high-throughput toxicogenomic-based technologies and studies related to exposure to individual heavy metal and/or mixtures and propose the underlying mechanism of action and toxicant signatures. Integrative multi-level expression analysis of the toxicity of heavy metals via system toxicology-based methodologies combined with statistical and computational tools might clarify the biological pathways involved in carcinogenic processes. Although standard in vitro and in vivo endpoint testing of mutagenicity and carcinogenicity are considered a complementary approach linked to disease, we also suggest that further evaluation of prominent biomarkers reflecting effects, responses, and disease susceptibility might be diagnostic. Furthermore, we discuss challenges in toxicogenomic applications for toxicological studies of metal mixtures and epidemiological research. Taken together, this review presents toxicogenomic data that will be useful for improvement of the knowledge of carcinogenesis and the development of better strategies for health risk assessment.

  5. Molecular mechanism of monodisperse colloidal tin-doped indium oxide nanocrystals by a hot-injection approach

    NASA Astrophysics Data System (ADS)

    Jin, Yizheng; Yi, Qing; Ren, Yuping; Wang, Xin; Ye, Zhizhen

    2013-04-01

    Molecular mechanisms and precursor conversion pathways associated with the reactions that generate colloidal nanocrystals are crucial for the development of rational synthetic protocols. In this study, Fourier transform infrared spectroscopy technique was employed to explore the molecular mechanism associated with the formation of tin-doped indium oxide (ITO) nanocrystals. We found that the reaction pathways of the indium precursor were not consistent with simple ligand replacements proposed in the literature. The resulting understanding inspired us to design a hot-injection approach to separate the ligand replacements of indium acetate and the aminolysis processes, generating quality ITO nanocrystals with decent size distributions. The hot-injection approach was readily applied to the synthesis of ITO nanocrystals with a broad range of tin doping. Structural, chemical, and optical analyses revealed effective doping of Sn4+ ions into the host lattices, leading to characteristic and tunable near-infrared surface plasmon resonance peaks. The size control of ITO nanocrystals by multiple hot-injections of metal precursors was also demonstrated.

  6. Molecular mechanism of monodisperse colloidal tin-doped indium oxide nanocrystals by a hot-injection approach

    PubMed Central

    2013-01-01

    Molecular mechanisms and precursor conversion pathways associated with the reactions that generate colloidal nanocrystals are crucial for the development of rational synthetic protocols. In this study, Fourier transform infrared spectroscopy technique was employed to explore the molecular mechanism associated with the formation of tin-doped indium oxide (ITO) nanocrystals. We found that the reaction pathways of the indium precursor were not consistent with simple ligand replacements proposed in the literature. The resulting understanding inspired us to design a hot-injection approach to separate the ligand replacements of indium acetate and the aminolysis processes, generating quality ITO nanocrystals with decent size distributions. The hot-injection approach was readily applied to the synthesis of ITO nanocrystals with a broad range of tin doping. Structural, chemical, and optical analyses revealed effective doping of Sn4+ ions into the host lattices, leading to characteristic and tunable near-infrared surface plasmon resonance peaks. The size control of ITO nanocrystals by multiple hot-injections of metal precursors was also demonstrated. PMID:23547801

  7. Systematic Analysis of the Molecular Mechanism Underlying Decidualization Using a Text Mining Approach

    PubMed Central

    Liu, Ji-Long; Wang, Tong-Song

    2015-01-01

    Decidualization is a crucial process for successful embryo implantation and pregnancy in humans. Defects in decidualization during early pregnancy are associated with several pregnancy complications, such as pre-eclampsia, intrauterine growth restriction and recurrent pregnancy loss. However, the mechanism underlying decidualization remains poorly understood. In the present study, we performed a systematic analysis of decidualization-related genes using text mining. We identified 286 genes for humans and 287 genes for mice respectively, with an overlap of 111 genes shared by both species. Through enrichment test, we demonstrated that although divergence was observed, the majority of enriched gene ontology terms and pathways were shared by both species, suggesting that functional categories were more conserved than individual genes. We further constructed a decidualization-related protein-protein interaction network consisted of 344 nodes connected via 1,541 edges. We prioritized genes in this network and identified 12 genes that may be key regulators of decidualization. These findings would provide some clues for further research on the mechanism underlying decidualization. PMID:26222155

  8. Systematic Analysis of the Molecular Mechanism Underlying Decidualization Using a Text Mining Approach.

    PubMed

    Liu, Ji-Long; Wang, Tong-Song

    2015-01-01

    Decidualization is a crucial process for successful embryo implantation and pregnancy in humans. Defects in decidualization during early pregnancy are associated with several pregnancy complications, such as pre-eclampsia, intrauterine growth restriction and recurrent pregnancy loss. However, the mechanism underlying decidualization remains poorly understood. In the present study, we performed a systematic analysis of decidualization-related genes using text mining. We identified 286 genes for humans and 287 genes for mice respectively, with an overlap of 111 genes shared by both species. Through enrichment test, we demonstrated that although divergence was observed, the majority of enriched gene ontology terms and pathways were shared by both species, suggesting that functional categories were more conserved than individual genes. We further constructed a decidualization-related protein-protein interaction network consisted of 344 nodes connected via 1,541 edges. We prioritized genes in this network and identified 12 genes that may be key regulators of decidualization. These findings would provide some clues for further research on the mechanism underlying decidualization. PMID:26222155

  9. Design-atom approach for the quantum mechanical/molecular mechanical covalent boundary: a design-carbon atom with five valence electrons.

    PubMed

    Xiao, Chuanyun; Zhang, Yingkai

    2007-09-28

    A critical issue underlying the accuracy and applicability of the combined quantum mechanical/molecular mechanical (QM/MM) methods is how to describe the QM/MM boundary across covalent bonds. Inspired by the ab initio pseudopotential theory, here we introduce a novel design atom approach for a more fundamental and transparent treatment of this QM/MM covalent boundary problem. The main idea is to replace the boundary atom of the active part with a design atom, which has a different number of valence electrons but very similar atomic properties. By modifying the Troullier-Martins scheme, which has been widely employed to construct norm-conserving pseudopotentials for density functional calculations, we have successfully developed a design-carbon atom with five valence electrons. Tests on a series of molecules yield very good structural and energetic results and indicate its transferability in describing a variety of chemical bonds, including double and triple bonds.

  10. Ecotoxicogenomic Approaches for Understanding Molecular Mechanisms of Environmental Chemical Toxicity Using Aquatic Invertebrate, Daphnia Model Organism

    PubMed Central

    Kim, Hyo Jeong; Koedrith, Preeyaporn; Seo, Young Rok

    2015-01-01

    Due to the rapid advent in genomics technologies and attention to ecological risk assessment, the term “ecotoxicogenomics” has recently emerged to describe integration of omics studies (i.e., transcriptomics, proteomics, metabolomics, and epigenomics) into ecotoxicological fields. Ecotoxicogenomics is defined as study of an entire set of genes or proteins expression in ecological organisms to provide insight on environmental toxicity, offering benefit in ecological risk assessment. Indeed, Daphnia is a model species to study aquatic environmental toxicity designated in the Organization for Economic Co-operation and Development’s toxicity test guideline and to investigate expression patterns using ecotoxicology-oriented genomics tools. Our main purpose is to demonstrate the potential utility of gene expression profiling in ecotoxicology by identifying novel biomarkers and relevant modes of toxicity in Daphnia magna. These approaches enable us to address adverse phenotypic outcomes linked to particular gene function(s) and mechanistic understanding of aquatic ecotoxicology as well as exploration of useful biomarkers. Furthermore, key challenges that currently face aquatic ecotoxicology (e.g., predicting toxicant responses among a broad spectrum of phytogenetic groups, predicting impact of temporal exposure on toxicant responses) necessitate the parallel use of other model organisms, both aquatic and terrestrial. By investigating gene expression profiling in an environmentally important organism, this provides viable support for the utility of ecotoxicogenomics. PMID:26035755

  11. Dynamical density functional theory for molecular and colloidal fluids: a microscopic approach to fluid mechanics.

    PubMed

    Archer, A J

    2009-01-01

    In recent years, a number of dynamical density functional theories (DDFTs) have been developed for describing the dynamics of the one-body density of both colloidal and atomic fluids. In the colloidal case, the particles are assumed to have stochastic equations of motion and theories exist for both the case when the particle motion is overdamped and also in the regime where inertial effects are relevant. In this paper, we extend the theory and explore the connections between the microscopic DDFT and the equations of motion from continuum fluid mechanics. In particular, starting from the Kramers equation, which governs the dynamics of the phase space probability distribution function for the system, we show that one may obtain an approximate DDFT that is a generalization of the Euler equation. This DDFT is capable of describing the dynamics of the fluid density profile down to the scale of the individual particles. As with previous DDFTs, the dynamical equations require as input the Helmholtz free energy functional from equilibrium density functional theory (DFT). For an equilibrium system, the theory predicts the same fluid one-body density profile as one would obtain from DFT. Making further approximations, we show that the theory may be used to obtain the mode coupling theory that is widely used for describing the transition from a liquid to a glassy state.

  12. Quantum mechanical and molecular mechanical simulation approaches bridging length and time scales for simulation of interface reactions in realistic environments

    NASA Astrophysics Data System (ADS)

    Knaup, J. M.; Tölle, P.; Köhler, Ch.; Frauenheim, Th.

    2009-10-01

    Computer-assisted design of functional materials requires methods that are able to simultaneously describe these with the necessary accuracy at the relevant time and length scales. One such possibility is the combination of classical interatomic force fields with density-functional based tight-binding (DFTB), an efficient and accurate quantum method. We employ this combination to study porous silicon dioxide functionalized with imidazole, which is used as an additive to polymer electrolyte membranes (PEM) for fuel cells applications. We analyze the water density and the dynamics of the functional groups at different temperatures by molecular dynamics simulation, whereas we calculate DFTB free energy barriers for proton transport reactions within the functionalized surface at different water contents. Combining both results, a macroscopic picture of the proton diffusion is drawn. Furthermore, we simulate the adsorption reactions of different components of an epoxide adhesive system on gamma alumina, using a direct coupling of DFTB and classical modeling. This yields direct chemical insight, how water and excess protons at the interface weaken the adhesion between epoxy polymers and natively oxidized aluminium.

  13. Mechanics of molecular motors

    NASA Astrophysics Data System (ADS)

    Visscher, Koen

    2001-03-01

    Molecular motors convert chemical energy into work by mechanisms that researchers are just starting to uncover. We have studied the coupling of chemistry to mechanics for kinesin, a motor protein that moves in a stepwise fashion along microtubules and is energized by the hydrolysis of ATP. Velocities of individual kinesin molecules at varying ATP concentrations and loads were recorded using a molecular force cl& a feedback-driven optical trap, which maintains constant loads on individual moving motor molecules. These measurements showed that kinesin requires only a single ATP molecule per mechanical step, and revealed the load-dependant biochemical transitions in the kinesin cycle where conformational changes are likely to occur. Modeling of the velocity data showed that kinesin mechanochemistry can be characterized by a mechanism that involves a thermally-activated and load-dependent isomerization directly following ATP binding. The model quantitatively accounts for velocity data over a wide range of loads and ATP concentrations, and indicates that movement may be accomplished through two sequential, non-identical, 4-nm sized substeps.

  14. Molecular mechanisms of etoposide

    PubMed Central

    Montecucco, Alessandra; Zanetta, Francesca; Biamonti, Giuseppe

    2015-01-01

    Etoposide derives from podophyllotoxin, a toxin found in the American Mayapple. It was first synthesized in 1966 and approved for cancer therapy in 1983 by the U.S. Food and Drug Administration (Hande, 1998[25]). Starting from 1980s several studies demonstrated that etoposide targets DNA topoisomerase II activities thus leading to the production of DNA breaks and eliciting a response that affects several aspects of cell metabolisms. In this review we will focus on molecular mechanisms that account for the biological effect of etoposide. PMID:26600742

  15. Understanding molecular structure from molecular mechanics.

    PubMed

    Allinger, Norman L

    2011-04-01

    Molecular mechanics gives us a well known model of molecular structure. It is less widely recognized that valence bond theory gives us structures which offer a direct interpretation of molecular mechanics formulations and parameters. The electronic effects well-known in physical organic chemistry can be directly interpreted in terms of valence bond structures, and hence quantitatively calculated and understood. The basic theory is outlined in this paper, and examples of the effects, and their interpretation in illustrative examples is presented.

  16. MOLECULAR MECHANISMS OF PHARMACONUTRIENTS

    PubMed Central

    Santora, R; Kozar, RA

    2009-01-01

    Nutritional supplementation has become the standard of care for management of critically ill patients. Traditionally, nutritional support in this patient population was intended to replete substrate deficiencies secondary to stress-induced catabolism. Recognition of the influence of certain nutrients on the immune and inflammatory response of the critically ill has led to the evolution of more sophisticated nutritional strategies and concepts. Administration of immune-enhancing formulas supplemented with a combination of glutamine, arginine, omega-3 fatty acids and nucleotides have been shown in most studies to reduce infectious outcomes. More recently, the separation of nutritional support from the provision of key nutrients, has led to a further appreciation of the immunomodulatory and anti-inflammatory benefits of isolated nutrients, such as glutamine and antioxidants. The purpose of this article is to review the molecular mechanisms that are unique to each class of frequently utilized nutrients. A better understanding of the specific molecular targets of immunonutrients will facilitate application of more refined nutritional therapies in critically ill patients. PMID:20080249

  17. MOLECULAR MECHANISMS OF PREECLAMPSIA

    PubMed Central

    Mutter, Walter P.; Karumanchi, S. Ananth

    2008-01-01

    Preeclampsia is a major cause of maternal, fetal, and neonatal mortality worldwide. The mechanisms that initiate preeclampsia in humans have been elusive, but some parts of the puzzle have begun to come together. A key discovery in the field was the realization that its major phenotypes, such as hypertension and proteinuria, are due to excess circulating soluble fms-like tyrosine kinase-1 (sFlt-1, also referred to as sVEGFR-1). sFlt-1 is an endogenous anti-angiogenic protein that is made by the placenta and acts by neutralizing the pro-angiogenic proteins vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). More recently, soluble endoglin, another circulating anti-angiogenic protein was found to synergize with sFlt1 and contribute to the pathogenesis of preeclampsia. Abnormalities in these circulating angiogenic proteins are not only present during clinical preeclampsia, but also antedate clinical symptoms by several weeks. This review will summarize our current understanding of the molecular mechanism of preeclampsia, with an emphasis on the recently characterized circulating anti-angiogenic proteins. PMID:17553534

  18. Understanding molecular mechanisms of traditional Chinese medicine for the treatment of influenza viruses infection by computational approaches.

    PubMed

    Gu, Shuo; Yin, Ning; Pei, Jianfeng; Lai, Luhua

    2013-11-01

    The battle against influenza is an enduring one. For hundreds of years, people have fought such small viruses with practices such as traditional Chinese medicine (TCM), however only recently has it been possible to use cutting-edge technology to investigate their mechanisms. Here, we re-created this ancient Chinese knowledge to explore the chemistry of herbs and elucidate their mechanism of action using molecular computational methods. Our results show that TCM compounds can inhibit influenza viral proteins in a multi-target/multi-component manner, revealing the versatility of TCM for treating different influenza virus subtypes, including the recently emerged H7N9.

  19. Molecular mechanisms of anesthesia.

    PubMed

    Ueda, I

    2001-03-01

    Anesthesia was a blessing to humankind. It is a miracle that simple molecules such as chloroform (CHCl3), diethyl ether (CH3.CH2.O.CH2.CH3), or nitrous oxide (N2O) induce a state of unconsciousness where patients can tolerate surgery. The diversity of the structures of these molecules indicates that there are no common receptors. The action of anesthetics is nonspecific and physical. After the demonstration by Meyer and Overton that anesthetic potencies correlate to their solubility into olive oil, the nonspecific lipid theories monopolized anesthesia theories for almost a century. The dominance of lipid theories invited repulsions against the nonspecificity idea. Protein theories that stress receptor bindings became the top mode. Nevertheless, the wide varieties of anesthetic molecules and the wide varieties of responding systems are difficult to reconcile with the specific interaction concept. This article discusses the recent progress and controversies on the molecular mechanisms of anesthesia. Anesthetics are unique drugs in pharmacology. They affect all macromolecules. The only comparable drugs are disinfectants. Both are nonspecific drugs. We use alcohols and phenols to wipe off the injection sites. We do not use penicillin or any other antibiotics for this purpose, because they are specific binders. Interestingly, these two nonspecific drugs opened the window for the modern medicine.

  20. Polarization effects in molecular mechanical force fields

    PubMed Central

    Cieplak, Piotr; Dupradeau, François-Yves; Duan, Yong; Wang, Junmei

    2014-01-01

    The focus here is on incorporating electronic polarization into classical molecular mechanical force fields used for macromolecular simulations. First, we briefly examine currently used molecular mechanical force fields and the current status of intermolecular forces as viewed by quantum mechanical approaches. Next, we demonstrate how some components of quantum mechanical energy are effectively incorporated into classical molecular mechanical force fields. Finally, we assess the modeling methods of one such energy component—polarization energy—and present an overview of polarizable force fields and their current applications. Incorporating polarization effects into current force fields paves the way to developing potentially more accurate, though more complex, parameterizations that can be used for more realistic molecular simulations. PMID:21828594

  1. A combined cryo-EM and molecular dynamics approach reveals the mechanism of ErmBL-mediated translation arrest.

    PubMed

    Arenz, Stefan; Bock, Lars V; Graf, Michael; Innis, C Axel; Beckmann, Roland; Grubmüller, Helmut; Vaiana, Andrea C; Wilson, Daniel N

    2016-01-01

    Nascent polypeptides can induce ribosome stalling, regulating downstream genes. Stalling of ErmBL peptide translation in the presence of the macrolide antibiotic erythromycin leads to resistance in Streptococcus sanguis. To reveal this stalling mechanism we obtained 3.6-Å-resolution cryo-EM structures of ErmBL-stalled ribosomes with erythromycin. The nascent peptide adopts an unusual conformation with the C-terminal Asp10 side chain in a previously unseen rotated position. Together with molecular dynamics simulations, the structures indicate that peptide-bond formation is inhibited by displacement of the peptidyl-tRNA A76 ribose from its canonical position, and by non-productive interactions of the A-tRNA Lys11 side chain with the A-site crevice. These two effects combine to perturb peptide-bond formation by increasing the distance between the attacking Lys11 amine and the Asp10 carbonyl carbon. The interplay between drug, peptide and ribosome uncovered here also provides insight into the fundamental mechanism of peptide-bond formation. PMID:27380950

  2. A combined cryo-EM and molecular dynamics approach reveals the mechanism of ErmBL-mediated translation arrest

    NASA Astrophysics Data System (ADS)

    Arenz, Stefan; Bock, Lars V.; Graf, Michael; Innis, C. Axel; Beckmann, Roland; Grubmüller, Helmut; Vaiana, Andrea C.; Wilson, Daniel N.

    2016-07-01

    Nascent polypeptides can induce ribosome stalling, regulating downstream genes. Stalling of ErmBL peptide translation in the presence of the macrolide antibiotic erythromycin leads to resistance in Streptococcus sanguis. To reveal this stalling mechanism we obtained 3.6-Å-resolution cryo-EM structures of ErmBL-stalled ribosomes with erythromycin. The nascent peptide adopts an unusual conformation with the C-terminal Asp10 side chain in a previously unseen rotated position. Together with molecular dynamics simulations, the structures indicate that peptide-bond formation is inhibited by displacement of the peptidyl-tRNA A76 ribose from its canonical position, and by non-productive interactions of the A-tRNA Lys11 side chain with the A-site crevice. These two effects combine to perturb peptide-bond formation by increasing the distance between the attacking Lys11 amine and the Asp10 carbonyl carbon. The interplay between drug, peptide and ribosome uncovered here also provides insight into the fundamental mechanism of peptide-bond formation.

  3. A combined cryo-EM and molecular dynamics approach reveals the mechanism of ErmBL-mediated translation arrest

    PubMed Central

    Arenz, Stefan; Bock, Lars V.; Graf, Michael; Innis, C. Axel; Beckmann, Roland; Grubmüller, Helmut; Vaiana, Andrea C.; Wilson, Daniel N.

    2016-01-01

    Nascent polypeptides can induce ribosome stalling, regulating downstream genes. Stalling of ErmBL peptide translation in the presence of the macrolide antibiotic erythromycin leads to resistance in Streptococcus sanguis. To reveal this stalling mechanism we obtained 3.6-Å-resolution cryo-EM structures of ErmBL-stalled ribosomes with erythromycin. The nascent peptide adopts an unusual conformation with the C-terminal Asp10 side chain in a previously unseen rotated position. Together with molecular dynamics simulations, the structures indicate that peptide-bond formation is inhibited by displacement of the peptidyl-tRNA A76 ribose from its canonical position, and by non-productive interactions of the A-tRNA Lys11 side chain with the A-site crevice. These two effects combine to perturb peptide-bond formation by increasing the distance between the attacking Lys11 amine and the Asp10 carbonyl carbon. The interplay between drug, peptide and ribosome uncovered here also provides insight into the fundamental mechanism of peptide-bond formation. PMID:27380950

  4. Molecular Approaches to Sarcoma Therapy

    PubMed Central

    Olsen, R. J.; Tarantolo, S. R.

    2002-01-01

    Soft tissue sarcomas comprise a heterogeneous group of aggressive tumors that have a relatively poor prognosis. Although conventional therapeutic regimens can effectively cytoreduce the overall tumor mass, they fail to consistently achieve a curative outcome. Alternative gene-based approaches that counteract the underlying neoplastic process by eliminating the clonal aberrations that potentiate malignant behavior have been proposed. As compared to the accumulation of gene alterations associated with epithelial carcinomas, sarcomas are frequently characterized by the unique presence of a single chromosomal translocation in each histological subtype. Similar to the Philadelphia chromosome associated with CML, these clonal abnormalities result in the fusion of two independent unrelated genes to generate a unique chimeric protein that displays aberrant activity believed to initiate cellular transformation. Secondary gene mutations may provide an additional growth advantage that further contributes to malignant progression. The recent clinical success of the tyrosine kinase inhibitor, STI571, suggests that therapeutic approaches specifically directed against essential survival factors in sarcoma cells may be effective. This review summarizes published approaches targeting a specific molecular mechanism associated with sarcomagenesis. The strategy and significance of published translational studies in six distinct areas are presented. These include: (1) the disruption of chimeric transcription factor activity; (2) inhibition of growth stimulatory post-translational modifications; (3) restoration of tumor suppressor function; (4) interference with angiogenesis; (5) induction of apoptotic pathways; and (6) introduction of toxic gene products. The potential for improving outcomes in sarcoma patients and the conceptual obstacles to be overcome are discussed. PMID:18521343

  5. Molecular mechanisms of meditation.

    PubMed

    Jindal, Vishal; Gupta, Sorab; Das, Ritwik

    2013-12-01

    Meditation is a complex process involving change in cognition, memory, and social and emotional control, and causes improvement in various cardiovascular, neurological, autoimmune, and renal pathologies. Meditation also become widely used in medical and psychological treatment therapies for stress-related physical and mental disorders. But still, biological mechanisms in terms of effect on brain and body are poorly understood. This paper explains the basic changes due to meditation in cerebral cortex, prefrontal area, cingulate gyrus, neurotransmitters, white matter, autonomic nervous system, limbic system, cytokines, endorphins, hormones, etc. The following is a review of the current literature regarding the various neurophysiological mechanisms, neuro-endocrine mechanisms, neurochemical substrates, etc. that underlies the complex processes of meditation. PMID:23737355

  6. Molecular mechanisms of meditation.

    PubMed

    Jindal, Vishal; Gupta, Sorab; Das, Ritwik

    2013-12-01

    Meditation is a complex process involving change in cognition, memory, and social and emotional control, and causes improvement in various cardiovascular, neurological, autoimmune, and renal pathologies. Meditation also become widely used in medical and psychological treatment therapies for stress-related physical and mental disorders. But still, biological mechanisms in terms of effect on brain and body are poorly understood. This paper explains the basic changes due to meditation in cerebral cortex, prefrontal area, cingulate gyrus, neurotransmitters, white matter, autonomic nervous system, limbic system, cytokines, endorphins, hormones, etc. The following is a review of the current literature regarding the various neurophysiological mechanisms, neuro-endocrine mechanisms, neurochemical substrates, etc. that underlies the complex processes of meditation.

  7. Molecular quantum mechanical gradients within the polarizable embedding approach--application to the internal vibrational Stark shift of acetophenone.

    PubMed

    List, Nanna Holmgaard; Beerepoot, Maarten T P; Olsen, Jógvan Magnus Haugaard; Gao, Bin; Ruud, Kenneth; Jensen, Hans Jørgen Aagaard; Kongsted, Jacob

    2015-01-21

    We present an implementation of analytical quantum mechanical molecular gradients within the polarizable embedding (PE) model to allow for efficient geometry optimizations and vibrational analysis of molecules embedded in large, geometrically frozen environments. We consider a variational ansatz for the quantum region, covering (multiconfigurational) self-consistent-field and Kohn-Sham density functional theory. As the first application of the implementation, we consider the internal vibrational Stark effect of the C=O group of acetophenone in different solvents and derive its vibrational linear Stark tuning rate using harmonic frequencies calculated from analytical gradients and computed local electric fields. Comparisons to PE calculations employing an enlarged quantum region as well as to a non-polarizable embedding scheme show that the inclusion of mutual polarization between acetophenone and water is essential in order to capture the structural modifications and the associated frequency shifts observed in water. For more apolar solvents, a proper description of dispersion and exchange-repulsion becomes increasingly important, and the quality of the optimized structures relies to a larger extent on the quality of the Lennard-Jones parameters. PMID:25612701

  8. Classical Electrodynamics Coupled to Quantum Mechanics for Calculation of Molecular Optical Properties: a RT-TDDFT/FDTD Approach

    SciTech Connect

    Chen, Hanning; McMahon, J. M.; Ratner, Mark A.; Schatz, George C.

    2010-09-02

    A new multiscale computational methodology was developed to effectively incorporate the scattered electric field of a plasmonic nanoparticle into a quantum mechanical (QM) optical property calculation for a nearby dye molecule. For a given location of the dye molecule with respect to the nanoparticle, a frequency-dependent scattering response function was first determined by the classical electrodynamics (ED) finite-difference time-domain (FDTD) approach. Subsequently, the time-dependent scattered electric field at the dye molecule was calculated using the FDTD scattering response function through a multidimensional Fourier transform to reflect the effect of polarization of the nanoparticle on the local field at the molecule. Finally, a real-time time-dependent density function theory (RT-TDDFT) approach was employed to obtain a desired optical property (such as absorption cross section) of the dye molecule in the presence of the nanoparticle’s scattered electric field. Our hybrid QM/ED methodology was demonstrated by investigating the absorption spectrum of the N3 dye molecule and the Raman spectrum of pyridine, both of which were shown to be significantly enhanced by a 20 nm diameter silver sphere. In contrast to traditional quantum mechanical optical calculations in which the field at the molecule is entirely determined by intensity and polarization direction of the incident light, in this work we show that the light propagation direction as well as polarization and intensity are important to nanoparticle-bound dye molecule response. At no additional computation cost compared to conventional ED and QM calculations, this method provides a reliable way to couple the response of the dye molecule’s individual electrons to the collective dielectric response of the nanoparticle.

  9. Molecular mechanism of preconditioning.

    PubMed

    Das, Manika; Das, Dipak K

    2008-04-01

    During the last 20 years, since the appearance of the first publication on ischemic preconditioning (PC), our knowledge of this phenomenon has increased exponentially. PC is defined as an increased tolerance to ischemia and reperfusion induced by previous sublethal period ischemia. This is the most powerful mechanism known to date for limiting the infract size. This adaptation occurs in a biphasic pattern (i) early preconditioning (lasts for 2-3 h) and (ii) late preconditioning (starting at 24 h lasting until 72-96 h after initial ischemia). Early preconditioning is more potent than delayed preconditioning in reducing infract size. Late preconditioning attenuates myocardial stunning and requires genomic activation with de novo protein synthesis. Early preconditioning depends on adenosine, opioids and to a lesser degree, on bradykinin and prostaglandins, released during ischemia. These molecules activate G-protein-coupled receptor, initiate activation of K(ATP) channel and generate oxygen-free radicals, and stimulate a series of protein kinases, which include protein kinase C, tyrosine kinase, and members of MAP kinase family. Late preconditioning is triggered by a similar sequence of events, but in addition essentially depends on newly synthesized proteins, which comprise iNOS, COX-2, manganese superoxide dismutase, and possibly heat shock proteins. The final mechanism of PC is still not very clear. The present review focuses on the possible role signaling molecules that regulate cardiomyocyte life and death during ischemia and reperfusion. PMID:18344203

  10. Molecular Mechanisms of Parturition

    PubMed Central

    1997-01-01

    The initial signal for triggering human parturition might be fetal but of trophoblastic origin. Concomitantly, this placental signal would have as its target not only the uterus but also the fetus by activating its hypothalamo-pituitary-adrenocortical axis. The latter would represent a second fetal signal which, at the fetomaternal interface, would amplify and define in time the mechanisms responsible for the onset of labor, implying changes in the myometrial and cervical extracellular matrix associated with the accession of the contractile phenotype for myometrial cells. At each phase of these processes in the utero-feto-placental system, the nature of these signals remains to be identified. Is there a single substance, or rather, and more likely, a combination of several? We appear to be in the presence of dynamic systems of a neuro-immuno-hormonal type which are difficult to describe. Nevertheless, steroid hormones appear to coordinate their successive equilibriums until they become irreversible. Such irreversibility constitutes the essential sign of parturition. PMID:18476161

  11. The IMOMM (Integrated Molecular Orbitals/Molecular Mechanics) Approach for Ligand-Stabilized Metal Clusters. Comparison to Full Density Functional Calculations for the Model Thiolate Cluster Cu13(SCH2CH3)8.

    PubMed

    Genest, Alexander; Woiterski, André; Krüger, Sven; Shor, Aleksey M; Rösch, Notker

    2006-01-01

    To validate the IMOMM (integrated molecular orbitals/molecular mechanics) method for ligand-stabilized transition metal clusters, we compare results of this combined quantum mechanical and molecular mechanical (QM/MM) approach, as implemented in the program ParaGauss (Kerdcharoen, T.; Birkenheuer, U.; Krüger, S.; Woiterski, A.; Rösch, N. Theor. Chem. Acc. 2003, 109, 285), to a full density functional (DF) treatment. For this purpose, we have chosen a model copper ethylthiolate cluster, Cu13(SCH2CH3)8 in D4h symmetry. The evaluation is based on 16 conformers of the cluster which exhibit single and bridging coordination of the ligands at the Cu13 cluster as well as various ligand orientations. For corresponding isomers, we obtained moderate deviations between QM and QM/MM results:  0.01-0.06 Å for pertinent bond lengths and up to ∼15° for bond angles. Ligand binding energies of the two approaches deviated less than 6 kcal/mol. The largest discrepancies between full DF and IMOMM results were found for isomers exhibiting short Cu-H and H-H contacts. We traced this back to the localization of different minima, reflecting the unequal performance of the DF and the force-field methods for nonbonding interactions. Thus, QM/MM results can be considered as more reliable because of the well-known limitations of standard exchange-correlation functionals for the description of nonbonding interactions for this class of systems.

  12. An investigation of the molecular mechanisms engaged before and after the development of Alzheimer disease neuropathology in Down syndrome: a proteomics approach.

    PubMed

    Cenini, Giovanna; Fiorini, Ada; Sultana, Rukhsana; Perluigi, Marzia; Cai, Jian; Klein, Jon B; Head, Elizabeth; Butterfield, D Allan

    2014-11-01

    Down syndrome (DS) is one of the most common causes of intellectual disability, owing to trisomy of all or part of chromosome 21. DS is also associated with the development of Alzheimer disease (AD) neuropathology after the age of 40 years. To better clarify the cellular and metabolic pathways that could contribute to the differences in DS brain, in particular those involved in the onset of neurodegeneration, we analyzed the frontal cortex of DS subjects with or without significant AD pathology in comparison with age-matched controls, using a proteomics approach. Proteomics represents an advantageous tool to investigate the molecular mechanisms underlying the disease. From these analyses, we investigated the effects that age, DS, and AD neuropathology could have on protein expression levels. Our results show overlapping and independent molecular pathways (including energy metabolism, oxidative damage, protein synthesis, and autophagy) contributing to DS, to aging, and to the presence of AD pathology in DS. Investigation of pathomechanisms involved in DS with AD may provide putative targets for therapeutic approaches to slow the development of AD.

  13. An Investigation of the Molecular Mechanisms Engaged Prior and Subsequent to the Development of Alzheimer Disease Neuropathology in Down Syndrome: A Proteomics Approach

    PubMed Central

    Cenini, Giovanna; Fiorini, Ada; Sultana, Rukhsana; Perluigi, Marzia; Cai, Jian; Klein, Jon B.; Head, Elizabeth; Butterfield, D. Allan

    2014-01-01

    Down syndrome (DS) is one of the most common causes of intellectual disability, due to trisomy of all or part of chromosome 21. DS is also associated with the development of Alzheimer disease (AD) neuropathology after the age of 40 years. To better clarify the cellular and metabolic pathways that could contribute to the differences in DS brain, in particular those involved in the onset of neurodegeneration, we analyzed the frontal cortex of DS subjects with or without significant AD pathology in comparison with age-matched controls, using a proteomics approach. Proteomics represents an advantageous tool to investigate the molecular mechanisms underlying the disease. From these analyses, we investigated the effects that age, DS, and AD neuropathology could have on protein expression levels. Our results show overlapping and independent molecular pathways (including energy metabolism, oxidative damage, protein synthesis and autophagy) contributing to DS, to aging and to the presence of AD pathology in DS. Investigation of pathomechanisms involved in DS with AD, may provide putative targets for therapeutic approaches to slow the development of AD. PMID:25151119

  14. [Molecular mechanisms for collective cell migration--perspectives and approaches from the studies on the actin-binding protein Girdin].

    PubMed

    Enomoto, Atsushi; Kato, Takuya; Asai, Naoya; Takahashi, Masahide

    2016-03-01

    In embryonal development and pathogenesis of diseases, cells often get connected and form small groups to undergo "collective migration", rather than spread out individually. The examples include the migration of neural crest cells and neuroblasts during development and the invasion of cancers in surrounding stroma, indicating the importance and significance of collective behavior of cells in the body. Recent studies have revealed the mechanisms for collective cell migration, which had seemed not to be the subject of traditional cell biology on single cells in culture. The heterogeneity in cell groups is also a key in understanding the mechanisms for collective cell migration. In this article, we describe recently emerging mechanisms for collective cell migration, with a particular focus on our studies on the actin-binding protein Girdin and tripartite motif containing 27. PMID:27025099

  15. A Systems Biological Approach Reveals Multiple Crosstalk Mechanism between Gram-Positive and Negative Bacterial Infections: An Insight into Core Mechanism and Unique Molecular Signatures

    PubMed Central

    Thangam, Berla; Ahmed, Shiek S. S. J.

    2014-01-01

    Background Bacterial infections remain a major threat and a leading cause of death worldwide. Most of the bacterial infections are caused by gram-positive and negative bacteria, which are recognized by Toll-like receptor (TLR) 2 and 4, respectively. Activation of these TLRs initiates multiple pathways that subsequently lead to effective immune response. Although, both the TLRs share common signaling mechanism yet they may exhibit specificity as well, resulting in the release of diverse range of inflammatory mediators which could be used as candidate biomolecules for bacterial infections. Results We adopted systems biological approach to identify signaling pathways mediated by TLRs to determine candidate molecules associated with bacterial infections. We used bioinformatics concepts, including literature mining to construct protein-protein interaction network, prioritization of TLRs specific nodes using microarray data and pathway analysis. Our constructed PPI network for TLR 2 (nodes: 4091 and edges: 66068) and TLR 4 (node: 4076 and edges: 67898) showed 3207 common nodes, indicating that both the TLRs might share similar signaling events that are attributed to cell migration, MAPK pathway and several inflammatory cascades. Our results propose the potential collaboration between the shared signaling pathways of both the receptors may enhance the immune response against invading pathogens. Further, to identify candidate molecules, the TLRs specific nodes were prioritized using microarray differential expressed genes. Of the top prioritized TLR 2 molecules, 70% were co-expressed. A similar trend was also observed within TLR 4 nodes. Further, most of these molecules were preferentially found in blood plasma for feasible diagnosis. Conclusions The analysis reveals the common and unique mechanism regulated by both the TLRs that provide a broad perspective of signaling events in bacterial infections. Further, the identified candidate biomolecules could potentially aid

  16. Molecular mechanisms of dendrite stability

    PubMed Central

    Koleske, Anthony J.

    2014-01-01

    In the developing brain, dendrite branches and dendritic spines form and turn over dynamically. By contrast, most dendrite arbors and dendritic spines in the adult brain are stable for months, years and possibly even decades. Emerging evidence reveals that dendritic spine and dendrite arbor stability have crucial roles in the correct functioning of the adult brain and that loss of stability is associated with psychiatric disorders and neurodegenerative diseases. Recent findings have provided insights into the molecular mechanisms that underlie long-term dendrite stabilization, how these mechanisms differ from those used to mediate structural plasticity and how they are disrupted in disease. PMID:23839597

  17. Molecular Mechanisms of Nickel Allergy

    PubMed Central

    Saito, Masako; Arakaki, Rieko; Yamada, Akiko; Tsunematsu, Takaaki; Kudo, Yasusei; Ishimaru, Naozumi

    2016-01-01

    Allergic contact hypersensitivity to metals is a delayed-type allergy. Although various metals are known to produce an allergic reaction, nickel is the most frequent cause of metal allergy. Researchers have attempted to elucidate the mechanisms of metal allergy using animal models and human patients. Here, the immunological and molecular mechanisms of metal allergy are described based on the findings of previous studies, including those that were recently published. In addition, the adsorption and excretion of various metals, in particular nickel, is discussed to further understand the pathogenesis of metal allergy. PMID:26848658

  18. Theoretical design of the cyclic lipopeptide nanotube as a molecular channel in the lipid bilayer, molecular dynamics and quantum mechanics approach.

    PubMed

    Khavani, Mohammad; Izadyar, Mohammad; Housaindokht, Mohammad Reza

    2015-10-14

    In this article, cyclic peptides (CP) with lipid substituents were theoretically designed. The dynamical behavior of the CP dimers and the cyclic peptide nanotube (CPNT) without lipid substituents in the solution (water and chloroform) during the 50 ns molecular dynamic (MD) simulations has been investigated. As a result, the CP dimers and CPNT in a non-polar solvent are more stable than in a polar solvent and CPNT is a good container for non-polar small molecules such as chloroform. The effect of the lipid substituents on the CP dimers and CPNT has been investigated in the next stage of our studies. Accordingly, these substituents increase the stability of the CP dimers and CPNT, significantly, in polar solvents. MM-PBSA and MM-GBSA calculations confirm that substitution has an important effect on the stability of the CP dimers and CPNT. Finally, the dynamical behavior of CPNT with lipid substituents in a fully hydrated DMPC bilayer shows the high ability of this structure for molecule transmission across the lipid membrane. This structure is stable enough to be used as a molecular channel. DFT calculations on the CP dimers in the gas phase, water and chloroform, indicate that H-bond formation is the driving force for dimerization. CP dimers are more stable in the gas phase in comparison to in solution. HOMO-LUMO orbital analysis indicates that the interaction of the CP units in the dimer structures is due to the molecular orbital interactions between the NH and CO groups.

  19. Superspreading: mechanisms and molecular design.

    PubMed

    Theodorakis, Panagiotis E; Müller, Erich A; Craster, Richard V; Matar, Omar K

    2015-03-01

    The intriguing ability of certain surfactant molecules to drive the superspreading of liquids to complete wetting on hydrophobic substrates is central to numerous applications that range from coating flow technology to enhanced oil recovery. Despite significant experimental efforts, the precise mechanisms underlying superspreading remain unknown to date. Here, we isolate these mechanisms by analyzing coarse-grained molecular dynamics simulations of surfactant molecules of varying molecular architecture and substrate affinity. We observe that for superspreading to occur, two key conditions must be simultaneously satisfied: the adsorption of surfactants from the liquid-vapor surface onto the three-phase contact line augmented by local bilayer formation. Crucially, this must be coordinated with the rapid replenishment of liquid-vapor and solid-liquid interfaces with surfactants from the interior of the droplet. This article also highlights and explores the differences between superspreading and conventional surfactants, paving the way for the design of molecular architectures tailored specifically for applications that rely on the control of wetting.

  20. Molecular Mechanism of TRP Channels

    PubMed Central

    Zheng, Jie

    2013-01-01

    Transient receptor potential (TRP) channels are cellular sensors for a wide spectrum of physical and chemical stimuli. They are involved in the formation of sight, hearing, touch, smell, taste, temperature, and pain sensation. TRP channels also play fundamental roles in cell signaling and allow the host cell to respond to benign or harmful environmental changes. As TRP channel activation is controlled by very diverse processes and, in many cases, exhibits complex polymodal properties, understanding how each TRP channel responds to its unique forms of activation energy is both crucial and challenging. The past two decades witnessed significant advances in understanding the molecular mechanisms that underlie TRP channels activation. This review focuses on our current understanding of the molecular determinants for TRP channel activation. PMID:23720286

  1. Molecular Approaches to Studying Denitrification

    NASA Astrophysics Data System (ADS)

    Voytek, M. A.

    2001-05-01

    Denitrification is carried out by a diverse array of microbes, mainly as an alternative mode of respiration that allows the organisms to respire using oxidized N compounds instead of oxygen. A common approach in biogeochemistry to the study of the regulation of denitrification is to assess activity by mass balance of substrates and products or direct rate measurements and has intrinsically assumed resource regulation of denitrification. Reported rates can vary significantly even among ecosystems characterized by similar environmental conditions, thus indicating that direct control by abiotic factors often is not sufficient to predict denitrification rates accurately in natural environments. Alternatively, a microbiological approach would proceed with the identification of the organisms responsible and an evaluation of the effect of environmental factors on the biochemical pathways involved. Traditional studies have relied on culturing techniques, such as most probable number enrichments, and have failed to assess the role of the predominately uncultivable members of the microbial community. A combination of biogeochemical measurements and the assessment of the microbial community is necessary and becoming increasingly possible with the development and application of molecular techniques. In order to understand how the composition and physiological behavior of the microbial community affects denitrification rates, we use a suite of molecular techniques developed for phylogenetic and metabolic characterization of denitrifying communities. Molecular tools available for quantifying denitrifying bacteria and assessing their diversity and activity are summarized. Their application is illustrated with examples from marine and freshwater environments. Emerging techniques and their application to ground water studies will be discussed.

  2. Network Based Approach in the Establishment of the Relationship between Type 2 Diabetes Mellitus and Its Complications at the Molecular Level Coupled with Molecular Docking Mechanism

    PubMed Central

    Rampogu Lemuel, Mary

    2016-01-01

    Diabetes mellitus (DM) is one of the major metabolic disorders that is currently threatening the world. DM is seen associated with obesity and diabetic retinopathy (DR). In the present paper we tried to evaluate the relationship between the three aliments at the gene level and further performed the molecular docking to identify the common drug for all the three diseases. We have adopted several software programs such as Phenopedia, VennViewer, and CDOCKER to accomplish the objective. Our results revealed six genes that commonly associated and are involved in the signalling pathway. Furthermore, evaluation of common gene association from the selected set of genes projected the presence of SIRT1 in all the three aliments. Therefore, we targeted protein 4KXQ which was produced from the gene SIRT1 and challenged it with eight phytochemicals, adopting the CDOCKER. C1 compound has displayed highest -CDOCKER energy and -CDOCKER interaction energy of 43.6905 and 43.3953, respectively. Therefore, this compound is regarded as the most potential lead molecule.

  3. Network Based Approach in the Establishment of the Relationship between Type 2 Diabetes Mellitus and Its Complications at the Molecular Level Coupled with Molecular Docking Mechanism

    PubMed Central

    Rampogu Lemuel, Mary

    2016-01-01

    Diabetes mellitus (DM) is one of the major metabolic disorders that is currently threatening the world. DM is seen associated with obesity and diabetic retinopathy (DR). In the present paper we tried to evaluate the relationship between the three aliments at the gene level and further performed the molecular docking to identify the common drug for all the three diseases. We have adopted several software programs such as Phenopedia, VennViewer, and CDOCKER to accomplish the objective. Our results revealed six genes that commonly associated and are involved in the signalling pathway. Furthermore, evaluation of common gene association from the selected set of genes projected the presence of SIRT1 in all the three aliments. Therefore, we targeted protein 4KXQ which was produced from the gene SIRT1 and challenged it with eight phytochemicals, adopting the CDOCKER. C1 compound has displayed highest -CDOCKER energy and -CDOCKER interaction energy of 43.6905 and 43.3953, respectively. Therefore, this compound is regarded as the most potential lead molecule. PMID:27699170

  4. Anticancer Molecular Mechanisms of Resveratrol

    PubMed Central

    Varoni, Elena M.; Lo Faro, Alfredo Fabrizio; Sharifi-Rad, Javad; Iriti, Marcello

    2016-01-01

    Resveratrol is a pleiotropic phytochemical belonging to the stilbene family. Though it is only significantly present in grape products, a huge amount of preclinical studies investigated its anticancer properties in a plethora of cellular and animal models. Molecular mechanisms of resveratrol involved signaling pathways related to extracellular growth factors and receptor tyrosine kinases; formation of multiprotein complexes and cell metabolism; cell proliferation and genome instability; cytoplasmic tyrosine kinase signaling (cytokine, integrin, and developmental pathways); signal transduction by the transforming growth factor-β super-family; apoptosis and inflammation; and immune surveillance and hormone signaling. Resveratrol also showed a promising role to counteract multidrug resistance: in adjuvant therapy, associated with 5-fluoruracyl and cisplatin, resveratrol had additive and/or synergistic effects increasing the chemosensitization of cancer cells. Resveratrol, by acting on diverse mechanisms simultaneously, has been emphasized as a promising, multi-target, anticancer agent, relevant in both cancer prevention and treatment. PMID:27148534

  5. Molecular Mechanisms of Synaptic Specificity

    PubMed Central

    Margeta, Milica A.; Shen, Kang

    2011-01-01

    Synapses are specialized junctions that mediate information flow between neurons and their targets. A striking feature of the nervous system is the specificity of its synaptic connections: an individual neuron will form synapses only with a small subset of available presynaptic and postsynaptic partners. Synaptic specificity has been classically thought to arise from homophilic or heterophilic interactions between adhesive molecules acting across the synaptic cleft. Over the past decade, many new mechanisms giving rise to synaptic specificity have been identified. Synapses can be specified by secreted molecules that promote or inhibit synaptogenesis, and their source can be a neighboring guidepost cell, not just presynaptic and postsynaptic neurons. Furthermore, lineage, fate, and timing of development can also play critical roles in shaping neural circuits. Future work utilizing large-scale screens will aim to elucidate the full scope of cellular mechanisms and molecular players that can give rise to synaptic specificity. PMID:19969086

  6. Molecular mechanisms of regulated necrosis.

    PubMed

    Galluzzi, Lorenzo; Kepp, Oliver; Krautwald, Stefan; Kroemer, Guido; Linkermann, Andreas

    2014-11-01

    It is now clear that apoptosis does not constitute the sole genetically encoded form of cell death. Rather, cells can spontaneously undertake or exogenously be driven into a cell death subroutine that manifests with necrotic features, yet can be inhibited by pharmacological and genetic interventions. As regulated necrosis (RN) plays a major role in both physiological scenarios (e.g., embryonic development) and pathological settings (e.g., ischemic disorders), consistent efforts have been made throughout the last decade toward the characterization of the molecular mechanisms that underlie this cell death modality. Contrarily to initial beliefs, RN does not invariably result from the activation of a receptor interacting protein kinase 3 (RIPK3)-dependent signaling pathway, but may be ignited by distinct molecular networks. Nowadays, various types of RN have been characterized, including (but not limited to) necroptosis, mitochondrial permeability transition (MPT)-dependent RN and parthanatos. Of note, the inhibition of only one of these modules generally exerts limited cytoprotective effects in vivo, underscoring the degree of interconnectivity that characterizes RN. Here, we review the signaling pathways, pathophysiological relevance and therapeutic implications of the major molecular cascades that underlie RN. PMID:24582829

  7. Molecular mechanisms of temperature adaptation.

    PubMed

    Bagriantsev, Sviatoslav N; Gracheva, Elena O

    2015-08-15

    Thermal perception is a fundamental physiological process pertaining to the vast majority of organisms. In vertebrates, environmental temperature is detected by the primary afferents of the somatosensory neurons in the skin, which express a 'choir' of ion channels tuned to detect particular temperatures. Nearly two decades of research have revealed a number of receptor ion channels that mediate the perception of several temperature ranges, but most still remain molecularly orphaned. Yet even within this well-researched realm, most of our knowledge largely pertains to two closely related species of rodents, mice and rats. While these are standard biomedical research models, mice and rats provide a limited perspective to elucidate the general principles that drive somatosensory evolution. In recent years, significant advances have been made in understanding the molecular mechanism of temperature adaptation in evolutionarily distant vertebrates and in organisms with acute thermal sensitivity. These studies have revealed the remarkable versatility of the somatosensory system and highlighted adaptations at the molecular level, which often include changes in biophysical properties of ion channels from the transient receptor potential family. Exploiting non-standard animal models has the potential to provide unexpected insights into general principles of thermosensation and thermoregulation, unachievable using the rodent model alone.

  8. Molecular mechanisms of temperature adaptation

    PubMed Central

    Bagriantsev, Sviatoslav N; Gracheva, Elena O

    2015-01-01

    Thermal perception is a fundamental physiological process pertaining to the vast majority of organisms. In vertebrates, environmental temperature is detected by the primary afferents of the somatosensory neurons in the skin, which express a ‘choir’ of ion channels tuned to detect particular temperatures. Nearly two decades of research have revealed a number of receptor ion channels that mediate the perception of several temperature ranges, but most still remain molecularly orphaned. Yet even within this well-researched realm, most of our knowledge largely pertains to two closely related species of rodents, mice and rats. While these are standard biomedical research models, mice and rats provide a limited perspective to elucidate the general principles that drive somatosensory evolution. In recent years, significant advances have been made in understanding the molecular mechanism of temperature adaptation in evolutionarily distant vertebrates and in organisms with acute thermal sensitivity. These studies have revealed the remarkable versatility of the somatosensory system and highlighted adaptations at the molecular level, which often include changes in biophysical properties of ion channels from the transient receptor potential family. Exploiting non-standard animal models has the potential to provide unexpected insights into general principles of thermosensation and thermoregulation, unachievable using the rodent model alone. PMID:25433072

  9. Molecular mechanisms of temperature adaptation.

    PubMed

    Bagriantsev, Sviatoslav N; Gracheva, Elena O

    2015-08-15

    Thermal perception is a fundamental physiological process pertaining to the vast majority of organisms. In vertebrates, environmental temperature is detected by the primary afferents of the somatosensory neurons in the skin, which express a 'choir' of ion channels tuned to detect particular temperatures. Nearly two decades of research have revealed a number of receptor ion channels that mediate the perception of several temperature ranges, but most still remain molecularly orphaned. Yet even within this well-researched realm, most of our knowledge largely pertains to two closely related species of rodents, mice and rats. While these are standard biomedical research models, mice and rats provide a limited perspective to elucidate the general principles that drive somatosensory evolution. In recent years, significant advances have been made in understanding the molecular mechanism of temperature adaptation in evolutionarily distant vertebrates and in organisms with acute thermal sensitivity. These studies have revealed the remarkable versatility of the somatosensory system and highlighted adaptations at the molecular level, which often include changes in biophysical properties of ion channels from the transient receptor potential family. Exploiting non-standard animal models has the potential to provide unexpected insights into general principles of thermosensation and thermoregulation, unachievable using the rodent model alone. PMID:25433072

  10. A Systems Biology Approach to the Coordination of Defensive and Offensive Molecular Mechanisms in the Innate and Adaptive Host-Pathogen Interaction Networks.

    PubMed

    Wu, Chia-Chou; Chen, Bor-Sen

    2016-01-01

    Infected zebrafish coordinates defensive and offensive molecular mechanisms in response to Candida albicans infections, and invasive C. albicans coordinates corresponding molecular mechanisms to interact with the host. However, knowledge of the ensuing infection-activated signaling networks in both host and pathogen and their interspecific crosstalk during the innate and adaptive phases of the infection processes remains incomplete. In the present study, dynamic network modeling, protein interaction databases, and dual transcriptome data from zebrafish and C. albicans during infection were used to infer infection-activated host-pathogen dynamic interaction networks. The consideration of host-pathogen dynamic interaction systems as innate and adaptive loops and subsequent comparisons of inferred innate and adaptive networks indicated previously unrecognized crosstalk between known pathways and suggested roles of immunological memory in the coordination of host defensive and offensive molecular mechanisms to achieve specific and powerful defense against pathogens. Moreover, pathogens enhance intraspecific crosstalk and abrogate host apoptosis to accommodate enhanced host defense mechanisms during the adaptive phase. Accordingly, links between physiological phenomena and changes in the coordination of defensive and offensive molecular mechanisms highlight the importance of host-pathogen molecular interaction networks, and consequent inferences of the host-pathogen relationship could be translated into biomedical applications.

  11. Molecular mechanisms of cryptococcal meningitis

    PubMed Central

    Liu, Tong-Bao; Perlin, David; Xue, Chaoyang

    2012-01-01

    Fungal meningitis is a serious disease caused by a fungal infection of the central nervous system (CNS) mostly in individuals with immune system deficiencies. Fungal meningitis is often fatal without proper treatment, and the mortality rate remains unacceptably high even with antifungal drug interventions. Currently, cryptococcal meningitis is the most common fungal meningitis in HIV-1/AIDS, and its disease mechanism has been extensively studied. The key steps for fungi to infect brain and cause meningitis after establishment of local infection are the dissemination of fungal cells to the bloodstream and invasion through the blood brain barrier to reach the CNS. In this review, we use cryptococcal CNS infection as an example to describe the current molecular understanding of fungal meningitis, including the establishment of the infection, dissemination, and brain invasion. Host and microbial factors that contribute to these infection steps are also discussed. PMID:22460646

  12. Molecular Mechanisms of Bacterial Pathogenicity

    NASA Astrophysics Data System (ADS)

    Fuchs, Thilo Martin

    Cautious optimism has arisen over recent decades with respect to the long struggle against bacteria, viruses, and parasites. This has been offset, however, by a fatal complacency stemming from previous successes such as the development of antimicrobial drugs, the eradication of smallpox, and global immunization programs. Infectious diseases nevertheless remain the world's leading cause of death, killing at least 17 million persons annually [61]. Diarrheal diseases caused by Vibrio cholerae or Shigella dysenteriae kill about 3 million persons every year, most of them young children: Another 4 million die of tuberculosis or tetanus. Outbreaks of diphtheria in Eastern Europe threatens the population with a disease that had previously seemed to be overcome. Efforts to control infectious diseases more comprehensively are undermined not only by socioeconomic conditions but also by the nature of the pathogenic organisms itself; some isolates of Staphylococcus aureus and Enterobacter have become so resistant to drugs by horizontal gene transfer that they are almost untreatable. In addition, the mechanism of genetic variability helps pathogens to evade the human immune system, thus compromising the development of powerful vaccines. Therefore detailed knowledge of the molecular mechanisms of microbial pathogenicity is absolutely necessary to develop new strategies against infectious diseases and thus to lower their impact on human health and social development.

  13. Molecular mechanisms of penile erection.

    PubMed

    Mas, Manuel

    2010-10-01

    The penis physiological states of flaccidity or erection, result from the contraction or relaxation, respectively, of smooth muscle cells in the corpora cavernosa (CSMCs). They result from the interaction of various inter and intracellular molecular signaling pathways. During the more usual state of flaccidity seems to predominate a tonic sympathetic activity, releasing noradrenaline (NA) and other agonists that generate contractile signals in the CSMCs, with the likely cooperation of endothelium-derived messengers. Through activation of membrane receptors in the CSMCs they raise the intracellular messengers inositol triphosphate (IP3) and diacylglycerol (DAG). This results in a transient increase in cytosolic calcium concentration [Ca2+]i that starts the contractile response which is further sustained by the parallel agonist-induced activation of a "calcium sensitizing" mechanism involving the RhoA/Rho-kinase pathway. Overexpression of the latter might contribute to several vascular disorders as hypertension, vasospasm or erectile dysfunction. On sexual stimulation the cavernous nerves release nitric oxide (NO) that starts the erectile response. They also release acetylcholine that stimulates the endothelium to generate a more sustained release of NO. NO diffuses into CSMCs and increases their intracellular levels of cyclic guanosin monophosphate (cGMP) which decreases [Ca2+]i and deactivates the calcium sensitizing mechanism, thus relaxing CSMCs. This main physiological pathway for CSMCs relaxation is helped by the cyclic adenosin monophosphate (cAMP) pathway activated by various intercellular messengers from neural or paracrine sources, including prostaglandins E (PGE). Different phosphodiesterase enzymes (PDEs) inactivate the cyclic nucleotides thereby limiting their erectogenic action. Indeed the pharmacological inhibition of PDEs, especially the cGMP-specific PDE5, greatly enhances the erectile responses. There are crosstalk mechanisms between the cGMP and c

  14. Molecular mechanisms of pancreatic carcinogenesis.

    PubMed

    Furukawa, Toru; Sunamura, Makoto; Horii, Akira

    2006-01-01

    Pancreatic ductal adenocarcinoma is one of the most fatal malignancies. Intensive investigation of molecular pathogenesis might lead to identifying useful molecules for diagnosis and treatment of the disease. Pancreatic ductal adenocarcinoma harbors complicated aberrations of alleles including losses of 1p, 6q, 9p, 12q, 17p, 18q, and 21q, and gains of 8q and 20q. Pancreatic cancer is usually initiated by mutation of KRAS and aberrant expression of SHH. Overexpression of AURKA mapping on 20q13.2 may significantly enhance overt tumorigenesity. Aberrations of tumor suppressor genes synergistically accelerate progression of the carcinogenic pathway through pancreatic intraepithelial neoplasia (PanIN) to invasive ductal adenocarcinoma. Abrogation of CDKN2A occurs in low-grade/early PanIN, whereas aberrations of TP53 and SMAD4 occur in high-grade/late PanIN. SMAD4 may play suppressive roles in tumorigenesis by inhibition of angiogenesis. Loss of 18q precedes SMAD4 inactivation, and restoration of chromosome 18 in pancreatic cancer cells results in tumor suppressive phenotypes regardless of SMAD4 status, indicating the possible existence of a tumor suppressor gene(s) other than SMAD4 on 18q. DUSP6 at 12q21-q22 is frequently abrogated by loss of expression in invasive ductal adenocarcinomas despite fairly preserved expression in PanIN, which suggests that DUSP6 works as a tumor suppressor in pancreatic carcinogenesis. Restoration of chromosome 12 also suppresses growths of pancreatic cancer cells despite the recovery of expression of DUSP6; the existence of yet another tumor suppressor gene on 12q is strongly suggested. Understanding the molecular mechanisms of pancreatic carcinogenesis will likely provide novel clues for preventing, detecting, and ultimately curing this life-threatening disease. PMID:16367914

  15. Molecular toxicity mechanism of nanosilver.

    PubMed

    McShan, Danielle; Ray, Paresh C; Yu, Hongtao

    2014-03-01

    Silver is an ancient antibiotic that has found many new uses due to its unique properties on the nanoscale. Due to its presence in many consumer products, the toxicity of nanosilver has become a hot topic. This review summarizes recent advances, particularly the molecular mechanism of nanosilver toxicity. The surface of nanosilver can easily be oxidized by O(2) and other molecules in the environmental and biological systems leading to the release of Ag(+), a known toxic ion. Therefore, nanosilver toxicity is closely related to the release of Ag(+). In fact, it is difficult to determine what portion of the toxicity is from the nano-form and what is from the ionic form. The surface oxidation rate is closely related to the nanosilver surface coating, coexisting molecules, especially thiol-containing compounds, lighting conditions, and the interaction of nanosilver with nucleic acids, lipid molecules, and proteins in a biological system. Nanosilver has been shown to penetrate the cell and become internalized. Thus, nanosilver often acts as a source of Ag(+) inside the cell. One of the main mechanisms of toxicity is that it causes oxidative stress through the generation of reactive oxygen species and causes damage to cellular components including DNA damage, activation of antioxidant enzymes, depletion of antioxidant molecules (e.g., glutathione), binding and disabling of proteins, and damage to the cell membrane. Several major questions remain to be answered: (1) the toxic contribution from the ionic form versus the nano-form; (2) key enzymes and signaling pathways responsible for the toxicity; and (3) effect of coexisting molecules on the toxicity and its relationship to surface coating.

  16. Molecular mechanisms of statin intolerance

    PubMed Central

    Franczyk, Beata; Toth, Peter P.; Rysz, Jacek; Banach, Maciej

    2016-01-01

    Statins reduce cardiovascular morbidity and mortality in primary and secondary prevention. Despite their efficacy, many persons are unable to tolerate statins due to adverse events such as hepatotoxicity and myalgia/myopathy. In the case of most patients, it seems that mild-to-moderate abnormalities in liver and muscle enzymes are not serious adverse effects and do not outweigh the benefits of coronary heart disease risk reduction. The risk for mortality or permanent organ damage ascribed to statin use is very small and limited to cases of myopathy and rhabdomyolysis. Statin-induced muscle-related adverse events comprise a highly heterogeneous clinical disorder with numerous, complex etiologies and a variety of genetic backgrounds. Every patient who presents with statin-related side effects cannot undergo the type of exhaustive molecular characterization that would include all of these mechanisms. Frequently the only solution is to either discontinue statin therapy/reduce the dose or attempt intermittent dosing strategies at a low dose. PMID:27279860

  17. Molecular mechanics of silk nanostructures under varied mechanical loading.

    PubMed

    Bratzel, Graham; Buehler, Markus J

    2012-06-01

    Spider dragline silk is a self-assembling tunable protein composite fiber that rivals many engineering fibers in tensile strength, extensibility, and toughness, making it one of the most versatile biocompatible materials and most inviting for synthetic mimicry. While experimental studies have shown that the peptide sequence and molecular structure of silk have a direct influence on the stiffness, toughness, and failure strength of silk, few molecular-level analyses of the nanostructure of silk assemblies, in particular, under variations of genetic sequences have been reported. In this study, atomistic-level structures of wildtype as well as modified MaSp1 protein from the Nephila clavipes spider dragline silk sequences, obtained using an in silico approach based on replica exchange molecular dynamics and explicit water molecular dynamics, are subjected to simulated nanomechanical testing using different force-control loading conditions including stretch, pull-out, and peel. The authors have explored the effects of the poly-alanine length of the N. clavipes MaSp1 peptide sequence and identify differences in nanomechanical loading conditions on the behavior of a unit cell of 15 strands with 840-990 total residues used to represent a cross-linking β-sheet crystal node in the network within a fibril of the dragline silk thread. The specific loading condition used, representing concepts derived from the protein network connectivity at larger scales, have a significant effect on the mechanical behavior. Our analysis incorporates stretching, pull-out, and peel testing to connect biochemical features to mechanical behavior. The method used in this study could find broad applications in de novo design of silk-like tunable materials for an array of applications. PMID:22020792

  18. Molecular mechanics of silk nanostructures under varied mechanical loading.

    PubMed

    Bratzel, Graham; Buehler, Markus J

    2012-06-01

    Spider dragline silk is a self-assembling tunable protein composite fiber that rivals many engineering fibers in tensile strength, extensibility, and toughness, making it one of the most versatile biocompatible materials and most inviting for synthetic mimicry. While experimental studies have shown that the peptide sequence and molecular structure of silk have a direct influence on the stiffness, toughness, and failure strength of silk, few molecular-level analyses of the nanostructure of silk assemblies, in particular, under variations of genetic sequences have been reported. In this study, atomistic-level structures of wildtype as well as modified MaSp1 protein from the Nephila clavipes spider dragline silk sequences, obtained using an in silico approach based on replica exchange molecular dynamics and explicit water molecular dynamics, are subjected to simulated nanomechanical testing using different force-control loading conditions including stretch, pull-out, and peel. The authors have explored the effects of the poly-alanine length of the N. clavipes MaSp1 peptide sequence and identify differences in nanomechanical loading conditions on the behavior of a unit cell of 15 strands with 840-990 total residues used to represent a cross-linking β-sheet crystal node in the network within a fibril of the dragline silk thread. The specific loading condition used, representing concepts derived from the protein network connectivity at larger scales, have a significant effect on the mechanical behavior. Our analysis incorporates stretching, pull-out, and peel testing to connect biochemical features to mechanical behavior. The method used in this study could find broad applications in de novo design of silk-like tunable materials for an array of applications.

  19. Molecular approaches to field studies of malaria.

    PubMed

    Beck, Hans-Peter; Tetteh, Kevin

    2008-12-01

    The third 'Molecular Approaches to Malaria' conference was held in Lorne, Australia, in February 2008 and provided extensive information on the application of molecular tools in field studies on malaria. In recent years, technological advances and capacity building in malaria-endemic countries have permitted molecular tools to be applied much more frequently and successfully with exciting new findings. In this review, Hans-Peter Beck and Kevin Tetteh report on the most recent findings using molecular tools in field studies.

  20. Molecular approaches to Taenia asiatica.

    PubMed

    Jeon, Hyeong-Kyu; Eom, Keeseon S

    2013-02-01

    Taenia solium, T. saginata, and T. asiatica are taeniid tapeworms that cause taeniasis in humans and cysticercosis in intermediate host animals. Taeniases remain an important public health concerns in the world. Molecular diagnostic methods using PCR assays have been developed for rapid and accurate detection of human infecting taeniid tapeworms, including the use of sequence-specific DNA probes, PCR-RFLP, and multiplex PCR. More recently, DNA diagnosis using PCR based on histopathological specimens such as 10% formalin-fixed paraffin-embedded and stained sections mounted on slides has been applied to cestode infections. The mitochondrial gene sequence is believed to be a very useful molecular marker for not only studying evolutionary relationships among distantly related taxa, but also for investigating the phylo-biogeography of closely related species. The complete sequence of the human Taenia tapeworms mitochondrial genomes were determined, and its organization and structure were compared to other human-tropic Taenia tapeworms for which complete mitochondrial sequence data were available. The multiplex PCR assay with the Ta4978F, Ts5058F, Tso7421F, and Rev7915 primers will be useful for differential diagnosis, molecular characterization, and epidemiological surveys of human Taenia tapeworms. PMID:23467738

  1. Molecular mechanisms of hepatic apoptosis

    PubMed Central

    Wang, K

    2014-01-01

    Apoptosis is a prominent feature of liver diseases. Causative factors such as alcohol, viruses, toxic bile acids, fatty acids, drugs, and immune response, can induce apoptotic cell death via membrane receptors and intracellular stress. Apoptotic signaling network, including membrane death receptor-mediated cascade, reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, lysosomal permeabilization, and mitochondrial dysfunction, is intermixed each other, but one mechanism may dominate at a particular stage. Mechanisms of hepatic apoptosis are complicated by multiple signaling pathways. The progression of liver disease is affected by the balance between apoptotic and antiapoptotic capabilities. Therapeutic options of liver injury are impacted by the clear understanding toward mechanisms of hepatic apoptosis. PMID:24434519

  2. A molecular mechanism for the origin of a key evolutionary innovation, the bird beak and palate, revealed by an integrative approach to major transitions in vertebrate history.

    PubMed

    Bhullar, Bhart-Anjan S; Morris, Zachary S; Sefton, Elizabeth M; Tok, Atalay; Tokita, Masayoshi; Namkoong, Bumjin; Camacho, Jasmin; Burnham, David A; Abzhanov, Arhat

    2015-07-01

    The avian beak is a key evolutionary innovation whose flexibility has permitted birds to diversify into a range of disparate ecological niches. We approached the problem of the mechanism behind this innovation using an approach bridging paleontology, comparative anatomy, and experimental developmental biology. First, we used fossil and extant data to show the beak is distinctive in consisting of fused premaxillae that are geometrically distinct from those of ancestral archosaurs. To elucidate underlying developmental mechanisms, we examined candidate gene expression domains in the embryonic face: the earlier frontonasal ectodermal zone (FEZ) and the later midfacial WNT-responsive region, in birds and several reptiles. This permitted the identification of an autapomorphic median gene expression region in Aves. To test the mechanism, we used inhibitors of both pathways to replicate in chicken the ancestral amniote expression. Altering the FEZ altered later WNT responsiveness to the ancestral pattern. Skeletal phenotypes from both types of experiments had premaxillae that clustered geometrically with ancestral fossil forms instead of beaked birds. The palatal region was also altered to a more ancestral phenotype. This is consistent with the fossil record and with the tight functional association of avian premaxillae and palate in forming a kinetic beak.

  3. Molecular Mechanisms Underlying Pituitary Pathogenesis.

    PubMed

    Sapochnik, Melanie; Nieto, Leandro Eduardo; Fuertes, Mariana; Arzt, Eduardo

    2016-04-01

    During the last years, progress has been made on the identification of mechanisms involved in anterior pituitary cell transformation and tumorigenesis. Oncogene activation, tumor suppressor gene inactivation, epigenetic changes, and microRNAs deregulation contribute to the initiation of pituitary tumors. Despite the high prevalence of pituitary adenomas, they are mostly benign, indicating that intrinsic mechanisms may regulate pituitary cell expansion. Senescence is characterized by an irreversible cell cycle arrest and represents an important protective mechanism against malignancy. Pituitary tumor transforming gene (PTTG) is an oncogene involved in early stages of pituitary tumor development, and also triggers a senescence response by activating DNA-damage signaling pathway. Cytokines, as well as many other factors, play an important role in pituitary physiology, affecting not only cell proliferation but also hormone secretion. Special interest is focused on interleukin-6 (IL-6) because its dual function of stimulating pituitary tumor cell growth but inhibiting normal pituitary cells proliferation. It has been demonstrated that IL-6 has a key role in promoting and maintenance of the senescence program in tumors. Senescence, triggered by PTTG activation and mediated by IL-6, may be a mechanism for explaining the benign nature of pituitary tumors.

  4. Molecular Mechanisms of Bone Metastasis.

    PubMed

    Weidle, Ulrich H; Birzele, Fabian; Kollmorgen, Gwendlyn; Rüger, Rüdiger

    2016-01-01

    Metastasis of breast and prostate cancer as well as multiple myeloma to the bones represents a significant medical problem. We herein discuss the molecular basis of the creation of pre-metastatic niches, the process of bone metastasis and the phenomenon of tumor dormancy in the bone marrow as well as its regulation. We describe the identification and validation of genes mediating bone metastasis by use of pre-clinical models of bone metastasis. Additionally, we discuss the role of small integrin binding N-linked glycoproteins (SIBLINGS), the chemokine/chemokine receptor CXCL12/CXCR4 pathway and the role of micro RNAs (miRNAs) as mediators of bone metastasis. Finally, we summarize clinical achievements for the treatment of bone metastases.

  5. Molecular pathogenesis and mechanisms of thyroid cancer

    PubMed Central

    Xing, Mingzhao

    2013-01-01

    Thyroid cancer is a common endocrine malignancy. There has been exciting progress in understanding its molecular pathogenesis in recent years, as best exemplified by the elucidation of the fundamental role of several major signalling pathways and related molecular derangements. Central to these mechanisms are the genetic and epigenetic alterations in these pathways, such as mutation, gene copy-number gain and aberrant gene methylation. Many of these molecular alterations represent novel diagnostic and prognostic molecular markers and therapeutic targets for thyroid cancer, which provide unprecedented opportunities for further research and clinical development of novel treatment strategies for this cancer. PMID:23429735

  6. Huntington Disease: Molecular Diagnostics Approach.

    PubMed

    Bastepe, Murat; Xin, Winnie

    2015-10-06

    Huntington disease (HD) is caused by expansion of a CAG trinucleotide repeat in the first exon of the Huntingtin (HTT) gene. Molecular testing of Huntington disease for diagnostic confirmation and disease prediction requires detection of the CAG repeat expansion. There are three main types of HD genetic testing: (1) diagnostic testing to confirm or rule out disease, (2) presymptomatic testing to determine whether an at-risk individual inherited the expanded allele, and (3) prenatal testing to determine whether the fetus has inherited the expanded allele. This unit includes protocols that describe the complementary use of polymerase chain reactions (PCR) and Southern blot hybridization to accurately measure the CAG trinucleotide repeat size and interpret the test results. In addition, an indirect linkage analysis that does not reveal the unwanted parental HD status in a prenatal testing will also be discussed.

  7. Molecular mechanism of sweetness sensation.

    PubMed

    DuBois, Grant E

    2016-10-01

    The current understanding of peripheral molecular events involved in sweet taste sensation in humans is reviewed. Included are discussions of the sweetener receptor T1R2/T1R3, its agonists, antagonists, positive allosteric modulators, the transduction of its activation in taste bud cells and the coding of its signaling to the CNS. Areas of incomplete understanding include 1) signal communication with afferent nerve fibers, 2) contrasting concentration/response (C/R) functions for high-potency (HP) sweeteners (hyperbolic) and carbohydrate (CHO) sweeteners (linear), 3) contrasting temporal profiles for HP sweeteners (delayed onset and extinction) and CHO sweeteners (rapid onset and extinction) and 4) contrasting adaptation behaviors for HP sweeteners (moderate to strong adaptation) and CHO sweeteners (low adaptation). Evidence based on the sweet water aftertastes of several novel sweetness inhibitors is presented providing new support for constitutive activity in T1R2/T1R3. And a model is developed to rationalize the linear C/R functions of CHO sweeteners and hyperbolic C/R functions of HP sweeteners, where the former may activate T1R2/T1R3 by both binding and constitutive activity modulation (i.e., without binding) and the latter activate T1R2/T1R3 only by binding. PMID:26992959

  8. A Hierarchical Approach to Fracture Mechanics

    NASA Technical Reports Server (NTRS)

    Saether, Erik; Taasan, Shlomo

    2004-01-01

    Recent research conducted under NASA LaRC's Creativity and Innovation Program has led to the development of an initial approach for a hierarchical fracture mechanics. This methodology unites failure mechanisms occurring at different length scales and provides a framework for a physics-based theory of fracture. At the nanoscale, parametric molecular dynamic simulations are used to compute the energy associated with atomic level failure mechanisms. This information is used in a mesoscale percolation model of defect coalescence to obtain statistics of fracture paths and energies through Monte Carlo simulations. The mathematical structure of predicted crack paths is described using concepts of fractal geometry. The non-integer fractal dimension relates geometric and energy measures between meso- and macroscales. For illustration, a fractal-based continuum strain energy release rate is derived for inter- and transgranular fracture in polycrystalline metals.

  9. Modelling approaches for evaluating multiscale tendon mechanics.

    PubMed

    Fang, Fei; Lake, Spencer P

    2016-02-01

    Tendon exhibits anisotropic, inhomogeneous and viscoelastic mechanical properties that are determined by its complicated hierarchical structure and varying amounts/organization of different tissue constituents. Although extensive research has been conducted to use modelling approaches to interpret tendon structure-function relationships in combination with experimental data, many issues remain unclear (i.e. the role of minor components such as decorin, aggrecan and elastin), and the integration of mechanical analysis across different length scales has not been well applied to explore stress or strain transfer from macro- to microscale. This review outlines mathematical and computational models that have been used to understand tendon mechanics at different scales of the hierarchical organization. Model representations at the molecular, fibril and tissue levels are discussed, including formulations that follow phenomenological and microstructural approaches (which include evaluations of crimp, helical structure and the interaction between collagen fibrils and proteoglycans). Multiscale modelling approaches incorporating tendon features are suggested to be an advantageous methodology to understand further the physiological mechanical response of tendon and corresponding adaptation of properties owing to unique in vivo loading environments.

  10. Molecular mechanisms of ventricular hypoplasia.

    PubMed

    Srivastava, D; Gottlieb, P D; Olson, E N

    2002-01-01

    We have established the beginnings of a road map to understand how ventricular cells become specified, differentiate, and expand into a functional cardiac chamber (Fig. 5). The transcriptional networks described here provide clear evidence that disruption of pathways affecting ventricular growth could be the underlying etiology in a subset of children born with malformation of the right or left ventricle. As we learn details of the precise mechanisms through which the critical factors function, the challenge will lie in devising innovative methods to augment or modify the effects of gene mutations on ventricular development. Because most congenital heart disease likely occurs in a setting of heterozygous, predisposing mutations of one or more genes, modulation of activity of critical pathways in a preventive fashion may be useful in averting disease in genetically susceptible individuals. PMID:12858532

  11. An approach to molecular composites

    NASA Astrophysics Data System (ADS)

    Krigbaum, W. R.; Preston, J.

    1982-12-01

    One objective was to demonstrate that a nematogen can be made to exhibit a cholesteric phase by the incorporation of chiral centers into the polymer chain. The Yamazaki reaction was used to introduce 3 mole percent of chiral L-valine into poly(p-benzamide). This was shown to form a lyotropic cholesteric phase by circular dichroism and the induced circular dichroism of an achiral dye. A disadvantage of the use of lyotropic mesomorphism was that few solvents were available and the production costs were high. The early lattice model treatment of Flory indicated that a highly extended molecular conformation was essential to the formation of this type of mesophase. It has been demonstrated that the melting point depression of a crystalline polymer by this type of mesophase will be quite small unless the polymer-solvent interaction is very favorable. This implies that the polymer solubility will only be sufficient for the formation of a lyotropic mesaphase for those few polymer-solvent systems in which the interactions were very favorable. It was found that the Yamazaki phosphorylation reaction could be made to yield aromatic polyamides of higher inherent viscosity by using a monomer having pre-formed amide linkages. It is believed that this occurs due to reduction in the byproducts of the polymerization.

  12. Molecular Mechanisms of Bone 18F-NaF Deposition

    PubMed Central

    Czernin, Johannes; Satyamurthy, Nagichettiar; Schiepers, Christiaan

    2011-01-01

    There is renewed interest in 18F-NaF bone imaging with PET or PET/CT. The current brief discussion focuses on the molecular mechanisms of 18F-NaF deposition in bone and presents model-based approaches to quantifying bone perfusion and metabolism in the context of preclinical and clinical applications of bone imaging with PET. PMID:21078790

  13. Quantitative analysis of surface tension of liquid nano-film with thickness: Two stage stability mechanism, molecular dynamics and thermodynamics approach

    NASA Astrophysics Data System (ADS)

    Peng, Tiefeng; Li, Qibin; Chen, Jie; Gao, Xuechao

    2016-11-01

    The effects of thickness on surface tension of aqueous nano-films under the same lateral size were studied by molecular dynamics (MD) simulations. The surface tension was found to decrease with decreasing thickness when film thickness is below 1.5 nm. Between 4 and 1.5 nm, the trend is for the surface tension to decrease but this is not as significant as between 1.5 and 1.2 nm. For the surface tension of salt nano-films, with low temperatures resulting in monotonous decreasing with thickness, while high temperature (e.g. 479 K) exhibited a first increase then decrease for surface tension with thickness. Filippini et al. (2014) suggested that surface tension is constant with the thickness as long as the sheet remains in one piece, also the decrease observed and as proposed by Werth et al. (2013) is not due to a confinement effect on Lennard-Jones systems. However, in this study for aqueous nano-films, a two stage mechanism was proposed to interpret this effect, for which the stability was classified according to thickness range and validated by disjoining pressure. The results are important in describing the role of surface tension in determining the behaviour of disjoining pressure.

  14. Molecular Mechanisms of Failure in Polymer Nanocomposites

    NASA Astrophysics Data System (ADS)

    Gersappe, Dilip

    2002-07-01

    Molecular dynamics simulations of polymers reinforced with nanoscopic filler particles reveal the mechanisms by which nanofillers improve the toughness of the material. We find that the mobility of the nanofiller particle, rather than its surface area, controls its ability to dissipate energy. Our results show similarities between the toughening mechanisms observed in polymer nanocomposites and those postulated for biological structural materials such as spider silk and abalone adhesive.

  15. Osteoarthritis Pathogenesis: A Review of Molecular Mechanisms

    PubMed Central

    Xia, Bingjiang; Chen, Di; Zhang, Jushi; Hu, Songfeng; Jin, Hongting; Tong, Peijian

    2016-01-01

    Osteoarthritis (OA), the most prevalent chronic joint disease, increases in prevalence with age, and affects majority of individuals over the age of 65 and is a leading musculoskeletal cause of impaired mobility in the elderly. Because the precise molecular mechanisms which are involved in the degradation of cartilage matrix and development of OA are poorly understood and there are currently no effective interventions to decelerate the progression of OA or retard the irreversible degradation of cartilage except for total joint replacement surgery. In this paper, the important molecular mechanisms related to OA pathogenesis will be summarized and new insights into potential molecular targets for the prevention and treatment of OA will be provided. PMID:25311420

  16. Neuroprotection by natural polyphenols: molecular mechanisms.

    PubMed

    Campos-Esparza, Maria del Rosario; Torres-Ramos, Mónica Adriana

    2010-12-01

    Polyphenols are the most abundant antioxidants in diet. These can be found in fruits, vegetables, beverages (tea, wine, juices, etc.), plants and some herbs. These compounds are capable of protecting neuronal cells in different in vivo and in vitro models through diverse intracellular targets. The focus of this review is aimed at presenting the role of some polyphenols on the molecular mechanism involve in neuroprotection through different biological processes like oxidative stress, excitotoxicity, apoptotic neuronal death, regulation of the kinase signal cascade and modulation of Ubiquitin-Proteasome pathway. The study of the molecular mechanisms involved in neuroprotection and the molecular targets of natural polyphenols are important in the discovery of a valuable tool for new and more advanced therapy in neurodegenerative diseases.

  17. General Anesthetics and Molecular Mechanisms of Unconsciousness

    PubMed Central

    Forman, Stuart A.; Chin, Victor A.

    2013-01-01

    General anesthetic agents are unique in clinical medicine, because they are the only drugs used to produce unconsciousness as a therapeutic goal. In contrast to older hypotheses that assumed all general anesthetics produce their central nervous system effects through a common mechanism, we outline evidence that general anesthesia represents a number of distinct pharmacological effects that are likely mediated by different neural circuits, and perhaps via different molecular targets. Within the context of this neurobiological framework, we review recent molecular pharmacological and transgenic animal studies. These studies reveal that different groups of general anesthetics, which can be discerned based on their clinical features, produce unconsciousness via distinct molecular targets and therefore via distinct mechanisms. We further postulate that different types of general anesthetics selectively disrupt different critical steps (perhaps in different neuronal circuits) in the processing of sensory information and memory that results in consciousness. PMID:18617817

  18. Disease resistance: Molecular mechanisms and biotechnological applications

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This special issue “Disease resistance: molecular mechanisms and biotechnological applications” contains 11 review articles and four original research papers. Research in the area of engineering for disease resistance continues to progress although only 10% of the transgenic plants registered for ...

  19. Ocular diseases: immunological and molecular mechanisms

    PubMed Central

    Song, Jing; Huang, Yi-Fei; Zhang, Wen-Jing; Chen, Xiao-Fei; Guo, Yu-Mian

    2016-01-01

    Many factors, such as environmental, microbial and endogenous stress, antigen localization, can trigger the immunological events that affect the ending of the diverse spectrum of ocular disorders. Significant advances in understanding of immunological and molecular mechanisms have been researched to improve the diagnosis and therapy for patients with ocular inflammatory diseases. Some kinds of ocular diseases are inadequately responsive to current medications; therefore, immunotherapy may be a potential choice as an alternative or adjunctive treatment, even in the prophylactic setting. This article first provides an overview of the immunological and molecular mechanisms concerning several typical and common ocular diseases; second, the functions of immunological roles in some of systemic autoimmunity will be discussed; third, we will provide a summary of the mechanisms that dictate immune cell trafficking to ocular local microenvironment in response to inflammation. PMID:27275439

  20. Teratogenic effects of thalidomide: molecular mechanisms.

    PubMed

    Ito, Takumi; Ando, Hideki; Handa, Hiroshi

    2011-05-01

    Fifty years ago, prescription of the sedative thalidomide caused a worldwide epidemic of multiple birth defects. The drug is now used in the treatment of leprosy and multiple myeloma. However, its use is limited due to its potent teratogenic activity. The mechanism by which thalidomide causes limb malformations and other developmental defects is a long-standing question. Multiple hypotheses exist to explain the molecular mechanism of thalidomide action. Among them, theories involving oxidative stress and anti-angiogenesis have been widely supported. Nevertheless, until recently, the direct target of thalidomide remained elusive. We identified a thalidomide-binding protein, cereblon (CRBN), as a primary target for thalidomide teratogenicity. Our data suggest that thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting its ubiquitin ligase activity. In this review, we summarize the biology of thalidomide, focusing on the molecular mechanisms of its teratogenic effects. In addition, we discuss the questions still to be addressed.

  1. Sampling Molecular Conformers in Solution with Quantum Mechanical Accuracy at a Nearly Molecular-Mechanics Cost.

    PubMed

    Rosa, Marta; Micciarelli, Marco; Laio, Alessandro; Baroni, Stefano

    2016-09-13

    We introduce a method to evaluate the relative populations of different conformers of molecular species in solution, aiming at quantum mechanical accuracy, while keeping the computational cost at a nearly molecular-mechanics level. This goal is achieved by combining long classical molecular-dynamics simulations to sample the free-energy landscape of the system, advanced clustering techniques to identify the most relevant conformers, and thermodynamic perturbation theory to correct the resulting populations, using quantum-mechanical energies from density functional theory. A quantitative criterion for assessing the accuracy thus achieved is proposed. The resulting methodology is demonstrated in the specific case of cyanin (cyanidin-3-glucoside) in water solution.

  2. Sampling Molecular Conformers in Solution with Quantum Mechanical Accuracy at a Nearly Molecular-Mechanics Cost.

    PubMed

    Rosa, Marta; Micciarelli, Marco; Laio, Alessandro; Baroni, Stefano

    2016-09-13

    We introduce a method to evaluate the relative populations of different conformers of molecular species in solution, aiming at quantum mechanical accuracy, while keeping the computational cost at a nearly molecular-mechanics level. This goal is achieved by combining long classical molecular-dynamics simulations to sample the free-energy landscape of the system, advanced clustering techniques to identify the most relevant conformers, and thermodynamic perturbation theory to correct the resulting populations, using quantum-mechanical energies from density functional theory. A quantitative criterion for assessing the accuracy thus achieved is proposed. The resulting methodology is demonstrated in the specific case of cyanin (cyanidin-3-glucoside) in water solution. PMID:27494227

  3. Geochemical Reaction Mechanism Discovery from Molecular Simulation

    SciTech Connect

    Stack, Andrew G.; Kent, Paul R. C.

    2014-11-10

    Methods to explore reactions using computer simulation are becoming increasingly quantitative, versatile, and robust. In this review, a rationale for how molecular simulation can help build better geochemical kinetics models is first given. We summarize some common methods that geochemists use to simulate reaction mechanisms, specifically classical molecular dynamics and quantum chemical methods and discuss their strengths and weaknesses. Useful tools such as umbrella sampling and metadynamics that enable one to explore reactions are discussed. Several case studies wherein geochemists have used these tools to understand reaction mechanisms are presented, including water exchange and sorption on aqueous species and mineral surfaces, surface charging, crystal growth and dissolution, and electron transfer. The impact that molecular simulation has had on our understanding of geochemical reactivity are highlighted in each case. In the future, it is anticipated that molecular simulation of geochemical reaction mechanisms will become more commonplace as a tool to validate and interpret experimental data, and provide a check on the plausibility of geochemical kinetic models.

  4. Geochemical Reaction Mechanism Discovery from Molecular Simulation

    DOE PAGES

    Stack, Andrew G.; Kent, Paul R. C.

    2014-11-10

    Methods to explore reactions using computer simulation are becoming increasingly quantitative, versatile, and robust. In this review, a rationale for how molecular simulation can help build better geochemical kinetics models is first given. We summarize some common methods that geochemists use to simulate reaction mechanisms, specifically classical molecular dynamics and quantum chemical methods and discuss their strengths and weaknesses. Useful tools such as umbrella sampling and metadynamics that enable one to explore reactions are discussed. Several case studies wherein geochemists have used these tools to understand reaction mechanisms are presented, including water exchange and sorption on aqueous species and mineralmore » surfaces, surface charging, crystal growth and dissolution, and electron transfer. The impact that molecular simulation has had on our understanding of geochemical reactivity are highlighted in each case. In the future, it is anticipated that molecular simulation of geochemical reaction mechanisms will become more commonplace as a tool to validate and interpret experimental data, and provide a check on the plausibility of geochemical kinetic models.« less

  5. Frontotemporal dementia: from molecular mechanisms to therapy.

    PubMed

    Haass, Christian; Neumann, Manuela

    2016-08-01

    Frontotemporal dementia (FTD) is a heterogeneous clinical syndrome characterized by frontotemporal lobar degeneration (FTLD). Neuropathologically, FTLD is characterized by abnormal protein deposits and almost all cases can now be classified into three major molecular subgroups based on specific accumulating proteins with the most common being FTLD-tau and FTLD-TDP (accounting for ~40% and 50%, respectively) and FTLD-FET (accounting for ~5-10%). In this special issue, the molecular and genetic basics as well as clinical approaches and therapeutics are reviewed in a series of articles. This article is part of the Frontotemporal Dementia special issue. PMID:27502123

  6. Cellular and molecular mechanisms underlying presynapse formation

    PubMed Central

    Chia, Poh Hui; Li, Pengpeng

    2013-01-01

    Synapse formation is a highly regulated process that requires the coordination of many cell biological events. Decades of research have identified a long list of molecular components involved in assembling a functioning synapse. Yet how the various steps, from transporting synaptic components to adhering synaptic partners and assembling the synaptic structure, are regulated and precisely executed during development and maintenance is still unclear. With the improvement of imaging and molecular tools, recent work in vertebrate and invertebrate systems has provided important insight into various aspects of presynaptic development, maintenance, and trans-synaptic signals, thereby increasing our understanding of how extrinsic organizers and intracellular mechanisms contribute to presynapse formation. PMID:24127213

  7. Polymer Fluid Dynamics: Continuum and Molecular Approaches.

    PubMed

    Bird, R B; Giacomin, A J

    2016-06-01

    To solve problems in polymer fluid dynamics, one needs the equations of continuity, motion, and energy. The last two equations contain the stress tensor and the heat-flux vector for the material. There are two ways to formulate the stress tensor: (a) One can write a continuum expression for the stress tensor in terms of kinematic tensors, or (b) one can select a molecular model that represents the polymer molecule and then develop an expression for the stress tensor from kinetic theory. The advantage of the kinetic theory approach is that one gets information about the relation between the molecular structure of the polymers and the rheological properties. We restrict the discussion primarily to the simplest stress tensor expressions or constitutive equations containing from two to four adjustable parameters, although we do indicate how these formulations may be extended to give more complicated expressions. We also explore how these simplest expressions are recovered as special cases of a more general framework, the Oldroyd 8-constant model. Studying the simplest models allows us to discover which types of empiricisms or molecular models seem to be worth investigating further. We also explore equivalences between continuum and molecular approaches. We restrict the discussion to several types of simple flows, such as shearing flows and extensional flows, which are of greatest importance in industrial operations. Furthermore, if these simple flows cannot be well described by continuum or molecular models, then it is not necessary to lavish time and energy to apply them to more complex flow problems. PMID:27276553

  8. Approaches towards molecular amplification for sensing.

    PubMed

    Goggins, Sean; Frost, Christopher G

    2016-06-01

    Diagnostic assays that rely on molecular interactions have come a long way; from initial reversible detection systems towards irreversible reaction indicator-based methods. More recently, the emergence of innovative molecular amplification methodologies has revolutionised sensing, allowing diagnostic assays to achieve ultra-low limits of detection. There have been a significant number of molecular amplification approaches developed over recent years to accommodate the wide variety of analytes that require sensitive detection. To celebrate this achievement, this comprehensive critical review has been compiled to give a broad overview of the many different approaches used to attain amplification in sensing with an aim to inspire the next generation of diagnostic assays looking to achieve the ultimate detection limit. This review has been created with the focus on how each conceptually unique molecular amplification methodology achieves amplification, not just its sensitivity, while highlighting any key processes. Excluded are any references that were not found to contain an obvious molecular amplifier or amplification component, or that did not use an appropriate signal readout that could be incorporated into a sensing application. Additionally, methodologies where amplification is achieved through advances in instrumentation are also excluded. Depending upon the type of approach employed, amplification strategies are divided into four categories: target, label, signal or receptor amplification. More recent, more complex protocols combine a number of approaches and are therefore categorised by which amplification component described within was considered as the biggest advancement. The advantages and disadvantages of each methodology are discussed along with any limits of detection, if stated in the original article. Any subsequent use of the methodology within sensing or any other application is also mentioned to draw attention to its practicality. The importance of

  9. Regulation of renal potassium secretion: molecular mechanisms.

    PubMed

    Welling, Paul A

    2013-05-01

    A new understanding of renal potassium balance has emerged as the molecular underpinnings of potassium secretion have become illuminated, highlighting the key roles of apical potassium channels, renal outer medullary potassium channel (ROMK) and Big Potassium (BK), in the aldosterone-sensitive distal nephron and collecting duct. These channels act as the final-regulated components of the renal potassium secretory machinery. Their activity, number, and driving forces are precisely modulated to ensure potassium excretion matches dietary potassium intake. Recent identification of the underlying regulatory mechanisms at the molecular level provides a new appreciation of the physiology and reveals a molecular insight to explain the paradoxic actions of aldosterone on potassium secretion. Here, we review the current state of knowledge in the field.

  10. Nonlinear vibrational excitations in molecular crystals molecular mechanics calculations

    NASA Astrophysics Data System (ADS)

    Pumilia, P.; Abbate, S.; Baldini, G.; Ferro, D. R.; Tubino, R.

    1992-03-01

    The coupling constant for vibrational solitons χ has been examined in a molecular mechanics model for acetanilide (ACN) molecular crystal. According to A.C. Scott, solitons can form and propagate in solid acetanilide over a threshold energy value. This can be regarded as a structural model for the spines of hydrogen bond chains stabilizing the α helical structure of proteins. A one dimensional hydrogen bond chain of ACN has been built, for which we have found that, even though experimental parameters are correctly predicted, the excessive rigidity of the isolated chain prevents the formation of a localized distortion around the excitation. Yet, C=O coupling value with softer lattice modes could be rather high, allowing self-trapping to take place.

  11. Molecular mechanisms of membrane interaction at implantation.

    PubMed

    Davidson, Lien M; Coward, Kevin

    2016-03-01

    Successful pregnancy is dependent upon the implantation of a competent embryo into a receptive endometrium. Despite major advancement in our understanding of reproductive medicine over the last few decades, implantation failure still occurs in both normal pregnancies and those created artificially by assisted reproductive technology (ART). Consequently, there is significant interest in elucidating the etiology of implantation failure. The complex multistep process of implantation begins when the developing embryo first makes contact with the plasma membrane of epithelial cells within the uterine environment. However, although this biological interaction marks the beginning of a fundamental developmental process, our knowledge of the intricate physiological and molecular processes involved remains sparse. In this synopsis, we aim to provide an overview of our current understanding of the morphological changes which occur to the plasma membrane of the uterine endothelium, and the molecular mechanisms that control communication between the early embryo and the endometrium during implantation. A multitude of molecular factors have been implicated in this complex process, including endometrial integrins, extracellular matrix molecules, adhesion molecules, growth factors, and ion channels. We also explore the development of in vitro models for embryo implantation to help researchers investigate mechanisms which may underlie implantation failure. Understanding the precise molecular pathways associated with implantation failure could help us to generate new prognostic/diagnostic biomarkers, and may identify novel therapeutic targets. PMID:26969610

  12. Molecular mechanism of the sweet taste enhancers

    PubMed Central

    Zhang, Feng; Klebansky, Boris; Fine, Richard M.; Liu, Haitian; Xu, Hong; Servant, Guy; Zoller, Mark; Tachdjian, Catherine; Li, Xiaodong

    2010-01-01

    Positive allosteric modulators of the human sweet taste receptor have been developed as a new way of reducing dietary sugar intake. Besides their potential health benefit, the sweet taste enhancers are also valuable tool molecules to study the general mechanism of positive allosteric modulations of T1R taste receptors. Using chimeric receptors, mutagenesis, and molecular modeling, we reveal how these sweet enhancers work at the molecular level. Our data argue that the sweet enhancers follow a similar mechanism as the natural umami taste enhancer molecules. Whereas the sweeteners bind to the hinge region and induce the closure of the Venus flytrap domain of T1R2, the enhancers bind close to the opening and further stabilize the closed and active conformation of the receptor. PMID:20173095

  13. Molecular mechanism for the umami taste synergism

    PubMed Central

    Zhang, Feng; Klebansky, Boris; Fine, Richard M.; Xu, Hong; Pronin, Alexey; Liu, Haitian; Tachdjian, Catherine; Li, Xiaodong

    2008-01-01

    Umami is one of the 5 basic taste qualities. The umami taste of L-glutamate can be drastically enhanced by 5′ ribonucleotides and the synergy is a hallmark of this taste quality. The umami taste receptor is a heteromeric complex of 2 class C G-protein-coupled receptors, T1R1 and T1R3. Here we elucidate the molecular mechanism of the synergy using chimeric T1R receptors, site-directed mutagenesis, and molecular modeling. We propose a cooperative ligand-binding model involving the Venus flytrap domain of T1R1, where L-glutamate binds close to the hinge region, and 5′ ribonucleotides bind to an adjacent site close to the opening of the flytrap to further stabilize the closed conformation. This unique mechanism may apply to other class C G-protein-coupled receptors. PMID:19104071

  14. Molecular mechanism of the sweet taste enhancers.

    PubMed

    Zhang, Feng; Klebansky, Boris; Fine, Richard M; Liu, Haitian; Xu, Hong; Servant, Guy; Zoller, Mark; Tachdjian, Catherine; Li, Xiaodong

    2010-03-01

    Positive allosteric modulators of the human sweet taste receptor have been developed as a new way of reducing dietary sugar intake. Besides their potential health benefit, the sweet taste enhancers are also valuable tool molecules to study the general mechanism of positive allosteric modulations of T1R taste receptors. Using chimeric receptors, mutagenesis, and molecular modeling, we reveal how these sweet enhancers work at the molecular level. Our data argue that the sweet enhancers follow a similar mechanism as the natural umami taste enhancer molecules. Whereas the sweeteners bind to the hinge region and induce the closure of the Venus flytrap domain of T1R2, the enhancers bind close to the opening and further stabilize the closed and active conformation of the receptor.

  15. Molecular mechanism for the umami taste synergism.

    PubMed

    Zhang, Feng; Klebansky, Boris; Fine, Richard M; Xu, Hong; Pronin, Alexey; Liu, Haitian; Tachdjian, Catherine; Li, Xiaodong

    2008-12-30

    Umami is one of the 5 basic taste qualities. The umami taste of L-glutamate can be drastically enhanced by 5' ribonucleotides and the synergy is a hallmark of this taste quality. The umami taste receptor is a heteromeric complex of 2 class C G-protein-coupled receptors, T1R1 and T1R3. Here we elucidate the molecular mechanism of the synergy using chimeric T1R receptors, site-directed mutagenesis, and molecular modeling. We propose a cooperative ligand-binding model involving the Venus flytrap domain of T1R1, where L-glutamate binds close to the hinge region, and 5' ribonucleotides bind to an adjacent site close to the opening of the flytrap to further stabilize the closed conformation. This unique mechanism may apply to other class C G-protein-coupled receptors.

  16. Molecular Mechanism of Biological Proton Transport

    SciTech Connect

    Pomes, R.

    1998-09-01

    Proton transport across lipid membranes is a fundamental aspect of biological energy transduction (metabolism). This function is mediated by a Grotthuss mechanism involving proton hopping along hydrogen-bonded networks embedded in membrane-spanning proteins. Using molecular simulations, the authors have explored the structural, dynamic, and thermodynamic properties giving rise to long-range proton translocation in hydrogen-bonded networks involving water molecules, or water wires, which are emerging as ubiquitous H{sup +}-transport devices in biological systems.

  17. Wilson's disease: a comprehensive review of the molecular mechanisms.

    PubMed

    Wu, Fei; Wang, Jing; Pu, Chunwen; Qiao, Liang; Jiang, Chunmeng

    2015-01-01

    Wilson's disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive inherited disorder resulting from abnormal copper metabolism. Reduced copper excretion causes an excessive deposition of the copper in many organs such as the liver, central nervous system (CNS), cornea, kidney, joints, and cardiac muscle where the physiological functions of the affected organs are impaired. The underlying molecular mechanisms for WD have been extensively studied. It is now believed that a defect in P-type adenosine triphosphatase (ATP7B), the gene encoding the copper transporting P-type ATPase, is responsible for hepatic copper accumulation. Deposited copper in the liver produces toxic effects via modulating several molecular pathways. WD can be a lethal disease if left untreated. A better understanding of the molecular mechanisms causing the aberrant copper deposition and organ damage is the key to developing effective management approaches.

  18. Molecular mechanisms of optic axon guidance

    NASA Astrophysics Data System (ADS)

    Inatani, Masaru

    2005-12-01

    Axon guidance is one of the critical processes during vertebrate central nervous system (CNS) development. The optic nerve, which contains the axons of retinal ganglion cells, has been used as a powerful model to elucidate some of the mechanisms underlying axon guidance because it is easily manipulated experimentally, and its function is well understood. Recent molecular biology studies have revealed that numerous guidance molecules control the development of the visual pathway. This review introduces the molecular mechanisms involved in each critical step during optic axon guidance. Axonal projections to the optic disc are thought to depend on adhesion molecules and inhibitory extracellular matrices such as chondroitin sulfate. The formation of the head of the optic nerve and the optic chiasm require ligand-receptor interactions between netrin-1 and the deleted in colorectal cancer receptor, and Slit proteins and Robo receptors, respectively. The gradient distributions of ephrin ligands and Eph receptors are essential for correct ipsilateral projections at the optic chiasm and the topographic mapping of axons in the superior colliculus/optic tectum. The precise gradient is regulated by transcription factors determining the retinal dorso-ventral and nasal-temporal polarities. Moreover, the axon guidance activities by Slit and semaphorin 5A require the existence of heparan sulfate, which binds to numerous guidance molecules. Recent discoveries about the molecular mechanisms underlying optic nerve guidance will facilitate progress in CNS developmental biology and axon-regeneration therapy.

  19. MOLECULAR MECHANISMS OF FEAR LEARNING AND MEMORY

    PubMed Central

    Johansen, Joshua P.; Cain, Christopher K.; Ostroff, Linnaea E.; LeDoux, Joseph E.

    2011-01-01

    Pavlovian fear conditioning is a useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Together, this research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals, and potentially for understanding fear related disorders, such as PTSD and phobias. PMID:22036561

  20. Molecular mechanics of mussel adhesion proteins

    NASA Astrophysics Data System (ADS)

    Qin, Zhao; Buehler, Markus J.

    2014-01-01

    Mussel foot protein (mfp), a natural glue produced by marine mussel, is an intriguing material because of its superior ability for adhesion in various environments. For example, a very small amount of this material is sufficient to affix a mussel to a substrate in water, providing structural support under extreme forces caused by the dynamic effects of waves. Towards a more complete understanding of its strength and underwater workability, it is necessary to understand the microscropic mechanisms by which the protein structure interacts with various substrates. However, none of the mussel proteins' structure is known, preventing us from directly using atomistic modeling to probe their structural and mechanical properties. Here we use an advanced molecular sampling technique to identify the molecular structures of two mussel foot proteins (mfp-3 and mfp-5) and use those structures to study their mechanics of adhesion, which is then incorporated into a continuum model. We calculate the adhesion energy of the mussel foot protein on a silica substrate, compute the adhesion strength based on results obtained from molecular modeling, and compare with experimental data. Our results show good agreement with experimental measurements, which validates the multiscale model. We find that the molecular structure of the folded mussel foot protein (ultimately defined by its genetic sequence) favors strong adhesion to substrates, where L-3,4-dihydroxyphenylalanine (or DOPA) protein subunits work in a cooperative manner to enhance adhesion. Our experimental data suggests a peak attachment force of 0.4±0.1 N, which compares favorably with the prediction from the multiscale model of Fc=0.21-0.33 N. The principles learnt from those results could guide the fabrication of new interfacial materials (e.g. composites) to integrate organic with inorganic surfaces in an effective manner.

  1. A mechanical micro molecular mass sensor

    PubMed Central

    Kurhekar, A. S.; Apte, P. R.

    2014-01-01

    One of the bio-sensing mechanisms is mechanical. Rather than measuring shift in resonance frequency, we adopt to measure the change in spring constant due to adsorption, as one of the fundamental sensing mechanism. This study explains determination of spring constant of a surface functionalized micro machined micro cantilever, which resonates in a trapezoidal cavity-on Silicon <100> wafer, with the resonating frequency of 7000 cycles per second. This thin-flimsy-oxide micro-cantilever has a typical shape, and the tip of the micro-cantilever is dip-coated with chemically and biologically active material. The change in mass, due to adsorption, is detected by measuring the change in spring constant. The Force-Distance spectroscopy is used to detect the change in spring constant. The experimental results, show that the mechanical sensing scheme used, permit this surface functionalized micro machined micro cantilever to be used as a molecular mass sensor. The mechanical spring behaviour of a micro-cantilever, a micro-mechanical device can be used to develop ultra-tech micro-mechanical system using computer interface. PMID:24459585

  2. A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-β-lactamase-1.

    PubMed

    Zhu, Kongkai; Lu, Junyan; Liang, Zhongjie; Kong, Xiangqian; Ye, Fei; Jin, Lu; Geng, Heji; Chen, Yong; Zheng, Mingyue; Jiang, Hualiang; Li, Jun-Qian; Luo, Cheng

    2013-03-01

    New Delhi metallo-β-lactamase-1 (NDM-1) has emerged as a major global threat to human health for its rapid rate of dissemination and ability to make pathogenic microbes resistant to almost all known β-lactam antibiotics. In addition, effective NDM-1 inhibitors have not been identified to date. In spite of the plethora of structural and kinetic data available, the accurate molecular characteristics of and details on the enzymatic reaction of NDM-1 hydrolyzing β-lactam antibiotics remain incompletely understood. In this study, a combined computational approach including molecular docking, molecular dynamics simulations and quantum mechanics/molecular mechanics calculations was performed to characterize the catalytic mechanism of meropenem catalyzed by NDM-1. The quantum mechanics/molecular mechanics results indicate that the ionized D124 is beneficial to the cleavage of the C-N bond within the β-lactam ring. Meanwhile, it is energetically favorable to form an intermediate if no water molecule coordinates to Zn2. Moreover, according to the molecular dynamics results, the conserved residue K211 plays a pivotal role in substrate binding and catalysis, which is quite consistent with previous mutagenesis data. Our study provides detailed insights into the catalytic mechanism of NDM-1 hydrolyzing meropenem β-lactam antibiotics and offers clues for the discovery of new antibiotics against NDM-1 positive strains in clinical studies.

  3. Molecular Mechanisms of Renal Ischemic Conditioning Strategies.

    PubMed

    Kierulf-Lassen, Casper; Nieuwenhuijs-Moeke, Gertrude J; Krogstrup, Nicoline V; Oltean, Mihai; Jespersen, Bente; Dor, Frank J M F

    2015-01-01

    Ischemia-reperfusion injury is the leading cause of acute kidney injury in a variety of clinical settings such as renal transplantation and hypovolemic and/or septic shock. Strategies to reduce ischemia-reperfusion injury are obviously clinically relevant. Ischemic conditioning is an inherent part of the renal defense mechanism against ischemia and can be triggered by short periods of intermittent ischemia and reperfusion. Understanding the signaling transduction pathways of renal ischemic conditioning can promote further clinical translation and pharmacological advancements in this era. This review summarizes research on the molecular mechanisms underlying both local and remote ischemic pre-, per- and postconditioning of the kidney. The different types of conditioning strategies in the kidney recruit similar powerful pro-survival mechanisms. Likewise, renal ischemic conditioning mobilizes many of the same protective signaling pathways as in other organs, but differences are recognized. PMID:26330099

  4. Molecular mechanisms of chemoresistance in gastric cancer.

    PubMed

    Shi, Wen-Jia; Gao, Jin-Bo

    2016-09-15

    Gastric cancer is the fourth most common cancer and the second leading cause of cancer deaths worldwide. Chemotherapy is one of the major treatments for gastric cancer, but drug resistance limits the effectiveness of chemotherapy, which results in treatment failure. Resistance to chemotherapy can be present intrinsically before the administration of chemotherapy or it can develop during chemotherapy. The mechanisms of chemotherapy resistance in gastric cancer are complex and multifactorial. A variety of factors have been demonstrated to be involved in chemoresistance, including the reduced intracellular concentrations of drugs, alterations in drug targets, the dysregulation of cell survival and death signaling pathways, and interactions between cancer cells and the tumor microenvironment. This review focuses on the molecular mechanisms of chemoresistance in gastric cancer and on recent studies that have sought to overcome the underlying mechanisms of chemoresistance. PMID:27672425

  5. Molecular mechanisms of chemoresistance in gastric cancer

    PubMed Central

    Shi, Wen-Jia; Gao, Jin-Bo

    2016-01-01

    Gastric cancer is the fourth most common cancer and the second leading cause of cancer deaths worldwide. Chemotherapy is one of the major treatments for gastric cancer, but drug resistance limits the effectiveness of chemotherapy, which results in treatment failure. Resistance to chemotherapy can be present intrinsically before the administration of chemotherapy or it can develop during chemotherapy. The mechanisms of chemotherapy resistance in gastric cancer are complex and multifactorial. A variety of factors have been demonstrated to be involved in chemoresistance, including the reduced intracellular concentrations of drugs, alterations in drug targets, the dysregulation of cell survival and death signaling pathways, and interactions between cancer cells and the tumor microenvironment. This review focuses on the molecular mechanisms of chemoresistance in gastric cancer and on recent studies that have sought to overcome the underlying mechanisms of chemoresistance.

  6. Molecular mechanisms for protein-encoded inheritance

    SciTech Connect

    Wiltzius, Jed J.W.; Landau, Meytal; Nelson, Rebecca; Sawaya, Michael R.; Apostol, Marcin I.; Goldschmidt, Lukasz; Soriaga, Angela B.; Cascio, Duilio; Rajashankar, Kanagalaghatta; Eisenberg, David

    2009-12-01

    In prion inheritance and transmission, strains are phenotypic variants encoded by protein 'conformations'. However, it is unclear how a protein conformation can be stable enough to endure transmission between cells or organisms. Here we describe new polymorphic crystal structures of segments of prion and other amyloid proteins, which offer two structural mechanisms for the encoding of prion strains. In packing polymorphism, prion strains are encoded by alternative packing arrangements (polymorphs) of {beta}-sheets formed by the same segment of a protein; in segmental polymorphism, prion strains are encoded by distinct {beta}-sheets built from different segments of a protein. Both forms of polymorphism can produce enduring conformations capable of encoding strains. These molecular mechanisms for transfer of protein-encoded information into prion strains share features with the familiar mechanism for transfer of nucleic acid-encoded information into microbial strains, including sequence specificity and recognition by noncovalent bonds.

  7. Molecular mechanisms of chemoresistance in gastric cancer

    PubMed Central

    Shi, Wen-Jia; Gao, Jin-Bo

    2016-01-01

    Gastric cancer is the fourth most common cancer and the second leading cause of cancer deaths worldwide. Chemotherapy is one of the major treatments for gastric cancer, but drug resistance limits the effectiveness of chemotherapy, which results in treatment failure. Resistance to chemotherapy can be present intrinsically before the administration of chemotherapy or it can develop during chemotherapy. The mechanisms of chemotherapy resistance in gastric cancer are complex and multifactorial. A variety of factors have been demonstrated to be involved in chemoresistance, including the reduced intracellular concentrations of drugs, alterations in drug targets, the dysregulation of cell survival and death signaling pathways, and interactions between cancer cells and the tumor microenvironment. This review focuses on the molecular mechanisms of chemoresistance in gastric cancer and on recent studies that have sought to overcome the underlying mechanisms of chemoresistance. PMID:27672425

  8. Molecular mechanisms of curcumin action: gene expression.

    PubMed

    Shishodia, Shishir

    2013-01-01

    Curcumin derived from the tropical plant Curcuma longa has a long history of use as a dietary agent, food preservative, and in traditional Asian medicine. It has been used for centuries to treat biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism, and sinusitis. The preventive and therapeutic properties of curcumin are associated with its antioxidant, anti-inflammatory, and anticancer properties. Extensive research over several decades has attempted to identify the molecular mechanisms of curcumin action. Curcumin modulates numerous molecular targets by altering their gene expression, signaling pathways, or through direct interaction. Curcumin regulates the expression of inflammatory cytokines (e.g., TNF, IL-1), growth factors (e.g., VEGF, EGF, FGF), growth factor receptors (e.g., EGFR, HER-2, AR), enzymes (e.g., COX-2, LOX, MMP9, MAPK, mTOR, Akt), adhesion molecules (e.g., ELAM-1, ICAM-1, VCAM-1), apoptosis related proteins (e.g., Bcl-2, caspases, DR, Fas), and cell cycle proteins (e.g., cyclin D1). Curcumin modulates the activity of several transcription factors (e.g., NF-κB, AP-1, STAT) and their signaling pathways. Based on its ability to affect multiple targets, curcumin has the potential for the prevention and treatment of various diseases including cancers, arthritis, allergies, atherosclerosis, aging, neurodegenerative disease, hepatic disorders, obesity, diabetes, psoriasis, and autoimmune diseases. This review summarizes the molecular mechanisms of modulation of gene expression by curcumin.

  9. Molecular mechanisms of curcumin action: gene expression.

    PubMed

    Shishodia, Shishir

    2013-01-01

    Curcumin derived from the tropical plant Curcuma longa has a long history of use as a dietary agent, food preservative, and in traditional Asian medicine. It has been used for centuries to treat biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism, and sinusitis. The preventive and therapeutic properties of curcumin are associated with its antioxidant, anti-inflammatory, and anticancer properties. Extensive research over several decades has attempted to identify the molecular mechanisms of curcumin action. Curcumin modulates numerous molecular targets by altering their gene expression, signaling pathways, or through direct interaction. Curcumin regulates the expression of inflammatory cytokines (e.g., TNF, IL-1), growth factors (e.g., VEGF, EGF, FGF), growth factor receptors (e.g., EGFR, HER-2, AR), enzymes (e.g., COX-2, LOX, MMP9, MAPK, mTOR, Akt), adhesion molecules (e.g., ELAM-1, ICAM-1, VCAM-1), apoptosis related proteins (e.g., Bcl-2, caspases, DR, Fas), and cell cycle proteins (e.g., cyclin D1). Curcumin modulates the activity of several transcription factors (e.g., NF-κB, AP-1, STAT) and their signaling pathways. Based on its ability to affect multiple targets, curcumin has the potential for the prevention and treatment of various diseases including cancers, arthritis, allergies, atherosclerosis, aging, neurodegenerative disease, hepatic disorders, obesity, diabetes, psoriasis, and autoimmune diseases. This review summarizes the molecular mechanisms of modulation of gene expression by curcumin. PMID:22996381

  10. Molecular mechanisms of prolactin and its receptor.

    PubMed

    Brooks, Charles L

    2012-08-01

    Prolactin and the prolactin receptors are members of a family of hormone/receptor pairs which include GH, erythropoietin, and other ligand/receptor pairs. The mechanisms of these ligand/receptor pairs have broad similarities, including general structures, ligand/receptor stoichiometries, and activation of several common signaling pathways. But significant variations in the structural and mechanistic details are present among these hormones and their type 1 receptors. The prolactin receptor is particularly interesting because it can be activated by three sequence-diverse human hormones: prolactin, GH, and placental lactogen. This system offers a unique opportunity to compare the detailed molecular mechanisms of these related hormone/receptor pairs. This review critically evaluates selected literature that informs these mechanisms, compares the mechanisms of the three lactogenic hormones, compares the mechanism with those of other class 1 ligand/receptor pairs, and identifies information that will be required to resolve mechanistic ambiguities. The literature describes distinct mechanistic differences between the three lactogenic hormones and their interaction with the prolactin receptor and describes more significant differences between the mechanisms by which other related ligands interact with and activate their receptors.

  11. Pseudospectral approach to relativistic molecular theory.

    PubMed

    Nakajima, Takahito; Hirao, Kimihiko

    2004-08-22

    The efficient relativistic Dirac-Hartree-Fock (DHF) and Dirac-Kohn-Sham (DKS) methods are proposed by an application of the pseudospectral (PS) approach. The present PS-DHF/DKS method is a relativistic extension of the PS-HF/KS method of Friesner, though we aim at higher numerical accuracy by elimination of superfluous arbitrariness. The relativistic PS-DHF/DKS method is implemented into our REL4D programs. Several PS applications to molecular systems show that the relativistic PS-DHF/DKS approach is more efficient than the traditional approach without a loss of accuracy. The present PS-DKS method successfully assigns and predicts the photoelectron spectra of hexacarbonyl complexes of tungsten and seaborgium theoretically.

  12. Measuring the mechanical properties of molecular conformers

    NASA Astrophysics Data System (ADS)

    Jarvis, S. P.; Taylor, S.; Baran, J. D.; Champness, N. R.; Larsson, J. A.; Moriarty, P.

    2015-09-01

    Scanning probe-actuated single molecule manipulation has proven to be an exceptionally powerful tool for the systematic atomic-scale interrogation of molecular adsorbates. To date, however, the extent to which molecular conformation affects the force required to push or pull a single molecule has not been explored. Here we probe the mechanochemical response of two tetra(4-bromophenyl)porphyrin conformers using non-contact atomic force microscopy where we find a large difference between the lateral forces required for manipulation. Remarkably, despite sharing very similar adsorption characteristics, variations in the potential energy surface are capable of prohibiting probe-induced positioning of one conformer, while simultaneously permitting manipulation of the alternative conformational form. Our results are interpreted in the context of dispersion-corrected density functional theory calculations which reveal significant differences in the diffusion barriers for each conformer. These results demonstrate that conformational variation significantly modifies the mechanical response of even simple porpyhrins, potentially affecting many other flexible molecules.

  13. Cellular and Molecular Mechanisms of AKI.

    PubMed

    Agarwal, Anupam; Dong, Zheng; Harris, Raymond; Murray, Patrick; Parikh, Samir M; Rosner, Mitchell H; Kellum, John A; Ronco, Claudio

    2016-05-01

    In this article, we review the current evidence for the cellular and molecular mechanisms of AKI, focusing on epithelial cell pathobiology and related cell-cell interactions, using ischemic AKI as a model. Highlighted are the clinical relevance of cellular and molecular targets that have been investigated in experimental models of ischemic AKI and how such models might be improved to optimize translation into successful clinical trials. In particular, development of more context-specific animal models with greater relevance to human AKI is urgently needed. Comorbidities that could alter patient susceptibility to AKI, such as underlying diabetes, aging, obesity, cancer, and CKD, should also be considered in developing these models. Finally, harmonization between academia and industry for more clinically relevant preclinical testing of potential therapeutic targets and better translational clinical trial design is also needed to achieve the goal of developing effective interventions for AKI. PMID:26860342

  14. Molecular Mechanics of Tip-Link Cadherins

    NASA Astrophysics Data System (ADS)

    Sotomayor, Marcos; Weihofen, Wilhelm A.; Gaudet, Rachelle; Corey, David P.

    2011-11-01

    The hair-cell tip link, a fine filament directly conveying force to mechanosensitive transduction channels, is likely composed of two proteins, protocadherin-15 and cadherin-23, whose mutation causes deafness. However, their complete molecular structure, elasticity, and deafness-related structural defects remain largely unknown. We present crystal structures of extracellular (EC) tip-link cadherin repeats involved in hereditary deafness and tip link formation. In addition, we show that the deafness mutation D101G, in the linker region between the repeats EC1 and EC2 of cadherin-23, causes a slight bend between repeats and decreases Ca2+ affinity. Molecular dynamics simulations suggest that tip-link cadherin repeats are stiff and that either removing Ca2+ or mutating Ca2+-binding residues reduces rigidity and unfolding strength. The structures and simulations also suggest mechanisms underlying inherited deafness and how cadherin-23 may bind with protocadherin-15 to form the tip link.

  15. Molecular Mechanisms of Sex Determination in Reptiles

    PubMed Central

    Rhen, T.; Schroeder, A.

    2010-01-01

    Charles Darwin first provided a lucid explanation of how gender differences evolve nearly 140 years ago. Yet, a disconnect remains between his theory of sexual selection and the mechanisms that underlie the development of males and females. In particular, comparisons between representatives of different phyla (i.e., flies and mice) reveal distinct genetic mechanisms for sexual differentiation. Such differences are hard to comprehend unless we study organisms that bridge the phylogenetic gap. Analysis of variation within monophyletic groups (i.e., amniotes) is just as important if we hope to elucidate the evolution of mechanisms underlying sexual differentiation. Here we review the molecular, cellular, morphological, and physiological changes associated with sex determination in reptiles. Most research on the molecular biology of sex determination in reptiles describes expression patterns for orthologs of mammalian sex-determining genes. Many of these genes have evolutionarily conserved expression profiles (i.e., DMRT1 and SOX9 are expressed at a higher level in developing testes vs. developing ovaries in all species), which suggests functional conservation. However, expression profiling alone does not test gene function and will not identify novel sex-determining genes or gene interactions. For that reason, we provide a prospectus on various techniques that promise to reveal new sex-determining genes and regulatory interactions among these genes. We offer specific examples of novel candidate genes and a new signaling pathway in support of these techniques. PMID:20145384

  16. Molecular mechanisms of sex determination in reptiles.

    PubMed

    Rhen, T; Schroeder, A

    2010-01-01

    Charles Darwin first provided a lucid explanation of how gender differences evolve nearly 140 years ago. Yet, a disconnect remains between his theory of sexual selection and the mechanisms that underlie the development of males and females. In particular, comparisons between representatives of different phyla (i.e., flies and mice) reveal distinct genetic mechanisms for sexual differentiation. Such differences are hard to comprehend unless we study organisms that bridge the phylogenetic gap. Analysis of variation within monophyletic groups (i.e., amniotes) is just as important if we hope to elucidate the evolution of mechanisms underlying sexual differentiation. Here we review the molecular, cellular, morphological, and physiological changes associated with sex determination in reptiles. Most research on the molecular biology of sex determination in reptiles describes expression patterns for orthologs of mammalian sex-determining genes. Many of these genes have evolutionarily conserved expression profiles (i.e., DMRT1 and SOX9 are expressed at a higher level in developing testes vs. developing ovaries in all species), which suggests functional conservation. However, expression profiling alone does not test gene function and will not identify novel sex-determining genes or gene interactions. For that reason, we provide a prospectus on various techniques that promise to reveal new sex-determining genes and regulatory interactions among these genes. We offer specific examples of novel candidate genes and a new signaling pathway in support of these techniques.

  17. Precursor directed synthesis - ``molecular'' mechanisms in the Soft Chemistry approaches and their use for template-free synthesis of metal, metal oxide and metal chalcogenide nanoparticles and nanostructures

    NASA Astrophysics Data System (ADS)

    Seisenbaeva, Gulaim A.; Kessler, Vadim G.

    2014-05-01

    This review provides an insight into the common reaction mechanisms in Soft Chemistry processes involved in nucleation, growth and aggregation of metal, metal oxide and chalcogenide nanoparticles starting from metal-organic precursors such as metal alkoxides, beta-diketonates, carboxylates and their chalcogene analogues and demonstrates how mastering the precursor chemistry permits us to control the chemical and phase composition, crystallinity, morphology, porosity and surface characteristics of produced nanomaterials.This review provides an insight into the common reaction mechanisms in Soft Chemistry processes involved in nucleation, growth and aggregation of metal, metal oxide and chalcogenide nanoparticles starting from metal-organic precursors such as metal alkoxides, beta-diketonates, carboxylates and their chalcogene analogues and demonstrates how mastering the precursor chemistry permits us to control the chemical and phase composition, crystallinity, morphology, porosity and surface characteristics of produced nanomaterials. To Professor David Avnir on his 65th birthday.

  18. Mechanisms of Ventricular Arrhythmias: From Molecular Fluctuations to Electrical Turbulence

    PubMed Central

    Qu, Zhilin; Weiss, James N.

    2015-01-01

    Ventricular arrhythmias have complex causes and mechanisms. Despite extensive investigation involving many clinical, experimental, and computational studies, effective biological therapeutics are still very limited. In this article, we review our current understanding of the mechanisms of ventricular arrhythmias by summarizing the state of knowledge spanning from the molecular scale to electrical wave behavior at the tissue and organ scales and how the complex nonlinear interactions integrate into the dynamics of arrhythmias in the heart. We discuss the challenges that we face in synthesizing these dynamics to develop safe and effective novel therapeutic approaches. PMID:25340965

  19. Molecular mechanisms of robustness in plants

    PubMed Central

    Lempe, Janne; Lachowiec, Jennifer; Sullivan, Alessandra. M.; Queitsch, Christine

    2012-01-01

    Robustness, the ability of organisms to buffer phenotypes against perturbations, has drawn renewed interest among developmental biologists and geneticists. A growing body of research supports an important role of robustness in the genotype to phenotype translation, with far- reaching implications for evolutionary processes and disease susceptibility. Like for animals and fungi, plant robustness is a function of genetic network architecture. Most perturbations are buffered; however, perturbation of network hubs destabilizes many traits. Here, we review recent advances in identifying molecular robustness mechanisms in plants that have been enabled by a combination of classical genetics and population genetics with genome-scale data. PMID:23279801

  20. Molecular Mechanisms of Inner Ear Development

    PubMed Central

    Wu, Doris K.; Kelley, Matthew W.

    2012-01-01

    The inner ear is a structurally complex vertebrate organ built to encode sound, motion, and orientation in space. Given its complexity, it is not surprising that inner ear dysfunction is a relatively common consequence of human genetic mutation. Studies in model organisms suggest that many genes currently known to be associated with human hearing impairment are active during embryogenesis. Hence, the study of inner ear development provides a rich context for understanding the functions of genes implicated in hearing loss. This chapter focuses on molecular mechanisms of inner ear development derived from studies of model organisms. PMID:22855724

  1. [Molecular mechanisms regulating the activity of macrophages].

    PubMed

    Onoprienko, L V

    2011-01-01

    This article reviews modern concepts of the most common types of macrophage activation: classical, alternative, and type II. Molecular mechanisms of induction and regulation of these three types of activation are discussed. Any population of macrophages was shown to change its properties depending on its microenvironment and concrete biological situation (the "functional plasticity of macrophages"). Many intermediate states of macrophages were described along with the most pronounced and well-known activation types (classical activation, alternative activation, and type II activation). These intermediate states are characterized by a variety of combinations of their biological properties, including elements of the three afore mentioned types of activation. Macrophage activity is regulated by a complex network of interrelated cascade mechanisms.

  2. Molecular machinery and mechanism of cell secretion.

    PubMed

    Jena, Bhanu P

    2005-05-01

    Secretion occurs in all living cells and involves the delivery of intracellular products to the cell exterior. Secretory products are packaged and stored in membranous sacs or vesicles within the cell. When the cell needs to secrete these products, the secretory vesicles containing them dock and fuse at plasma membrane-associated supramolecular structures, called porosomes, to release their contents. Specialized cells for neurotransmission, enzyme secretion, or hormone release use a highly regulated secretory process. Similar to other fundamental cellular processes, cell secretion is precisely regulated. During secretion, swelling of secretory vesicles results in a build-up of intravesicular pressure, allowing expulsion of vesicular contents. The extent of vesicle swelling dictates the amount of vesicular contents expelled. The discovery of the porosome as the universal secretory machinery, its isolation, its structure and dynamics at nanometer resolution and in real time, and its biochemical composition and functional reconstitution into artificial lipid membrane have been determined. The molecular mechanism of secretory vesicle swelling and the fusion of opposing bilayers, that is, the fusion of secretory vesicle membrane at the base of the porosome membrane, have also been resolved. These findings reveal, for the first time, the universal molecular machinery and mechanism of secretion in cells.

  3. Molecular Mechanisms of Thoracic Aortic Dissection

    PubMed Central

    Wu, Darrell; Shen, Ying H.; Russell, Ludivine; Coselli, Joseph S.; LeMaire, Scott A.

    2013-01-01

    Thoracic aortic dissection (TAD) is a highly lethal vascular disease. In many patients with TAD, the aorta progressively dilates and ultimately ruptures. Dissection formation, progression, and rupture cannot be reliably prevented pharmacologically because the molecular mechanisms of aortic wall degeneration are poorly understood. The key histopathologic feature of TAD is medial degeneration, a process characterized by smooth muscle cell depletion and extracellular matrix degradation. These structural changes have a profound impact on the functional properties of the aortic wall and can result from excessive protease-mediated destruction of the extracellular matrix, altered signaling pathways, and altered gene expression. Review of the literature reveals differences in the processes that lead to ascending versus descending and sporadic versus hereditary TAD. These differences add to the complexity of this disease. Although tremendous progress has been made in diagnosing and treating TAD, a better understanding of the molecular, cellular, and genetic mechanisms that cause this disease is necessary to developing more effective preventative and therapeutic treatment strategies. PMID:23856125

  4. Hyperinsulinemic Hypoglycemia – The Molecular Mechanisms

    PubMed Central

    Nessa, Azizun; Rahman, Sofia A.; Hussain, Khalid

    2016-01-01

    Under normal physiological conditions, pancreatic β-cells secrete insulin to maintain fasting blood glucose levels in the range 3.5–5.5 mmol/L. In hyperinsulinemic hypoglycemia (HH), this precise regulation of insulin secretion is perturbed so that insulin continues to be secreted in the presence of hypoglycemia. HH may be due to genetic causes (congenital) or secondary to certain risk factors. The molecular mechanisms leading to HH involve defects in the key genes regulating insulin secretion from the β-cells. At this moment, in time genetic abnormalities in nine genes (ABCC8, KCNJ11, GCK, SCHAD, GLUD1, SLC16A1, HNF1A, HNF4A, and UCP2) have been described that lead to the congenital forms of HH. Perinatal stress, intrauterine growth retardation, maternal diabetes mellitus, and a large number of developmental syndromes are also associated with HH in the neonatal period. In older children and adult’s insulinoma, non-insulinoma pancreatogenous hypoglycemia syndrome and post bariatric surgery are recognized causes of HH. This review article will focus mainly on describing the molecular mechanisms that lead to unregulated insulin secretion. PMID:27065949

  5. Molecular genetic approaches to understanding disease.

    PubMed Central

    Savill, J.

    1997-01-01

    Molecular genetics has greatly increased the understanding of diseases in which there is a single gene defect such as cystic fibrosis. Discovering the gene responsible and its function not only helps determine the pathogenesis of the disease but also offers a possible treatment-gene therapy. Polygenic disorders such as diabetes may soon yield their secrets to the same approach. Animal models of genetic diseases are proving useful research tools, and transgenesis has made xenografting possible. Furthermore, antisense technology allows specific inhibition of undesirably overexpressed genes such as those driving unwanted vascular cell proliferation and restenosis after angioplasty. The completion of the human genome project should make the search for "disease" gene much quicker and will increase still further the importance of these gene based approaches toward diseases. PMID:9006475

  6. Molecular biology approaches in bioadhesion research

    PubMed Central

    Rodrigues, Marcelo; Lengerer, Birgit; Ostermann, Thomas

    2014-01-01

    Summary The use of molecular biology tools in the field of bioadhesion is still in its infancy. For new research groups who are considering taking a molecular approach, the techniques presented here are essential to unravelling the sequence of a gene, its expression and its biological function. Here we provide an outline for addressing adhesion-related genes in diverse organisms. We show how to gradually narrow down the number of candidate transcripts that are involved in adhesion by (1) generating a transcriptome and a differentially expressed cDNA list enriched for adhesion-related transcripts, (2) setting up a BLAST search facility, (3) perform an in situ hybridization screen, and (4) functional analyses of selected genes by using RNA interference knock-down. Furthermore, latest developments in genome-editing are presented as new tools to study gene function. By using this iterative multi-technologies approach, the identification, isolation, expression and function of adhesion-related genes can be studied in most organisms. These tools will improve our understanding of the diversity of molecules used for adhesion in different organisms and these findings will help to develop innovative bio-inspired adhesives. PMID:25161834

  7. Screened Electrostatic Interactions in Molecular Mechanics.

    PubMed

    Wang, Bo; Truhlar, Donald G

    2014-10-14

    In a typical application of molecular mechanics (MM), the electrostatic interactions are calculated from parametrized partial atomic charges treated as point charges interacting by radial Coulomb potentials. This does not usually yield accurate electrostatic interactions at van der Waals distances, but this is compensated by additional parametrized terms, for example Lennard-Jones potentials. In the present work, we present a scheme involving radial screened Coulomb potentials that reproduces the accurate electrostatics much more accurately. The screening accounts for charge penetration of one subsystem's charge cloud into that of another subsystem, and it is incorporated into the interaction potential in a way similar to what we proposed in a previous article (J. Chem. Theory Comput. 2010, 6, 3330) for combined quantum mechanical and molecular mechanical (QM/MM) simulations, but the screening parameters are reoptimized for MM. The optimization is carried out with electrostatic-potential-fitted partial atomic charges, but the optimized parameters should be useful with any realistic charge model. In the model we employ, the charge density of an atom is approximated as the sum of a point charge representing the nucleus and inner electrons and a smeared charge representing the outermost electrons; in particular, for all atoms except hydrogens, the smeared charge represents the two outermost electrons in the present model. We find that the charge penetration effect can cause very significant deviations from the popular point-charge model, and by comparison to electrostatic interactions calculated by symmetry-adapted perturbation theory, we find that the present results are considerably more accurate than point-charge electrostatic interactions. The mean unsigned error in electrostatics for a large and diverse data set (192 interaction energies) decreases from 9.2 to 3.3 kcal/mol, and the error in the electrostatics for 10 water dimers decreases from 1.7 to 0.5 kcal

  8. Screened Electrostatic Interactions in Molecular Mechanics.

    PubMed

    Wang, Bo; Truhlar, Donald G

    2014-10-14

    In a typical application of molecular mechanics (MM), the electrostatic interactions are calculated from parametrized partial atomic charges treated as point charges interacting by radial Coulomb potentials. This does not usually yield accurate electrostatic interactions at van der Waals distances, but this is compensated by additional parametrized terms, for example Lennard-Jones potentials. In the present work, we present a scheme involving radial screened Coulomb potentials that reproduces the accurate electrostatics much more accurately. The screening accounts for charge penetration of one subsystem's charge cloud into that of another subsystem, and it is incorporated into the interaction potential in a way similar to what we proposed in a previous article (J. Chem. Theory Comput. 2010, 6, 3330) for combined quantum mechanical and molecular mechanical (QM/MM) simulations, but the screening parameters are reoptimized for MM. The optimization is carried out with electrostatic-potential-fitted partial atomic charges, but the optimized parameters should be useful with any realistic charge model. In the model we employ, the charge density of an atom is approximated as the sum of a point charge representing the nucleus and inner electrons and a smeared charge representing the outermost electrons; in particular, for all atoms except hydrogens, the smeared charge represents the two outermost electrons in the present model. We find that the charge penetration effect can cause very significant deviations from the popular point-charge model, and by comparison to electrostatic interactions calculated by symmetry-adapted perturbation theory, we find that the present results are considerably more accurate than point-charge electrostatic interactions. The mean unsigned error in electrostatics for a large and diverse data set (192 interaction energies) decreases from 9.2 to 3.3 kcal/mol, and the error in the electrostatics for 10 water dimers decreases from 1.7 to 0.5 kcal

  9. Boltzmann's Approach to Statistical Mechanics

    NASA Astrophysics Data System (ADS)

    Goldstein, Sheldon

    In the last quarter of the nineteenth century, Ludwig Boltzmann explained how irreversible macroscopic laws, in particular the second law of thermodynamics, originate in the time-reversible laws of microscopic physics. Boltzmann's analysis, the essence of which I shall review here, is basically correct. The most famous criticisms of Boltzmann's later work on the subject have little merit. Most twentieth century innovations - such as the identification of the state of a physical system with a probability distribution \\varrho on its phase space, of its thermodynamic entropy with the Gibbs entropy of \\varrho, and the invocation of the notions of ergodicity and mixing for the justification of the foundations of statistical mechanics - are thoroughly misguided.

  10. Molecular mechanisms that control endothelial cell contacts.

    PubMed

    Vestweber, D

    2000-02-01

    Endothelial cell contacts control the permeability of the blood vessel wall. This allows the endothelium to form a barrier for solutes, macromolecules, and leukocytes between the vessel lumen and the interstitial space. Loss of this barrier function in pathophysiological situations can lead to extracellular oedema. The ability of leukocytes to enter tissue at sites of inflammation is dependent on molecular mechanisms that allow leukocytes to adhere to the endothelium and to migrate through the endothelial cell layer and the underlying basal lamina. It is a commonly accepted working hypothesis that inter-endothelial cell contacts are actively opened and closed during this process. Angiogenesis is another important process that requires well-controlled regulation of inter-endothelial cell contacts. The formation of new blood vessels by sprouting from pre-existing vessels depends on the loosening of established endothelial cell contacts and the migration of endothelial cells that form the outgrowing sprouts. This review focuses on the molecular composition of endothelial cell surface proteins and proteins of the cytoskeletal undercoat of the plasma membrane at sites of inter-endothelial cell contacts and discusses the current knowledge about the potential role of such molecules in the regulation of endothelial cell contacts. PMID:10685062

  11. Measuring the mechanical properties of molecular conformers

    PubMed Central

    Jarvis, S. P.; Taylor, S.; Baran, J. D.; Champness, N. R.; Larsson, J. A.; Moriarty, P.

    2015-01-01

    Scanning probe-actuated single molecule manipulation has proven to be an exceptionally powerful tool for the systematic atomic-scale interrogation of molecular adsorbates. To date, however, the extent to which molecular conformation affects the force required to push or pull a single molecule has not been explored. Here we probe the mechanochemical response of two tetra(4-bromophenyl)porphyrin conformers using non-contact atomic force microscopy where we find a large difference between the lateral forces required for manipulation. Remarkably, despite sharing very similar adsorption characteristics, variations in the potential energy surface are capable of prohibiting probe-induced positioning of one conformer, while simultaneously permitting manipulation of the alternative conformational form. Our results are interpreted in the context of dispersion-corrected density functional theory calculations which reveal significant differences in the diffusion barriers for each conformer. These results demonstrate that conformational variation significantly modifies the mechanical response of even simple porpyhrins, potentially affecting many other flexible molecules. PMID:26388232

  12. Cellular and Molecular Mechanisms of Palatogenesis

    PubMed Central

    Lan, Yu; Xu, Jingyue; Jiang, Rulang

    2015-01-01

    Palatogenesis involves the initiation, growth, morphogenesis, and fusion of the primary and secondary palatal shelves from initially separate facial prominences during embryogenesis to form the intact palate separating the oral cavity from the nostrils. The palatal shelves consist mainly of cranial neural crest-derived mesenchyme cells covered under a simple embryonic epithelium. Growth and patterning of the palatal shelves are controlled by reciprocal epithelial-mesenchymal interactions regulated by multiple signaling pathways and transcription factors. During palatal shelf outgrowth, the embryonic epithelium develops a “teflon” coat consisting of a single, continuous layer of periderm cells that prevents the facial prominences and palatal shelves from forming aberrant inter-epithelial adhesions. Palatal fusion involves not only spatiotemporally-regulated disruption of the periderm but also dynamic cellular and molecular processes that result in adhesion and intercalation of the palatal medial edge epithelia to form an inter-shelf epithelial seam, and subsequent dissolution of the epithelial seam to form the intact roof of the oral cavity. The complexity of regulation of these morphogenetic processes is reflected by the common occurrence of cleft palate in humans. This review will summarize major recent advances and discuss major remaining gaps in the understanding of cellular and molecular mechanisms controlling palatogenesis. PMID:26589921

  13. Molecular mechanism of mitochondrial membrane fusion.

    PubMed

    Griffin, Erik E; Detmer, Scott A; Chan, David C

    2006-01-01

    Mitochondrial fusion requires coordinated fusion of the outer and inner membranes. This process leads to exchange of contents, controls the shape of mitochondria, and is important for mitochondrial function. Two types of mitochondrial GTPases are essential for mitochondrial fusion. On the outer membrane, the fuzzy onions/mitofusin proteins form complexes in trans that mediate homotypic physical interactions between adjacent mitochondria and are likely directly involved in outer membrane fusion. Associated with the inner membrane, the OPA1 dynamin-family GTPase maintains membrane structure and is a good candidate for mediating inner membrane fusion. In yeast, Ugo1p binds to both of these GTPases to form a fusion complex, although a related protein has yet to be found in mammals. An understanding of the molecular mechanism of fusion may have implications for Charcot-Marie-Tooth subtype 2A and autosomal dominant optic atrophy, neurodegenerative diseases caused by mutations in Mfn2 and OPA1.

  14. Unraveling proteins: a molecular mechanics study.

    PubMed Central

    Rohs, R; Etchebest, C; Lavery, R

    1999-01-01

    An internal coordinate molecular mechanics study of unfolding peptide chains by external stretching has been carried out to predict the type of force spectra that may be expected from single-molecule manipulation experiments currently being prepared. Rather than modeling the stretching of a given protein, we have looked at the behavior of simple secondary structure elements (alpha-helix, beta-ribbon, and interacting alpha-helices) to estimate the magnitude of the forces involved in their unfolding or separation and the dependence of these forces on the way pulling is carried out as well as on the length of the structural elements. The results point to a hierarchy of forces covering a surprisingly large range and to important orientational effects in the response to external stress. PMID:10233091

  15. Integrative network analysis reveals molecular mechanisms of blood pressure regulation.

    PubMed

    Huan, Tianxiao; Meng, Qingying; Saleh, Mohamed A; Norlander, Allison E; Joehanes, Roby; Zhu, Jun; Chen, Brian H; Zhang, Bin; Johnson, Andrew D; Ying, Saixia; Courchesne, Paul; Raghavachari, Nalini; Wang, Richard; Liu, Poching; O'Donnell, Christopher J; Vasan, Ramachandran; Munson, Peter J; Madhur, Meena S; Harrison, David G; Yang, Xia; Levy, Daniel

    2015-01-01

    Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP-associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3,679 individuals, using network approaches. BP transcriptomic signatures at the single-gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression-related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP-related genes were uncovered. As proof-of-concept, we validated SH2B3, one of the top key drivers, using Sh2b3(-/-) mice. We found that a significant number of genes predicted to be regulated by SH2B3 in gene networks are perturbed in Sh2b3(-/-) mice, which demonstrate an exaggerated pressor response to angiotensin II infusion. Our findings may help to identify novel targets for the prevention or treatment of hypertension.

  16. Integrative network analysis reveals molecular mechanisms of blood pressure regulation.

    PubMed

    Huan, Tianxiao; Meng, Qingying; Saleh, Mohamed A; Norlander, Allison E; Joehanes, Roby; Zhu, Jun; Chen, Brian H; Zhang, Bin; Johnson, Andrew D; Ying, Saixia; Courchesne, Paul; Raghavachari, Nalini; Wang, Richard; Liu, Poching; O'Donnell, Christopher J; Vasan, Ramachandran; Munson, Peter J; Madhur, Meena S; Harrison, David G; Yang, Xia; Levy, Daniel

    2015-04-01

    Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP-associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3,679 individuals, using network approaches. BP transcriptomic signatures at the single-gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression-related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP-related genes were uncovered. As proof-of-concept, we validated SH2B3, one of the top key drivers, using Sh2b3−/− mice. We found that a significant number of genes predicted to be regulated by SH2B3 in gene networks are perturbed in Sh2b3−/− mice, which demonstrate an exaggerated pressor response to angiotensin II infusion. Our findings may help to identify novel targets for the prevention or treatment of hypertension.

  17. Exact and Optimal Quantum Mechanics/Molecular Mechanics Boundaries.

    PubMed

    Sun, Qiming; Chan, Garnet Kin-Lic

    2014-09-01

    Motivated by recent work in density matrix embedding theory, we define exact link orbitals that capture all quantum mechanical (QM) effects across arbitrary quantum mechanics/molecular mechanics (QM/MM) boundaries. Exact link orbitals are rigorously defined from the full QM solution, and their number is equal to the number of orbitals in the primary QM region. Truncating the exact set yields a smaller set of link orbitals optimal with respect to reproducing the primary region density matrix. We use the optimal link orbitals to obtain insight into the limits of QM/MM boundary treatments. We further analyze the popular general hybrid orbital (GHO) QM/MM boundary across a test suite of molecules. We find that GHOs are often good proxies for the most important optimal link orbital, although there is little detailed correlation between the detailed GHO composition and optimal link orbital valence weights. The optimal theory shows that anions and cations cannot be described by a single link orbital. However, expanding to include the second most important optimal link orbital in the boundary recovers an accurate description. The second optimal link orbital takes the chemically intuitive form of a donor or acceptor orbital for charge redistribution, suggesting that optimal link orbitals can be used as interpretative tools for electron transfer. We further find that two optimal link orbitals are also sufficient for boundaries that cut across double bonds. Finally, we suggest how to construct "approximately" optimal link orbitals for practical QM/MM calculations.

  18. Thermal force approach to molecular evolution.

    PubMed

    Braun, Dieter; Libchaber, Albert

    2004-06-01

    Recent experiments are discussed where temperature gradients across mesoscopic pores are shown to provide essential mechanisms for autonomous molecular evolution. On the one hand, laminar thermal convection can drive DNA replication as the molecules are continuously cycled between hot and cold regions of a chamber. On the other hand, thermophoresis can accumulate charged biopolymers in similar convection settings. The experiments show that temperature differences analogous to those across porous rocks present a robust nonequilibrium boundary condition to feed the replication and accumulation of evolving molecules. It is speculated that similar nonequilibrium conditions near porous submarine hydrothermal mounds could have triggered the origin of life. In such a scenario, the encapsulation of cells with membranes would be a later development. It is expected that detailed studies of mesoscopic boundary conditions under nonequilibrium conditions will reveal new connecting pieces in the fascinating puzzle of the origins of life. PMID:16204812

  19. Computational approaches to detect allosteric pathways in transmembrane molecular machines.

    PubMed

    Stolzenberg, Sebastian; Michino, Mayako; LeVine, Michael V; Weinstein, Harel; Shi, Lei

    2016-07-01

    Many of the functions of transmembrane proteins involved in signal processing and transduction across the cell membrane are determined by allosteric couplings that propagate the functional effects well beyond the original site of activation. Data gathered from breakthroughs in biochemistry, crystallography, and single molecule fluorescence have established a rich basis of information for the study of molecular mechanisms in the allosteric couplings of such transmembrane proteins. The mechanistic details of these couplings, many of which have therapeutic implications, however, have only become accessible in synergy with molecular modeling and simulations. Here, we review some recent computational approaches that analyze allosteric coupling networks (ACNs) in transmembrane proteins, and in particular the recently developed Protein Interaction Analyzer (PIA) designed to study ACNs in the structural ensembles sampled by molecular dynamics simulations. The power of these computational approaches in interrogating the functional mechanisms of transmembrane proteins is illustrated with selected examples of recent experimental and computational studies pursued synergistically in the investigation of secondary active transporters and GPCRs. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.

  20. The strawberry plant defense mechanism: a molecular review.

    PubMed

    Amil-Ruiz, Francisco; Blanco-Portales, Rosario; Muñoz-Blanco, Juan; Caballero, José L

    2011-11-01

    Strawberry, a small fruit crop of great importance throughout the world, has been considered a model plant system for Rosaceae, and is susceptible to a large variety of phytopathogenic organisms. Most components and mechanisms of the strawberry defense network remain poorly understood. However, from current knowledge, it seems clear that the ability of a strawberry plant to respond efficiently to pathogens relies first on the physiological status of injured tissue (pre-formed mechanisms of defense) and secondly on the general ability to recognize and identify the invaders by surface plant receptors, followed by a broad range of induced mechanisms, which include cell wall reinforcement, production of reactive oxygen species, phytoalexin generation and pathogenesis-related protein accumulation. Dissection of these physiological responses at a molecular level will provide valuable information to improve future breeding strategies for new strawberry varieties and to engineer strawberry plants for durable and broad-spectrum disease resistance. In turn, this will lead to a reduction in use of chemicals and in environmental risks. Advances in the understanding of the molecular interplay between plant (mainly those considered model systems) and various classes of microbial pathogens have been made in the last two decades. However, major progress in the genetics and molecular biology of strawberry is still needed to uncover fully the way in which this elaborate plant innate immune system works. These fundamental insights will provide a conceptual framework for rational human intervention through new strawberry research approaches. In this review, we will provide a comprehensive overview and discuss recent advances in molecular research on strawberry defense mechanisms against pathogens.

  1. Quantum mechanics/molecular mechanics restrained electrostatic potential fitting.

    PubMed

    Burger, Steven K; Schofield, Jeremy; Ayers, Paul W

    2013-12-01

    We present a quantum mechanics/molecular mechanics (QM/MM) method to evaluate the partial charges of amino acid residues for use in MM potentials based on their protein environment. For each residue of interest, the nearby residues are included in the QM system while the rest of the protein is treated at the MM level of theory. After a short structural optimization, the partial charges of the central residue are fit to the electrostatic potential using the restrained electrostatic potential (RESP) method. The resulting charges and electrostatic potential account for the individual environment of the residue, although they lack the transferable nature of library partial charges. To evaluate the quality of the QM/MM RESP charges, thermodynamic integration is used to measure the pKa shift of the aspartic acid residues in three different proteins, turkey egg lysozyme, beta-cryptogein, and Thioredoxin. Compared to the AMBER ff99SB library values, the QM/MM RESP charges show better agreement between the calculated and experimental pK(a) values for almost all of the residues considered.

  2. Molecular mechanisms of hypolipidemic effects of curcumin.

    PubMed

    Zingg, Jean-Marc; Hasan, Syeda T; Meydani, Mohsen

    2013-01-01

    Recent evidence suggests potential benefits from phytochemicals and micronutrients in reducing the elevated oxidative and lipid-mediated stress associated with inflammation, obesity, and atherosclerosis. These compounds may either directly scavenge reactive oxygen or nitrogen species or they may modulate the activity of signal transduction enzymes leading to changes in the expression of antioxidant genes. Alternatively, they may reduce plasma lipid levels by modulating lipid metabolic genes in tissues and thus reduce indirectly lipid-mediated oxidative and endoplasmic reticulum stress through their hypolipidemic effect. Here we review the proposed molecular mechanisms by which curcumin, a polyphenol present in the rhizomes of turmeric (Curcuma longa) spice, influences oxidative and lipid-mediated stress in the vascular system. At the molecular level, mounting experimental evidence suggests that curcumin may act chemically as scavenger of free radicals and/or influences signal transduction (e.g., Akt, AMPK) and modulates the activity of specific transcription factors (e.g., FOXO1/3a, NRF2, SREBP1/2, CREB, CREBH, PPARγ, and LXRα) that regulate the expression of genes involved in free radicals scavenging (e.g., catalase, MnSOD, and heme oxygenase-1) and lipid homeostasis (e.g., aP2/FABP4, CD36, HMG-CoA reductase, and carnitine palmitoyltransferase-I (CPT-1)). At the cellular level, curcumin may induce a mild oxidative and lipid-metabolic stress leading to an adaptive cellular stress response by hormetic stimulation of these cellular antioxidant defense systems and lipid metabolic enzymes. The resulting lower oxidative and lipid-mediated stress may not only explain the beneficial effects of curcumin on inflammation, cardiovascular, and neurodegenerative disease, but may also contribute to the increase in maximum life-span observed in animal models.

  3. Molecular mechanisms for tumour resistance to chemotherapy.

    PubMed

    Pan, Shu-Ting; Li, Zhi-Ling; He, Zhi-Xu; Qiu, Jia-Xuan; Zhou, Shu-Feng

    2016-08-01

    Chemotherapy is one of the prevailing methods used to treat malignant tumours, but the outcome and prognosis of tumour patients are not optimistic. Cancer cells gradually generate resistance to almost all chemotherapeutic drugs via a variety of distinct mechanisms and pathways. Chemotherapeutic resistance, either intrinsic or acquired, is caused and sustained by reduced drug accumulation and increased drug export, alterations in drug targets and signalling transduction molecules, increased repair of drug-induced DNA damage, and evasion of apoptosis. In order to better understand the mechanisms of chemoresistance, this review highlights our current knowledge of the role of altered drug metabolism and transport and deregulation of apoptosis and autophagy in the development of tumour chemoresistance. Reduced intracellular activation of prodrugs (e.g. thiotepa and tegafur) or enhanced drug inactivation by Phase I and II enzymes contributes to the development of chemoresistance. Both primary and acquired resistance can be caused by alterations in the transport of anticancer drugs which is mediated by a variety of drug transporters such as P-glycoprotein (P-gp), multidrug resistance associated proteins, and breast cancer resistance protein. Presently there is a line of evidence indicating that deregulation of programmed cell death including apoptosis and autophagy is also an important mechanism for tumour resistance to anticancer drugs. Reversal of chemoresistance is likely via pharmacological and biological approaches. Further studies are warranted to grasp the full picture of how each type of cancer cells develop resistance to anticancer drugs and to identify novel strategies to overcome it.

  4. Molecular mechanisms for tumour resistance to chemotherapy.

    PubMed

    Pan, Shu-Ting; Li, Zhi-Ling; He, Zhi-Xu; Qiu, Jia-Xuan; Zhou, Shu-Feng

    2016-08-01

    Chemotherapy is one of the prevailing methods used to treat malignant tumours, but the outcome and prognosis of tumour patients are not optimistic. Cancer cells gradually generate resistance to almost all chemotherapeutic drugs via a variety of distinct mechanisms and pathways. Chemotherapeutic resistance, either intrinsic or acquired, is caused and sustained by reduced drug accumulation and increased drug export, alterations in drug targets and signalling transduction molecules, increased repair of drug-induced DNA damage, and evasion of apoptosis. In order to better understand the mechanisms of chemoresistance, this review highlights our current knowledge of the role of altered drug metabolism and transport and deregulation of apoptosis and autophagy in the development of tumour chemoresistance. Reduced intracellular activation of prodrugs (e.g. thiotepa and tegafur) or enhanced drug inactivation by Phase I and II enzymes contributes to the development of chemoresistance. Both primary and acquired resistance can be caused by alterations in the transport of anticancer drugs which is mediated by a variety of drug transporters such as P-glycoprotein (P-gp), multidrug resistance associated proteins, and breast cancer resistance protein. Presently there is a line of evidence indicating that deregulation of programmed cell death including apoptosis and autophagy is also an important mechanism for tumour resistance to anticancer drugs. Reversal of chemoresistance is likely via pharmacological and biological approaches. Further studies are warranted to grasp the full picture of how each type of cancer cells develop resistance to anticancer drugs and to identify novel strategies to overcome it. PMID:27097837

  5. Extrapolated gradientlike algorithms for molecular dynamics and celestial mechanics simulations.

    PubMed

    Omelyan, I P

    2006-09-01

    A class of symplectic algorithms is introduced to integrate the equations of motion in many-body systems. The algorithms are derived on the basis of an advanced gradientlike decomposition approach. Its main advantage over the standard gradient scheme is the avoidance of time-consuming evaluations of force gradients by force extrapolation without any loss of precision. As a result, the efficiency of the integration improves significantly. The algorithms obtained are analyzed and optimized using an error-function theory. The best among them are tested in actual molecular dynamics and celestial mechanics simulations for comparison with well-known nongradient and gradient algorithms such as the Störmer-Verlet, Runge-Kutta, Cowell-Numerov, Forest-Ruth, Suzuki-Chin, and others. It is demonstrated that for moderate and high accuracy, the extrapolated algorithms should be considered as the most efficient for the integration of motion in molecular dynamics simulations. PMID:17025782

  6. Extrapolated gradientlike algorithms for molecular dynamics and celestial mechanics simulations.

    PubMed

    Omelyan, I P

    2006-09-01

    A class of symplectic algorithms is introduced to integrate the equations of motion in many-body systems. The algorithms are derived on the basis of an advanced gradientlike decomposition approach. Its main advantage over the standard gradient scheme is the avoidance of time-consuming evaluations of force gradients by force extrapolation without any loss of precision. As a result, the efficiency of the integration improves significantly. The algorithms obtained are analyzed and optimized using an error-function theory. The best among them are tested in actual molecular dynamics and celestial mechanics simulations for comparison with well-known nongradient and gradient algorithms such as the Störmer-Verlet, Runge-Kutta, Cowell-Numerov, Forest-Ruth, Suzuki-Chin, and others. It is demonstrated that for moderate and high accuracy, the extrapolated algorithms should be considered as the most efficient for the integration of motion in molecular dynamics simulations.

  7. The molecular mechanism and physiological role of cytoplasmic streaming.

    PubMed

    Tominaga, Motoki; Ito, Kohji

    2015-10-01

    Cytoplasmic streaming occurs widely in plants ranging from algae to angiosperms. However, the molecular mechanism and physiological role of cytoplasmic streaming have long remained unelucidated. Recent molecular genetic approaches have identified specific myosin members (XI-2 and XI-K as major and XI-1, XI-B, and XI-I as minor motive forces) for the generation of cytoplasmic streaming among 13 myosin XIs in Arabidopsis thaliana. Simultaneous knockout of these myosin XI members led to a reduced velocity of cytoplasmic streaming and marked defects of plant development. Furthermore, the artificial modifications of myosin XI-2 velocity changed plant and cell sizes along with the velocity of cytoplasmic streaming. Therefore, we assume that cytoplasmic streaming is one of the key regulators in determining plant size.

  8. Teaching Classical Statistical Mechanics: A Simulation Approach.

    ERIC Educational Resources Information Center

    Sauer, G.

    1981-01-01

    Describes a one-dimensional model for an ideal gas to study development of disordered motion in Newtonian mechanics. A Monte Carlo procedure for simulation of the statistical ensemble of an ideal gas with fixed total energy is developed. Compares both approaches for a pseudoexperimental foundation of statistical mechanics. (Author/JN)

  9. Molecular mechanisms regulating CD13-mediated adhesion

    PubMed Central

    Ghosh, Mallika; Gerber, Claire; Rahman, M Mamunur; Vernier, Kaitlyn M; Pereira, Flavia E; Subramani, Jaganathan; Caromile, Leslie A; Shapiro, Linda H

    2014-01-01

    CD13/Aminopeptidase N is a transmembrane metalloproteinase that is expressed in many tissues where it regulates various cellular functions. In inflammation, CD13 is expressed on myeloid cells, is up-regulated on endothelial cells at sites of inflammation and mediates monocyte/endothelial adhesion by homotypic interactions. In animal models the lack of CD13 alters the profiles of infiltrating inflammatory cells at sites of ischaemic injury. Here, we found that CD13 expression is enriched specifically on the pro-inflammatory subset of monocytes, suggesting that CD13 may regulate trafficking and function of specific subsets of immune cells. To further dissect the mechanisms regulating CD13-dependent trafficking we used the murine model of thioglycollate-induced sterile peritonitis. Peritoneal monocytes, macrophages and dendritic cells were significantly decreased in inflammatory exudates from global CD13KO animals when compared with wild-type controls. Furthermore, adoptive transfer of wild-type and CD13KO primary myeloid cells, or wild-type myeloid cells pre-treated with CD13-blocking antibodies into thioglycollate-challenged wild-type recipients demonstrated fewer CD13KO or treated cells in the lavage, suggesting that CD13 expression confers a competitive advantage in trafficking. Similarly, both wild-type and CD13KO cells were reduced in infiltrates in CD13KO recipients, confirming that both monocytic and endothelial CD13 contribute to trafficking. Finally, murine monocyte cell lines expressing mouse/human chimeric CD13 molecules demonstrated that the C-terminal domain of the protein mediates CD13 adhesion. Therefore, this work verifies that the altered inflammatory trafficking in CD13KO mice is the result of aberrant myeloid cell subset trafficking and further defines the molecular mechanisms underlying this regulation. PMID:24627994

  10. Decomposition of Amino Diazeniumdiolates (NONOates): Molecular Mechanisms

    SciTech Connect

    Shaikh, Nizamuddin; Valiev, Marat; Lymar, Sergei V.

    2014-08-23

    Although diazeniumdiolates (X[N(O)NO]-) are extensively used in biochemical, physiological, and pharmacological studies due to their ability to slowly release NO and/or its congeneric nitroxyl, the mechanisms of these processes remain obscure. In this work, we used a combination of spectroscopic, kinetic, and computational techniques to arrive at a qualitatively consistent molecular mechanism for decomposition of amino diazeniumdiolates (amino NONOates: R2N[N(O)NO]-, where R = -N(C2H5)2 (1), -N(C3H4NH2)2 (2), or -N(C2H4NH2)2 (3)). Decomposition of these NONOates is triggered by protonation of their [NN(O)NO]- group with apparent pKa and decomposition rate constants of 4.6 and 1 s-1 for 1-H, 3.5 and 83 x 10-3 s-1 for 2-H, and 3.8 and 3.3 x 10-3 s-1 for 3-H. Although protonation occurs mainly on the O atoms of the functional group, only the minor R2N(H)N(O)NO tautomer (population ~0.01%, for 1) undergoes the N-N heterolytic bond cleavage (k ~102 s-1 for 1) leading to amine and NO. Decompositions of protonated amino NONOates are strongly temperature-dependent; activation enthalpies are 20.4 and 19.4 kcal/mol for 1 and 2, respectively, which includes contributions from both the tautomerization and bond cleavage. The bond cleavage rates exhibit exceptional sensitivity to the nature of R substituents which strongly modulate activation entropy. At pH < 2, decompositions of all these NONOates are subject to additional acid catalysis that occurs through di-protonation of the [NN(O)NO]- group.

  11. Decomposition of amino diazeniumdiolates (NONOates): Molecular mechanisms

    DOE PAGES

    Shaikh, Nizamuddin; Valiev, Marat; Lymar, Sergei V.

    2014-08-23

    Although diazeniumdiolates (X[N(O)NO]-) are extensively used in biochemical, physiological, and pharmacological studies due to their ability to release NO and/or its congeneric nitroxyl, the mechanisms of these processes remain obscure. In this work, we used a combination of spectroscopic, kinetic, and computational techniques to arrive at a quantitatively consistent molecular mechanism for decomposition of amino diazeniumdiolates (amino NONOates: R2N[N(O)NO]-, where R = —N(C2H5)2(1), —N(C3H4NH2)2(2), or —N(C2H4NH2)2(3)). Decomposition of these NONOates is triggered by protonation of their [NN(O)NO]- group with the apparent pKa and decomposition rate constants of 4.6 and 1 s-1 for 1; 3.5 and 0.083 s-1 for 2; andmore » 3.8 and 0.0033 s-1 for 3. Although protonation occurs mainly on the O atoms of the functional group, only the minor R2N(H)N(O)NO tautomer (population ~ 10-7, for 1) undergoes the N—N heterolytic bond cleavage (kd ~ 107 s-1 for 1) leading to amine and NO. Decompositions of protonated amino NONOates are strongly temperature-dependent; activation enthalpies are 20.4 and 19.4 kcal/mol for 1 and 2, respectively, which includes contributions from both the tautomerization and bond cleavage. Thus, the bond cleavage rates exhibit exceptional sensitivity to the nature of R substituents which strongly modulate activation entropy. At pH < 2, decompositions of all three NONOates that have been investigated are subject to additional acid catalysis that occurs through di-protonation of the [NN(O)NO]- group.« less

  12. Rectification mechanism in diblock oligomer molecular diodes.

    PubMed

    Oleynik, I I; Kozhushner, M A; Posvyanskii, V S; Yu, L

    2006-03-10

    We investigated a mechanism of rectification in diblock oligomer diode molecules that have recently been synthesized and showed a pronounced asymmetry in the measured I-V spectrum. The observed rectification effect is due to the resonant nature of electron transfer in the system and the localization properties of bound state wave functions of resonant states of the tunneling electron interacting with an asymmetric molecule in an electric field. The asymmetry of the tunneling wave function is enhanced or weakened depending on the polarity of the applied bias. The conceptually new theoretical approach, the Green's function theory of sub-barrier scattering, is able to provide a physically transparent explanation of this rectification effect based on the concept of the bound state spectrum of a tunneling electron. The theory predicts the characteristic features of the I-V spectrum in qualitative agreement with experiment. PMID:16606295

  13. Molecular Mechanisms Underlying Peritoneal EMT and Fibrosis

    PubMed Central

    Strippoli, Raffaele; Moreno-Vicente, Roberto; Battistelli, Cecilia; Cicchini, Carla; Noce, Valeria; Amicone, Laura; Marchetti, Alessandra; del Pozo, Miguel Angel; Tripodi, Marco

    2016-01-01

    Peritoneal dialysis is a form of renal replacement alternative to the hemodialysis. During this treatment, the peritoneal membrane acts as a permeable barrier for exchange of solutes and water. Continual exposure to dialysis solutions, as well as episodes of peritonitis and hemoperitoneum, can cause acute/chronic inflammation and injury to the peritoneal membrane, which undergoes progressive fibrosis, angiogenesis, and vasculopathy, eventually leading to discontinuation of the peritoneal dialysis. Among the different events controlling this pathological process, epithelial to mesenchymal transition of mesothelial cells plays a main role in the induction of fibrosis and in subsequent functional deterioration of the peritoneal membrane. Here, the main extracellular inducers and cellular players are described. Moreover, signaling pathways acting during this process are elucidated, with emphasis on signals delivered by TGF-β family members and by Toll-like/IL-1β receptors. The understanding of molecular mechanisms underlying fibrosis of the peritoneal membrane has both a basic and a translational relevance, since it may be useful for setup of therapies aimed at counteracting the deterioration as well as restoring the homeostasis of the peritoneal membrane. PMID:26941801

  14. Molecular Mechanisms Underlying Psychological Stress and Cancer.

    PubMed

    Shin, Kyeong Jin; Lee, Yu Jin; Yang, Yong Ryoul; Park, Seorim; Suh, Pann-Ghill; Follo, Matilde Yung; Cocco, Lucio; Ryu, Sung Ho

    2016-01-01

    Psychological stress is an emotion experienced when people are under mental pressure or encounter unexpected problems. Extreme or repetitive stress increases the risk of developing human disease, including cardiovascular disease (CVD), immune diseases, mental disorders, and cancer. Several studies have shown an association between psychological stress and cancer growth and metastasis in animal models and case studies of cancer patients. Stress induces the secretion of stress-related mediators, such as catecholamine, cortisol, and oxytocin, via the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis or the sympathetic nervous system (SNS). These stress-related hormones and neurotransmitters adversely affect stress-induced tumor progression and cancer therapy. Catecholamine is the primary factor that influences tumor progression. It can regulate diverse cellular signaling pathways through adrenergic receptors (ADRs), which are expressed by several types of cancer cells. Activated ADRs enhance the proliferation and invasion abilities of cancer cells, alter cell activity in the tumor microenvironment, and regulate the interaction between cancer and its microenvironment to promote tumor progression. Additionally, other stress mediators, such as glucocorticoids and oxytocin, and their cognate receptors are involved in stress-induced cancer growth and metastasis. Here, we will review how each receptor-mediated signal cascade contributes to tumor initiation and progression and discuss how we can use these molecular mechanisms for cancer therapy.

  15. Molecular mechanisms underlying chemical liver injury

    PubMed Central

    Gu, Xinsheng; Manautou, Jose E.

    2013-01-01

    The liver is necessary for survival. Its strategic localisation, blood flow and prominent role in the metabolism of xenobiotics render this organ particularly susceptible to injury by chemicals to which we are ubiquitously exposed. The pathogenesis of most chemical-induced liver injuries is initiated by the metabolic conversion of chemicals into reactive intermediate species, such as electrophilic compounds or free radicals, which can potentially alter the structure and function of cellular macromolecules. Many reactive intermediate species can produce oxidative stress, which can be equally detrimental to the cell. When protective defences are overwhelmed by excess toxicant insult, the effects of reactive intermediate species lead to deregulation of cell signalling pathways and dysfunction of biomolecules, leading to failure of target organelles and eventual cell death. A myriad of genetic factors determine the susceptibility of specific individuals to chemical-induced liver injury. Environmental factors, lifestyle choices and pre-existing pathological conditions also have roles in the pathogenesis of chemical liver injury. Research aimed at elucidating the molecular mechanism of the pathogenesis of chemical-induced liver diseases is fundamental for preventing or devising new modalities of treatment for liver injury by chemicals. PMID:22306029

  16. Molecular mechanisms of failure in polymer nanocomposites

    NASA Astrophysics Data System (ADS)

    Gersappe, Dilip

    2003-03-01

    With the emergence of synthetic methods that can produce nanometer sized fillers, resulting in an enormous increase of surface area, polymers reinforced with nanoscale particles should offer the possibility of vastly improved properties. However, experimental evidence suggests that the paradigms that have been used for conventional filled composites cannot account for the behavior of nanocomposites. We examine the role that spherical nanofillers play on the rheology and the strength of the nanocomposite by using Molecular Dynamics simulations. We find that the enhancement of properties in nanocomposites is a result of the equivalence of time scales for motion for the polymer and the filler. We show that the mobility of the nanofiller, rather than its surface area, is key to the performance of the nanocomposite and that this mobility is a complex function of the size of the filler, the attraction between the polymer and the filler, and the thermodynamic state of the matrix. Our results show similarities between the toughening mechanisms in polymer nanocomposites and those postulated for naturally occurring biological materials which also contain nanoscaled assemblies, such as spider silk and abalone adhesive.

  17. Cellular and molecular mechanisms in liver fibrogenesis.

    PubMed

    Novo, Erica; Cannito, Stefania; Paternostro, Claudia; Bocca, Claudia; Miglietta, Antonella; Parola, Maurizio

    2014-04-15

    Liver fibrogenesis is a dynamic and highly integrated molecular, tissue and cellular process, potentially reversible, that drives the progression of chronic liver diseases (CLD) towards liver cirrhosis and hepatic failure. Hepatic myofibroblasts (MFs), the pro-fibrogenic effector cells, originate mainly from activation of hepatic stellate cells and portal fibroblasts being characterized by a proliferative and survival attitude. MFs also contract in response to vasoactive agents, sustain angiogenesis and recruit and modulate activity of cells of innate or adaptive immunity. Chronic activation of wound healing and oxidative stress as well as derangement of epithelial-mesenchymal interactions are "major" pro-fibrogenic mechanisms, whatever the etiology. However, literature has outlined a complex network of pro-fibrogenic factors and mediators proposed to modulate CLD progression, with some of them being at present highly debated in the field, including the role of epithelial to mesenchymal transition and Hedgehog signaling pathways. Hypoxia and angiogenesis as well as inflammasomes are recently emerged as ubiquitous pro-inflammatory and pro-fibrogenic determinants whereas adipokines are mostly involved in CLD related to metabolic disturbances (metabolic syndrome and/or obesity and type 2 diabetes). Finally, autophagy as well as natural killer and natural killer-T cells have been recently proposed to significantly affect fibrogenic CLD progression. PMID:24631571

  18. [Molecular mechanisms of peroxisome biogenesis in yeasts].

    PubMed

    Sibirnyĭ, A A

    2012-01-01

    Peroxisomes contain oxidases generating hydrogen peroxide, and catalase degrading this toxic compound. Another characteristic function of each eukaryotic peroxisome, from yeast to man, is fatty acid beta-oxidation. However, in peroxisomes a variety of other metabolic pathways are located. In fungi, peroxisomes contain enzymes involved in catabolism of unusual carbon and nitrogen sources (methanol, purines, D-amino acids, pipecolynic acid, sarcosine, glycolate, spermidine etc) as well as biosynthesis of lysine in yeasts and penicillin in mycelial fungi. Impairment of peroxisomal structure and functions causes many human disorders. The similar defects have been identified in yeast mutants defective in peroxisomal biogenesis. Peroxisomal biogenesis is actively studied during last two decades using uni- and multicellular model systems. It was observed that many aspects of peroxisomal biogenesis and proteins involved in this process display striking similarity between all eukaryotes, from yeasts to humans. Yeast is a convenient model system for this kind of research. Current review summarizes data on molecular events of peroxisomal biogenesis, functions of peroxine proteins, import of peroxisomal matrix and membrane proteins and on mechanisms of peroxisomedivision and inheritance. PMID:22642098

  19. Molecular cytotoxicity mechanisms of allyl alcohol (acrolein) in budding yeast.

    PubMed

    Golla, Upendarrao; Bandi, Goutham; Tomar, Raghuvir S

    2015-06-15

    Allyl alcohol (AA) is one of the environmental pollutants used as a herbicide and industrial chemical. AA undergoes enzymatic oxidation in vivo to form Acrolein (Acr), a highly reactive and ubiquitous environmental toxicant. The exposure to AA/Acr has detrimental effects on cells and is highly fatal. In corroboration to the current literature describing AA/Acr toxicity, this study aimed to investigate the molecular cytotoxicity mechanisms of AA/Acr using budding yeast as a eukaryotic model organism. Genome-wide transcriptome analysis of cells treated with a sublethal dose of AA (0.4 mM) showed differential regulation of approximately 30% of the yeast genome. Functional enrichment analysis of the AA transcriptome revealed that genes belong to diverse cellular processes including the cell cycle, DNA damage repair, metal homeostasis, stress response genes, ribosomal biogenesis, metabolism, meiosis, ubiquitination, cell morphogenesis, and transport. Moreover, we have identified novel molecular targets of AA/Acr through genetic screening, which belongs to oxidative stress, DNA damage repair, iron homeostasis, and cell wall integrity. This study also demonstrated the epigenetic basis of AA/Acr toxicity mediated through histone tails and chromatin modifiers. Interestingly, our study disclosed the use of pyrazole and ethanol as probable antidotes for AA intoxication. For the first time, this study also demonstrated the reproductive toxicity of AA/Acr using the yeast gametogenesis (spermatogenesis) model. Altogether, this study unravels the molecular mechanisms of AA/Acr cytotoxicity and facilitates the prediction of biomarkers for toxicity assessment and therapeutic approaches. PMID:25919230

  20. Approaches to USJ Formation Beyond Molecular Implantation

    SciTech Connect

    Hatem, C.; Renau, A.; Godet, L.; Kontos, A.; Papasouliotis, G.; England, J.; Arevalo, E.

    2008-11-03

    As junction depth requirements approach sub 10 nm and the sensitivity to residual implant damage continues to increase, the capability to produce abrupt, shallow profiles while maintaining low residual damage becomes a difficult challenge. Implantation induced amorphization has been widely applied to reduce channeling tails of implanted dopant profiles for integrated circuit manufacturing. This has been required to meet aggressive junction depth targets. The problem, however, is that pre-amorphization creates high defect densities that remain near the former amorphous-crystalline interface post anneal. These end of range (EOR) defects become of greater concern as the industry begins to move towards millisecond anneal technologies. Millisecond anneal, while capable of close to diffusionless activation and abrupt junctions, has caused concern for its inability to fully repair these EOR defects. There has been a recent focus on removing traditional PAI through molecular implantation with limited success. Towards this end we have investigated alternative techniques to reduce EOR damage while maintaining the junction depth, sheet resistance and abruptness. Here we describe the results of two of these techniques. The subsequent reduction in EOR through the use of each process and the resultant Rs, junction depth and abruptness are detailed.

  1. Approaches to airborne molecular contamination assessment

    NASA Astrophysics Data System (ADS)

    Riddle Vogt, Sarah; Landoni, Cristian

    2011-03-01

    Airborne molecular contamination (AMC) assessment approaches can vary greatly between different fabs and even between different divisions within a given company. Some companies have very rigorous testing schedules (such as those needed to maintain tool warranties) while others feel AMC testing is only necessary when they are having a problem. While choosing to only test for AMC when a trouble arises may be cost effective in the short term it can have significant impacts on tools, in particular tool optics, and product losses due to defects which can cost significantly more in the long term than the AMC testing would have. Another critical issue in assessing AMC is what species you should be testing for. Some volatile species may not cause an issue in your process while part-per-trillion volume (pptv) amounts of others can do serious damage to your tools and/or products. Knowledge of which volatile compounds can cause problems in your applications and at what levels is crucial in deciding what type of AMC assessment to perform and at what frequency. Typically four classes of AMC are routinely monitored in clean rooms and tool environments: acids, bases, hydrocarbons, and refractory compounds. Real world examples will be presented using the solely solid-state trap collection methods utilized by SAES Pure Gas.

  2. Features of Knowledge Building in Biology: Understanding Undergraduate Students' Ideas about Molecular Mechanisms

    ERIC Educational Resources Information Center

    Southard, Katelyn; Wince, Tyler; Meddleton, Shanice; Bolger, Molly S.

    2016-01-01

    Research has suggested that teaching and learning in molecular and cellular biology (MCB) is difficult. We used a new lens to understand undergraduate reasoning about molecular mechanisms: the knowledge-integration approach to conceptual change. Knowledge integration is the dynamic process by which learners acquire new ideas, develop connections…

  3. Drugs meeting the molecular basis of diabetic kidney disease: bridging from molecular mechanism to personalized medicine.

    PubMed

    Lambers Heerspink, Hiddo J; Oberbauer, Rainer; Perco, Paul; Heinzel, Andreas; Heinze, Georg; Mayer, Gert; Mayer, Bernd

    2015-08-01

    Diabetic kidney disease (DKD) is a complex, multifactorial disease and is associated with a high risk of renal and cardiovascular morbidity and mortality. Clinical practice guidelines for diabetes recommend essentially identical treatments for all patients without taking into account how the individual responds to the instituted therapy. Yet, individuals vary widely in how they respond to medications and therefore optimal therapy differs between individuals. Understanding the underlying molecular mechanisms of variability in drug response will help tailor optimal therapy. Polymorphisms in genes related to drug pharmacokinetics have been used to explore mechanisms of response variability in DKD, but with limited success. The complex interaction between genetic make-up and environmental factors on the abundance of proteins and metabolites renders pharmacogenomics alone insufficient to fully capture response variability. A complementary approach is to attribute drug response variability to individual variability in underlying molecular mechanisms involved in the progression of disease. The interplay of different processes (e.g. inflammation, fibrosis, angiogenesis, oxidative stress) appears to drive disease progression, but the individual contribution of each process varies. Drugs at the other hand address specific targets and thereby interfere in certain disease-associated processes. At this level, biomarkers may help to gain insight into which specific pathophysiological processes are involved in an individual followed by a rational assessment whether a specific drug's mode of action indeed targets the relevant process at hand. This article describes the conceptual background and data-driven workflow developed by the SysKid consortium aimed at improving characterization of the molecular mechanisms underlying DKD at the interference of the molecular impact of individual drugs in order to tailor optimal therapy to individual patients. PMID:26209732

  4. Molecular and Mechanical Causes of Microtubule Catastrophe and Aging.

    PubMed

    Zakharov, Pavel; Gudimchuk, Nikita; Voevodin, Vladimir; Tikhonravov, Alexander; Ataullakhanov, Fazoil I; Grishchuk, Ekaterina L

    2015-12-15

    Tubulin polymers, microtubules, can switch abruptly from the assembly to shortening. These infrequent transitions, termed "catastrophes", affect numerous cellular processes but the underlying mechanisms are elusive. We approached this complex stochastic system using advanced coarse-grained molecular dynamics modeling of tubulin-tubulin interactions. Unlike in previous simplified models of dynamic microtubules, the catastrophes in this model arise owing to fluctuations in the composition and conformation of a growing microtubule tip, most notably in the number of protofilament curls. In our model, dynamic evolution of the stochastic microtubule tip configurations over a long timescale, known as the system's "aging", gives rise to the nonexponential distribution of microtubule lifetimes, consistent with experiment. We show that aging takes place in the absence of visible changes in the microtubule wall or tip, as this complex molecular-mechanical system evolves slowly and asymptotically toward the steady-state level of the catastrophe-promoting configurations. This new, to our knowledge, theoretical basis will assist detailed mechanistic investigations of the mechanisms of action of different microtubule-binding proteins and drugs, thereby enabling accurate control over the microtubule dynamics to treat various pathologies. PMID:26682815

  5. A Practical Quantum Mechanics Molecular Mechanics Method for the Dynamical Study of Reactions in Biomolecules.

    PubMed

    Mendieta-Moreno, Jesús I; Marcos-Alcalde, Iñigo; Trabada, Daniel G; Gómez-Puertas, Paulino; Ortega, José; Mendieta, Jesús

    2015-01-01

    Quantum mechanics/molecular mechanics (QM/MM) methods are excellent tools for the modeling of biomolecular reactions. Recently, we have implemented a new QM/MM method (Fireball/Amber), which combines an efficient density functional theory method (Fireball) and a well-recognized molecular dynamics package (Amber), offering an excellent balance between accuracy and sampling capabilities. Here, we present a detailed explanation of the Fireball method and Fireball/Amber implementation. We also discuss how this tool can be used to analyze reactions in biomolecules using steered molecular dynamics simulations. The potential of this approach is shown by the analysis of a reaction catalyzed by the enzyme triose-phosphate isomerase (TIM). The conformational space and energetic landscape for this reaction are analyzed without a priori assumptions about the protonation states of the different residues during the reaction. The results offer a detailed description of the reaction and reveal some new features of the catalytic mechanism. In particular, we find a new reaction mechanism that is characterized by the intramolecular proton transfer from O1 to O2 and the simultaneous proton transfer from Glu 165 to C2.

  6. Molecular mechanisms of autosomal recessive hypercholesterolemia.

    PubMed

    Wilund, Kenneth R; Yi, Ming; Campagna, Filomena; Arca, Marcello; Zuliani, Giovanni; Fellin, Renato; Ho, Yiu-Kee; Garcia, J Victor; Hobbs, Helen H; Cohen, Jonathan C

    2002-11-15

    Mutations in the phosphotyrosine-binding domain protein ARH cause autosomal recessive hypercholesterolemia (ARH), an inherited form of hypercholesterolemia due to a tissue-specific defect in the removal of low density lipoproteins (LDL) from the circulation. LDL uptake by the LDL receptor (LDLR) is markedly reduced in the liver but is normal or only moderately impaired in cultured fibroblasts of ARH patients. To define the molecular mechanism underlying ARH we examined ARH mRNA and protein in fibroblasts and lymphocytes from six probands with different ARH mutations. None of the probands had detectable full-length ARH protein in fibroblasts or lymphoblasts. Five probands were homozygous for mutations that introduced premature termination codons. No relationship was apparent between the site of the mutation in ARH and the amount of mRNA. The only mutation identified in the remaining proband was a SINE VNTR Alu (SVA) retroposon insertion in intron 1, which was associated with no detectable ARH mRNA. (125)I-LDL degradation was normal in ARH fibroblasts, as previously reported. In contrast, LDLR function was markedly reduced in ARH lymphoblasts, despite a 2-fold increase in LDL cell surface binding in these cells. These data indicate that all ARH mutations characterized to date preclude the synthesis of full-length ARH and that ARH is required for normal LDLR function in lymphocytes and hepatocytes, but not in fibroblasts. Residual LDLR function in cells that do not require ARH may explain why ARH patients have lower plasma LDL levels than do patients with homozygous familial hypercholesterolemia who have no functional LDLRs. PMID:12417523

  7. Silica Synthesis by Sponges: Unanticipated Molecular Mechanism

    NASA Astrophysics Data System (ADS)

    Morse, D. E.; Weaver, J. C.

    2001-12-01

    substitutions of specific amino acid sidechains, in conjunction with computer-assisted molecular modeling and biomimetic synthesis, allowed us to probe the determinants of catalytic activity and confirm the identification of the amino acid sidechains required for hydrolysis of the silicon alkoxides. If, as suggested by the data of others, silicic acid is conjugated with organic moieties after its transport into the cell, the catalytic mechanism described here may be important in biosilicification by sponges. As is often the case, we have been better able to answer mechanistic questions about "how" silica can be formed biologically, than "why" the diversity of structures is elaborated. Studies of spicule formation during cellular regeneration in Tethya aurantia reveal that synthesis of the larger silica needles (megascleres) and smaller starburst-shaped microscleres may be independently regulated, presumably at the genetic level. The spatial segregation of these morphologically-distinct spicule types within the sponge further suggests an adaptive significance of the different skeletal elements.

  8. Relations among fields: Mendelian, cytological and molecular mechanisms.

    PubMed

    Darden, Lindley

    2005-06-01

    Philosophers have proposed various kinds of relations between Mendelian genetics and molecular biology: reduction, replacement, explanatory extension. This paper argues that the two fields are best characterized as investigating different, serially integrated, hereditary mechanisms. The mechanisms operate at different times and contain different working entities. The working entities of the mechanisms of Mendelian heredity are chromosomes, whose movements serve to segregate alleles and independently assort genes in different linkage groups. The working entities of numerous mechanisms of molecular biology are larger and smaller segments of DNA plus related molecules. Discovery of molecular DNA mechanisms filled black boxes that were noted, but unilluminated, by Mendelian genetics.

  9. Theoretical study of molecular vibrations in electron momentum spectroscopy experiments on furan: an analytical versus a molecular dynamical approach.

    PubMed

    Morini, Filippo; Deleuze, Michael S; Watanabe, Noboru; Takahashi, Masahiko

    2015-03-01

    The influence of thermally induced nuclear dynamics (molecular vibrations) in the initial electronic ground state on the valence orbital momentum profiles of furan has been theoretically investigated using two different approaches. The first of these approaches employs the principles of Born-Oppenheimer molecular dynamics, whereas the so-called harmonic analytical quantum mechanical approach resorts to an analytical decomposition of contributions arising from quantized harmonic vibrational eigenstates. In spite of their intrinsic differences, the two approaches enable consistent insights into the electron momentum distributions inferred from new measurements employing electron momentum spectroscopy and an electron impact energy of 1.2 keV. Both approaches point out in particular an appreciable influence of a few specific molecular vibrations of A1 symmetry on the 9a1 momentum profile, which can be unravelled from considerations on the symmetry characteristics of orbitals and their energy spacing.

  10. Theoretical study of molecular vibrations in electron momentum spectroscopy experiments on furan: An analytical versus a molecular dynamical approach

    SciTech Connect

    Morini, Filippo; Deleuze, Michael S.; Watanabe, Noboru; Takahashi, Masahiko

    2015-03-07

    The influence of thermally induced nuclear dynamics (molecular vibrations) in the initial electronic ground state on the valence orbital momentum profiles of furan has been theoretically investigated using two different approaches. The first of these approaches employs the principles of Born-Oppenheimer molecular dynamics, whereas the so-called harmonic analytical quantum mechanical approach resorts to an analytical decomposition of contributions arising from quantized harmonic vibrational eigenstates. In spite of their intrinsic differences, the two approaches enable consistent insights into the electron momentum distributions inferred from new measurements employing electron momentum spectroscopy and an electron impact energy of 1.2 keV. Both approaches point out in particular an appreciable influence of a few specific molecular vibrations of A{sub 1} symmetry on the 9a{sub 1} momentum profile, which can be unravelled from considerations on the symmetry characteristics of orbitals and their energy spacing.

  11. Recent molecular approaches to understanding astrocyte function in vivo

    PubMed Central

    Davila, David; Thibault, Karine; Fiacco, Todd A.; Agulhon, Cendra

    2013-01-01

    Astrocytes are a predominant glial cell type in the nervous systems, and are becoming recognized as important mediators of normal brain function as well as neurodevelopmental, neurological, and neurodegenerative brain diseases. Although numerous potential mechanisms have been proposed to explain the role of astrocytes in the normal and diseased brain, research into the physiological relevance of these mechanisms in vivo is just beginning. In this review, we will summarize recent developments in innovative and powerful molecular approaches, including knockout mouse models, transgenic mouse models, and astrocyte-targeted gene transfer/expression, which have led to advances in understanding astrocyte biology in vivo that were heretofore inaccessible to experimentation. We will examine the recently improved understanding of the roles of astrocytes – with an emphasis on astrocyte signaling – in the context of both the healthy and diseased brain, discuss areas where the role of astrocytes remains debated, and suggest new research directions. PMID:24399932

  12. An Approach with Hybrid Segmental Mechanics.

    PubMed

    Mishra, Harsh Ashok; Maurya, Raj Kumar

    2016-06-01

    Present case report provides an insight into the hybrid segmental mechanics with treatment of 13-year-old male, considering the side effects of sole continuous arch wire sliding mechanics. Patient was diagnosed as a case of skeletal class I jaw relationship, low mandibular plane angle, class II molar relation on right and class I molar relation on left side, anterior cross bite, crowding of 12mm in upper, 5mm in lower arch. He also had proclined upper and lower anteriors by 2mm, convex profile and incompetent lips. Total treatment duration was 20 months, during which segmental canine retraction was performed with TMA (Titanium, Molybdenum, Aluminum) 'T' loop retraction spring followed by consolidation of spaces with continuous arch mechanics. Most of the treatment objectives were met with good intraoral and facial results within reasonable framework of time. This approach used traditional twin brackets, which offered the versatility to use continuous arch-wire mechanics, segmental mechanics and hybrid sectional mechanics.

  13. Integral Equation Theory of Molecular Solvation Coupled with Quantum Mechanical/Molecular Mechanics Method in NWChem Package

    SciTech Connect

    Chuev, Gennady N.; Valiev, Marat; Fedotova, Marina V.

    2012-04-10

    We have developed a hybrid approach based on a combination of integral equation theory of molecular liquids and QM/MM methodology in NorthWest computational Chemistry (NWChem) software package. We have split the evaluations into conse- quent QM/MM and statistical mechanics calculations based on the one-dimensional reference interaction site model, which allows us to reduce signicantly the time of computation. The method complements QM/MM capabilities existing in the NWChem package. The accuracy of the presented method was tested through com- putation of water structure around several organic solutes and their hydration free energies. We have also evaluated the solvent effect on the conformational equilibria. The applicability and limitations of the developed approach are discussed.

  14. Use of Nonequilibrium Work Methods to Compute Free Energy Differences Between Molecular Mechanical and Quantum Mechanical Representations of Molecular Systems.

    PubMed

    Hudson, Phillip S; Woodcock, H Lee; Boresch, Stefan

    2015-12-01

    Carrying out free energy simulations (FES) using quantum mechanical (QM) Hamiltonians remains an attractive, albeit elusive goal. Renewed efforts in this area have focused on using "indirect" thermodynamic cycles to connect "low level" simulation results to "high level" free energies. The main obstacle to computing converged free energy results between molecular mechanical (MM) and QM (ΔA(MM→QM)), as recently demonstrated by us and others, is differences in the so-called "stiff" degrees of freedom (e.g., bond stretching) between the respective energy surfaces. Herein, we demonstrate that this problem can be efficiently circumvented using nonequilibrium work (NEW) techniques, i.e., Jarzynski's and Crooks' equations. Initial applications of computing ΔA(NEW)(MM→QM), for blocked amino acids alanine and serine as well as to generate butane's potentials of mean force via the indirect QM/MM FES method, showed marked improvement over traditional FES approaches. PMID:26539729

  15. Use of Nonequilibrium Work Methods to Compute Free Energy Differences Between Molecular Mechanical and Quantum Mechanical Representations of Molecular Systems.

    PubMed

    Hudson, Phillip S; Woodcock, H Lee; Boresch, Stefan

    2015-12-01

    Carrying out free energy simulations (FES) using quantum mechanical (QM) Hamiltonians remains an attractive, albeit elusive goal. Renewed efforts in this area have focused on using "indirect" thermodynamic cycles to connect "low level" simulation results to "high level" free energies. The main obstacle to computing converged free energy results between molecular mechanical (MM) and QM (ΔA(MM→QM)), as recently demonstrated by us and others, is differences in the so-called "stiff" degrees of freedom (e.g., bond stretching) between the respective energy surfaces. Herein, we demonstrate that this problem can be efficiently circumvented using nonequilibrium work (NEW) techniques, i.e., Jarzynski's and Crooks' equations. Initial applications of computing ΔA(NEW)(MM→QM), for blocked amino acids alanine and serine as well as to generate butane's potentials of mean force via the indirect QM/MM FES method, showed marked improvement over traditional FES approaches.

  16. Molecular Mechanics: The Method and Its Underlying Philosophy.

    ERIC Educational Resources Information Center

    Boyd, Donald B.; Lipkowitz, Kenny B.

    1982-01-01

    Molecular mechanics is a nonquantum mechanical method for solving problems concerning molecular geometries and energy. Methodology based on: the principle of combining potential energy functions of all structural features of a particular molecule into a total force field; derivation of basic equations; and use of available computer programs is…

  17. Comparison of Quantum Mechanics and Molecular Mechanics Dimerization Energy Landscapes for Pairs of Ring-Containing Amino Acids in Proteins

    SciTech Connect

    Morozov, Alexandre V.; Misura M. S., Kira; Tsemekhman, Kiril; Baker, David

    2004-06-17

    A promising approach to developing improved potential functions for modeling macromolecular interactions consists of combining protein structural analysis, quantum mechanical calculations on small molecule models, and molecular mechanics potential decomposition. Here we apply this approach to the interactions of pairs of ring-containing amino acids in proteins. We find reasonable qualitative agreement between molecular mechanics and quantum chemistry calculations, both over one-dimensional projections of the binding free energy landscape for amino acid homodimers and over a set of homodimers and heterodimers from experimentally observed protein crystal structures. The molecular mechanics landscapes are a sum of charge-charge and Lennard-Jones contributions; short-range quantum mechanical effects such as charge transfer appear not to be significant in ring side chain interactions. We also find a reasonable degree of correlation between the molecular mechanics energy landscapes and the distributions of dimer geometries observed in protein structures, suggesting that the intrinsic dimer interaction energies do contribute to packing of side chains in proteins rather than being overwhelmed by the numerous interactions with other protein atoms and solvent. These results demonstrate that interactions involving aromatic residues and proline can be fairly well modeled using current molecular mechanics force fields, but there is still room for improvement, particularly for interactions involving proline and tyrosine.

  18. The Mechanism Design Approach to Student Assignment

    ERIC Educational Resources Information Center

    Pathak, Parag A.

    2011-01-01

    The mechanism design approach to student assignment involves the theoretical, empirical, and experimental study of systems used to allocate students into schools around the world. Recent practical experience designing systems for student assignment has raised new theoretical questions for the theory of matching and assignment. This article reviews…

  19. Quantum mechanical molecular dynamics studies of chemical systems

    NASA Astrophysics Data System (ADS)

    Pavese, Marc

    Methods for including quantum mechanical effects in molecular dynamics (MD) simulations are discussed in this thesis. The thesis focuses on the path integral centroid molecular dynamics (CMD) algorithm. This algorithm is first described and then used in simulations of low temperature para-hydrogen, and also in simulations of the excess proton in water clusters and in the bulk. The CMD method allows one to include the effects of nuclear quantization approximately while still maintaining a quasi-classical, trajectory based, description of the dynamics. The effects of quantization of the electronic degrees of freedom are also discussed. These effects are usually taken into account implicitly through parameterized potential functions. However, methods for including the quantum electronic degrees of freedom explicitly in a MD simulation are also discussed in this thesis. Most notably, the Car-Parrinello method, which combines density functional theory (DFT) with MD, is employed with the CMD algorithm. This yields a method which takes explicit account of the quantum electrons and nuclei. Thus, this work represents one feasible approach for considering the quantum nature of all the degrees of freedom of the system while still maintaining an MD framework. In the concluding remarks, future directions and possibilities for this type of approach are discussed.

  20. The Role of Gln61 in HRas GTP Hydrolysis: A Quantum Mechanics/Molecular Mechanics Study

    PubMed Central

    Martín-García, Fernando; Mendieta-Moreno, Jesús Ignacio; López-Viñas, Eduardo; Gómez-Puertas, Paulino; Mendieta, Jesús

    2012-01-01

    Activation of the water molecule involved in GTP hydrolysis within the HRas⋅RasGAP system is analyzed using a tailored approach based on hybrid quantum mechanics/molecular mechanics (QM/MM) simulation. A new path emerges: transfer of a proton from the attacking water molecule to a second water molecule, then a different proton is transferred from this second water molecule to the GTP. Gln61 will stabilize the transient OH− and H3O+ molecules thus generated. This newly proposed mechanism was generated by using, for the first time to our knowledge, the entire HRas-RasGAP protein complex in a QM/MM simulation context. It also offers a rational explanation for previous experimental results regarding the decrease of GTPase rate found in the HRas Q61A mutant and the increase exhibited by the HRas Q61E mutant. PMID:22225809

  1. Phosphorylation Reaction in cAPK Protein Kinase - Free Energy Quantum Mechanic/Molecular Mechanics Simulations.

    SciTech Connect

    Valiev, Marat; Yang, Jie; Adams, Joseph; Taylor, Susan S.; Weare, John H.

    2007-11-29

    Protein kinases catalyze the transfer of the γ-phosphoryl group from ATP, a key regulatory process governing signalling pathways in eukaryotic cells. The structure of the active site in these enzymes is highly conserved implying common catalytic mechanism. In this work we investigate the reaction process in cAPK protein kinase (PKA) using a combined quantum mechanics and molecular mechanics approach. The novel computational features of our work include reaction pathway determination with nudged elastic band methodology and calculation of free energy profiles of the reaction process taking into account finite temperature fluctuations of the protein environment. We find that the transfer of the γ-phosphoryl group in the protein environment is an exothermic reaction with the reaction barrier of 15 kcal/mol.

  2. The cognitive life of mechanical molecular models.

    PubMed

    Charbonneau, Mathieu

    2013-12-01

    The use of physical models of molecular structures as research tools has been central to the development of biochemistry and molecular biology. Intriguingly, it has received little attention from scholars of science. In this paper, I argue that these physical models are not mere three-dimensional representations but that they are in fact very special research tools: they are cognitive augmentations. Despite the fact that they are external props, these models serve as cognitive tools that augment and extend the modeler's cognitive capacities and performance in molecular modeling tasks. This cognitive enhancement is obtained because of the way the modeler interacts with these models, the models' materiality contributing to the solving of the molecule's structure. Furthermore, I argue that these material models and their component parts were designed, built and used specifically to serve as cognitive facilitators and cognitive augmentations.

  3. Developing accurate molecular mechanics force fields for conjugated molecular systems.

    PubMed

    Do, Hainam; Troisi, Alessandro

    2015-10-14

    A rapid method to parameterize the intramolecular component of classical force fields for complex conjugated molecules is proposed. The method is based on a procedure of force matching with a reference electronic structure calculation. It is particularly suitable for those applications where molecular dynamics simulations are used to generate structures that are therefore analysed by electronic structure methods, because it is possible to build force fields that are consistent with electronic structure calculations that follow classical simulations. Such applications are commonly encountered in organic electronics, spectroscopy of complex systems and photobiology (e.g. photosynthetic systems). We illustrate the method by parameterizing the force fields of a molecule used in molecular semiconductors (2,2-dicyanovinyl-capped S,N-heteropentacene or DCV-SN5), a polymeric semiconductor (thieno[3,2-b]thiophene-diketopyrrolopyrrole TT-DPP) and a chromophore embedded in a protein environment (15,16-dihydrobiliverdin or DBV) where several hundreds of parameters need to be optimized in parallel.

  4. Shaping mitotic chromosomes: From classical concepts to molecular mechanisms

    PubMed Central

    Kschonsak, Marc; Haering, Christian H

    2015-01-01

    How eukaryotic genomes are packaged into compact cylindrical chromosomes in preparation for cell divisions has remained one of the major unsolved questions of cell biology. Novel approaches to study the topology of DNA helices inside the nuclei of intact cells, paired with computational modeling and precise biomechanical measurements of isolated chromosomes, have advanced our understanding of mitotic chromosome architecture. In this Review Essay, we discuss – in light of these recent insights – the role of chromatin architecture and the functions and possible mechanisms of SMC protein complexes and other molecular machines in the formation of mitotic chromosomes. Based on the information available, we propose a stepwise model of mitotic chromosome condensation that envisions the sequential generation of intra-chromosomal linkages by condensin complexes in the context of cohesin-mediated inter-chromosomal linkages, assisted by topoisomerase II. The described scenario results in rod-shaped metaphase chromosomes ready for their segregation to the cell poles. PMID:25988527

  5. Shaping mitotic chromosomes: From classical concepts to molecular mechanisms.

    PubMed

    Kschonsak, Marc; Haering, Christian H

    2015-07-01

    How eukaryotic genomes are packaged into compact cylindrical chromosomes in preparation for cell divisions has remained one of the major unsolved questions of cell biology. Novel approaches to study the topology of DNA helices inside the nuclei of intact cells, paired with computational modeling and precise biomechanical measurements of isolated chromosomes, have advanced our understanding of mitotic chromosome architecture. In this Review Essay, we discuss - in light of these recent insights - the role of chromatin architecture and the functions and possible mechanisms of SMC protein complexes and other molecular machines in the formation of mitotic chromosomes. Based on the information available, we propose a stepwise model of mitotic chromosome condensation that envisions the sequential generation of intra-chromosomal linkages by condensin complexes in the context of cohesin-mediated inter-chromosomal linkages, assisted by topoisomerase II. The described scenario results in rod-shaped metaphase chromosomes ready for their segregation to the cell poles.

  6. Molecular approaches in the diagnosis of dermatophytosis.

    PubMed

    Kanbe, Toshio

    2008-01-01

    Dermatophytosis is one of the most common infectious diseases in the world and can be caused by several dermatophyte species. These species are closely related in genetic structure in spite of different phenotypic and ecological features. The morphological similarity, variability, and polymorphism of dermatophytes have meant that species identification for dermatophytes is time consuming and requires a significant degree of knowledge and technological expertise. Molecular biology-based techniques have solved problems concerning the morphology-based identification of dermatophytes and have improved our knowledge on the epidemiology of dermatophytosis. Further development of molecular diagnosis of dermatophytosis requires the investigation of additional molecular markers for diagnostic tools targeting multiple loci as well as the improvement of techniques.

  7. Molecular mechanisms involved in convergent crop domestication.

    PubMed

    Lenser, Teresa; Theißen, Günter

    2013-12-01

    Domestication has helped to understand evolution. We argue that, vice versa, novel insights into evolutionary principles could provide deeper insights into domestication. Molecular analyses have demonstrated that convergent phenotypic evolution is often based on molecular changes in orthologous genes or pathways. Recent studies have revealed that during plant domestication the causal mutations for convergent changes in key traits are likely to be located in particular genes. These insights may contribute to defining candidate genes for genetic improvement during the domestication of new plant species. Such efforts may help to increase the range of arable crops available, thus increasing crop biodiversity and food security to help meet the predicted demands of the continually growing global population under rapidly changing environmental conditions.

  8. Molecular chaperones: functional mechanisms and nanotechnological applications

    NASA Astrophysics Data System (ADS)

    Rosario Fernández-Fernández, M.; Sot, Begoña; María Valpuesta, José

    2016-08-01

    Molecular chaperones are a group of proteins that assist in protein homeostasis. They not only prevent protein misfolding and aggregation, but also target misfolded proteins for degradation. Despite differences in structure, all types of chaperones share a common general feature, a surface that recognizes and interacts with the misfolded protein. This and other, more specialized properties can be adapted for various nanotechnological purposes, by modification of the original biomolecules or by de novo design based on artificial structures.

  9. Characterizing Cardiac Molecular Mechanisms of Mammalian Hibernation via Quantitative Proteogenomics.

    PubMed

    Vermillion, Katie L; Jagtap, Pratik; Johnson, James E; Griffin, Timothy J; Andrews, Matthew T

    2015-11-01

    This study uses advanced proteogenomic approaches in a nonmodel organism to elucidate cardioprotective mechanisms used during mammalian hibernation. Mammalian hibernation is characterized by drastic reductions in body temperature, heart rate, metabolism, and oxygen consumption. These changes pose significant challenges to the physiology of hibernators, especially for the heart, which maintains function throughout the extreme conditions, resembling ischemia and reperfusion. To identify novel cardioadaptive strategies, we merged large-scale RNA-seq data with large-scale iTRAQ-based proteomic data in heart tissue from 13-lined ground squirrels (Ictidomys tridecemlineatus) throughout the circannual cycle. Protein identification and data analysis were run through Galaxy-P, a new multiomic data analysis platform enabling effective integration of RNA-seq and MS/MS proteomic data. Galaxy-P uses flexible, modular workflows that combine customized sequence database searching and iTRAQ quantification to identify novel ground squirrel-specific protein sequences and provide insight into molecular mechanisms of hibernation. This study allowed for the quantification of 2007 identified cardiac proteins, including over 350 peptide sequences derived from previously uncharacterized protein products. Identification of these peptides allows for improved genomic annotation of this nonmodel organism, as well as identification of potential splice variants, mutations, and genome reorganizations that provides insights into novel cardioprotective mechanisms used during hibernation.

  10. An Approach with Hybrid Segmental Mechanics.

    PubMed

    Mishra, Harsh Ashok; Maurya, Raj Kumar

    2016-06-01

    Present case report provides an insight into the hybrid segmental mechanics with treatment of 13-year-old male, considering the side effects of sole continuous arch wire sliding mechanics. Patient was diagnosed as a case of skeletal class I jaw relationship, low mandibular plane angle, class II molar relation on right and class I molar relation on left side, anterior cross bite, crowding of 12mm in upper, 5mm in lower arch. He also had proclined upper and lower anteriors by 2mm, convex profile and incompetent lips. Total treatment duration was 20 months, during which segmental canine retraction was performed with TMA (Titanium, Molybdenum, Aluminum) 'T' loop retraction spring followed by consolidation of spaces with continuous arch mechanics. Most of the treatment objectives were met with good intraoral and facial results within reasonable framework of time. This approach used traditional twin brackets, which offered the versatility to use continuous arch-wire mechanics, segmental mechanics and hybrid sectional mechanics. PMID:27504427

  11. Molecular Mechanisms of External Genitalia Development

    PubMed Central

    Blaschko, Sarah D.; Cunha, Gerald R.; Baskin, Laurence S.

    2012-01-01

    External genitalia development occurs through a combination of hormone independent, hormone dependent, and endocrine pathways. Perturbation of these pathways can lead to abnormal external genitalia development. We review human and animal mechanisms of normal and abnormal external genitalia development, and we evaluate abnormal mechanisms that lead to hypospadias. We also discuss recent laboratory findings that further our understanding of animal models of hypospadias. PMID:22790208

  12. Symposium on molecular and cellular mechanisms of mutagenesis

    SciTech Connect

    Not Available

    1981-01-01

    These proceedings contain abstracts only of the 21 papers presented at the Sympsoium. The papers dealt with molecular mechanisms of mutagenesis and cellular responses to chemical and physical mutagenic agents. (ERB)

  13. Imaging approaches to optimize molecular therapies.

    PubMed

    Weissleder, Ralph; Schwaiger, Markus C; Gambhir, Sanjiv Sam; Hricak, Hedvig

    2016-09-01

    Imaging, including its use for innovative tissue sampling, is slowly being recognized as playing a pivotal role in drug development, clinical trial design, and more effective delivery and monitoring of molecular therapies. The challenge is that, while a considerable number of new imaging technologies and new targeted tracers have been developed for cancer imaging in recent years, the technologies are neither evenly distributed nor evenly implemented. Furthermore, many imaging innovations are not validated and are not ready for widespread use in drug development or in clinical trial designs. Inconsistent and often erroneous use of terminology related to quantitative imaging biomarkers has also played a role in slowing their development and implementation. We examine opportunities for, and challenges of, the use of imaging biomarkers to facilitate development of molecular therapies and to accelerate progress in clinical trial design. In the future, in vivo molecular imaging, image-guided tissue sampling for mutational analyses ("high-content biopsies"), and noninvasive in vitro tests ("liquid biopsies") will likely be used in various combinations to provide the best possible monitoring and individualized treatment plans for cancer patients. PMID:27605550

  14. Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities

    PubMed Central

    Lefevre, Sophie; Sliwa, Dominika; Seguin, Alexandra; Camadro, Jean-Michel; Lesuisse, Emmanuel

    2010-01-01

    Abstract Mitochondrial dysfunction and oxidative damage are at the origin of numerous neurodegenerative diseases like Friedreich ataxia and Alzheimer and Parkinson diseases. Friedreich ataxia (FRDA) is the most common hereditary ataxia, with one individual affected in 50,000. This disease is characterized by progressive degeneration of the central and peripheral nervous systems, cardiomyopathy, and increased incidence of diabetes mellitus. FRDA is caused by a dynamic mutation, a GAA trinucleotide repeat expansion, in the first intron of the FXN gene. Fewer than 5% of the patients are heterozygous and carry point mutations in the other allele. The molecular consequences of the GAA triplet expansion is transcription silencing and reduced expression of the encoded mitochondrial protein, frataxin. The precise cellular role of frataxin is not known; however, it is clear now that several mitochondrial functions are not performed correctly in patient cells. The affected functions include respiration, iron–sulfur cluster assembly, iron homeostasis, and maintenance of the redox status. This review highlights the molecular mechanisms that underlie the disease phenotypes and the different hypothesis about the function of frataxin. In addition, we present an overview of the most recent therapeutic approaches for this severe disease that actually has no efficient treatment. Antioxid. Redox Signal. 13, 0000–0000. PMID:20156111

  15. Molecular and trophic mechanisms of tumorigenesis.

    PubMed

    Levy, Andy

    2008-03-01

    A significant proportion of pituitary macroadenomas, and by definition all microadenomas, regain trophic stability after an initial period of deregulated growth. Classical proto-oncogene activation and tumor suppressor mutation are rarely responsible, and no histologic or molecular markers reliably predict behavior. GNAS1 activation and the mutations associated with multiple endocrine neoplasia type 1 and Carney complex, aryl hydrocarbon receptor interacting protein gene mutations, and a narrowing region of chromosome 11q13 in familial isolated acromegaly together account for such a small proportion of pituitary adenomas that the pituitary adenoma pathogenic epiphany is surely yet to come. PMID:18226729

  16. Light-powered, artificial molecular pumps: a minimalistic approach

    PubMed Central

    Ragazzon, Giulio; Baroncini, Massimo; Silvi, Serena; Venturi, Margherita

    2015-01-01

    Summary The realization of artificial molecular motors capable of converting energy into mechanical work is a fascinating challenge of nanotechnology and requires reactive systems that can operate away from chemical equilibrium. This article describes the design and construction of a simple, supramolecular ensemble in which light irradiation causes the directional transit of a macrocycle along a nonsymmetric molecular axle, thus forming the basis for the development of artificial molecular pumps. PMID:26665081

  17. Instructional Approach to Molecular Electronic Structure Theory

    ERIC Educational Resources Information Center

    Dykstra, Clifford E.; Schaefer, Henry F.

    1977-01-01

    Describes a graduate quantum mechanics projects in which students write a computer program that performs ab initio calculations on the electronic structure of a simple molecule. Theoretical potential energy curves are produced. (MLH)

  18. Etiologies and molecular mechanisms of communication disorders

    PubMed Central

    Smith, Shelley D.; Grigorenko, Elena; Willcutt, Erik; Pennington, Bruce F.; Olson, Richard K.; DeFries, John C.

    2010-01-01

    Quantitative behavioral genetic studies have made it clear that communication disorders such as reading disability (RD), language impairment (LI), and autism spectrum disorders (ASD) follow some basic principles: 1) Complex disorders have complex causes, in that each clinical disorder is influenced by a number of separate genes; and 2) at least some behaviorally related disorders are influenced by the same genes. Recent advances in molecular and statistical methods have confirmed these principles and are now leading to an understanding of the genes that may be involved in these disorders and how their disruption may affect the development of the brain. The prospect is that the genes involved in these disorders will define a network of interacting neurologic functions, and that perturbations of different elements of this network will produce susceptibilities for different disorders. Such knowledge would clarify the underlying deficits in these disorders and could lead to revised diagnostic conceptions. These goals are still in the future, however. Identifying the individual genes in such a network is painstaking, and there have been seemingly contradictory studies along the way. Improvements in study design and additional functional analysis of genes is gradually clarifying many of these issues. When combined with careful phenotypic studies, molecular genetic studies have the potential to refine the clinical definitions of communication disorders and influence their remediation. PMID:20814255

  19. Molecular mechanisms of STIM/Orai communication

    PubMed Central

    Derler, Isabella; Jardin, Isaac

    2016-01-01

    Ca2+ entry into the cell via store-operated Ca2+ release-activated Ca2+ (CRAC) channels triggers diverse signaling cascades that affect cellular processes like cell growth, gene regulation, secretion, and cell death. These store-operated Ca2+ channels open after depletion of intracellular Ca2+ stores, and their main features are fully reconstituted by the two molecular key players: the stromal interaction molecule (STIM) and Orai. STIM represents an endoplasmic reticulum-located Ca2+ sensor, while Orai forms a highly Ca2+-selective ion channel in the plasma membrane. Functional as well as mutagenesis studies together with structural insights about STIM and Orai proteins provide a molecular picture of the interplay of these two key players in the CRAC signaling cascade. This review focuses on the main experimental advances in the understanding of the STIM1-Orai choreography, thereby establishing a portrait of key mechanistic steps in the CRAC channel signaling cascade. The focus is on the activation of the STIM proteins, the subsequent coupling of STIM1 to Orai1, and the consequent structural rearrangements that gate the Orai channels into the open state to allow Ca2+ permeation into the cell. PMID:26825122

  20. Hybrid schemes based on quantum mechanics/molecular mechanics simulations goals to success, problems, and perspectives.

    PubMed

    Ferrer, Silvia; Ruiz-Pernía, Javier; Martí, Sergio; Moliner, Vicent; Tuñón, Iñaki; Bertrán, Juan; Andrés, Juan

    2011-01-01

    The development of characterization techniques, advanced synthesis methods, as well as molecular modeling has transformed the study of systems in a well-established research field. The current research challenges in biocatalysis and biotransformation evolve around enzyme discovery, design, and optimization. How can we find or create enzymes that catalyze important synthetic reactions, even reactions that may not exist in nature? What is the source of enzyme catalytic power? To answer these and other related questions, the standard strategies have evolved from trial-and-error methodologies based on chemical knowledge, accumulated experience, and common sense into a clearly multidisciplinary science that allows one to reach the molecular design of tailor-made enzyme catalysts. This is even more so when one refers to enzyme catalysts, for which the detailed structure and composition are known and can be manipulated to introduce well-defined residues which can be implicated in the chemical rearrangements taking place in the active site. The methods and techniques of theoretical and computational chemistry are becoming more and more important in both understanding the fundamental biological roles of enzymes and facilitating their utilization in biotechnology. Improvement of the catalytic function of enzymes is important from scientific and industrial viewpoints, and to put this fact in the actual perspective as well as the potentialities, we recommend the very recent report of Sanderson [Sanderson, K. (2011). Chemistry: enzyme expertise. Nature 471, 397.]. Great fundamental advances have been made toward the ab initio design of enzyme catalysts based on molecular modeling. This has been based on the molecular mechanistic knowledge of the reactions to be catalyzed, together with the development of advanced synthesis and characterization techniques. The corresponding molecular mechanism can be studied by means of powerful quantum chemical calculations. The catalytic

  1. Molecular Mechanisms of Action of BPA.

    PubMed

    Acconcia, Filippo; Pallottini, Valentina; Marino, Maria

    2015-01-01

    Bisphenol A (BPA) exposure has been associated with serious endocrine-disrupting effects in humans and wildlife. Toxicological and epidemiological studies evidenced that BPA increases body mass index and disrupts normal cardiovascular physiology by interfering with endogenous hormones in rodents, nonhuman primates, and cell culture test systems. The BPA concentration derived from these experiments were used by government regulatory agencies to determine the safe exposure levels of BPA in humans. However, accumulating literature in vivo and in vitro indicate that at concentrations lower than that reported in toxicological studies, BPA could elicit a different endocrine-disrupting capacity. To further complicate this picture, BPA effects rely on several and diverse mechanisms that converge upon endocrine and reproductive systems. If all or just few of these mechanisms concur to the endocrine-disrupting potential of low doses of BPA is at present still unclear. Thus, taking into account that the incidence and/or prevalence of health problems associated with endocrine disruption have increased worldwide, the goal of the present review is to give an overview of the many mechanisms of BPA action in order to decipher whether different mechanisms are at the root of the effect of low dose of BPA on endocrine system. PMID:26740804

  2. Selectivity and molecular mechanisms of toxicity

    SciTech Connect

    DeMatteis, F. ); Lock, E. A. )

    1987-01-01

    This book contains 11 chapters. Some of the titles are: Mechanisms of genotoxicity of chlorinated aliphatic hydrocarbons; Drugs as suicide substrates of cytochrome P-450; Cellular specific toxicity in the lung; The nephrotoxicity of haloalkane and haloalkene glutathione conjugates; and dioxin and organotin compounds as model immunotoxic chemicals.

  3. Molecular and Mechanical Behavior of Elastomers.

    ERIC Educational Resources Information Center

    Etzel, A. J.; And Others

    1986-01-01

    Describes an experiment in which stretching a rubber band can be used to compare the statistical theory of rubber elasticity with its continuum mechanics counterpart. Employs the use of the equation of the state of rubber elasticity and the Mooney-Rivlin equation. (TW)

  4. Molecular Mechanisms of Action of BPA

    PubMed Central

    Acconcia, Filippo; Pallottini, Valentina

    2015-01-01

    Bisphenol A (BPA) exposure has been associated with serious endocrine-disrupting effects in humans and wildlife. Toxicological and epidemiological studies evidenced that BPA increases body mass index and disrupts normal cardiovascular physiology by interfering with endogenous hormones in rodents, nonhuman primates, and cell culture test systems. The BPA concentration derived from these experiments were used by government regulatory agencies to determine the safe exposure levels of BPA in humans. However, accumulating literature in vivo and in vitro indicate that at concentrations lower than that reported in toxicological studies, BPA could elicit a different endocrine-disrupting capacity. To further complicate this picture, BPA effects rely on several and diverse mechanisms that converge upon endocrine and reproductive systems. If all or just few of these mechanisms concur to the endocrine-disrupting potential of low doses of BPA is at present still unclear. Thus, taking into account that the incidence and/or prevalence of health problems associated with endocrine disruption have increased worldwide, the goal of the present review is to give an overview of the many mechanisms of BPA action in order to decipher whether different mechanisms are at the root of the effect of low dose of BPA on endocrine system. PMID:26740804

  5. Molecular Mechanisms of Action of BPA.

    PubMed

    Acconcia, Filippo; Pallottini, Valentina; Marino, Maria

    2015-01-01

    Bisphenol A (BPA) exposure has been associated with serious endocrine-disrupting effects in humans and wildlife. Toxicological and epidemiological studies evidenced that BPA increases body mass index and disrupts normal cardiovascular physiology by interfering with endogenous hormones in rodents, nonhuman primates, and cell culture test systems. The BPA concentration derived from these experiments were used by government regulatory agencies to determine the safe exposure levels of BPA in humans. However, accumulating literature in vivo and in vitro indicate that at concentrations lower than that reported in toxicological studies, BPA could elicit a different endocrine-disrupting capacity. To further complicate this picture, BPA effects rely on several and diverse mechanisms that converge upon endocrine and reproductive systems. If all or just few of these mechanisms concur to the endocrine-disrupting potential of low doses of BPA is at present still unclear. Thus, taking into account that the incidence and/or prevalence of health problems associated with endocrine disruption have increased worldwide, the goal of the present review is to give an overview of the many mechanisms of BPA action in order to decipher whether different mechanisms are at the root of the effect of low dose of BPA on endocrine system.

  6. The molecular mechanism of the catalase reaction.

    PubMed

    Alfonso-Prieto, Mercedes; Biarnés, Xevi; Vidossich, Pietro; Rovira, Carme

    2009-08-26

    Catalases are ubiquitous enzymes that prevent cell oxidative damage by degrading hydrogen peroxide to water and oxygen (2H(2)O(2) --> 2 H(2)O + O(2)) with high efficiency. The enzyme is first oxidized to a high-valent iron intermediate, known as Compound I (Cpd I) which, in contrast to other hydroperoxidases, is reduced back to the resting state by further reacting with H(2)O(2). By means of hybrid QM/MM Car-Parrinello metadynamics simulations, we have investigated the mechanism of the reduction of Compound I by H(2)O(2) in Helicobacter pylori catalase (HPC) and Penicillium vitale catalase (PVC). We found that the Cpd I-H(2)O(2) complex evolves to a Cpd II-like species through the transfer of a hydrogen atom from the peroxide to the oxoferryl unit. To complete the reaction, two mechanisms may be operative: a His-mediated (Fita-Rossmann) mechanism, which involves the distal His as an acid-base catalyst mediating the transfer of a proton (associated with an electron transfer), and a direct mechanism, in which a hydrogen atom transfer occurs. Independently of the mechanism, the reaction proceeds by two one-electron transfers rather than one two-electron transfer, as has long been the lore. The calculations provide a detailed view of the atomic and electronic reorganizations during the reaction, and highlight the key role of the distal residues to assist the reaction. Additional calculations on the in silico HPC His56Gly mutant and gas-phase models provide clues to understand the requirements for the reaction to proceed with low barriers. PMID:19653683

  7. Mechanism of Molecular Exchange in Copolymer Micelles

    NASA Astrophysics Data System (ADS)

    Choi, Soo-Hyung; Lodge, Timothy; Bates, Frank

    2010-03-01

    Compared to thermodynamic structure, much less has been known about the kinetics of block copolymer micelles which should underlay the attainment of thermodynamic equilibrium. In this presentation, molecular exchange between spherical micelles formed by isotopically labeled diblock copolymers was investigated using time-resolved small-angle neutron scattering. Two pairs of structurally matched poly(styrene-b-ethylene-alt-propylene) (PS-PEP) were synthesized and dispersed in isotopic mixture of squalane, highly selective to PEP block. Each pair includes polymers with fully deuterated (dPS-PEP) and a normal (hPS-PEP) PS blocks. Temperature dependence of the micelle exchange rate R(t) is consistent with melt dynamics for the core polymer. Furthermore, R(t) is significantly sensitive to the core block length N due to the thermodynamic penalty associated with ejecting a core block into the solvent. This hypersensitivity, combined with modest polydispersity in N, leads to an approximately logarithmic decay in R(t).

  8. Molecular mechanisms in multiple myeloma drug resistance

    PubMed Central

    Nikesitch, Nicholas; Ling, Silvia C W

    2016-01-01

    Multiple myeloma (MM) is predominantly an incurable malignancy despite high-dose chemotherapy, autologous stem cell transplant and novel agents. MM is a genetically heterogeneous disease and the complexity increases as the disease progresses to a more aggressive stage. MM arises from a plasma cell, which produces and secretes non-functioning immunoglobulins. Most MM cells are sensitive to proteasome inhibitors (PIs), which have become the main drug in the treatment of newly diagnosed and relapsed MM. However, not all MM is sensitive to PIs. This review summarises the literature regarding molecular biology of MM with a focus on the unfolded protein response and explores how this could affect drug sensitivity and progression of disease. PMID:26598624

  9. Molecular mechanisms of synaptic remodeling in alcoholism.

    PubMed

    Kyzar, Evan J; Pandey, Subhash C

    2015-08-01

    Alcohol use and alcohol addiction represent dysfunctional brain circuits resulting from neuroadaptive changes during protracted alcohol exposure and its withdrawal. Alcohol exerts a potent effect on synaptic plasticity and dendritic spine formation in specific brain regions, providing a neuroanatomical substrate for the pathophysiology of alcoholism. Epigenetics has recently emerged as a critical regulator of gene expression and synaptic plasticity-related events in the brain. Alcohol exposure and withdrawal induce changes in crucial epigenetic processes in the emotional brain circuitry (amygdala) that may be relevant to the negative affective state defined as the "dark side" of addiction. Here, we review the literature concerning synaptic plasticity and epigenetics, with a particular focus on molecular events related to dendritic remodeling during alcohol abuse and alcoholism. Targeting epigenetic processes that modulate synaptic plasticity may yield novel treatments for alcoholism.

  10. Molecular mechanisms of polyploidy and hybrid vigor.

    PubMed

    Chen, Z Jeffrey

    2010-02-01

    Hybrids such as maize (Zea mays) or domestic dog (Canis lupus familiaris) grow bigger and stronger than their parents. This is also true for allopolyploids such as wheat (Triticum spp.) or frog (i.e. Xenopus and Silurana) that contain two or more sets of chromosomes from different species. The phenomenon, known as hybrid vigor or heterosis, was systematically characterized by Charles Darwin (1876). The rediscovery of heterosis in maize a century ago has revolutionized plant and animal breeding and production. Although genetic models for heterosis have been rigorously tested, the molecular bases remain elusive. Recent studies have determined the roles of nonadditive gene expression, small RNAs, and epigenetic regulation, including circadian-mediated metabolic pathways, in hybrid vigor, which could lead to better use and exploitation of the increased biomass and yield in hybrids and allopolyploids for food, feed, and biofuels.

  11. Emerging mechanisms of molecular pathology in ALS.

    PubMed

    Peters, Owen M; Ghasemi, Mehdi; Brown, Robert H

    2015-05-01

    Amyotrophic lateral sclerosis (ALS) is a devastating degenerative disease characterized by progressive loss of motor neurons in the motor cortex, brainstem, and spinal cord. Although defined as a motor disorder, ALS can arise concurrently with frontotemporal lobal dementia (FTLD). ALS begins focally but disseminates to cause paralysis and death. About 10% of ALS cases are caused by gene mutations, and more than 40 ALS-associated genes have been identified. While important questions about the biology of this disease remain unanswered, investigations of ALS genes have delineated pathogenic roles for (a) perturbations in protein stability and degradation, (b) altered homeostasis of critical RNA- and DNA-binding proteins, (c) impaired cytoskeleton function, and (d) non-neuronal cells as modifiers of the ALS phenotype. The rapidity of progress in ALS genetics and the subsequent acquisition of insights into the molecular biology of these genes provide grounds for optimism that meaningful therapies for ALS are attainable. PMID:25932674

  12. Molecular mechanisms of polyploidy and hybrid vigor

    PubMed Central

    Chen, Z. Jeffrey

    2010-01-01

    Hybrids such as maize (Zea mays) or domestic dog (Canis lupus familiaris) grow bigger and stronger than their parents. This is also true for allopolyploids such as wheat (Triticum spp.) or frog (i.e. Xenopus and Silurana) that contain two or more sets of chromosomes from different species. The phenomenon, known as hybrid vigor or heterosis, was systematically characterized by Charles Darwin (1876). The rediscovery of heterosis in maize a century ago has revolutionized plant and animal breeding and production. Although genetic models for heterosis have been rigorously tested, the molecular bases remain elusive. Recent studies have determined the roles of nonadditive gene expression, small RNAs, and epigenetic regulation, including circadian-mediated metabolic pathways, in hybrid vigor and incompatibility, which could lead to better use and exploitation of the increased biomass and yield in hybrids and allopolyploids for food, feed, and biofuels. PMID:20080432

  13. How Molecular Structure Affects Mechanical Properties of an Advanced Polymer

    NASA Technical Reports Server (NTRS)

    Nicholson, Lee M.; Whitley, Karen S.; Gates, Thomas S.; Hinkley, Jeffrey A.

    2000-01-01

    density was performed over a range of temperatures below the glass transition temperature. The physical characterization, elastic properties and notched tensile strength all as a function of molecular weight and test temperature were determined. For the uncrosslinked SI material, it was shown that notched tensile strength is a strong function of both temperature and molecular weight, whereas stiffness is only a strong function of temperature. For the crosslinked PETI-SI material, it was shown that the effect of crosslinking significantly enhances the mechanical performance of the low molecular weight material; comparable to that exhibited by the high molecular weight material.

  14. Novel molecular approaches to cystic fibrosis gene therapy

    PubMed Central

    Lee, Tim W. R.; Matthews, David A.; Blair, G. Eric

    2005-01-01

    Gene therapy holds promise for the treatment of a range of inherited diseases, such as cystic fibrosis. However, efficient delivery and expression of the therapeutic transgene at levels sufficient to result in phenotypic correction of cystic fibrosis pulmonary disease has proved elusive. There are many reasons for this lack of progress, both macroscopically in terms of airway defence mechanisms and at the molecular level with regard to effective cDNA delivery. This review of approaches to cystic fibrosis gene therapy covers these areas in detail and highlights recent progress in the field. For gene therapy to be effective in patients with cystic fibrosis, the cDNA encoding the cystic fibrosis transmembrane conductance regulator protein must be delivered effectively to the nucleus of the epithelial cells lining the bronchial tree within the lungs. Expression of the transgene must be maintained at adequate levels for the lifetime of the patient, either by repeat dosage of the vector or by targeting airway stem cells. Clinical trials of gene therapy for cystic fibrosis have demonstrated proof of principle, but gene expression has been limited to 30 days at best. Results suggest that viral vectors such as adenovirus and adeno-associated virus are unsuited to repeat dosing, as the immune response reduces the effectiveness of each subsequent dose. Nonviral approaches, such as cationic liposomes, appear more suited to repeat dosing, but have been less effective. Current work regarding non-viral gene delivery is now focused on understanding the mechanisms involved in cell entry, endosomal escape and nuclear import of the transgene. There is now increasing evidence to suggest that additional ligands that facilitate endosomal escape or contain a nuclear localization signal may enhance liposome-mediated gene delivery. Much progress in this area has been informed by advances in our understanding of the mechanisms by which viruses deliver their genomes to the nuclei of host

  15. Molecular mechanisms regulating NLRP3 inflammasome activation

    PubMed Central

    Jo, Eun-Kyeong; Kim, Jin Kyung; Shin, Dong-Min; Sasakawa, Chihiro

    2016-01-01

    Inflammasomes are multi-protein signaling complexes that trigger the activation of inflammatory caspases and the maturation of interleukin-1β. Among various inflammasome complexes, the NLRP3 inflammasome is best characterized and has been linked with various human autoinflammatory and autoimmune diseases. Thus, the NLRP3 inflammasome may be a promising target for anti-inflammatory therapies. In this review, we summarize the current understanding of the mechanisms by which the NLRP3 inflammasome is activated in the cytosol. We also describe the binding partners of NLRP3 inflammasome complexes activating or inhibiting the inflammasome assembly. Our knowledge of the mechanisms regulating NLRP3 inflammasome signaling and how these influence inflammatory responses offers further insight into potential therapeutic strategies to treat inflammatory diseases associated with dysregulation of the NLRP3 inflammasome. PMID:26549800

  16. Vancomycin Molecular Interactions: Antibiotic and Enantioselective Mechanisms

    NASA Astrophysics Data System (ADS)

    Ward, Timothy J.; Gilmore, Aprile; Ward, Karen; Vowell, Courtney

    Medical studies established that vancomycin and other related macrocyclic antibiotics have an enhanced antimicrobial activity when they are associated as dimers. The carbohydrate units attached to the vancomycin basket have an essential role in the dimerization reaction. Covalently synthesized dimers were found active against vancomycin-resistant bacterial strains. A great similarity between antibiotic potential and enantioselectivity was established. A covalent vancomycin dimer was studied in capillary electrophoresis producing excellent chiral separation of dansyl amino acids. Balhimycin is a macrocyclic glycopeptide structurally similar to vancomycin. The small differences are, however, responsible for drastic differences in enantioselectivity in the same experimental conditions. Contributions from studies examining vancomycin's mechanism for antimicrobial activity have substantially aided our understanding of its mechanism in chiral recognition.

  17. Physical mechanisms of biological molecular motors

    NASA Astrophysics Data System (ADS)

    Miller, John H., Jr.; Vajrala, Vijayanand; Infante, Hans L.; Claycomb, James R.; Palanisami, Akilan; Fang, Jie; Mercier, George T.

    2009-03-01

    Biological motors generally fall into two categories: (1) those that convert chemical into mechanical energy via hydrolysis of a nucleoside triphosphate, usually adenosine triphosphate, regarded as life's chemical currency of energy and (2) membrane bound motors driven directly by an ion gradient and/or membrane potential. Here we argue that electrostatic interactions play a vital role for both types of motors and, therefore, the tools of physics can greatly contribute to understanding biological motors.

  18. Molecular mechanisms of bone formation in spondyloarthritis.

    PubMed

    González-Chávez, Susana Aideé; Quiñonez-Flores, Celia María; Pacheco-Tena, César

    2016-07-01

    Spondyloarthritis comprise a group of inflammatory rheumatic diseases characterized by its association to HLA-B27 and the presence of arthritis and enthesitis. The pathogenesis involves both an inflammatory process and new bone formation, which eventually lead to ankylosis of the spine. To date, the intrinsic mechanisms of the pathogenic process have not been fully elucidated, and our progress is remarkable in the identification of therapeutic targets to achieve the control of the inflammatory process, yet our ability to inhibit the excessive bone formation is still insufficient. The study of new bone formation in spondyloarthritis has been mostly conducted in animal models of the disease and only few experiments have been done using human biopsies. The deregulation and overexpression of molecules involved in the osteogenesis process have been observed in bone cells, mesenchymal cells, and fibroblasts. The signaling associated to the excessive bone formation is congruent with those involved in the physiological processes of bone remodeling. Bone morphogenetic proteins and Wnt pathways have been found deregulated in this disease; however, the cause for uncontrolled stimulation remains unknown. Mechanical stress appears to play an important role in the pathological osteogenesis process; nevertheless, the association of other important factors, such as the presence of HLA-B27 and environmental factors, remains uncertain. The present review summarizes the experimental findings that describe the signaling pathways involved in the new bone formation process in spondyloarthritis in animal models and in human biopsies. The role of mechanical stress as the trigger of these pathways is also reviewed. PMID:26838262

  19. Doublet-mechanical approach to elastic homogenization

    SciTech Connect

    Ferrari, M.; Hanford, D.

    1996-10-01

    The process of deducing the overall properties of multi-phase media from phase properties and distributional data is referred to as homogenization. Two prominent homogenization modes are (1) the so-called direct, or concentrator-based approaches; and (2) the so-called mathematical homogenization, or cell-based method. Within the direct method one can classify the Eshelby, the Mori-Tanaka, the Voigt, the Reuss, and the ploy-inclusion approaches. As was proven by one of the authors (MF) in recent publications, none of the existing approaches satisfies even most elementary admissibility criteria for the general bi-phase composite, i.e., the search for general concentrators is still far from complete. The mathematical homogenization method, developed by Tartar and Sanchez-Palencia among others, reduces the overall effective property prediction to the numerical solution of a representative cell problem. In this paper, the methods of the Doublet Mechanics (DM) of V.T. Granik and M. Ferrari are employed to address both the concentrator problem of the direct approach, and the cell problem of mathematical homogenization. In the former, a choice of macroscopic concentrator is determined exactly from the closed-form solution of a micromechanical problem. The latter problem is solved by identifying the representative micro-level volume with an assembly of points with translational regularity, and employing the discrete-continuum transition that underlies DM.

  20. Molecular mechanisms underlying the exceptional adaptations of batoid fins

    PubMed Central

    Nakamura, Tetsuya; Klomp, Jeff; Pieretti, Joyce; Schneider, Igor; Gehrke, Andrew R.; Shubin, Neil H.

    2015-01-01

    Extreme novelties in the shape and size of paired fins are exemplified by extinct and extant cartilaginous and bony fishes. Pectoral fins of skates and rays, such as the little skate (Batoid, Leucoraja erinacea), show a strikingly unique morphology where the pectoral fin extends anteriorly to ultimately fuse with the head. This results in a morphology that essentially surrounds the body and is associated with the evolution of novel swimming mechanisms in the group. In an approach that extends from RNA sequencing to in situ hybridization to functional assays, we show that anterior and posterior portions of the pectoral fin have different genetic underpinnings: canonical genes of appendage development control posterior fin development via an apical ectodermal ridge (AER), whereas an alternative Homeobox (Hox)–Fibroblast growth factor (Fgf)–Wingless type MMTV integration site family (Wnt) genetic module in the anterior region creates an AER-like structure that drives anterior fin expansion. Finally, we show that GLI family zinc finger 3 (Gli3), which is an anterior repressor of tetrapod digits, is expressed in the posterior half of the pectoral fin of skate, shark, and zebrafish but in the anterior side of the pelvic fin. Taken together, these data point to both highly derived and deeply ancestral patterns of gene expression in skate pectoral fins, shedding light on the molecular mechanisms behind the evolution of novel fin morphologies. PMID:26644578

  1. Molecular mechanisms underlying the exceptional adaptations of batoid fins.

    PubMed

    Nakamura, Tetsuya; Klomp, Jeff; Pieretti, Joyce; Schneider, Igor; Gehrke, Andrew R; Shubin, Neil H

    2015-12-29

    Extreme novelties in the shape and size of paired fins are exemplified by extinct and extant cartilaginous and bony fishes. Pectoral fins of skates and rays, such as the little skate (Batoid, Leucoraja erinacea), show a strikingly unique morphology where the pectoral fin extends anteriorly to ultimately fuse with the head. This results in a morphology that essentially surrounds the body and is associated with the evolution of novel swimming mechanisms in the group. In an approach that extends from RNA sequencing to in situ hybridization to functional assays, we show that anterior and posterior portions of the pectoral fin have different genetic underpinnings: canonical genes of appendage development control posterior fin development via an apical ectodermal ridge (AER), whereas an alternative Homeobox (Hox)-Fibroblast growth factor (Fgf)-Wingless type MMTV integration site family (Wnt) genetic module in the anterior region creates an AER-like structure that drives anterior fin expansion. Finally, we show that GLI family zinc finger 3 (Gli3), which is an anterior repressor of tetrapod digits, is expressed in the posterior half of the pectoral fin of skate, shark, and zebrafish but in the anterior side of the pelvic fin. Taken together, these data point to both highly derived and deeply ancestral patterns of gene expression in skate pectoral fins, shedding light on the molecular mechanisms behind the evolution of novel fin morphologies. PMID:26644578

  2. The Electrical Response to Injury: Molecular Mechanisms and Wound Healing

    PubMed Central

    Reid, Brian; Zhao, Min

    2014-01-01

    Significance: Natural, endogenous electric fields (EFs) and currents arise spontaneously after wounding of many tissues, especially epithelia, and are necessary for normal healing. This wound electrical activity is a long-lasting and regulated response. Enhancing or inhibiting this electrical activity increases or decreases wound healing, respectively. Cells that are responsible for wound closure such as corneal epithelial cells or skin keratinocytes migrate directionally in EFs of physiological magnitude. However, the mechanisms of how the wound electrical response is initiated and regulated remain unclear. Recent Advances: Wound EFs and currents appear to arise by ion channel up-regulation and redistribution, which are perhaps triggered by an intracellular calcium wave or cell depolarization. We discuss the possibility of stimulation of wound healing via pharmacological enhancement of the wound electric signal by stimulation of ion pumping. Critical Issues: Chronic wounds are a major problem in the elderly and diabetic patient. Any strategy to stimulate wound healing in these patients is desirable. Applying electrical stimulation directly is problematic, but pharmacological enhancement of the wound signal may be a promising strategy. Future Directions: Understanding the molecular regulation of wound electric signals may reveal some fundamental mechanisms in wound healing. Manipulating fluxes of ions and electric currents at wounds might offer new approaches to achieve better wound healing and to heal chronic wounds. PMID:24761358

  3. Molecular Mechanisms of Chronic Intermittent Hypoxia and Hypertension

    PubMed Central

    Sunderram, J.; Androulakis, I.P.

    2013-01-01

    Obstructive sleep apnea (OSA) is characterized by episodes of repeated airway obstruction resulting in cessation (apnea) or reduction (hypopnea) in airflow during sleep. These events lead to intermittent hypoxia and hypercapnia, sleep fragmentation, and changes in intrathoracic pressure, and are associated with a marked surge in sympathetic activity and an abrupt increase in blood pressure. Blood pressure remains elevated during wakefulness despite the absence of obstructive events resulting in a high prevalence of hypertension in patients with OSA. There is substantial evidence that suggests that chronic intermittent hypoxia (CIH) leads to sustained sympathoexcitation during the day and changes in vasculature resulting in hypertension in patients with OSA. Mechanisms of sympathoexcitation include augmentation of peripheral chemoreflex sensitivity and a direct effect on central sites of sympathetic regulation. Interestingly, the vascular changes that occur with CIH have been ascribed to the same molecules that have been implicated in the augmented sympathetic tone in CIH. This review will discuss the hypothesized molecular mechanisms involved in the development of hypertension with CIH, will build a conceptual model for the development of hypertension following CIH, and will propose a systems biology approach in further elucidating the relationship between CIH and the development of hypertension. PMID:23140119

  4. Molecular Mechanisms of Circadian Regulation During Spaceflight

    NASA Technical Reports Server (NTRS)

    Zanello, Susana; Boyle, Richard

    2011-01-01

    Disruption of the regular environmental circadian cues in addition to stringent and demanding operational schedules are two main factors that undoubtedly impact sleep patterns and vigilant performance in the astronaut crews during spaceflight. Most research is focused on the behavioral aspects of the risk of circadian desynchronization, characterized by fatigue and health and performance decrement. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate this risk. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. The molecular clock consists of sets of proteins that perform different functions within the clock machinery: circadian oscillators (genes whose expression levels cycle during the day, keep the pass of cellular time and regulate downstream effector genes), the effector or output genes (those which impact the physiology of the tissue or organism), and the input genes (responsible for sensing the environmental cues that allow circadian entrainment). The main environmental cue is light. As opposed to the known photoreceptors (rods and cones), the non-visual light stimulus is received by a subset of the population of retinal ganglion cells called intrinsically photosensitive retinal ganglion cells (ipRGC) that express melanopsin (opsin 4 -Opn4-) as the photoreceptor. We hypothesize that spaceflight may affect ipRGC and melanopsin expression, which may be a contributing cause of circadian disruption during spaceflight. To answer this question, eyes from albino Balb/cJ mice aboard STS-133 were collected for histological analysis and gene expression profiling of the retina at 1 and 7 days after landing. Both vivarium and AEM (animal enclosure module) mice were used as ground controls. Opn4 expression was analyzed by real time RT/qPCR and retinal sections were stained for Opn4

  5. A theoretical study of the molecular mechanism of the GAPDH Trypanosoma cruzi enzyme involving iodoacetate inhibitor

    NASA Astrophysics Data System (ADS)

    Carneiro, Agnaldo Silva; Lameira, Jerônimo; Alves, Cláudio Nahum

    2011-10-01

    The glyceraldehyde-3-phosphate dehydrogenase enzyme (GAPDH) is an important biological target for the development of new chemotherapeutic agents against Chagas disease. In this Letter, the inhibition mechanism of GAPDH involving iodoacetate (IAA) inhibitor was studied using the hybrid quantum mechanical/molecular mechanical (QM/MM) approach and molecular dynamic simulations. Analysis of the potential energy surface and potential of mean force show that the covalent attachment of IAA inhibitor to the active site of the enzyme occurs as a concerted process. In addition, the energy terms decomposition shows that NAD+ plays an important role in stabilization of the reagents and transition state.

  6. [Molecular mechanism at the presynaptic active zone].

    PubMed

    Ohtsuka, Toshihisa

    2011-07-01

    Our higher brain functions such as learning and memory, emotion, and consciousness depend on the precise regulation of complicated neural networks in the brain. Neurons communicate with each other through the synapse, which comprise 3 regions: the presynapse, synaptic cleft, and postsynapse. The active zone (AZ) beneath the presynaptic membrane is the principal site for Ca2+ -dependent neurotransmitter release: AZ is involved in determining the site for docking and synaptic vesicle fusion. Presently, the full molecular composition of AZ is unclear, but it is known to contain several AZ-specific proteins, including cytomatrix of the active zone-associated protein (CAST)/ERC2, ELKS, RIM1, Munc13-1, Piccolo/Aczonin, and Bassoon. CAST and ELKS are novel active zone proteins that directly bind to Rab3-interacting molecules (RIMs), Bassoon, and Piccolo, and are thought to play a role in neurotransmitter release by binding these to AZ proteins. In this review, current advances in studies on AZ structure and function have been summarized, and the focus is mainly on protein-protein interactions among the AZ proteins.

  7. Ultraviolet radiation and skin cancer: molecular mechanisms.

    PubMed

    Hussein, Mahmoud R

    2005-03-01

    Every living organism on the surface of the earth is exposed to the ultraviolet (UV) fraction of the sunlight. This electromagnetic energy has both life-giving and life-endangering effects. UV radiation can damage DNA and thus mutagenize several genes involved in the development of the skin cancer. The presence of typical signature of UV-induced mutations on these genes indicates that the ultraviolet-B part of sunlight is responsible for the evolution of cutaneous carcinogenesis. During this process, variable alterations of the oncogenic, tumor-suppressive, and cell-cycle control signaling pathways occur. These pathways include (a) mutated PTCH (in the mitogenic Sonic Hedgehog pathway) and mutated p53 tumor-suppressor gene in basal cell carcinomas, (b) an activated mitogenic ras pathway and mutated p53 in squamous cell carcinomas, and (c) an activated ras pathway, inactive p16, and p53 tumor suppressors in melanomas. This review presents background information about the skin optics, UV radiation, and molecular events involved in photocarcinogenesis.

  8. Dissecting the Molecular Mechanisms of Electrotactic Effects

    PubMed Central

    Bonazzi, Daria; Minc, Nicolas

    2014-01-01

    Significance: Steady electric fields (EFs) surround cells and tissues in vivo and may regulate cellular behavior during development, wound healing, or tissue regeneration. Application of exogenous EFs of similar magnitude as those found in vivo can direct migration, growth, and division in most cell types, ranging from bacteria to mammalian cells. These EF effects have therapeutic potential, for instance, in accelerating wound healing or improving nerve repair. EFs are thought to signal through the plasma membrane to locally activate or recruit components of the cytoskeleton and the polarity machinery. How EFs might function to steer polarity is, however, poorly understood at a molecular level. Recent Advances: Here, we review recent work introducing genetically tractable systems, such as yeast and Dictyostelium cells, that begin to identify proteins and pathways involved in this response both at the level of ion transport at the membrane and at the level of cytoskeleton regulation. Critical Issues: These studies highlight the complexity of these EF effects and bring important novel views on core polarity regulation. Future Directions: Future work pursuing initial screening in model organisms should generate broad mechanistic understanding of electrotactic effects. PMID:24761354

  9. Multiple Sclerosis: Molecular Mechanisms and Therapeutic Opportunities

    PubMed Central

    Miljković, Djordje; Spasojević, Ivan

    2013-01-01

    Abstract The pathophysiology of multiple sclerosis (MS) involves several components: redox, inflammatory/autoimmune, vascular, and neurodegenerative. All of them are supported by the intertwined lines of evidence, and none of them should be written off. However, the exact mechanisms of MS initiation, its development, and progression are still elusive, despite the impressive pace by which the data on MS are accumulating. In this review, we will try to integrate the current facts and concepts, focusing on the role of redox changes and various reactive species in MS. Knowing the schedule of initial changes in pathogenic factors and the key turning points, as well as understanding the redox processes involved in MS pathogenesis is the way to enable MS prevention, early treatment, and the development of therapies that target specific pathophysiological components of the heterogeneous mechanisms of MS, which could alleviate the symptoms and hopefully stop MS. Pertinent to this, we will outline (i) redox processes involved in MS initiation; (ii) the role of reactive species in inflammation; (iii) prooxidative changes responsible for neurodegeneration; and (iv) the potential of antioxidative therapy. Antioxid. Redox Signal. 19, 2286–2334. PMID:23473637

  10. Membrane curvature in cell biology: An integration of molecular mechanisms.

    PubMed

    Jarsch, Iris K; Daste, Frederic; Gallop, Jennifer L

    2016-08-15

    Curving biological membranes establishes the complex architecture of the cell and mediates membrane traffic to control flux through subcellular compartments. Common molecular mechanisms for bending membranes are evident in different cell biological contexts across eukaryotic phyla. These mechanisms can be intrinsic to the membrane bilayer (either the lipid or protein components) or can be brought about by extrinsic factors, including the cytoskeleton. Here, we review examples of membrane curvature generation in animals, fungi, and plants. We showcase the molecular mechanisms involved and how they collaborate and go on to highlight contexts of curvature that are exciting areas of future research. Lessons from how membranes are bent in yeast and mammals give hints as to the molecular mechanisms we expect to see used by plants and protists.

  11. Membrane curvature in cell biology: An integration of molecular mechanisms.

    PubMed

    Jarsch, Iris K; Daste, Frederic; Gallop, Jennifer L

    2016-08-15

    Curving biological membranes establishes the complex architecture of the cell and mediates membrane traffic to control flux through subcellular compartments. Common molecular mechanisms for bending membranes are evident in different cell biological contexts across eukaryotic phyla. These mechanisms can be intrinsic to the membrane bilayer (either the lipid or protein components) or can be brought about by extrinsic factors, including the cytoskeleton. Here, we review examples of membrane curvature generation in animals, fungi, and plants. We showcase the molecular mechanisms involved and how they collaborate and go on to highlight contexts of curvature that are exciting areas of future research. Lessons from how membranes are bent in yeast and mammals give hints as to the molecular mechanisms we expect to see used by plants and protists. PMID:27528656

  12. Molecular Mechanisms of Circadian Regulation During Spaceflight

    NASA Technical Reports Server (NTRS)

    Zanello, S. B.; Boyle, R.

    2012-01-01

    The physiology of both vertebrates and invertebrates follows internal rhythms coordinated in phase with the 24-hour daily light cycle. This circadian clock is governed by a central pacemaker, the suprachiasmatic nucleus (SCN) in the brain. However, peripheral circadian clocks or oscillators have been identified in most tissues. How the central and peripheral oscillators are synchronized is still being elucidated. Light is the main environmental cue that entrains the circadian clock. Under the absence of a light stimulus, the clock continues its oscillation in a free-running condition. In general, three functional compartments of the circadian clock are defined. The vertebrate retina contains endogenous clocks that control many aspects of retinal physiology, including retinal sensitivity to light, neurohormone synthesis (melatonin and dopamine), rod disk shedding, signalling pathways and gene expression. Neurons with putative local circadian rhythm generation are found among all the major neuron populations in the mammalian retina. In the mouse, clock genes and function are more localized to the inner retinal and ganglion cell layers. The photoreceptor, however, secrete melatonin which may still serve a an important circadian signal. The reception and transmission of the non-visual photic stimulus resides in a small subpopulation (1-3%) or retinal ganglion cells (RGC) that express the pigment melanopsin (Opn4) and are called intrisically photoreceptive RGC (ipRGC). Melanopsin peak absorption is at 420 nm and all the axons of the ipRGC reach the SCN. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate the risk of fatigue and health and performance decrement due to circadian rhythm disruption. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. We hypothesize that spaceflight may affect ip

  13. Photodynamic therapy: Biophysical mechanisms and molecular responses

    NASA Astrophysics Data System (ADS)

    Mitra, Soumya

    In photodynamic therapy (PDT), photochemical reactions induced by optical activation of sensitizer molecules cause destruction of the target tissue. In this thesis we present results of several related studies, which investigated the influence of photophysical properties and photobleaching mechanisms of sensitizers and oxygen-dependent tissue optical properties on PDT treatment efficacy. The bleaching mechanism of the sensitizer meso-tetra hydroxyphenyl chlorin (mTHPC) is examined indirectly using measurements of photochemical oxygen consumption during PDT irradiation of multicell tumor spheroids. Analysis of the results with a theoretical model of oxygen diffusion that incorporates the effects of sensitizer photobleaching shows that mTHPC is degraded via a singlet-oxygen (1O2)-mediated bleaching process. The analysis allows us to extract photophysical parameters of mTHPC which are used to account for its enhanced clinical photodynamic potency in comparison to that of Photofrin. Evaluation of the spatially-resolved fluorescence in confocal optical sections of intact spheroids during PDT irradiation allows for the direct experimental verification of mTHPC's 1O2-mediated bleaching mechanism. The technique is also used to investigate the complex bleaching kinetics of Photofrin. The results allow us to successfully reconcile apparently contradictory experimental observations and to confirm the predictions of a new theoretical model in which both 1O2 and excited triplet sensitizer molecules are allowed to contribute to photobleaching. Based on studies performed in tissue-simulating erythrocyte phantoms and in a murine tumor model in vivo, we present clinically relevant results which indicate that a shift toward increased hemoglobin-oxygen saturation due to improved tissue oxygenation reduces PDT treatment beam attenuation and may allow for more effective treatment of deeper lesions. Finally, we investigate the induction of the stress protein, heat shock protein 70 (HSP

  14. MOLECULAR TARGETS AND MECHANISMS FOR ETHANOL ACTION IN GLYCINE RECEPTORS

    PubMed Central

    Perkins, Daya I.; Trudell, James R.; Crawford, Daniel K.; Alkana, Ronald L.; Davies, Daryl L.

    2010-01-01

    Glycine receptors (GlyRs) are recognized as the primary mediators of neuronal inhibition in the spinal cord, brain stem and higher brain regions known to be sensitive to ethanol. Building evidence supports the notion that ethanol acting on GlyRs causes at least a subset of its behavioral effects and may be involved in modulating ethanol intake. For over two decades, GlyRs have been studied at the molecular level as targets for ethanol action. Despite the advances in understanding the effects of ethanol in vivo and in vitro, the precise molecular sites and mechanisms of action for ethanol in ligand-gated ion channels in general, and in GlyRs specifically, are just now starting to become understood. The present review focuses on advances in our knowledge produced by using molecular biology, pressure antagonism, electrophysiology and molecular modeling strategies over the last two decades to probe, identify and model the initial molecular sites and mechanisms of ethanol action in GlyRs. The molecular targets on the GlyR are covered on a global perspective, which includes the intracellular, transmembrane and extracellular domains. The latter has received increasing attention in recent years. Recent molecular models of the sites of ethanol action in GlyRs and their implications to our understanding of possible mechanism of ethanol action and novel targets for drug development in GlyRs are discussed. PMID:20399807

  15. Molecular mechanisms of DAX1 action.

    PubMed

    Iyer, Anita K; McCabe, Edward R B

    2004-01-01

    DAX1 (dosage sensitive sex reversal (DSS), adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1) encoded by the gene NR0B1, is an unusual orphan nuclear receptor that when mutated causes AHC with associated hypogonadotropic hypogonadism (HH), and when duplicated causes DSS. DAX1 expression has been shown in all regions of the hypothalamic-pituitary-adrenal-gonadal (HPAG) axis during development and in adult tissues, suggesting a critical role for DAX1 in the normal development and function of this axis. Steroidogenic factor 1 (SF1, NR5A1) knockout mice show similar developmental defects as AHC and HH patients, but paradoxically, DAX1 is a negative coregulator of SF1 transactivation. The function of DAX1 as an antagonist of SF1 in gonadal development is consistent with the fact that in humans, duplication of the region of the X chromosome containing DAX1 causes a similar phenotype as mutations in SF1. However, how disruption of DAX1 leads to adrenal, hypothalamic, and pituitary developmental defects similar to SF1 disruption remains to be clarified. The exact mechanism of DAX1 action in each of these tissues during adulthood and critical stages of development are not fully understood. Recent evidence suggests a broader functional role for DAX1 as a negative coregulator of estrogen receptor (ER, NR3A1-2), liver receptor homologue-1 (LRH-1, NR5A2), androgen receptor (AR, NR3C4), and progesterone receptor (PR, NR3C3), each by distinct repression mechanisms. DAX1 may have pleiotropic roles in addition to its function as a negative regulator of steroidogenesis during the development and adult function of the HPAG axis.

  16. Molecular approach to intracellular cargo transport

    NASA Astrophysics Data System (ADS)

    Yildiz, Ahmet

    2010-03-01

    Landmark discoveries in the study of cytoplasmic motors have been made through advances in single molecule biophysics and detailed mechanistic models exist for kinesin and dynein. However, the function of motors in physiological conditions has not been carefully tested. In cells, more than few dyneins can attach to the same cargo and interact with the opposite polarity motors of kinesin. To study the molecular crosstalk between the motors, we have used intraflagellar transport (IFT) in Chlamydomonas reinhardtii as a model system. Ultrahigh spatio-temporal tracking of single cargo movement showed that IFT particles move for long distances unidirectionally with 8 nm increments, agreeing with measured step sizes of kinesin and dynein. To measure how many motors transport each cargo, we have linked large polystyrene beads to internal IFT particles through a transmembrane protein. Force measurements indicated that, on average, 3-4 motors transport cargoes in each direction. The results showed that IFT motors are tightly coordinated and might be involved in recycling each other to the appropriate end of the flagellum.

  17. Molecular approaches to treatments for cocaine abuse

    NASA Astrophysics Data System (ADS)

    Flippen-Anderson, Judith L.; George, Clifford; Deschamps, Jeffrey R.

    2003-02-01

    Cocaine is a potent stimulant of the central nervous system with severe addiction potential. Its abuse is a major problem worldwide. The exact mechanism of action of cocaine is still uncertain but it is known that its reinforcing and stimulant effects are related to its ability to inhibit the membrane bound dopamine transporter (DAT). This paper discusses efforts that are underway to identify ligands for possible use in the treatment of cocaine abuse. Much of this effort has been focussed on understanding cocaine interactions at DAT receptor sites.

  18. Free Energies of Chemical Reactions in Solution and in Enzymes with Ab Initio Quantum Mechanics/Molecular Mechanics Methods

    NASA Astrophysics Data System (ADS)

    Hu, Hao; Yang, Weitao

    2008-05-01

    Combined quantum mechanics/molecular mechanics (QM/MM) methods provide an accurate and efficient energetic description of complex chemical and biological systems, leading to significant advances in the understanding of chemical reactions in solution and in enzymes. Here we review progress in QM/MM methodology and applications, focusing on ab initio QM-based approaches. Ab initio QM/MM methods capitalize on the accuracy and reliability of the associated quantum-mechanical approaches, however, at a much higher computational cost compared with semiempirical quantum-mechanical approaches. Thus reaction-path and activation free-energy calculations based on ab initio QM/MM methods encounter unique challenges in simulation timescales and phase-space sampling. This review features recent developments overcoming these challenges and enabling accurate free-energy determination for reaction processes in solution and in enzymes, along with applications.

  19. Free energies of chemical reactions in solution and in enzymes with ab initio quantum mechanics/molecular mechanics methods.

    PubMed

    Hu, Hao; Yang, Weitao

    2008-01-01

    Combined quantum mechanics/molecular mechanics (QM/MM) methods provide an accurate and efficient energetic description of complex chemical and biological systems, leading to significant advances in the understanding of chemical reactions in solution and in enzymes. Here we review progress in QM/MM methodology and applications, focusing on ab initio QM-based approaches. Ab initio QM/MM methods capitalize on the accuracy and reliability of the associated quantum-mechanical approaches, however, at a much higher computational cost compared with semiempirical quantum-mechanical approaches. Thus reaction-path and activation free-energy calculations based on ab initio QM/MM methods encounter unique challenges in simulation timescales and phase-space sampling. This review features recent developments overcoming these challenges and enabling accurate free-energy determination for reaction processes in solution and in enzymes, along with applications.

  20. Molecular mechanisms of LRRK2 regulation

    NASA Astrophysics Data System (ADS)

    Webber, Philip Jeffrey

    Non-synonymous mutations in LRRK2 are the most common known cause of familial and sporadic Parkinson's disease (PD). The dominant inheritance of these mutations in familial PD suggests a gain-of-function mechanism. Increased kinase activity observed in the most common PD associated LRRK2 mutation G2019S suggests that kinase activity is central to disease. However, not all mutations associated with disease are reported to alter kinase activity and controversy exists in the literature about the effects of mutations appearing in the GTPase domain on kinase activity. The studies conducted as a part of this work aim to characterize the mechanisms that regulate LRRK2 kinase activity and the effects of mutations on enzymatic activity of LRRK2 protein. LRRK2 is a large protein with multiple predicted functional domains including two enzymatic domains in the same protein, the small ras-like GTPase domain and a serine-threonine protein kinase domain. Previous studies indicate that LRRK2 kinase is dependent on a functional GTPase domain and binding to GTP is required for kinase activity. Recent work detailed in this dissertation indicates a complex and reciprocal relationship between kinase and GTPase domains. LRRK2 kinase activity is dependent on adapting a homo-dimer that is augmented by PD mutations that increase LRRK2 kinase activity. Activated LRRK2 autophosphorylates the GTPase and c-terminus of Ras (COR) domains robustly. Phosphorylation of these domains is required for normal activity, as preventing autophosphorylation of these sites drastically lowers kinase activity and GTP binding while phosphorylation maintains baseline activity while still reducing GTP binding. Furthermore, we have developed antibodies specific to autophosphorylation residues that track with LRRK2 kinase activity in vitro. While no measurable activity was detected from treated LRRK2 in vivo, LRRK2 protein purified from brain tissue treated with inflammatory stimuli such as LPS, which increases

  1. Excited States and Photochemistry of Chromophores in the Photoactive Proteins Explored by the Combined Quantum Mechanical and Molecular Mechanical Calculations.

    PubMed

    Liu, Lihong; Cui, Ganglong; Fang, Wei-Hai

    2015-01-01

    A photoactive protein usually contains a unique chromophore that is responsible for the initial photoresponse and functions of the photoactive protein are determined by the interaction between the chromophore and its protein surroundings. The combined quantum mechanical and molecular mechanical (QM/MM) approach is demonstrated to be a very useful tool for exploring structures and functions of a photoactive protein with the chromophore and its protein surroundings treated by the QM and MM methods, respectively. In this review, we summarize the basic formulas of the QM/MM approach and emphasize its applications to excited states and photoreactions of chromophores in rhodopsin protein, photoactive yellow protein, and green fluorescent protein. PMID:26415847

  2. Comparison of molecular mechanics, semi-empirical quantum mechanical, and density functional theory methods for scoring protein-ligand interactions.

    PubMed

    Yilmazer, Nusret Duygu; Korth, Martin

    2013-07-11

    Correctly ranking protein-ligand interactions with respect to overall free energy of binding is a grand challenge for virtual drug design. Here we compare the performance of various quantum chemical approaches for tackling this so-called "scoring" problem. Relying on systematically generated benchmark sets of large protein/ligand model complexes based on the PDBbind database, we show that the performance depends first of all on the general level of theory. Comparing classical molecular mechanics (MM), semiempirical quantum mechanical (SQM), and density functional theory (DFT) based methods, we find that enhanced SQM approaches perform very similar to DFT methods and substantially different from MM potentials.

  3. Comparison of molecular mechanics, semi-empirical quantum mechanical, and density functional theory methods for scoring protein-ligand interactions.

    PubMed

    Yilmazer, Nusret Duygu; Korth, Martin

    2013-07-11

    Correctly ranking protein-ligand interactions with respect to overall free energy of binding is a grand challenge for virtual drug design. Here we compare the performance of various quantum chemical approaches for tackling this so-called "scoring" problem. Relying on systematically generated benchmark sets of large protein/ligand model complexes based on the PDBbind database, we show that the performance depends first of all on the general level of theory. Comparing classical molecular mechanics (MM), semiempirical quantum mechanical (SQM), and density functional theory (DFT) based methods, we find that enhanced SQM approaches perform very similar to DFT methods and substantially different from MM potentials. PMID:23758433

  4. Molecular Mechanisms of Bacterial Mercury Transformation

    SciTech Connect

    smith, jeremy

    2014-04-15

    Mercury (Hg) is a major global pollutant arising from both natural and anthropogenic sources. Defining the factors that determine the relative affinities of different ligands for the mercuric ion, Hg2+, is critical to understanding its speciation, transformation, and bioaccumulation in the environment. Here, we used quantum chemistry to dissect the relative binding free energies for a series of inorganic anion complexes of Hg2+. The results show that, whereas in the gas phase the binding affinity of two identical anionic ligands (forming HgL2) increases with ligand (L–) hardness, in contrast, in the aqueous phase the affinity increases with ligand softness. This switch in affinity upon hydration is shown to result mostly from interactions with only a small number (e.g. one or two) of water molecules. The results yield a clear, robust periodic trend within the chalcogenide and halide groups and are in agreement with the well-known experimentally observed preference of Hg2+ for soft ligands. By comparing the Hg2+ binding of one with two anions, the gas phase preferences are found to arise from the enhancement of reactivity of the cationic complex (HgL+) with the hardness of L–. The approach establishes a theoretical basis for understanding Hg speciation in the biosphere.

  5. Molecular Mechanisms of α-Synuclein Neurodegeneration

    PubMed Central

    Waxman, Elisa A.; Giasson, Benoit I.

    2009-01-01

    α-Synuclein is an abundant highly charged protein that is normally predominantly localized around synaptic vesicles in presynatic terminals. Although the function of this protein is still ill-defined, genetic studies have demonstrated that point mutations or genetic alteration (duplications or triplications) that increase the number of copies of the α-synuclein (SCNA) gene can cause Parkinson’s disease or the related disorder dementia with Lewy bodies. α-Synuclein can aberrantly polymerize into fibrils with typical amyloid properties, and these fibrils are the major component of many types of pathological inclusions, including Lewy bodies, which are associated with neurodegenerative diseases, such as Parkinson’s disease. Genetic studies have clearly established that alteration in the α-synuclein gene can lead to neuronal demise. Although there is substantial evidence supporting the toxic nature of α-synuclein inclusions, other modes of toxicity such as oligomers have been proposed. In this review, some of the evidence for the different mechanisms of α-synuclein toxicity is presented and discussed. PMID:18955133

  6. Remarks on mechanical approach to observable Universe

    SciTech Connect

    Eingorn, Maxim; Zhuk, Alexander E-mail: ai.zhuk2@gmail.com

    2014-05-01

    We consider the Universe deep inside the cell of uniformity. At these scales, the Universe is filled with inhomogeneously distributed discrete structures (galaxies, groups and clusters of galaxies), which perturb the background Friedmann model. Here, the mechanical approach (Eingorn and Zhuk, 2012) is the most appropriate to describe the dynamics of the inhomogeneities which is defined, on the one hand, by gravitational potentials of inhomogeneities and, on the other hand, by the cosmological expansion of the Universe. In this paper, we present additional arguments in favor of this approach. First, we estimate the size of the cell of uniformity. With the help of the standard methods of statistical physics and for the galaxies of the type of the Milky Way and Andromeda, we get that it is of the order of 190 Mpc which is rather close to observations. Then, we show that the nonrelativistic approximation (with respect to the peculiar velocities) is valid for z∼<10, i.e. approximately for 13 billion years from the present moment. We consider scalar perturbations and, within the ΛCDM model, justify the main equations. Moreover, we demonstrate that radiation can be naturally incorporated into our scheme. This emphasizes the viability of our approach. This approach gives a possibility to analyze different cosmological models and compare them with the observable Universe. For example, we indicate some problematic aspects of the spatially flat models. Such models require a rather specific distribution of the inhomogeneities to get a finite potential at any points outside gravitating masses. We also criticize the application of the Schwarzschild-de Sitter solution to the description of the motion of test bodies on the cosmological background.

  7. Molecular mechanisms of dominant expression in porphyria.

    PubMed

    Badminton, M N; Elder, G H

    2005-01-01

    Partial deficiency of enzymes in the haem synthetic pathway gives rise to a group of seven inherited metabolic disorders, the porphyrias. Each deficiency is associated with a characteristic increase in haem precursors that correlates with the symptoms associated with individual porphyrias and allows accurate diagnosis. Two types of clinical presentation occur separately or in combination; acute life-threatening neurovisceral attacks and/or cutaneous symptoms. Five of the porphyrias are low-penetrance autosomal dominant conditions in which clinical expression results from additional factors that act by increasing demand for haem or by causing an additional decrease in enzyme activity or by a combination of these effects. These include both genetic and environmental factors. In familial porphyria cutanea tarda (PCTF), environmental factors that include alcohol, exogenous oestrogens and hepatotropic viruses result in inhibition of hepatic enzyme activity via a mechanism that involves excess iron accumulation. In erythropoietic protoporphyria (EPP), co-inheritance of a functional polymorphism in trans to a null ferrochelatase allele accounts for most clinically overt cases. In the autosomal dominant acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria), acute neurovisceral attacks occur in a minority of those who inherit one of these disorders. Although various exogenous (e.g. drugs, alcohol) and endogenous factors (e.g. hormones) have been identified as provoking acute attacks, these do not provide a full explanation for the low penetrance of these disorders. It seems probable that genetic background influences susceptibility to acute attacks, but the genes that are involved have not yet been identified.

  8. Frictional granular mechanics: A variational approach

    SciTech Connect

    Holtzman, R.; Silin, D.B.; Patzek, T.W.

    2009-10-16

    The mechanical properties of a cohesionless granular material are evaluated from grain-scale simulations. Intergranular interactions, including friction and sliding, are modeled by a set of contact rules based on the theories of Hertz, Mindlin, and Deresiewicz. A computer generated, three-dimensional, irregular pack of spherical grains is loaded by incremental displacement of its boundaries. Deformation is described by a sequence of static equilibrium configurations of the pack. A variational approach is employed to find the equilibrium configurations by minimizing the total work against the intergranular loads. Effective elastic moduli are evaluated from the intergranular forces and the deformation of the pack. Good agreement between the computed and measured moduli, achieved with no adjustment of material parameters, establishes the physical soundness of the proposed model.

  9. Molecular Targeted Approaches in Mantle Cell lymphoma.

    PubMed Central

    Weniger, Marc A.; Wiestner, Adrian

    2011-01-01

    Mantle cell lymphoma (MCL) is a malignancy of mature B cells characterized by the translocation t(11;14) that leads to aberrant expression of cyclin D1. Response to first-line chemotherapy is good but most patients relapse resulting in a median survival of 5-7 years. The important PI3K/AKT/mTOR pathway can be targeted with small molecules. mTOR inhibitors have clinical activity and temsirolimus has been approved in Europe. Second generation mTOR inhibitors and the PI3K inhibitor CAL-101 offer additional means to target the pathway. Promising results with the BTK inhibitor PCI-32765 suggest that B-cell receptor signaling could play a role. For unknown reasons, MCL appears to be particularly sensitive to disruption of protein homeostasis. The proteasome inhibitor bortezomib achieves responses in up to 50% of relapsed patients. Much work has been done in elucidating the mechanism of its cytotoxicity, its incorporation into combination therapies, and the development of second generation proteasome inhibitors. Deacetylase and HSP90 inhibitors are also promising classes of drugs that can synergize with proteasome inhibitors. Finally, BH3 mimetics are emerging as tools to sensitize tumor cells to chemotherapy. Participation in clinical trials offers patients an immediate chance to benefit from these advances and is essential to maintain the momentum of progress. PMID:21782064

  10. Molecular mechanisms responsible for formation of Golgi ribbon.

    PubMed

    Mironov, Alexander A; Beznoussenko, Galina V

    2011-01-01

    The formation of the Golgi ribbon takes place in protists and metazoans. It is especially prominent in mammalian cells during interphase. Golgi ribbon formation represents an orchestrated sequence of events based not only on different molecular mechanisms but also on discrete cellular functions. Mechanisms responsible for the generation of the Golgi ribbon include Golgi centralization, cis- and trans-Golgins, molecular machines responsible for the fusion of cargo domains with cisternal rims, and several other less studied factors. Here, we substantiate the hypothesis that cis-Golgins function mostly not as tethering factors, but are responsible for the attachment of the cis-most cisternae to the medial Golgi stacks, whereas trans-Golgins are responsible for the attachment of the trans-most cisterna to the medial Golgi stacks. This hypothesis is tested analyzing predictions derived from it and related to molecular mechanisms responsible for mitotic fragmentation of Golgi stacks.

  11. Molecular and Physiological Mechanisms of Membrane Receptor Systems Functioning

    PubMed Central

    Severin, E.S.; Savvateeva, M.V.

    2011-01-01

    Molecular physiology is a new interdisciplinary field of knowledge that looks into how complicated biological systems function. The living cell is a relatively simple, but at the same time very sophisticated biological system. After the sequencing of the human genome, molecular physiology has endeavored to investigate the systems of cellular interactions at a completely new level based on knowledge of the spatial organization and functions of receptors, their ligands, and protein-protein interactions. In recent years, the achievements in molecular physiology have centered on the study of sensor reception mechanisms and intercellular data transfer, as well as the immune system physiology, amongst other processes. PMID:22649671

  12. A Resonance Approach to Cochlear Mechanics

    PubMed Central

    Bell, Andrew

    2012-01-01

    Background How does the cochlea analyse sound into its component frequencies? In the 1850s Helmholtz thought it occurred by resonance, whereas a century later Békésy's work indicated a travelling wave. The latter answer seemed to settle the question, but with the discovery in 1978 that the cochlea emits sound, the mechanics of the cochlea was back on the drawing board. Recent studies have raised questions about whether the travelling wave, as currently understood, is adequate to explain observations. Approach Applying basic resonance principles, this paper revisits the question. A graded bank of harmonic oscillators with cochlear-like frequencies and quality factors is simultaneously excited, and it is found that resonance gives rise to similar frequency responses, group delays, and travelling wave velocities as observed by experiment. The overall effect of the group delay gradient is to produce a decelerating wave of peak displacement moving from base to apex at characteristic travelling wave speeds. The extensive literature on chains of coupled oscillators is considered, and the occurrence of travelling waves, pseudowaves, phase plateaus, and forced resonance in such systems is noted. Conclusion and significance This alternative approach to cochlear mechanics shows that a travelling wave can simply arise as an apparently moving amplitude peak which passes along a bank of resonators without carrying energy. This highlights the possible role of the fast pressure wave and indicates how phase delays and group delays of a set of driven harmonic oscillators can generate an apparent travelling wave. It is possible to view the cochlea as a chain of globally forced coupled oscillators, and this model incorporates fundamental aspects of both the resonance and travelling wave theories. PMID:23144835

  13. Molecular deformation mechanisms of the wood cell wall material.

    PubMed

    Jin, Kai; Qin, Zhao; Buehler, Markus J

    2015-02-01

    Wood is a biological material with outstanding mechanical properties resulting from its hierarchical structure across different scales. Although earlier work has shown that the cellular structure of wood is a key factor that renders it excellent mechanical properties at light weight, the mechanical properties of the wood cell wall material itself still needs to be understood comprehensively. The wood cell wall material features a fiber reinforced composite structure, where cellulose fibrils act as stiff fibers, and hemicellulose and lignin molecules act as soft matrix. The angle between the fiber direction and the loading direction has been found to be the key factor controlling the mechanical properties. However, how the interactions between theses constitutive molecules contribute to the overall properties is still unclear, although the shearing between fibers has been proposed as a primary deformation mechanism. Here we report a molecular model of the wood cell wall material with atomistic resolution, used to assess the mechanical behavior under shear loading in order to understand the deformation mechanisms at the molecular level. The model includes an explicit description of cellulose crystals, hemicellulose, as well as lignin molecules arranged in a layered nanocomposite. The results obtained using this model show that the wood cell wall material under shear loading deforms in an elastic and then plastic manner. The plastic regime can be divided into two parts according to the different deformation mechanisms: yielding of the matrix and sliding of matrix along the cellulose surface. Our molecular dynamics study provides insights of the mechanical behavior of wood cell wall material at the molecular level, and paves a way for the multi-scale understanding of the mechanical properties of wood.

  14. A quantum-mechanics molecular-mechanics scheme for extended systems.

    PubMed

    Hunt, Diego; Sanchez, Veronica M; Scherlis, Damián A

    2016-08-24

    We introduce and discuss a hybrid quantum-mechanics molecular-mechanics (QM-MM) approach for Car-Parrinello DFT simulations with pseudopotentials and planewaves basis, designed for the treatment of periodic systems. In this implementation the MM atoms are considered as additional QM ions having fractional charges of either sign, which provides conceptual and computational simplicity by exploiting the machinery already existing in planewave codes to deal with electrostatics in periodic boundary conditions. With this strategy, both the QM and MM regions are contained in the same supercell, which determines the periodicity for the whole system. Thus, while this method is not meant to compete with non-periodic QM-MM schemes able to handle extremely large but finite MM regions, it is shown that for periodic systems of a few hundred atoms, our approach provides substantial savings in computational times by treating classically a fraction of the particles. The performance and accuracy of the method is assessed through the study of energetic, structural, and dynamical aspects of the water dimer and of the aqueous bulk phase. Finally, the QM-MM scheme is applied to the computation of the vibrational spectra of water layers adsorbed at the TiO2 anatase (1 0 1) solid-liquid interface. This investigation suggests that the inclusion of a second monolayer of H2O molecules is sufficient to induce on the first adsorbed layer, a vibrational dynamics similar to that taking place in the presence of an aqueous environment. The present QM-MM scheme appears as a very interesting tool to efficiently perform molecular dynamics simulations of complex condensed matter systems, from solutions to nanoconfined fluids to different kind of interfaces.

  15. A quantum-mechanics molecular-mechanics scheme for extended systems

    NASA Astrophysics Data System (ADS)

    Hunt, Diego; Sanchez, Veronica M.; Scherlis, Damián A.

    2016-08-01

    We introduce and discuss a hybrid quantum-mechanics molecular-mechanics (QM-MM) approach for Car–Parrinello DFT simulations with pseudopotentials and planewaves basis, designed for the treatment of periodic systems. In this implementation the MM atoms are considered as additional QM ions having fractional charges of either sign, which provides conceptual and computational simplicity by exploiting the machinery already existing in planewave codes to deal with electrostatics in periodic boundary conditions. With this strategy, both the QM and MM regions are contained in the same supercell, which determines the periodicity for the whole system. Thus, while this method is not meant to compete with non-periodic QM-MM schemes able to handle extremely large but finite MM regions, it is shown that for periodic systems of a few hundred atoms, our approach provides substantial savings in computational times by treating classically a fraction of the particles. The performance and accuracy of the method is assessed through the study of energetic, structural, and dynamical aspects of the water dimer and of the aqueous bulk phase. Finally, the QM-MM scheme is applied to the computation of the vibrational spectra of water layers adsorbed at the TiO2 anatase (1 0 1) solid–liquid interface. This investigation suggests that the inclusion of a second monolayer of H2O molecules is sufficient to induce on the first adsorbed layer, a vibrational dynamics similar to that taking place in the presence of an aqueous environment. The present QM-MM scheme appears as a very interesting tool to efficiently perform molecular dynamics simulations of complex condensed matter systems, from solutions to nanoconfined fluids to different kind of interfaces.

  16. A quantum-mechanics molecular-mechanics scheme for extended systems

    NASA Astrophysics Data System (ADS)

    Hunt, Diego; Sanchez, Veronica M.; Scherlis, Damián A.

    2016-08-01

    We introduce and discuss a hybrid quantum-mechanics molecular-mechanics (QM-MM) approach for Car-Parrinello DFT simulations with pseudopotentials and planewaves basis, designed for the treatment of periodic systems. In this implementation the MM atoms are considered as additional QM ions having fractional charges of either sign, which provides conceptual and computational simplicity by exploiting the machinery already existing in planewave codes to deal with electrostatics in periodic boundary conditions. With this strategy, both the QM and MM regions are contained in the same supercell, which determines the periodicity for the whole system. Thus, while this method is not meant to compete with non-periodic QM-MM schemes able to handle extremely large but finite MM regions, it is shown that for periodic systems of a few hundred atoms, our approach provides substantial savings in computational times by treating classically a fraction of the particles. The performance and accuracy of the method is assessed through the study of energetic, structural, and dynamical aspects of the water dimer and of the aqueous bulk phase. Finally, the QM-MM scheme is applied to the computation of the vibrational spectra of water layers adsorbed at the TiO2 anatase (1 0 1) solid-liquid interface. This investigation suggests that the inclusion of a second monolayer of H2O molecules is sufficient to induce on the first adsorbed layer, a vibrational dynamics similar to that taking place in the presence of an aqueous environment. The present QM-MM scheme appears as a very interesting tool to efficiently perform molecular dynamics simulations of complex condensed matter systems, from solutions to nanoconfined fluids to different kind of interfaces.

  17. A quantum-mechanics molecular-mechanics scheme for extended systems.

    PubMed

    Hunt, Diego; Sanchez, Veronica M; Scherlis, Damián A

    2016-08-24

    We introduce and discuss a hybrid quantum-mechanics molecular-mechanics (QM-MM) approach for Car-Parrinello DFT simulations with pseudopotentials and planewaves basis, designed for the treatment of periodic systems. In this implementation the MM atoms are considered as additional QM ions having fractional charges of either sign, which provides conceptual and computational simplicity by exploiting the machinery already existing in planewave codes to deal with electrostatics in periodic boundary conditions. With this strategy, both the QM and MM regions are contained in the same supercell, which determines the periodicity for the whole system. Thus, while this method is not meant to compete with non-periodic QM-MM schemes able to handle extremely large but finite MM regions, it is shown that for periodic systems of a few hundred atoms, our approach provides substantial savings in computational times by treating classically a fraction of the particles. The performance and accuracy of the method is assessed through the study of energetic, structural, and dynamical aspects of the water dimer and of the aqueous bulk phase. Finally, the QM-MM scheme is applied to the computation of the vibrational spectra of water layers adsorbed at the TiO2 anatase (1 0 1) solid-liquid interface. This investigation suggests that the inclusion of a second monolayer of H2O molecules is sufficient to induce on the first adsorbed layer, a vibrational dynamics similar to that taking place in the presence of an aqueous environment. The present QM-MM scheme appears as a very interesting tool to efficiently perform molecular dynamics simulations of complex condensed matter systems, from solutions to nanoconfined fluids to different kind of interfaces. PMID:27352028

  18. Reaction Mechanism of Mycobacterium Tuberculosis Glutamine Synthetase Using Quantum Mechanics/Molecular Mechanics Calculations.

    PubMed

    Moreira, Cátia; Ramos, Maria J; Fernandes, Pedro Alexandrino

    2016-06-27

    This paper is devoted to the understanding of the reaction mechanism of mycobacterium tuberculosis glutamine synthetase (mtGS) with atomic detail, using computational quantum mechanics/molecular mechanics (QM/MM) methods at the ONIOM M06-D3/6-311++G(2d,2p):ff99SB//B3LYP/6-31G(d):ff99SB level of theory. The complete reaction undergoes a three-step mechanism: the spontaneous transfer of phosphate from ATP to glutamate upon ammonium binding (ammonium quickly loses a proton to Asp54), the attack of ammonia on phosphorylated glutamate (yielding protonated glutamine), and the deprotonation of glutamine by the leaving phosphate. This exothermic reaction has an activation free energy of 21.5 kcal mol(-1) , which is consistent with that described for Escherichia coli glutamine synthetase (15-17 kcal mol(-1) ). The participating active site residues have been identified and their role and energy contributions clarified. This study provides an insightful atomic description of the biosynthetic reaction that takes place in this enzyme, opening doors for more accurate studies for developing new anti-tuberculosis therapies.

  19. Reaction Mechanism of Mycobacterium Tuberculosis Glutamine Synthetase Using Quantum Mechanics/Molecular Mechanics Calculations.

    PubMed

    Moreira, Cátia; Ramos, Maria J; Fernandes, Pedro Alexandrino

    2016-06-27

    This paper is devoted to the understanding of the reaction mechanism of mycobacterium tuberculosis glutamine synthetase (mtGS) with atomic detail, using computational quantum mechanics/molecular mechanics (QM/MM) methods at the ONIOM M06-D3/6-311++G(2d,2p):ff99SB//B3LYP/6-31G(d):ff99SB level of theory. The complete reaction undergoes a three-step mechanism: the spontaneous transfer of phosphate from ATP to glutamate upon ammonium binding (ammonium quickly loses a proton to Asp54), the attack of ammonia on phosphorylated glutamate (yielding protonated glutamine), and the deprotonation of glutamine by the leaving phosphate. This exothermic reaction has an activation free energy of 21.5 kcal mol(-1) , which is consistent with that described for Escherichia coli glutamine synthetase (15-17 kcal mol(-1) ). The participating active site residues have been identified and their role and energy contributions clarified. This study provides an insightful atomic description of the biosynthetic reaction that takes place in this enzyme, opening doors for more accurate studies for developing new anti-tuberculosis therapies. PMID:27225077

  20. Molecular Mimicry as a Mechanism of Autoimmune Disease

    PubMed Central

    Cusick, Matthew F.; Libbey, Jane E.; Fujinami, Robert S.

    2012-01-01

    A variety of mechanisms have been suggested as the means by which infections can initiate and/or exacerbate autoimmune diseases. One mechanism is molecular mimicry, where a foreign antigen shares sequence or structural similarities with self-antigens. Molecular mimicry has typically been characterized on an antibody or T cell level. However, structural relatedness between pathogen and self does not account for T cell activation in a number of autoimmune diseases. A proposed mechanism that could have been misinterpreted for molecular mimicry is the expression of dual T cell receptors (TCR) on a single T cell. These T cells have dual reactivity to both foreign and self-antigens leaving the host vulnerable to foreign insults capable of triggering an autoimmune response. In this review, we briefly discuss what is known about molecular mimicry followed by a discussion of the current understanding of dual TCRs. Finally, we discuss three mechanisms, including molecular mimicry, dual TCRs and chimeric TCRs, by which dual reactivity of the T cell may play a role in autoimmune diseases. PMID:22095454

  1. Physiological and molecular biochemical mechanisms of bile formation

    PubMed Central

    Reshetnyak, Vasiliy Ivanovich

    2013-01-01

    This review considers the physiological and molecular biochemical mechanisms of bile formation. The composition of bile and structure of a bile canaliculus, biosynthesis and conjugation of bile acids, bile phospholipids, formation of bile micellar structures, and enterohepatic circulation of bile acids are described. In general, the review focuses on the molecular physiology of the transporting systems of the hepatocyte sinusoidal and apical membranes. Knowledge of physiological and biochemical basis of bile formation has implications for understanding the mechanisms of development of pathological processes, associated with diseases of the liver and biliary tract. PMID:24259965

  2. Final Report - Molecular Mechanisms of Bacterial Mercury Transformation - UCSF

    SciTech Connect

    Miller, Susan M.

    2014-04-24

    The bacterial mercury resistance (mer) operon functions in Hg biogeochemistry and bioremediation by converting reactive inorganic Hg(II) and organic [RHg(II)]1+ mercurials to relatively inert monoatomic mercury vapor, Hg(0). Its genes regulate operon expression (MerR, MerD, MerOP), import Hg(II) (MerT, MerP, and MerC), and demethylate (MerB) and reduce (MerA) mercurials. We focus on how these components interact with each other and with the host cell to allow cells to survive and detoxify Hg compounds. Understanding how this ubiquitous detoxification system fits into the biology and ecology of its bacterial host is essential to guide interventions that support and enhance Hg remediation. In the current overall project we focused on two aspects of this system: (1) investigations of the energetics of Hg(II)-ligand binding interactions, and (2) both experimental and computational approaches to investigating the molecular mechanisms of Hg(II) acquisition by MerA and intramolecular transfer of Hg(II) prior to reduction within the MerA enzyme active site. Computational work was led by Prof. Jeremy Smith and took place at the University of Tennessee, while experimental work on MerA was led by Prof. Susan Miller and took place at the University of California San Francisco.

  3. Lost in Transcription: Molecular Mechanisms that Control HIV Latency

    PubMed Central

    Taube, Ran; Peterlin, Boris Matija

    2013-01-01

    Highly active antiretroviral therapy (HAART) has limited the replication and spread of the human immunodeficiency virus (HIV). However, despite treatment, HIV infection persists in latently infected reservoirs, and once therapy is interrupted, viral replication rebounds quickly. Extensive efforts are being directed at eliminating these cell reservoirs. This feat can be achieved by reactivating latent HIV while administering drugs that prevent new rounds of infection and allow the immune system to clear the virus. However, current approaches to HIV eradication have not been effective. Moreover, as HIV latency is multifactorial, the significance of each of its molecular mechanisms is still under debate. Among these, transcriptional repression as a result of reduced levels and activity of the positive transcription elongation factor b (P-TEFb: CDK9/cyclin T) plays a significant role. Therefore, increasing levels of P-TEFb expression and activity is an excellent strategy to stimulate viral gene expression. This review summarizes the multiple steps that cause HIV to enter into latency. It positions the interplay between transcriptionally active and inactive host transcriptional activators and their viral partner Tat as valid targets for the development of new strategies to reactivate latent viral gene expression and eradicate HIV. PMID:23518577

  4. Molecular mechanisms of scar-sourced axon growth inhibitors

    PubMed Central

    Ohtake, Yosuke; Li, Shuxin

    2014-01-01

    Astrogliosis is a defense response of the CNS to minimize primary damage and to repair injured tissues, but it ultimately generates harmful effects by upregulating inhibitory molecules to suppress neuronal elongation and forming potent barriers to axon regeneration. Chondroitin sulfate proteoglycans (CSPGs) are highly expressed by reactive scars and are potent contributors to the non-permissive environment in mature CNS. Surmounting strong inhibition by CSPG-rich scar is an important therapeutic goal for achieving functional recovery after CNS injuries. Currently, enzymatic digestion of CSPGs with locally applied chondroitinase ABC is the main in vivo approach to overcome scar inhibition, but several disadvantages may prevent using this bacterial enzyme as a therapeutic option for patients. A better understanding of molecular mechanisms underlying CSPG function may facilitate development of new effective therapies to overcome scar-mediated inhibition. Previous studies support that CSPGs act by non-specifically hindering the binding of matrix molecules to their cell surface receptors through steric interactions, but two members of the leukocyte common antigen related (LAR) phosphatase subfamily, protein tyrosine phosphatase σ and LAR, are functional receptors that bind CSPGs with high affinity and mediate CSPG inhibition. CSPGs may also act by binding two receptors for myelin-associated growth inhibitors, Nogo receptors 1 and 3. Thus, CSPGs inhibit axon growth through multiple mechanisms, making them especially potent and difficult therapeutic targets. Identification of CSPG receptors is not only important for understanding the scar-mediated growth suppression, but also for developing novel and selective therapies to promote axon sprouting and/or regeneration after CNS injuries. PMID:25192646

  5. Molecular Mechanism of Acrylamide Neurotoxicity: Lessons Learned from Organic Chemistry

    PubMed Central

    Gavin, Terrence

    2012-01-01

    Background: Acrylamide (ACR) produces cumulative neurotoxicity in exposed humans and laboratory animals through a direct inhibitory effect on presynaptic function. Objectives: In this review, we delineate how knowledge of chemistry provided an unprecedented understanding of the ACR neurotoxic mechanism. We also show how application of the hard and soft, acids and bases (HSAB) theory led to the recognition that the α,β-unsaturated carbonyl structure of ACR is a soft electrophile that preferentially forms covalent bonds with soft nucleophiles. Methods: In vivo proteomic and in chemico studies demonstrated that ACR formed covalent adducts with highly nucleophilic cysteine thiolate groups located within active sites of presynaptic proteins. Additional research showed that resulting protein inactivation disrupted nerve terminal processes and impaired neurotransmission. Discussion: ACR is a type-2 alkene, a chemical class that includes structurally related electrophilic environmental pollutants (e.g., acrolein) and endogenous mediators of cellular oxidative stress (e.g., 4-hydroxy-2-nonenal). Members of this chemical family produce toxicity via a common molecular mechanism. Although individual environmental concentrations might not be toxicologically relevant, exposure to an ambient mixture of type-2 alkene pollutants could pose a significant risk to human health. Furthermore, environmentally derived type-2 alkenes might act synergistically with endogenously generated unsaturated aldehydes to amplify cellular damage and thereby accelerate human disease/injury processes that involve oxidative stress. Conclusions: These possibilities have substantial implications for environmental risk assessment and were realized through an understanding of ACR adduct chemistry. The approach delineated here can be broadly applied because many toxicants of different chemical classes are electrophiles that produce toxicity by interacting with cellular proteins. PMID:23060388

  6. Single-cell approaches for molecular classification of endocrine tumors

    PubMed Central

    Koh, James; Allbritton, Nancy L.; Sosa, Julie A.

    2015-01-01

    Purpose of review In this review, we summarize recent developments in single-cell technologies that can be employed for the functional and molecular classification of endocrine cells in normal and neoplastic tissue. Recent findings The emergence of new platforms for the isolation, analysis, and dynamic assessment of individual cell identity and reactive behavior enables experimental deconstruction of intratumoral heterogeneity and other contexts, where variability in cell signaling and biochemical responsiveness inform biological function and clinical presentation. These tools are particularly appropriate for examining and classifying endocrine neoplasias, as the clinical sequelae of these tumors are often driven by disrupted hormonal responsiveness secondary to compromised cell signaling. Single-cell methods allow for multidimensional experimental designs incorporating both spatial and temporal parameters with the capacity to probe dynamic cell signaling behaviors and kinetic response patterns dependent upon sequential agonist challenge. Summary Intratumoral heterogeneity in the provenance, composition, and biological activity of different forms of endocrine neoplasia presents a significant challenge for prognostic assessment. Single-cell technologies provide an array of powerful new approaches uniquely well suited for dissecting complex endocrine tumors. Studies examining the relationship between clinical behavior and tumor compositional variations in cellular activity are now possible, providing new opportunities to deconstruct the underlying mechanisms of endocrine neoplasia. PMID:26632769

  7. Molecular Approaches to Understand Nutritional Potential of Coarse Cereals.

    PubMed

    Singh, Amit Kumar; Singh, Rakesh; Subramani, Rajkumar; Kumar, Rajesh; Wankhede, Dhammaprakash P

    2016-06-01

    Coarse grains are important group of crops that constitutes staple food for large population residing primarily in the arid and semi-arid regions of the world. Coarse grains are designated as nutri-cereals as they are rich in essential amino acids, minerals and vitamins. In spite of having several nutritional virtues in coarse grain as mentioned above, there is still scope for improvement in quality parameters such as cooking qualities, modulation of nutritional constituents and reduction or elimination of anti-nutritional factors. Besides its use in traditional cooking, coarse grains have been used mainly in the weaning food preparation and other malted food production. Improvement in quality parameters will certainly increase consumer's preference for coarse grains and increase their demand. The overall genetic gain in quality traits of economic importance in the cultivated varieties will enhance their industrial value and simultaneously increase income of farmers growing these varieties. The urgent step for improvement of quality traits in coarse grains requires a detailed understanding of molecular mechanisms responsible for varied level of different nutritional contents in different genotypes of these crops. In this review we have discussed the progresses made in understanding of coarse grain biology with various omics tool coupled with modern breeding approaches and the current status with regard to our effort towards dissecting traits related to improvement of quality and nutritional constituents of grains. PMID:27252585

  8. Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation

    NASA Astrophysics Data System (ADS)

    Arosio, Paolo; Michaels, Thomas C. T.; Linse, Sara; Månsson, Cecilia; Emanuelsson, Cecilia; Presto, Jenny; Johansson, Jan; Vendruscolo, Michele; Dobson, Christopher M.; Knowles, Tuomas P. J.

    2016-03-01

    It is increasingly recognized that molecular chaperones play a key role in modulating the formation of amyloid fibrils, a process associated with a wide range of human disorders. Understanding the detailed mechanisms by which they perform this function, however, has been challenging because of the great complexity of the protein aggregation process itself. In this work, we build on a previous kinetic approach and develop a model that considers pairwise interactions between molecular chaperones and different protein species to identify the protein components targeted by the chaperones and the corresponding microscopic reaction steps that are inhibited. We show that these interactions conserve the topology of the unperturbed reaction network but modify the connectivity weights between the different microscopic steps. Moreover, by analysing several protein-molecular chaperone systems, we reveal the striking diversity in the microscopic mechanisms by which molecular chaperones act to suppress amyloid formation.

  9. Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation

    PubMed Central

    Arosio, Paolo; Michaels, Thomas C. T.; Linse, Sara; Månsson, Cecilia; Emanuelsson, Cecilia; Presto, Jenny; Johansson, Jan; Vendruscolo, Michele; Dobson, Christopher M.; Knowles, Tuomas P. J.

    2016-01-01

    It is increasingly recognized that molecular chaperones play a key role in modulating the formation of amyloid fibrils, a process associated with a wide range of human disorders. Understanding the detailed mechanisms by which they perform this function, however, has been challenging because of the great complexity of the protein aggregation process itself. In this work, we build on a previous kinetic approach and develop a model that considers pairwise interactions between molecular chaperones and different protein species to identify the protein components targeted by the chaperones and the corresponding microscopic reaction steps that are inhibited. We show that these interactions conserve the topology of the unperturbed reaction network but modify the connectivity weights between the different microscopic steps. Moreover, by analysing several protein-molecular chaperone systems, we reveal the striking diversity in the microscopic mechanisms by which molecular chaperones act to suppress amyloid formation. PMID:27009901

  10. Antigenic variation: Molecular and genetic mechanisms of relapsing disease

    SciTech Connect

    Cruse, J.M.; Lewis, R.E.

    1987-01-01

    This book contains 10 chapters. They are: Contemporary Concepts of Antigenic Variation; Antigenic Variation in the Influenza Viruses; Mechanisms of Escape of Visna Lentiviruses from Immunological Control; A Review of Antigenic Variation by the Equine Infectious Anemia Virus; Biologic and Molecular Variations in AIDS Retrovirus Isolates; Rabies Virus Infection: Genetic Mutations and the Impact on Viral Pathogenicity and Immunity; Immunobiology of Relapsing Fever; Antigenic Variation in African Trypanosomes; Antigenic Variation and Antigenic Diversity in Malaria; and Mechanisms of Immune Evasion in Schistosomiasis.

  11. Resveratrol and calcium signaling: molecular mechanisms and clinical relevance.

    PubMed

    McCalley, Audrey E; Kaja, Simon; Payne, Andrew J; Koulen, Peter

    2014-06-05

    Resveratrol is a naturally occurring compound contributing to cellular defense mechanisms in plants. Its use as a nutritional component and/or supplement in a number of diseases, disorders, and syndromes such as chronic diseases of the central nervous system, cancer, inflammatory diseases, diabetes, and cardiovascular diseases has prompted great interest in the underlying molecular mechanisms of action. The present review focuses on resveratrol, specifically its isomer trans-resveratrol, and its effects on intracellular calcium signaling mechanisms. As resveratrol's mechanisms of action are likely pleiotropic, its effects and interactions with key signaling proteins controlling cellular calcium homeostasis are reviewed and discussed. The clinical relevance of resveratrol's actions on excitable cells, transformed or cancer cells, immune cells and retinal pigment epithelial cells are contrasted with a review of the molecular mechanisms affecting calcium signaling proteins on the plasma membrane, cytoplasm, endoplasmic reticulum, and mitochondria. The present review emphasizes the correlation between molecular mechanisms of action that have recently been identified for resveratrol and their clinical implications.

  12. Molecular mechanism of bacterial type 1 and P pili assembly.

    PubMed

    Busch, Andreas; Phan, Gilles; Waksman, Gabriel

    2015-03-01

    The formation of adhesive surface structures called pili or fimbriae ('bacterial hair') is an important contributor towards bacterial pathogenicity and persistence. To fight often chronic or recurrent bacterial infections such as urinary tract infections, it is necessary to understand the molecular mechanism of the nanomachines assembling such pili. Here, we focus on the so far best-known pilus assembly machinery: the chaperone-usher pathway producing the type 1 and P pili, and highlight the most recently acquired structural knowledge. First, we describe the subunits' structure and the molecular role of the periplasmic chaperone. Second, we focus on the outer-membrane usher structure and the catalytic mechanism of usher-mediated pilus biogenesis. Finally, we describe how the detailed understanding of the chaperone-usher pathway at a molecular level has paved the way for the design of a new generation of bacterial inhibitors called 'pilicides'. PMID:25624519

  13. Resolving the molecular mechanism of cadherin catch bond formation

    SciTech Connect

    Manibog, Kristine; Li, Hui; Rakshit, Sabyasachi; Sivasankar, Sanjeevi

    2014-06-02

    Classical cadherin Ca(2+)-dependent cell-cell adhesion proteins play key roles in embryogenesis and in maintaining tissue integrity. Cadherins mediate robust adhesion by binding in multiple conformations. One of these adhesive states, called an X-dimer, forms catch bonds that strengthen and become longer lived in the presence of mechanical force. Here we use single-molecule force-clamp spectroscopy with an atomic force microscope along with molecular dynamics and steered molecular dynamics simulations to resolve the molecular mechanisms underlying catch bond formation and the role of Ca(2+) ions in this process. Our data suggest that tensile force bends the cadherin extracellular region such that they form long-lived, force-induced hydrogen bonds that lock X-dimers into tighter contact. When Ca(2+) concentration is decreased, fewer de novo hydrogen bonds are formed and catch bond formation is eliminated

  14. Mechanistic insights into Mg2+-independent prenylation by CloQ from classical molecular mechanics and hybrid quantum mechanics/molecular mechanics molecular dynamics simulations.

    PubMed

    Bayse, Craig A; Merz, Kenneth M

    2014-08-01

    Understanding the mechanism of prenyltransferases is important to the design of engineered proteins capable of synthesizing derivatives of naturally occurring therapeutic agents. CloQ is a Mg(2+)-independent aromatic prenyltransferase (APTase) that transfers a dimethylallyl group to 4-hydroxyphenylpyruvate in the biosynthetic pathway for clorobiocin. APTases consist of a common ABBA fold that defines a β-barrel containing the reaction cavity. Positively charged basic residues line the inside of the β-barrel of CloQ to activate the pyrophosphate leaving group to replace the function of the Mg(2+) cofactor in other APTases. Classical molecular dynamics simulations of CloQ, its E281G and F68S mutants, and the related NovQ were used to explore the binding of the 4-hydroxyphenylpyruvate (4HPP) and dimethylallyl diphosphate substrates in the reactive cavity and the role of various conserved residues. Hybrid quantum mechanics/molecular mechanics potential of mean force (PMF) calculations show that the effect of the replacement of the Mg(2+) cofactor with basic residues yields a similar activation barrier for prenylation to Mg(2+)-dependent APTases like NphB. The topology of the binding pocket for 4HPP is important for selective prenylation at the ortho position of the ring. Methylation at this position alters the conformation of the substrate for O-prenylation at the phenol group. Further, a two-dimensional PMF scan shows that a "reverse" prenylation product may be a possible target for protein engineering.

  15. Investigation of deformation mechanisms of staggered nanocomposites using molecular dynamics

    NASA Astrophysics Data System (ADS)

    Mathiazhagan, S.; Anup, S.

    2016-08-01

    Biological materials with nanostructure of regularly or stair-wise staggered arrangements of hard platelets reinforced in a soft protein matrix have superior mechanical properties. Applications of these nanostructures to ceramic matrix composites could enhance their toughness. Using molecular dynamics simulations, mechanical behaviour of the bio-inspired nanocomposites is studied. Regularly staggered model shows better flow behaviour compared to stair-wise staggered model due to the symmetrical crack propagation along the interface. Though higher stiffness and strength are obtained for stair-wise staggered models, rapid crack propagation reduces the toughness. Arresting this crack propagation could lead to superior mechanical properties in stair-wise staggered models.

  16. Molecular mechanisms of neuropathological changes in Alzheimer's disease: a review.

    PubMed

    Serý, Omar; Povová, Jana; Míšek, Ivan; Pešák, Lukáš; Janout, Vladimir

    2013-01-01

    More than 100 years after description of Alzheimer's disease (AD), two major pathological processes observed already by Alois Alzheimer, remain as the main explanation of the pathogenesis of Alzheimer's disease. Important molecular interactions leading to AD neuropathology were described in amyloid cascade and in tau protein function. No clinical trials with novel therapies based on amyloid cascade and tau protein hypotheses have been successful. The main aim of recent research is focused on the question what is primary mechanism leading to the molecular development of AD pathology. Promising explanation of triggering mechanism can be seen in vascular pathology that have direct influence on the development of pathological processes typical for Alzheimer disease. Novel insight into a number of cellular signaling mechanisms, as well as mitochondrial function in Alzheimer disease could also bring explanations of initial processes leading to the development of this pathology.

  17. Electron transport properties of single molecular junctions under mechanical modulations

    NASA Astrophysics Data System (ADS)

    Zhou, Jianfeng; Guo, Cunlan; Xu, Bingqian

    2012-04-01

    Electron transport behaviors of single molecular junctions are very sensitive to the atomic scale molecule-metal electrode contact interfaces, which have been difficult to control. We used a modified scanning probe microscope-break junction technique (SPM-BJT) to control the dynamics of the contacts and simultaneously monitor both the conductance and force. First, by fitting the measured data into a modified multiple tunneling barrier model, the static contact resistances, corresponding to the different contact conformations of single alkanedithiol and alkanediamine molecular junctions, were identified. Second, the changes of contact decay constant were measured under mechanical extensions of the molecular junctions, which helped to classify the different single molecular conductance sets into specific microscopic conformations of the molecule-electrode contacts. Third, by monitoring the changes of force and contact decay constant with the mechanical extensions, the changes of conductance were found to be caused by the changes of contact bond length and by the atomic reorganizations near the contact bond. This study provides a new insight into the understanding of the influences of contact conformations, especially the effect of changes of dynamic contact conformation on electron transport through single molecular junctions.

  18. Molecular mechanisms of peritoneal dissemination in gastric cancer

    PubMed Central

    Kanda, Mitsuro; Kodera, Yasuhiro

    2016-01-01

    Peritoneal dissemination represents a devastating form of gastric cancer (GC) progression with a dismal prognosis. There is no effective therapy for this condition. The 5-year survival rate of patients with peritoneal dissemination is 2%, even including patients with only microscopic free cancer cells without macroscopic peritoneal nodules. The mechanism of peritoneal dissemination of GC involves several steps: detachment of cancer cells from the primary tumor, survival in the free abdominal cavity, attachment to the distant peritoneum, invasion into the subperitoneal space and proliferation with angiogenesis. These steps are not mutually exclusive, and combinations of different molecular mechanisms can occur in each process of peritoneal dissemination. A comprehensive understanding of the molecular events involved in peritoneal dissemination is important and should be systematically pursued. It is crucial to identify novel strategies for the prevention of this condition and for identification of markers of prognosis and the development of molecular-targeted therapies. In this review, we provide an overview of recently published articles addressing the molecular mechanisms of peritoneal dissemination of GC to provide an update on what is currently known in this field and to propose novel promising candidates for use in diagnosis and as therapeutic targets. PMID:27570420

  19. Molecular mechanisms of peritoneal dissemination in gastric cancer.

    PubMed

    Kanda, Mitsuro; Kodera, Yasuhiro

    2016-08-14

    Peritoneal dissemination represents a devastating form of gastric cancer (GC) progression with a dismal prognosis. There is no effective therapy for this condition. The 5-year survival rate of patients with peritoneal dissemination is 2%, even including patients with only microscopic free cancer cells without macroscopic peritoneal nodules. The mechanism of peritoneal dissemination of GC involves several steps: detachment of cancer cells from the primary tumor, survival in the free abdominal cavity, attachment to the distant peritoneum, invasion into the subperitoneal space and proliferation with angiogenesis. These steps are not mutually exclusive, and combinations of different molecular mechanisms can occur in each process of peritoneal dissemination. A comprehensive understanding of the molecular events involved in peritoneal dissemination is important and should be systematically pursued. It is crucial to identify novel strategies for the prevention of this condition and for identification of markers of prognosis and the development of molecular-targeted therapies. In this review, we provide an overview of recently published articles addressing the molecular mechanisms of peritoneal dissemination of GC to provide an update on what is currently known in this field and to propose novel promising candidates for use in diagnosis and as therapeutic targets. PMID:27570420

  20. Chordoma: an update on the pathophysiology and molecular mechanisms.

    PubMed

    Sun, Xin; Hornicek, Francis; Schwab, Joseph H

    2015-12-01

    Chordoma is a rare low-grade primary malignant skeletal tumor, which is presumed to derive from notochord remnants. The pathogenesis of chordoma has not been fully elucidated. However, recent advances in the molecular biology studies have identified brachyury underlying the initiation and progression of chordoma cells. More efforts have been made on accumulating evidence of the notochordal origin of chordoma, discovering signaling pathways and identifying crucial targets in chordomagenesis. In this review, we summarize the most recent research findings and focus on the pathophysiology and molecular mechanisms of chordoma.

  1. A statistical mechanics approach to Granovetter theory

    NASA Astrophysics Data System (ADS)

    Barra, Adriano; Agliari, Elena

    2012-05-01

    In this paper we try to bridge breakthroughs in quantitative sociology/econometrics, pioneered during the last decades by Mac Fadden, Brock-Durlauf, Granovetter and Watts-Strogatz, by introducing a minimal model able to reproduce essentially all the features of social behavior highlighted by these authors. Our model relies on a pairwise Hamiltonian for decision-maker interactions which naturally extends the multi-populations approaches by shifting and biasing the pattern definitions of a Hopfield model of neural networks. Once introduced, the model is investigated through graph theory (to recover Granovetter and Watts-Strogatz results) and statistical mechanics (to recover Mac-Fadden and Brock-Durlauf results). Due to the internal symmetries of our model, the latter is obtained as the relaxation of a proper Markov process, allowing even to study its out-of-equilibrium properties. The method used to solve its equilibrium is an adaptation of the Hamilton-Jacobi technique recently introduced by Guerra in the spin-glass scenario and the picture obtained is the following: shifting the patterns from [-1,+1]→[0.+1] implies that the larger the amount of similarities among decision makers, the stronger their relative influence, and this is enough to explain both the different role of strong and weak ties in the social network as well as its small-world properties. As a result, imitative interaction strengths seem essentially a robust request (enough to break the gauge symmetry in the couplings), furthermore, this naturally leads to a discrete choice modelization when dealing with the external influences and to imitative behavior à la Curie-Weiss as the one introduced by Brock and Durlauf.

  2. Fractal Globules: A New Approach to Artificial Molecular Machines

    PubMed Central

    Avetisov, Vladik A.; Ivanov, Viktor A.; Meshkov, Dmitry A.; Nechaev, Sergei K.

    2014-01-01

    The over-damped relaxation of elastic networks constructed by contact maps of hierarchically folded fractal (crumpled) polymer globules was investigated in detail. It was found that the relaxation dynamics of an anisotropic fractal globule is very similar to the behavior of biological molecular machines like motor proteins. When it is perturbed, the system quickly relaxes to a low-dimensional manifold, M, with a large basin of attraction and then slowly approaches equilibrium, not escaping M. Taking these properties into account, it is suggested that fractal globules, even those made by synthetic polymers, are artificial molecular machines that can transform perturbations into directed quasimechanical motion along a defined path. PMID:25418305

  3. Fractal globules: a new approach to artificial molecular machines.

    PubMed

    Avetisov, Vladik A; Ivanov, Viktor A; Meshkov, Dmitry A; Nechaev, Sergei K

    2014-11-18

    The over-damped relaxation of elastic networks constructed by contact maps of hierarchically folded fractal (crumpled) polymer globules was investigated in detail. It was found that the relaxation dynamics of an anisotropic fractal globule is very similar to the behavior of biological molecular machines like motor proteins. When it is perturbed, the system quickly relaxes to a low-dimensional manifold, M, with a large basin of attraction and then slowly approaches equilibrium, not escaping M. Taking these properties into account, it is suggested that fractal globules, even those made by synthetic polymers, are artificial molecular machines that can transform perturbations into directed quasimechanical motion along a defined path. PMID:25418305

  4. Fractal globules: a new approach to artificial molecular machines.

    PubMed

    Avetisov, Vladik A; Ivanov, Viktor A; Meshkov, Dmitry A; Nechaev, Sergei K

    2014-11-18

    The over-damped relaxation of elastic networks constructed by contact maps of hierarchically folded fractal (crumpled) polymer globules was investigated in detail. It was found that the relaxation dynamics of an anisotropic fractal globule is very similar to the behavior of biological molecular machines like motor proteins. When it is perturbed, the system quickly relaxes to a low-dimensional manifold, M, with a large basin of attraction and then slowly approaches equilibrium, not escaping M. Taking these properties into account, it is suggested that fractal globules, even those made by synthetic polymers, are artificial molecular machines that can transform perturbations into directed quasimechanical motion along a defined path.

  5. Ab initio quantum chemical and mixed quantum mechanics/molecular mechanics (QM/MM) methods for studying enzymatic catalysis.

    PubMed

    Friesner, Richard A; Guallar, Victor

    2005-01-01

    We describe large scale ab initio quantum chemical and mixed quantum mechanics/molecular mechanics (QM/MM) methods for studying enzymatic reactions. First, technical aspects of the methodology are reviewed, including the hybrid density functional theory (DFT) methods that are typically employed for the QM aspect of the calculations, and various approaches to defining the interface between the QM and MM regions in QM/MM approaches. The modeling of the enzymatic catalytic cycle for three examples--methane monooxygenase, cytochrome P450, and triose phosphate isomerase--are discussed in some depth, followed by a brief summary of other systems that have been investigated by ab initio methods over the past several years. Finally, a discussion of the qualitative and quantitative conclusions concerning enzymatic catalysis that are available from modern ab initio approaches is presented, followed by a conclusion briefly summarizing future prospects.

  6. Molecularly guided therapy of neuroblastoma: a review of different approaches.

    PubMed

    Tonini, Gian Paolo; Pistoia, Vito

    2006-01-01

    Neuroblastoma (NB) is the most frequent extra-cranial solid tumor and the first cause of lethality in pre-school age children. NB accounts for 9-10% of pediatric tumors and affects more than ten thousand children a year. It originates from the sympathetic nervous system and is characterized by heterogeneous pathological and clinical presentation. Stage 4 NB represents approximately 50% of the cases and shows metastatic dissemination at onset; its prognosis is grim, with 20% of the patients surviving at 5 years from diagnosis in spite of aggressive chemotherapy with autologous hematopoietic stem cell support. Novel therapeutic strategies are urgently needed to improve the prognosis of stage 4 NB patients. Here we review the most promising approaches to NB treatment that have already reached clinical testing or have proved to be successful in preclinical models of the disease. All of these approaches are molecularly guided, since their rational development has benefited from the enormous amount of information on the biology of neuroblastoma gathered through molecular biology and genetics studies. The following topics are reviewed: MYCN oncogene amplification as parameter for therapeutic decision, minimal residual disease, immunotherapy, gene therapy, differentiation and apoptotic therapy, anti-angiogenic therapy, gene expression profiling as tool for generating novel therapeutic approaches. Although several efforts are still needed to reach a significant cure of patients with neuroblastoma, molecularly guided approaches have opened new ways to neuroblastoma treatment and can represent useful models for other cancers of either childhood or adulthood.

  7. Atomistic insight into the catalytic mechanism of glycosyltransferases by combined quantum mechanics/molecular mechanics (QM/MM) methods.

    PubMed

    Tvaroška, Igor

    2015-02-11

    Glycosyltransferases catalyze the formation of glycosidic bonds by assisting the transfer of a sugar residue from donors to specific acceptor molecules. Although structural and kinetic data have provided insight into mechanistic strategies employed by these enzymes, molecular modeling studies are essential for the understanding of glycosyltransferase catalyzed reactions at the atomistic level. For such modeling, combined quantum mechanics/molecular mechanics (QM/MM) methods have emerged as crucial. These methods allow the modeling of enzymatic reactions by using quantum mechanical methods for the calculation of the electronic structure of the active site models and treating the remaining enzyme environment by faster molecular mechanics methods. Herein, the application of QM/MM methods to glycosyltransferase catalyzed reactions is reviewed, and the insight from modeling of glycosyl transfer into the mechanisms and transition states structures of both inverting and retaining glycosyltransferases are discussed.

  8. Molecular Mechanisms of the Formation and Progression of Intracranial Aneurysms

    PubMed Central

    KATAOKA, Hiroharu

    2015-01-01

    Until recently, only a little was understood about molecular mechanisms of the development of an intracranial aneurysm (IA). Recent advancements over the last decade in the field of genetics and molecular biology have provided us a wide variety of evidences supporting the notion that chronic inflammation is closely associated with the pathogenesis of IA development. In the field of genetics, large-scale Genome-wide association studies (GWAS) has identified some IA susceptible loci and genes related to cell cycle and endothelial function. Researches in molecular biology using human samples and animal models have revealed the common pathway of the initiation, progression, and rupture of IAs. IA formation begins with endothelial dysfunction followed by pathological remodeling with degenerative changes of vascular walls. Medical treatments inhibiting inflammatory cascades in IA development are likely to prevent IA progression and rupture. Statins and aspirin are expected to suppress IA progression by their anti-inflammatory effects. Decoy oligodeoxynucleotides (ODNs) inhibiting inflammatory transcription factors such as nuclear factor kappa-B (NF-κB) and Ets-1 are the other promising choice of the prevention of IA development. Further clarification of molecular mechanisms of the formation and progression of IAs will shed light to the pathogenesis of IA development and provide insight into novel diagnostic and therapeutic strategies for IAs. PMID:25761423

  9. Molecular mechanisms of desiccation tolerance in resurrection plants.

    PubMed

    Gechev, Tsanko S; Dinakar, Challabathula; Benina, Maria; Toneva, Valentina; Bartels, Dorothea

    2012-10-01

    Resurrection plants are a small but diverse group of land plants characterized by their tolerance to extreme drought or desiccation. They have the unique ability to survive months to years without water, lose most of the free water in their vegetative tissues, fall into anabiosis, and, upon rewatering, quickly regain normal activity. Thus, they are fundamentally different from other drought-surviving plants such as succulents or ephemerals, which cope with drought by maintaining higher steady state water potential or via a short life cycle, respectively. This review describes the unique physiological and molecular adaptations of resurrection plants enabling them to withstand long periods of desiccation. The recent transcriptome analysis of Craterostigma plantagineum and Haberlea rhodopensis under drought, desiccation, and subsequent rehydration revealed common genetic pathways with other desiccation-tolerant species as well as unique genes that might contribute to the outstanding desiccation tolerance of the two resurrection species. While some of the molecular responses appear to be common for both drought stress and desiccation, resurrection plants also possess genes that are highly induced or repressed during desiccation with no apparent sequence homologies to genes of other species. Thus, resurrection plants are potential sources for gene discovery. Further proteome and metabolome analyses of the resurrection plants contributed to a better understanding of molecular mechanisms that are involved in surviving severe water loss. Understanding the cellular mechanisms of desiccation tolerance in this unique group of plants may enable future molecular improvement of drought tolerance in crop plants.

  10. Polycystic liver diseases: advanced insights into the molecular mechanisms.

    PubMed

    Perugorria, Maria J; Masyuk, Tatyana V; Marin, Jose J; Marzioni, Marco; Bujanda, Luis; LaRusso, Nicholas F; Banales, Jesus M

    2014-12-01

    Polycystic liver diseases are genetic disorders characterized by progressive bile duct dilatation and/or cyst development. The large volume of hepatic cysts causes different symptoms and complications such as abdominal distension, local pressure with back pain, hypertension, gastro-oesophageal reflux and dyspnea as well as bleeding, infection and rupture of the cysts. Current therapeutic strategies are based on surgical procedures and pharmacological management, which partially prevent or ameliorate the disease. However, as these treatments only show short-term and/or modest beneficial effects, liver transplantation is the only definitive therapy. Therefore, interest in understanding the molecular mechanisms involved in disease pathogenesis is increasing so that new targets for therapy can be identified. In this Review, the genetic mechanisms underlying polycystic liver diseases and the most relevant molecular pathways of hepatic cystogenesis are discussed. Moreover, the main clinical and preclinical studies are highlighted and future directions in basic as well as clinical research are indicated.

  11. Cellular and Molecular Mechanisms of Arrhythmia by Oxidative Stress

    PubMed Central

    Sovari, Ali A.

    2016-01-01

    Current therapies for arrhythmia using ion channel blockade, catheter ablation, or an implantable cardioverter defibrillator have limitations, and it is important to search for new antiarrhythmic therapeutic targets. Both atrial fibrillation and heart failure, a condition with increased arrhythmic risk, are associated with excess amount of reactive oxygen species (ROS). There are several possible ways for ROS to induce arrhythmia. ROS can cause focal activity and reentry. ROS alter multiple cardiac ionic currents. ROS promote cardiac fibrosis and impair gap junction function, resulting in reduced myocyte coupling and facilitation of reentry. In order to design effective antioxidant drugs for treatment of arrhythmia, it is essential to explore the molecular mechanisms by which ROS exert these arrhythmic effects. Activation of Ca2+/CaM-dependent kinase II, c-Src tyrosine kinase, protein kinase C, and abnormal splicing of cardiac sodium channels are among the recently discovered molecular mechanisms of ROS-induced arrhythmia. PMID:26981310

  12. Derivation of a Molecular Mechanics Force Field for Cholesterol

    SciTech Connect

    Cournia, Zoe; Vaiana, Andrea C.; Smith, Jeremy C.; Ullmann, G. Matthias M.

    2004-01-01

    As a necessary step toward realistic cholesterol:biomembrane simulations, we have derived CHARMM molecular mechanics force-field parameters for cholesterol. For the parametrization we use an automated method that involves fitting the molecular mechanics potential to both vibrational frequencies and eigenvector projections derived from quantum chemical calculations. Results for another polycyclic molecule, rhodamine 6G, are also given. The usefulness of the method is thus demonstrated by the use of reference data from two molecules at different levels of theory. The frequency-matching plots for both cholesterol and rhodamine 6G show overall agreement between the CHARMM and quantum chemical normal modes, with frequency matching for both molecules within the error range found in previous benchmark studies.

  13. [Molecular mechanisms of the plague pathogenic agent interaction with invertebrates].

    PubMed

    Kutyrev, V V; Eroshenko, G A; Popov, N V; Vidiaeva, N A; Konnov, N P

    2009-01-01

    Microbe Russian Anti-Plague Research Institute, Saratov, Russia The literature data and experimental results of the authors on the molecular basis of plague agent interaction with invertebrates are discussed. The details of the plague agent life cycle, its genome organization, and molecular genetic mechanisms of its survival in flea vector and on the nematode cuticule are discussed. The experimental data about the ability to form biofilms at abiotic and biotic surfaces in the Yersinia pestis strains of the main and non-main subspecies are presented. Mechanisms of horizontal and vertical transmission of plague agent are considered. The suggestion about participation of the new member in the complex parasitic biocenosis (nematode, vector parasite) is put forward. PMID:20050160

  14. Some Fundamental Molecular Mechanisms of Contractility in Fibrous Macromolecules

    PubMed Central

    Mandelkern, L.

    1967-01-01

    The fundamental molecular mechanisms of contractility and tension development in fibrous macromolecules are developed from the point of view of the principles of polymer physical chemistry. The problem is treated in a general manner to encompass the behavior of all macromolecular systems irrespective of their detailed chemical structure and particular function, if any. Primary attention is given to the contractile process which accompanies the crystal-liquid transition in axially oriented macromolecular systems. The theoretical nature of the process is discussed, and many experimental examples are given from the literature which demonstrate the expected behavior. Experimental attention is focused on the contraction of fibrous proteins, and the same underlying molecular mechanism is shown to be operative for a variety of different systems. PMID:6050598

  15. Engineering molecular mechanics: an efficient static high temperature molecular simulation technique.

    PubMed

    Subramaniyan, Arun K; Sun, C T

    2008-07-16

    Inspired by the need for an efficient molecular simulation technique, we have developed engineering molecular mechanics (EMM) as an alternative molecular simulation technique to model high temperature (T>0 K) phenomena. EMM simulations are significantly more computationally efficient than conventional techniques such as molecular dynamics simulations. The advantage of EMM is achieved by converting the dynamic atomistic system at high temperature (T>0 K) into an equivalent static system. Fundamentals of the EMM methodology are derived using thermal expansion to modify the interatomic potential. Temperature dependent interatomic potentials are developed to account for the temperature effect. The efficiency of EMM simulations is demonstrated by simulating the temperature dependence of elastic constants of copper and nickel and the thermal stress developed in a confined copper system.

  16. Molecular simulation of the reversible mechanical unfolding of proteins.

    PubMed

    Rathore, Nitin; Yan, Qiliang; de Pablo, Juan J

    2004-03-22

    In this work we have combined a Wang-Landau sampling scheme [F. Wang and D. Landau, Phys. Rev. Lett. 86, 2050 (2001)] with an expanded ensemble formalism to yield a simple and powerful method for computing potentials of mean force. The new method is implemented to investigate the mechanical deformation of proteins. Comparisons are made with analytical results for simple model systems such as harmonic springs and Rouse chains. The method is then illustrated on a model 15-residue alanine molecule in an implicit solvent. Results for mechanical unfolding of this oligopeptide are compared to those of steered molecular dynamics calculations.

  17. The molecular mechanisms of acquired proteasome inhibitor resistance

    PubMed Central

    Kale, Andrew J.; Moore, Bradley S.

    2012-01-01

    The development of proteasome inhibitors (PIs) has transformed the treatment of multiple myeloma and mantle cell lymphoma. To date, two PIs have been FDA approved, the boronate peptide bortezomib and, most recently, the epoxyketone peptide carfilzomib. However, intrinsic and acquired resistance to PIs, for which the underlying mechanisms are poorly understood, may limit their efficacy. In this perspective, we discuss recent advances in the molecular understanding of PI resistance through acquired bortezomib resistance in human cell lines to evolved saliniosporamide A (marizomib) resistance in nature. Resistance mechanisms discussed include the upregulation of proteasome subunits and mutations of the catalytic β-subunits. Additionally, we explore potential strategies to overcome PI resistance. PMID:22978849

  18. Multiscale mechanobiology: mechanics at the molecular, cellular, and tissue levels.

    PubMed

    Guo, Chin-Lin; Harris, Nolan C; Wijeratne, Sithara S; Frey, Eric W; Kiang, Ching-Hwa

    2013-06-03

    Mechanical force is present in all aspects of living systems. It affects the conformation of molecules, the shape of cells, and the morphology of tissues. All of these are crucial in architecture-dependent biological functions. Nanoscience of advanced materials has provided knowledge and techniques that can be used to understand how mechanical force is involved in biological systems, as well as to open new avenues to tailor-made bio-mimetic materials with desirable properties.In this article, we describe models and show examples of how force is involved in molecular functioning, cell shape patterning, and tissue morphology.

  19. Wilson’s Disease: A Comprehensive Review of the Molecular Mechanisms

    PubMed Central

    Wu, Fei; Wang, Jing; Pu, Chunwen; Qiao, Liang; Jiang, Chunmeng

    2015-01-01

    Wilson’s disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive inherited disorder resulting from abnormal copper metabolism. Reduced copper excretion causes an excessive deposition of the copper in many organs such as the liver, central nervous system (CNS), cornea, kidney, joints, and cardiac muscle where the physiological functions of the affected organs are impaired. The underlying molecular mechanisms for WD have been extensively studied. It is now believed that a defect in P-type adenosine triphosphatase (ATP7B), the gene encoding the copper transporting P-type ATPase, is responsible for hepatic copper accumulation. Deposited copper in the liver produces toxic effects via modulating several molecular pathways. WD can be a lethal disease if left untreated. A better understanding of the molecular mechanisms causing the aberrant copper deposition and organ damage is the key to developing effective management approaches. PMID:25803104

  20. Simulated scaling method for localized enhanced sampling and simultaneous "alchemical" free energy simulations: a general method for molecular mechanical, quantum mechanical, and quantum mechanical/molecular mechanical simulations.

    PubMed

    Li, Hongzhi; Fajer, Mikolai; Yang, Wei

    2007-01-14

    A potential scaling version of simulated tempering is presented to efficiently sample configuration space in a localized region. The present "simulated scaling" method is developed with a Wang-Landau type of updating scheme in order to quickly flatten the distributions in the scaling parameter lambdam space. This proposal is meaningful for a broad range of biophysical problems, in which localized sampling is required. Besides its superior capability and robustness in localized conformational sampling, this simulated scaling method can also naturally lead to efficient "alchemical" free energy predictions when dual-topology alchemical hybrid potential is applied; thereby simultaneously, both of the chemically and conformationally distinct portions of two end point chemical states can be efficiently sampled. As demonstrated in this work, the present method is also feasible for the quantum mechanical and quantum mechanical/molecular mechanical simulations.

  1. Molecular mechanisms and proposed targets for selected anticancer gold compounds.

    PubMed

    Casini, Angela; Messori, Luigi

    2011-01-01

    Nowadays, gold compounds constitute a family of very promising experimental agents for cancer treatment. Indeed, several gold(I) and gold(III) compounds were shown to manifest outstanding antiproliferative properties in vitro against selected human tumor cell lines and some of them performed remarkably well even in tumor models in vivo. Notably, the peculiar chemical properties of the gold centre impart innovative pharmacological profiles to gold-based metallodrugs most likely in relation to novel molecular mechanisms. The precise mechanisms through which cytotoxic gold compounds produce their biological effects are still largely unknown. Within this frame, the major aim of this review is to define the possible modes of action and the most probable biomolecular targets for a few representative gold compounds on which extensive biochemical and cellular data have been gathered. In particular, we will focus on auranofin and analogues, on gold(III) porphyrins and gold(III) dithiocarbamates. For these three families markedly distinct molecular mechanisms were recently invoked: a direct mitochondrial mechanism involving thioredoxin reductase inhibition in the case of the gold(I) complexes, the influence on some apoptotic proteins--i.e. MAPKs and Bcl-2--for gold(III) porphyrins, and the proteasome inhibition for gold(III) dithiocarbamates. In a few cases the distinct mechanisms may overlap. The general perspectives for the development of new gold compounds as effective anticancer agents with innovative modes of action are critically discussed. PMID:22039866

  2. Molecular mechanisms for vascular complications of targeted cancer therapies.

    PubMed

    Gopal, Srila; Miller, Kenneth B; Jaffe, Iris Z

    2016-10-01

    Molecularly targeted anti-cancer therapies have revolutionized cancer treatment by improving both quality of life and survival in cancer patients. However, many of these drugs are associated with cardiovascular toxicities that are sometimes dose-limiting. Moreover, the long-term cardiovascular consequences of these drugs, some of which are used chronically, are not yet known. Although the scope and mechanisms of the cardiac toxicities are better defined, the mechanisms for vascular toxicities are only beginning to be elucidated. This review summarizes what is known about the vascular adverse events associated with three classes of novel anti-cancer therapies: vascular endothelial growth factor (VEGF) inhibitors, breakpoint cluster-Abelson (BCR-ABL) kinase inhibitors used to treat chronic myelogenous leukaemia (CML) and immunomodulatory agents (IMiDs) used in myeloma therapeutics. Three of the best described vascular toxicities are reviewed including hypertension, increased risk of acute cardiovascular ischaemic events and arteriovenous thrombosis. The available data regarding the mechanism by which each therapy causes vascular complication are summarized. When data are limited, potential mechanisms are inferred from the known effects of inhibiting each target on vascular cell function and disease. Enhanced understanding of the molecular mechanisms of vascular side effects of targeted cancer therapy is necessary to effectively manage cancer patients and to design safer targeted cancer therapies for the future. PMID:27612952

  3. Molecular mechanisms of hookworm disease: stealth, virulence, and vaccines.

    PubMed

    Pearson, Mark S; Tribolet, Leon; Cantacessi, Cinzia; Periago, Maria Victoria; Valero, Maria Adela; Valerio, Maria Adela; Jariwala, Amar R; Hotez, Peter; Diemert, David; Loukas, Alex; Bethony, Jeffrey

    2012-07-01

    Hookworms produce a vast repertoire of structurally and functionally diverse molecules that mediate their long-term survival and pathogenesis within a human host. Many of these molecules are secreted by the parasite, after which they interact with critical components of host biology, including processes that are key to host survival. The most important of these interactions is the hookworm's interruption of nutrient acquisition by the host through its ingestion and digestion of host blood. This results in iron deficiency and eventually the microcytic hypochromic anemia or iron deficiency anemia that is the clinical hallmark of hookworm infection. Other molecular mechanisms of hookworm infection cause a systematic suppression of the host immune response to both the parasite and to bystander antigens (eg, vaccines or allergens). This is achieved by a series of molecules that assist the parasite in the stealthy evasion of the host immune response. This review will summarize the current knowledge of the molecular mechanisms used by hookworms to survive for extended periods in the human host (up to 7 years or longer) and examine the pivotal contributions of these molecular mechanisms to chronic hookworm parasitism and host clinical outcomes.

  4. Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

    PubMed Central

    Ahmad, Saif; Bhatia, Kanchan; Kannan, Annapoorna; Gangwani, Laxman

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA. PMID:27042141

  5. Genomic and molecular mechanisms for efficient biodegradation of aromatic dye.

    PubMed

    Sun, Su; Xie, Shangxian; Chen, Hu; Cheng, Yanbing; Shi, Yan; Qin, Xing; Dai, Susie Y; Zhang, Xiaoyu; Yuan, Joshua S

    2016-01-25

    Understanding the molecular mechanisms for aromatic compound degradation is crucial for the development of effective bioremediation strategies. We report the discovery of a novel phenomenon for improved degradation of Direct Red 5B azo dye by Irpex lacteus CD2 with lignin as a co-substrate. Transcriptomics analysis was performed to elucidate the molecular mechanisms of aromatic degradation in white rot fungus by comparing dye, lignin, and dye/lignin combined treatments. A full spectrum of lignin degradation peroxidases, oxidases, radical producing enzymes, and other relevant components were up-regulated under DR5B and lignin treatments. Lignin induced genes complemented the DR5B induced genes to provide essential enzymes and redox conditions for aromatic compound degradation. The transcriptomics analysis was further verified by manganese peroxidase (MnP) protein over-expression, as revealed by proteomics, dye decolorization assay by purified MnP and increased hydroxyl radical levels, as indicated by an iron reducing activity assay. Overall, the molecular and genomic mechanisms indicated that effective aromatic polymer degradation requires synergistic enzymes and radical-mediated oxidative reactions to form an effective network of chemical processes. This study will help to guide the development of effective bioremediation and biomass degradation strategies.

  6. Crosstalk Between Apoptosis and Autophagy: Molecular Mechanisms and Therapeutic Strategies in Cancer

    PubMed Central

    El-Khattouti, Abdelouahid; Selimovic, Denis; Haikel, Youssef; Hassan, Mohamed

    2013-01-01

    Both apoptosis and autophagy are highly conserved processes that besides their role in the maintenance of the organismal and cellular homeostasis serve as a main target of tumor therapeutics. Although their important roles in the modulation of tumor therapeutic strategies have been widely reported, the molecular actions of both apoptosis and autophagy are counteracted by cancer protective mechanisms. While apoptosis is a tightly regulated process that is implicated in the removal of damaged or unwanted cells, autophagy is a cellular catabolic pathway that is involved in lysosomal degradation and recycling of proteins and organelles, and thereby is considered an important survival/protective mechanism for cancer cells in response to metabolic stress or chemotherapy. Although the relationship between autophagy and cell death is very complicated and has not been characterized in detail, the molecular mechanisms that control this relationship are considered to be a relevant target for the development of a therapeutic strategy for tumor treatment. In this review, we focus on the molecular mechanisms of apoptosis, autophagy, and those of the crosstalk between apoptosis and autophagy in order to provide insight into the molecular mechanisms that may be essential for the balance between cell survival and death as well as their role as targets for the development of novel therapeutic approaches. PMID:25278778

  7. A Universal Electrode Approach for Automated Electrochemical Molecular Analyses

    PubMed Central

    Sin, Mandy L. Y.; Gau, Vincent; Liao, Joseph C.; Wong, P. K.

    2014-01-01

    Transforming microfluidics-based biosensing systems from laboratory research into clinical reality remains an elusive goal despite decades of intensive research. A fundamental obstacle for the development of fully automated microfluidic diagnostic systems is the lack of an effective strategy for combining pumping, sample preparation, and detection modules into an integrated biosensing platform. Herein, we report a universal electrode approach, which incorporates DC electrolytic pumping, AC electrokinetic sample preparation, and self-assembled monolayer based electrochemical sensing on a single microfluidic platform, to automate complicated molecular analysis procedures that will enable biosensing applications in non-traditional healthcare settings. Using the universal electrode approach, major microfluidic operations required in molecular analyses, such as pumping, mixing, washing, and sensing can be performed in a single platform. We demonstrate the universal electrode platform for detecting bacterial 16S rRNA, a phylogenetic marker, toward rapid diagnostics of urinary tract infection. Since only electronic interfaces are required to operate the platform, the universal electrode approach represents an effective system integration strategy to realize the potential of microfluidics in molecular diagnostics at the point of care. PMID:24860248

  8. Molecular Mechanisms of Age-Related Sleep Loss in the Fruit Fly

    PubMed Central

    Robertson, Meagan; Keene, Alex C.

    2013-01-01

    Across phyla, aging is associated with reduced sleep duration and efficiency. Both aging and sleep involve complex genetic architecture and diverse cell types and are heavily influenced by diet and environment. Therefore, understanding the molecular mechanisms of age-dependent changes in sleep will require integrative approaches that go beyond examining these two processes independently. The fruit fly, Drosophila melanogaster, provides a genetically amenable system for dissecting the molecular basis of these processes. In this review, we examine the role of metabolism and circadian rhythms in age-dependent sleep loss. PMID:23594925

  9. Reaction Mechanisms in Carbohydrate-Active Enzymes: Glycoside Hydrolases and Glycosyltransferases. Insights from ab Initio Quantum Mechanics/Molecular Mechanics Dynamic Simulations.

    PubMed

    Ardèvol, Albert; Rovira, Carme

    2015-06-24

    Carbohydrate-active enzymes such as glycoside hydrolases (GHs) and glycosyltransferases (GTs) are of growing importance as drug targets. The development of efficient competitive inhibitors and chaperones to treat diseases related to these enzymes requires a detailed knowledge of their mechanisms of action. In recent years, sophisticated first-principles modeling approaches have significantly advanced in our understanding of the catalytic mechanisms of GHs and GTs, not only the molecular details of chemical reactions but also the significant implications that just the conformational dynamics of a sugar ring can have on these mechanisms. Here we provide an overview of the progress that has been made in the past decade, combining molecular dynamics simulations with density functional theory to solve these sweet mysteries of nature.

  10. Integrated genomics and molecular breeding approaches for dissecting the complex quantitative traits in crop plants.

    PubMed

    Kujur, Alice; Saxena, Maneesha S; Bajaj, Deepak; Laxmi; Parida, Swarup K

    2013-12-01

    The enormous population growth, climate change and global warming are now considered major threats to agriculture and world's food security. To improve the productivity and sustainability of agriculture, the development of highyielding and durable abiotic and biotic stress-tolerant cultivars and/climate resilient crops is essential. Henceforth, understanding the molecular mechanism and dissection of complex quantitative yield and stress tolerance traits is the prime objective in current agricultural biotechnology research. In recent years, tremendous progress has been made in plant genomics and molecular breeding research pertaining to conventional and next-generation whole genome, transcriptome and epigenome sequencing efforts, generation of huge genomic, transcriptomic and epigenomic resources and development of modern genomics-assisted breeding approaches in diverse crop genotypes with contrasting yield and abiotic stress tolerance traits. Unfortunately, the detailed molecular mechanism and gene regulatory networks controlling such complex quantitative traits is not yet well understood in crop plants. Therefore, we propose an integrated strategies involving available enormous and diverse traditional and modern -omics (structural, functional, comparative and epigenomics) approaches/resources and genomics-assisted breeding methods which agricultural biotechnologist can adopt/utilize to dissect and decode the molecular and gene regulatory networks involved in the complex quantitative yield and stress tolerance traits in crop plants. This would provide clues and much needed inputs for rapid selection of novel functionally relevant molecular tags regulating such complex traits to expedite traditional and modern marker-assisted genetic enhancement studies in target crop species for developing high-yielding stress-tolerant varieties.

  11. Linking traits based on their shared molecular mechanisms

    PubMed Central

    Oren, Yael; Nachshon, Aharon; Frishberg, Amit; Wilentzik, Roni; Gat-Viks, Irit

    2015-01-01

    There is growing recognition that co-morbidity and co-occurrence of disease traits are often determined by shared genetic and molecular mechanisms. In most cases, however, the specific mechanisms that lead to such trait–trait relationships are yet unknown. Here we present an analysis of a broad spectrum of behavioral and physiological traits together with gene-expression measurements across genetically diverse mouse strains. We develop an unbiased methodology that constructs potentially overlapping groups of traits and resolves their underlying combination of genetic loci and molecular mechanisms. For example, our method predicts that genetic variation in the Klf7 gene may influence gene transcripts in bone marrow-derived myeloid cells, which in turn affect 17 behavioral traits following morphine injection; this predicted effect of Klf7 is consistent with an in vitro perturbation of Klf7 in bone marrow cells. Our analysis demonstrates the utility of studying hidden causative mechanisms that lead to relationships between complex traits. DOI: http://dx.doi.org/10.7554/eLife.04346.001 PMID:25781485

  12. Hyperthermophilic Enzymes: Sources, Uses, and Molecular Mechanisms for Thermostability

    PubMed Central

    Vieille, Claire; Zeikus, Gregory J.

    2001-01-01

    Enzymes synthesized by hyperthermophiles (bacteria and archaea with optimal growth temperatures of >80°C), also called hyperthermophilic enzymes, are typically thermostable (i.e., resistant to irreversible inactivation at high temperatures) and are optimally active at high temperatures. These enzymes share the same catalytic mechanisms with their mesophilic counterparts. When cloned and expressed in mesophilic hosts, hyperthermophilic enzymes usually retain their thermal properties, indicating that these properties are genetically encoded. Sequence alignments, amino acid content comparisons, crystal structure comparisons, and mutagenesis experiments indicate that hyperthermophilic enzymes are, indeed, very similar to their mesophilic homologues. No single mechanism is responsible for the remarkable stability of hyperthermophilic enzymes. Increased thermostability must be found, instead, in a small number of highly specific alterations that often do not obey any obvious traffic rules. After briefly discussing the diversity of hyperthermophilic organisms, this review concentrates on the remarkable thermostability of their enzymes. The biochemical and molecular properties of hyperthermophilic enzymes are described. Mechanisms responsible for protein inactivation are reviewed. The molecular mechanisms involved in protein thermostabilization are discussed, including ion pairs, hydrogen bonds, hydrophobic interactions, disulfide bridges, packing, decrease of the entropy of unfolding, and intersubunit interactions. Finally, current uses and potential applications of thermophilic and hyperthermophilic enzymes as research reagents and as catalysts for industrial processes are described. PMID:11238984

  13. Theoretical modeling of large molecular systems. Advances in the local self consistent field method for mixed quantum mechanics/molecular mechanics calculations.

    PubMed

    Monari, Antonio; Rivail, Jean-Louis; Assfeld, Xavier

    2013-02-19

    Molecular mechanics methods can efficiently compute the macroscopic properties of a large molecular system but cannot represent the electronic changes that occur during a chemical reaction or an electronic transition. Quantum mechanical methods can accurately simulate these processes, but they require considerably greater computational resources. Because electronic changes typically occur in a limited part of the system, such as the solute in a molecular solution or the substrate within the active site of enzymatic reactions, researchers can limit the quantum computation to this part of the system. Researchers take into account the influence of the surroundings by embedding this quantum computation into a calculation of the whole system described at the molecular mechanical level, a strategy known as the mixed quantum mechanics/molecular mechanics (QM/MM) approach. The accuracy of this embedding varies according to the types of interactions included, whether they are purely mechanical or classically electrostatic. This embedding can also introduce the induced polarization of the surroundings. The difficulty in QM/MM calculations comes from the splitting of the system into two parts, which requires severing the chemical bonds that link the quantum mechanical subsystem to the classical subsystem. Typically, researchers replace the quantoclassical atoms, those at the boundary between the subsystems, with a monovalent link atom. For example, researchers might add a hydrogen atom when a C-C bond is cut. This Account describes another approach, the Local Self Consistent Field (LSCF), which was developed in our laboratory. LSCF links the quantum mechanical portion of the molecule to the classical portion using a strictly localized bond orbital extracted from a small model molecule for each bond. In this scenario, the quantoclassical atom has an apparent nuclear charge of +1. To achieve correct bond lengths and force constants, we must take into account the inner shell of

  14. Osteoblast dysfunctions in bone diseases: from cellular and molecular mechanisms to therapeutic strategies.

    PubMed

    Marie, Pierre J

    2015-04-01

    Several metabolic, genetic and oncogenic bone diseases are characterized by defective or excessive bone formation. These abnormalities are caused by dysfunctions in the commitment, differentiation or survival of cells of the osteoblast lineage. During the recent years, significant advances have been made in our understanding of the cellular and molecular mechanisms underlying the osteoblast dysfunctions in osteoporosis, skeletal dysplasias and primary bone tumors. This led to suggest novel therapeutic approaches to correct these abnormalities such as the modulation of WNT signaling, the pharmacological modulation of proteasome-mediated protein degradation, the induction of osteoprogenitor cell differentiation, the repression of cancer cell proliferation and the manipulation of epigenetic mechanisms. This article reviews our current understanding of the major cellular and molecular mechanisms inducing osteoblastic cell abnormalities in age-related bone loss, genetic skeletal dysplasias and primary bone tumors, and discusses emerging therapeutic strategies to counteract the osteoblast abnormalities in these disorders of bone formation.

  15. Physiological, Molecular and Genetic Mechanisms of Long-Term Habituation

    SciTech Connect

    Calin-Jageman, Robert J

    2009-09-12

    Work funded on this grant has explored the mechanisms of long-term habituation, a ubiquitous form of learning that plays a key role in basic cognitive functioning. Specifically, behavioral, physiological, and molecular mechanisms of habituation have been explored using a simple model system, the tail-elicited siphon-withdrawal reflex (T-SWR) in the marine mollusk Aplysia californica. Substantial progress has been made on the first and third aims, providing some fundamental insights into the mechanisms by which memories are stored. We have characterized the physiological correlates of short- and long-term habituation. We found that short-term habituation is accompanied by a robust sensory adaptation, whereas long-term habituation is accompanied by alterations in sensory and interneuron synaptic efficacy. Thus, our data indicates memories can be shifted between different sites in a neural network as they are consolidated from short to long term. At the molecular level, we have accomplished microarray analysis comparing gene expression in both habituated and control ganglia. We have identified a network of putatively regulated transcripts that seems particularly targeted towards synaptic changes (e.g. SNAP25, calmodulin) . We are now beginning additional work to confirm regulation of these transcripts and build a more detailed understanding of the cascade of molecular events leading to the permanent storage of long-term memories. On the third aim, we have fostered a nascent neuroscience program via a variety of successful initiatives. We have funded over 11 undergraduate neuroscience scholars, several of whom have been recognized at national and regional levels for their research. We have also conducted a pioneering summer research program for community college students which is helping enhance access of underrepresented groups to life science careers. Despite minimal progress on the second aim, this project has provided a) novel insight into the network mechanisms by

  16. Studies on the molecular mechanisms of seed germination.

    PubMed

    Han, Chao; Yang, Pingfang

    2015-05-01

    Seed germination that begins with imbibition and ends with radicle emergence is the first step for plant growth. Successful germination is not only crucial for seedling establishment but also important for crop yield. After being dispersed from mother plant, seed undergoes continuous desiccation in ecosystem and selects proper environment to trigger germination. Owing to the contribution of transcriptomic, proteomic, and molecular biological studies, molecular aspect of seed germination is elucidated well in Arabidopsis. Recently, more and more proteomic and genetic studies concerning cereal seed germination were performed on rice (Oryza sativa) and barley (Hordeum vulgare), which possess completely different seed structure and domestication background with Arabidopsis. In this review, both the common features and the distinct mechanisms of seed germination are compared among different plant species including Arabidopsis, rice, and maize. These features include morphological changes, cell and its related structure recovery, metabolic activation, hormone behavior, and transcription and translation activation. This review will provide more comprehensive insights into the molecular mechanisms of seed germination.

  17. Molecular mechanisms of mutagenesis determined by the recombinant DNA technology

    SciTech Connect

    Lee, W.R.

    1985-01-01

    A study of the alteration of the DNA in the mutant gene can determine mechanisms of mutation by distinguishing between mutations induced by transition, transversion, frameshifts of a single base and deletions involving many base pairs. The association of a specific pattern of response with a mutagen will permit detecting mutants induced by the mutagen with a reduced background by removing mutations induced by other mechanisms from the pool of potential mutants. From analyses of studies that have been conducted, it is quite apparent that there are substantial differences among mutagens in their modes of action. Of 31 x-ray induced mutants, 20 were large deletions while only 3 showed normal Southern blots. Only one mutant produced a sub-unit polypeptide of normal molecular weight and charge in the in vivo test whereas in vitro synthesis produced a second one. In contrast, nine of thirteen EMS induced mutants produced cross-reacting proteins with sub-unit polypeptide molecular weights equivalent to wild type. Two of three ENU induced mutants recently analyzed in our laboratory produced protein with sub-unit polypeptide molecular weight and electrical charge similar to the wild type stock in which the mutants were induced. One ENU induced mutation is a large deletion. 21 refs., 1 fig.

  18. Studies on the molecular mechanisms of seed germination.

    PubMed

    Han, Chao; Yang, Pingfang

    2015-05-01

    Seed germination that begins with imbibition and ends with radicle emergence is the first step for plant growth. Successful germination is not only crucial for seedling establishment but also important for crop yield. After being dispersed from mother plant, seed undergoes continuous desiccation in ecosystem and selects proper environment to trigger germination. Owing to the contribution of transcriptomic, proteomic, and molecular biological studies, molecular aspect of seed germination is elucidated well in Arabidopsis. Recently, more and more proteomic and genetic studies concerning cereal seed germination were performed on rice (Oryza sativa) and barley (Hordeum vulgare), which possess completely different seed structure and domestication background with Arabidopsis. In this review, both the common features and the distinct mechanisms of seed germination are compared among different plant species including Arabidopsis, rice, and maize. These features include morphological changes, cell and its related structure recovery, metabolic activation, hormone behavior, and transcription and translation activation. This review will provide more comprehensive insights into the molecular mechanisms of seed germination. PMID:25597791

  19. Molecular mechanisms of foliar water uptake in a desert tree

    PubMed Central

    Yan, Xia; Zhou, Maoxian; Dong, Xicun; Zou, Songbing; Xiao, Honglang; Ma, Xiao-Fei

    2015-01-01

    Water deficits severely affect growth, particularly for the plants in arid and semiarid regions of the world. In addition to precipitation, other subsidiary water, such as dew, fog, clouds and small rain showers, may also be absorbed by leaves in a process known as foliar water uptake. With the severe scarcity of water in desert regions, this process is increasingly becoming a necessity. Studies have reported on physical and physiological processes of foliar water uptake. However, the molecular mechanisms remain less understood. As major channels for water regulation and transport, aquaporins (AQPs) are involved in this process. However, due to the regulatory complexity and functional diversity of AQPs, their molecular mechanism for foliar water uptake remains unclear. In this study, Tamarix ramosissima, a tree species widely distributed in desert regions, was investigated for gene expression patterns of AQPs and for sap flow velocity. Our results suggest that the foliar water uptake of T. ramosissima occurs in natural fields at night when the humidity is over a threshold of 85 %. The diurnal gene expression pattern of AQPs suggests that most AQP gene expressions display a circadian rhythm, and this could affect both photosynthesis and transpiration. At night, the PIP2-1 gene is also upregulated with increased relative air humidity. This gene expression pattern may allow desert plants to regulate foliar water uptake to adapt to extreme drought. This study suggests a molecular basis of foliar water uptake in desert plants. PMID:26567212

  20. Molecular mechanisms of foliar water uptake in a desert tree.

    PubMed

    Yan, Xia; Zhou, Maoxian; Dong, Xicun; Zou, Songbing; Xiao, Honglang; Ma, Xiao-Fei

    2015-11-12

    Water deficits severely affect growth, particularly for the plants in arid and semiarid regions of the world. In addition to precipitation, other subsidiary water, such as dew, fog, clouds and small rain showers, may also be absorbed by leaves in a process known as foliar water uptake. With the severe scarcity of water in desert regions, this process is increasingly becoming a necessity. Studies have reported on physical and physiological processes of foliar water uptake. However, the molecular mechanisms remain less understood. As major channels for water regulation and transport, aquaporins (AQPs) are involved in this process. However, due to the regulatory complexity and functional diversity of AQPs, their molecular mechanism for foliar water uptake remains unclear. In this study, Tamarix ramosissima, a tree species widely distributed in desert regions, was investigated for gene expression patterns of AQPs and for sap flow velocity. Our results suggest that the foliar water uptake of T. ramosissima occurs in natural fields at night when the humidity is over a threshold of 85 %. The diurnal gene expression pattern of AQPs suggests that most AQP gene expressions display a circadian rhythm, and this could affect both photosynthesis and transpiration. At night, the PIP2-1 gene is also upregulated with increased relative air humidity. This gene expression pattern may allow desert plants to regulate foliar water uptake to adapt to extreme drought. This study suggests a molecular basis of foliar water uptake in desert plants.

  1. Genetic and molecular mechanisms leading to eosinophilic esophagitis.

    PubMed

    Holvoet, S; Blanchard, C

    2014-04-01

    From the epidemiologic studies, to the first genome wide association study in 2010, the understanding of the molecular pathogenesis of EoE has been both inspiring and puzzling. Epidemiologic studies have highlighted the contribution of the genetic in the EoE disease by emphasizing the presence of familial type of EoE, but has also revealed the complexity of its transmission that does not follow a Mendelian inheritance. The molecular pathogenesis advances have helped in the understanding of the mechanisms underlying this esophageal inflammation but has also allow the identification of candidate genes for which single nucleotide polymorphisms (SNP) are associated with the disease. Recently, the genome wide analysis of more than half a million single nucleotide polymorphism has allowed the identification of gene variations associated with the EoE disease and has led to substantial advance in the understanding of the molecular mechanisms leading to EoE. Undeniably, EoE is a complex polygenic disease and we certainly are only at the ground level of its detailed comprehension. PMID:25075658

  2. Molecular mechanisms of foliar water uptake in a desert tree.

    PubMed

    Yan, Xia; Zhou, Maoxian; Dong, Xicun; Zou, Songbing; Xiao, Honglang; Ma, Xiao-Fei

    2015-01-01

    Water deficits severely affect growth, particularly for the plants in arid and semiarid regions of the world. In addition to precipitation, other subsidiary water, such as dew, fog, clouds and small rain showers, may also be absorbed by leaves in a process known as foliar water uptake. With the severe scarcity of water in desert regions, this process is increasingly becoming a necessity. Studies have reported on physical and physiological processes of foliar water uptake. However, the molecular mechanisms remain less understood. As major channels for water regulation and transport, aquaporins (AQPs) are involved in this process. However, due to the regulatory complexity and functional diversity of AQPs, their molecular mechanism for foliar water uptake remains unclear. In this study, Tamarix ramosissima, a tree species widely distributed in desert regions, was investigated for gene expression patterns of AQPs and for sap flow velocity. Our results suggest that the foliar water uptake of T. ramosissima occurs in natural fields at night when the humidity is over a threshold of 85 %. The diurnal gene expression pattern of AQPs suggests that most AQP gene expressions display a circadian rhythm, and this could affect both photosynthesis and transpiration. At night, the PIP2-1 gene is also upregulated with increased relative air humidity. This gene expression pattern may allow desert plants to regulate foliar water uptake to adapt to extreme drought. This study suggests a molecular basis of foliar water uptake in desert plants. PMID:26567212

  3. Deciphering molecular mechanism underlying hypolipidemic activity of echinocystic Acid.

    PubMed

    Han, Li; Lai, Peng; Du, Jun-Rong

    2014-01-01

    Our previous study showed that a triterpene mixture, consisting of echinocystic acid (EA) and oleanolic acid (OA) at a ratio of 4 : 1, dose-dependently ameliorated the hyperlipidemia and atherosclerosis in rabbits fed with high fat/high cholesterol diets. This study was aimed at exploring the mechanisms underlying antihyperlipidemic effect of EA. Molecular docking simulation of EA was performed using Molegro Virtual Docker (version: 4.3.0) to investigate the potential targets related to lipid metabolism. Based on the molecular docking information, isotope labeling method or spectrophotometry was applied to examine the effect of EA on the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, acyl-CoA:cholesterol acyltransferase (ACAT), and diacylglycerol acyltransferase (DGAT) in rat liver microsomes. Our results revealed a strong affinity of EA towards ACAT and DGAT in molecular docking analysis, while low binding affinity existed between EA and HMG-CoA reductase as well as between EA and cholesteryl ester transfer protein. Consistent with the results of molecular docking, in vitro enzyme activity assays showed that EA inhibited ACAT and DGAT, with IC50 values of 103 and 139  μ M, respectively, and exhibited no significant effect on HMG-CoA reductase activity. The present findings suggest that EA may exert hypolipidemic effect by inhibiting the activity of ACAT and DGAT. PMID:24669228

  4. Treating electrostatics with Wolf summation in combined quantum mechanical and molecular mechanical simulations

    SciTech Connect

    Ojeda-May, Pedro; Pu, Jingzhi

    2015-11-07

    The Wolf summation approach [D. Wolf et al., J. Chem. Phys. 110, 8254 (1999)], in the damped shifted force (DSF) formalism [C. J. Fennell and J. D. Gezelter, J. Chem. Phys. 124, 234104 (2006)], is extended for treating electrostatics in combined quantum mechanical and molecular mechanical (QM/MM) molecular dynamics simulations. In this development, we split the QM/MM electrostatic potential energy function into the conventional Coulomb r{sup −1} term and a term that contains the DSF contribution. The former is handled by the standard machinery of cutoff-based QM/MM simulations whereas the latter is incorporated into the QM/MM interaction Hamiltonian as a Fock matrix correction. We tested the resulting QM/MM-DSF method for two solution-phase reactions, i.e., the association of ammonium and chloride ions and a symmetric SN{sub 2} reaction in which a methyl group is exchanged between two chloride ions. The performance of the QM/MM-DSF method was assessed by comparing the potential of mean force (PMF) profiles with those from the QM/MM-Ewald and QM/MM-isotropic periodic sum (IPS) methods, both of which include long-range electrostatics explicitly. For ion association, the QM/MM-DSF method successfully eliminates the artificial free energy drift observed in the QM/MM-Cutoff simulations, in a remarkable agreement with the two long-range-containing methods. For the SN{sub 2} reaction, the free energy of activation obtained by the QM/MM-DSF method agrees well with both the QM/MM-Ewald and QM/MM-IPS results. The latter, however, requires a greater cutoff distance than QM/MM-DSF for a proper convergence of the PMF. Avoiding time-consuming lattice summation, the QM/MM-DSF method yields a 55% reduction in computational cost compared with the QM/MM-Ewald method. These results suggest that, in addition to QM/MM-IPS, the QM/MM-DSF method may serve as another efficient and accurate alternative to QM/MM-Ewald for treating electrostatics in condensed-phase simulations of chemical

  5. Treating electrostatics with Wolf summation in combined quantum mechanical and molecular mechanical simulations

    NASA Astrophysics Data System (ADS)

    Ojeda-May, Pedro; Pu, Jingzhi

    2015-11-01

    The Wolf summation approach [D. Wolf et al., J. Chem. Phys. 110, 8254 (1999)], in the damped shifted force (DSF) formalism [C. J. Fennell and J. D. Gezelter, J. Chem. Phys. 124, 234104 (2006)], is extended for treating electrostatics in combined quantum mechanical and molecular mechanical (QM/MM) molecular dynamics simulations. In this development, we split the QM/MM electrostatic potential energy function into the conventional Coulomb r-1 term and a term that contains the DSF contribution. The former is handled by the standard machinery of cutoff-based QM/MM simulations whereas the latter is incorporated into the QM/MM interaction Hamiltonian as a Fock matrix correction. We tested the resulting QM/MM-DSF method for two solution-phase reactions, i.e., the association of ammonium and chloride ions and a symmetric SN2 reaction in which a methyl group is exchanged between two chloride ions. The performance of the QM/MM-DSF method was assessed by comparing the potential of mean force (PMF) profiles with those from the QM/MM-Ewald and QM/MM-isotropic periodic sum (IPS) methods, both of which include long-range electrostatics explicitly. For ion association, the QM/MM-DSF method successfully eliminates the artificial free energy drift observed in the QM/MM-Cutoff simulations, in a remarkable agreement with the two long-range-containing methods. For the SN2 reaction, the free energy of activation obtained by the QM/MM-DSF method agrees well with both the QM/MM-Ewald and QM/MM-IPS results. The latter, however, requires a greater cutoff distance than QM/MM-DSF for a proper convergence of the PMF. Avoiding time-consuming lattice summation, the QM/MM-DSF method yields a 55% reduction in computational cost compared with the QM/MM-Ewald method. These results suggest that, in addition to QM/MM-IPS, the QM/MM-DSF method may serve as another efficient and accurate alternative to QM/MM-Ewald for treating electrostatics in condensed-phase simulations of chemical reactions.

  6. AMMOS: Automated Molecular Mechanics Optimization tool for in silico Screening

    PubMed Central

    Pencheva, Tania; Lagorce, David; Pajeva, Ilza; Villoutreix, Bruno O; Miteva, Maria A

    2008-01-01

    Background Virtual or in silico ligand screening combined with other computational methods is one of the most promising methods to search for new lead compounds, thereby greatly assisting the drug discovery process. Despite considerable progresses made in virtual screening methodologies, available computer programs do not easily address problems such as: structural optimization of compounds in a screening library, receptor flexibility/induced-fit, and accurate prediction of protein-ligand interactions. It has been shown that structural optimization of chemical compounds and that post-docking optimization in multi-step structure-based virtual screening approaches help to further improve the overall efficiency of the methods. To address some of these points, we developed the program AMMOS for refining both, the 3D structures of the small molecules present in chemical libraries and the predicted receptor-ligand complexes through allowing partial to full atom flexibility through molecular mechanics optimization. Results The program AMMOS carries out an automatic procedure that allows for the structural refinement of compound collections and energy minimization of protein-ligand complexes using the open source program AMMP. The performance of our package was evaluated by comparing the structures of small chemical entities minimized by AMMOS with those minimized with the Tripos and MMFF94s force fields. Next, AMMOS was used for full flexible minimization of protein-ligands complexes obtained from a mutli-step virtual screening. Enrichment studies of the selected pre-docked complexes containing 60% of the initially added inhibitors were carried out with or without final AMMOS minimization on two protein targets having different binding pocket properties. AMMOS was able to improve the enrichment after the pre-docking stage with 40 to 60% of the initially added active compounds found in the top 3% to 5% of the entire compound collection. Conclusion The open source AMMOS

  7. Molecular mechanisms of cognitive dysfunction following traumatic brain injury

    PubMed Central

    Walker, Kendall R.; Tesco, Giuseppina

    2013-01-01

    Traumatic brain injury (TBI) results in significant disability due to cognitive deficits particularly in attention, learning and memory, and higher-order executive functions. The role of TBI in chronic neurodegeneration and the development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and most recently chronic traumatic encephalopathy (CTE) is of particular importance. However, despite significant effort very few therapeutic options exist to prevent or reverse cognitive impairment following TBI. In this review, we present experimental evidence of the known secondary injury mechanisms which contribute to neuronal cell loss, axonal injury, and synaptic dysfunction and hence cognitive impairment both acutely and chronically following TBI. In particular we focus on the mechanisms linking TBI to the development of two forms of dementia: AD and CTE. We provide evidence of potential molecular mechanisms involved in modulating Aβ and Tau following TBI and provide evidence of the role of these mechanisms in AD pathology. Additionally we propose a mechanism by which Aβ generated as a direct result of TBI is capable of exacerbating secondary injury mechanisms thereby establishing a neurotoxic cascade that leads to chronic neurodegeneration. PMID:23847533

  8. Molecular Characterization of Transgenic Events Using Next Generation Sequencing Approach.

    PubMed

    Guttikonda, Satish K; Marri, Pradeep; Mammadov, Jafar; Ye, Liang; Soe, Khaing; Richey, Kimberly; Cruse, James; Zhuang, Meibao; Gao, Zhifang; Evans, Clive; Rounsley, Steve; Kumpatla, Siva P

    2016-01-01

    Demand for the commercial use of genetically modified (GM) crops has been increasing in light of the projected growth of world population to nine billion by 2050. A prerequisite of paramount importance for regulatory submissions is the rigorous safety assessment of GM crops. One of the components of safety assessment is molecular characterization at DNA level which helps to determine the copy number, integrity and stability of a transgene; characterize the integration site within a host genome; and confirm the absence of vector DNA. Historically, molecular characterization has been carried out using Southern blot analysis coupled with Sanger sequencing. While this is a robust approach to characterize the transgenic crops, it is both time- and resource-consuming. The emergence of next-generation sequencing (NGS) technologies has provided highly sensitive and cost- and labor-effective alternative for molecular characterization compared to traditional Southern blot analysis. Herein, we have demonstrated the successful application of both whole genome sequencing and target capture sequencing approaches for the characterization of single and stacked transgenic events and compared the results and inferences with traditional method with respect to key criteria required for regulatory submissions. PMID:26908260

  9. Molecular Characterization of Transgenic Events Using Next Generation Sequencing Approach

    PubMed Central

    Mammadov, Jafar; Ye, Liang; Soe, Khaing; Richey, Kimberly; Cruse, James; Zhuang, Meibao; Gao, Zhifang; Evans, Clive; Rounsley, Steve; Kumpatla, Siva P.

    2016-01-01

    Demand for the commercial use of genetically modified (GM) crops has been increasing in light of the projected growth of world population to nine billion by 2050. A prerequisite of paramount importance for regulatory submissions is the rigorous safety assessment of GM crops. One of the components of safety assessment is molecular characterization at DNA level which helps to determine the copy number, integrity and stability of a transgene; characterize the integration site within a host genome; and confirm the absence of vector DNA. Historically, molecular characterization has been carried out using Southern blot analysis coupled with Sanger sequencing. While this is a robust approach to characterize the transgenic crops, it is both time- and resource-consuming. The emergence of next-generation sequencing (NGS) technologies has provided highly sensitive and cost- and labor-effective alternative for molecular characterization compared to traditional Southern blot analysis. Herein, we have demonstrated the successful application of both whole genome sequencing and target capture sequencing approaches for the characterization of single and stacked transgenic events and compared the results and inferences with traditional method with respect to key criteria required for regulatory submissions. PMID:26908260

  10. Molecular Characterization of Transgenic Events Using Next Generation Sequencing Approach.

    PubMed

    Guttikonda, Satish K; Marri, Pradeep; Mammadov, Jafar; Ye, Liang; Soe, Khaing; Richey, Kimberly; Cruse, James; Zhuang, Meibao; Gao, Zhifang; Evans, Clive; Rounsley, Steve; Kumpatla, Siva P

    2016-01-01

    Demand for the commercial use of genetically modified (GM) crops has been increasing in light of the projected growth of world population to nine billion by 2050. A prerequisite of paramount importance for regulatory submissions is the rigorous safety assessment of GM crops. One of the components of safety assessment is molecular characterization at DNA level which helps to determine the copy number, integrity and stability of a transgene; characterize the integration site within a host genome; and confirm the absence of vector DNA. Historically, molecular characterization has been carried out using Southern blot analysis coupled with Sanger sequencing. While this is a robust approach to characterize the transgenic crops, it is both time- and resource-consuming. The emergence of next-generation sequencing (NGS) technologies has provided highly sensitive and cost- and labor-effective alternative for molecular characterization compared to traditional Southern blot analysis. Herein, we have demonstrated the successful application of both whole genome sequencing and target capture sequencing approaches for the characterization of single and stacked transgenic events and compared the results and inferences with traditional method with respect to key criteria required for regulatory submissions.

  11. Molecular Mechanisms of Compartmentalization and Biomineralization in Magnetotactic Bacteria

    PubMed Central

    Komeili, Arash

    2011-01-01

    Magnetotactic bacteria are remarkable organisms with the ability to exploit the earth’s magnetic field for navigational purposes. To do this, they build specialized compartments called magnetosomes that consist of a lipid membrane and a crystalline magnetic mineral. These organisms have the potential to serve as models for the study of compartmentalization as well as biomineralization in bacteria. Additionally, they offer the opportunity to design applications that take advantage of the particular properties of magnetosomes. In recent years, a sustained effort to identify the molecular basis of this process has resulted in a clearer understanding of the magnetosome formation and biomineralization. Here, I present an overview of magnetotactic bacteria and explore the possible molecular mechanisms of membrane remodeling, protein sorting, cytoskeletal organization, iron transport and biomineralization that lead to the formation of a functional magnetosome organelle. PMID:22092030

  12. Survivin and Tumorigenesis: Molecular Mechanisms and Therapeutic Strategies

    PubMed Central

    Chen, Xun; Duan, Ning; Zhang, Caiguo; Zhang, Wentao

    2016-01-01

    Survivin is the smallest member of the inhibitor of apoptosis protein family, which has key roles in regulating cell division and inhibiting apoptosis by blocking caspase activation. Survivin is highly expressed in most human cancers, such as lung, pancreatic and breast cancers, relative to normal tissues. Aberrant survivin expression is associated with tumor cell proliferation, progression, angiogenesis, therapeutic resistance, and poor prognosis. Studies on the underlying molecular mechanisms indicate that survivin is involved in the regulation of cytokinesis and cell cycle progression, as well as participates in a variety of signaling pathways such as the p53, Wnt, hypoxia, transforming growth factor, and Notch signaling pathways. In this review, recent progress in understanding the molecular basis of survivin is discussed. Therapeutic strategies targeting survivin in preclinical studies are also briefly summarized. PMID:26918045

  13. Mechanical actuators at the nanoscale: molecular propellers, paddles and wheels

    NASA Astrophysics Data System (ADS)

    Vukovic, Lela; Wang, Boyang; Kral, Petr

    2010-03-01

    We model by molecular dynamics simulations nanosystems that could realize mechanical action in nanofluidics. First, we study molecular propellers formed by carbon nanotube rotors with attached aromatic blades that can pump liquids with efficiency dependent on the chemistry of the liquid-blade interface [1]. Next, we investigate nanorods with photoactive surfaces that can roll on water when driven by light [2]. Their rolling motion is realized when chromophores attached to their surfaces become anisotropically polarized by light and attracted to water. Finally, we examine nanoscale pumping induced by deformable nanoscale blades [3]. We show that the length, polarity, frequency and amplitude of oscillations of the nanoblades control their efficiency of water pumping.[4pt] [1] B. Wang and P. Kr'al, . Rev. Lett. 98, 266102 (2007).[0pt] [2] L. Vukovic and P. Kr'al, submitted.[0pt] [3] L. Vukovic, D. Astumian and P. Kr'al, in preparation.

  14. A systems approach to chile harvest mechanization

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This article reviews nearly half a century of published research on harvest mechanization of C. annuum var. annuum cultivars, focusing on chile for canning and fresh markets. At present, most of the crop is still harvested by hand, displacing production to locations where labor costs are low. Mech...

  15. Molecular interactions and crystal packing in nematogen: Computational thermodynamic approach

    NASA Astrophysics Data System (ADS)

    Lakshmi Praveen, P.; Ojha, Durga P.

    2011-10-01

    A computational thermodynamic approach of molecular interactions in a nematogen p-n-alkyl benzoic acid ( nBAC) molecule with an alkyl group butyl (4BAC) has been carried out with respect to translational and orientational motion. The atomic net charge and dipole moment at each atomic center were evaluated using the complete neglect differential overlap (CNDO/2) method. The modified Rayleigh-Schrödinger perturbation theory along with multicentered-multipole expansion method were employed to evaluate long-range intermolecular interactions, while a 6-exp potential function was assumed for short-range interactions. Various possible geometrical arrangements of molecular pairs with regard to different energy components were considered, and the energetically favorable configuration was found to understand the crystal packing picture. Furthermore, these interaction energy values are taken as input to calculate the configurational entropy at room temperature (300 K), nematic-isotropic transition temperature (386 K) and above transition temperature (450 K) during different modes of interactions. An attempt has been made to describe interactions in a nematogen at molecular level, through which one can simplify the system to make the model computationally feasible in understanding the delicate interplay between energy and entropy, that accounts for mesomorphism and there by to analyze the molecular structure of a nematogen.

  16. Molecular beacons: a new approach to plant virus detection.

    PubMed

    Eun, A J; Wong, S M

    2000-03-01

    ABSTRACT Molecular beacons are single-stranded nucleic acid molecules with a stem-loop conformation. The stem portion consists of complementary sequences at the 5' and 3' terminals of the molecule, while the loop portion consists of probe sequences that are complementary to the target sequences of choice. A fluorescent moiety is attached to one end, while a quenching moiety is attached to the opposite end. Reverse transcription-polymerase chain reactions are carried out with primers that amplify specific genome sequences of interest, yielding targets complementary to their respective molecular beacons for subsequent detection. Here, we have designed four molecular beacons specific to the RNA-dependent RNA polymerase and coat protein genes of two orchid viruses, namely Cymbidium mosaic virus (CymMV) and Odontoglossum ringspot virus (ORSV). This technology is successfully applied to detect as little as 0.5 ng of viral RNA of both orchid viruses simultaneously in 100 mg of coinfected Oncidium orchid leaves. This rapid and specific technique is applicable to the orchid industry, which routinely carries out virus indexing and screening for virus-resistant cultivars. We belief that use of this molecular beacon approach can be extended to the detection of multiple plant viruses in various crops.

  17. Combined quantum mechanics/molecular mechanics (QM/MM) methods in computational enzymology.

    PubMed

    van der Kamp, Marc W; Mulholland, Adrian J

    2013-04-23

    Computational enzymology is a rapidly maturing field that is increasingly integral to understanding mechanisms of enzyme-catalyzed reactions and their practical applications. Combined quantum mechanics/molecular mechanics (QM/MM) methods are important in this field. By treating the reacting species with a quantum mechanical method (i.e., a method that calculates the electronic structure of the active site) and including the enzyme environment with simpler molecular mechanical methods, enzyme reactions can be modeled. Here, we review QM/MM methods and their application to enzyme-catalyzed reactions to investigate fundamental and practical problems in enzymology. A range of QM/MM methods is available, from cheaper and more approximate methods, which can be used for molecular dynamics simulations, to highly accurate electronic structure methods. We discuss how modeling of reactions using such methods can provide detailed insight into enzyme mechanisms and illustrate this by reviewing some recent applications. We outline some practical considerations for such simulations. Further, we highlight applications that show how QM/MM methods can contribute to the practical development and application of enzymology, e.g., in the interpretation and prediction of the effects of mutagenesis and in drug and catalyst design.

  18. Description of ionization in the molecular approach to atomic collisions

    SciTech Connect

    Harel, C.; Jouin, H.; Pons, B.; Errea, L.F.; Mendez, L.; Riera, A.

    1997-01-01

    Molecular treatments of atomic collisions have traditionally been restricted to low nuclear velocities because of their failure to reproduce the fall of the capture cross sections at higher velocities. The limitation has recently been seen to be due to their description of ionizing processes. This feature is shown here to be a general one for multicharged ion-atom collisions. Its origin and characteristics are described and illustrated for the prototypical Li{sup 3+}+H(1s) reaction. Ionization appears as a result of the inertia of the electron cloud to adiabatically follow the nuclear motion. This gives rise to nonadiabatic transitions, which represent an ionizing flux whenever the nuclear velocity is high enough that the energy of the traveling molecular orbitals involved is positive in both moving atomic reference frames. Two strongly connected mechanisms appear, corresponding to the relative translational and rotational nuclear motions. Because of the finiteness of the basis, these mechanisms terminate with unphysical trapping effects. While interesting {ital per se}, knowledge of these features is also useful with respect to improving molecular treatments of atomic collisions with the addition of pseudostates. {copyright} {ital 1996} {ital The American Physical Society}

  19. Steered Molecular Dynamics Methods Applied to Enzyme Mechanism and Energetics.

    PubMed

    Ramírez, C L; Martí, M A; Roitberg, A E

    2016-01-01

    One of the main goals of chemistry is to understand the underlying principles of chemical reactions, in terms of both its reaction mechanism and the thermodynamics that govern it. Using hybrid quantum mechanics/molecular mechanics (QM/MM)-based methods in combination with a biased sampling scheme, it is possible to simulate chemical reactions occurring inside complex environments such as an enzyme, or aqueous solution, and determining the corresponding free energy profile, which provides direct comparison with experimental determined kinetic and equilibrium parameters. Among the most promising biasing schemes is the multiple steered molecular dynamics method, which in combination with Jarzynski's Relationship (JR) allows obtaining the equilibrium free energy profile, from a finite set of nonequilibrium reactive trajectories by exponentially averaging the individual work profiles. However, obtaining statistically converged and accurate profiles is far from easy and may result in increased computational cost if the selected steering speed and number of trajectories are inappropriately chosen. In this small review, using the extensively studied chorismate to prephenate conversion reaction, we first present a systematic study of how key parameters such as pulling speed, number of trajectories, and reaction progress are related to the resulting work distributions and in turn the accuracy of the free energy obtained with JR. Second, and in the context of QM/MM strategies, we introduce the Hybrid Differential Relaxation Algorithm, and show how it allows obtaining more accurate free energy profiles using faster pulling speeds and smaller number of trajectories and thus smaller computational cost.

  20. Sexual polyploidization in plants – cytological mechanisms and molecular regulation

    PubMed Central

    De Storme, Nico; Geelen, Danny

    2013-01-01

    In the plant kingdom, events of whole genome duplication or polyploidization are generally believed to occur via alterations of the sexual reproduction process. Thereby, diploid pollen and eggs are formed that contain the somatic number of chromosomes rather than the gametophytic number. By participating in fertilization, these so-called 2n gametes generate polyploid offspring and therefore constitute the basis for the establishment of polyploidy in plants. In addition, diplogamete formation, through meiotic restitution, is an essential component of apomixis and also serves as an important mechanism for the restoration of F1 hybrid fertility. Characterization of the cytological mechanisms and molecular factors underlying 2n gamete formation is therefore not only relevant for basic plant biology and evolution, but may also provide valuable cues for agricultural and biotechnological applications (e.g. reverse breeding, clonal seeds). Recent data have provided novel insights into the process of 2n pollen and egg formation and have revealed multiple means to the same end. Here, we summarize the cytological mechanisms and molecular regulatory networks underlying 2n gamete formation, and outline important mitotic and meiotic processes involved in the ectopic induction of sexual polyploidization. PMID:23421646

  1. Steered Molecular Dynamics Methods Applied to Enzyme Mechanism and Energetics.

    PubMed

    Ramírez, C L; Martí, M A; Roitberg, A E

    2016-01-01

    One of the main goals of chemistry is to understand the underlying principles of chemical reactions, in terms of both its reaction mechanism and the thermodynamics that govern it. Using hybrid quantum mechanics/molecular mechanics (QM/MM)-based methods in combination with a biased sampling scheme, it is possible to simulate chemical reactions occurring inside complex environments such as an enzyme, or aqueous solution, and determining the corresponding free energy profile, which provides direct comparison with experimental determined kinetic and equilibrium parameters. Among the most promising biasing schemes is the multiple steered molecular dynamics method, which in combination with Jarzynski's Relationship (JR) allows obtaining the equilibrium free energy profile, from a finite set of nonequilibrium reactive trajectories by exponentially averaging the individual work profiles. However, obtaining statistically converged and accurate profiles is far from easy and may result in increased computational cost if the selected steering speed and number of trajectories are inappropriately chosen. In this small review, using the extensively studied chorismate to prephenate conversion reaction, we first present a systematic study of how key parameters such as pulling speed, number of trajectories, and reaction progress are related to the resulting work distributions and in turn the accuracy of the free energy obtained with JR. Second, and in the context of QM/MM strategies, we introduce the Hybrid Differential Relaxation Algorithm, and show how it allows obtaining more accurate free energy profiles using faster pulling speeds and smaller number of trajectories and thus smaller computational cost. PMID:27497165

  2. Molecular mechanisms of dominance evolution in Müllerian mimicry.

    PubMed

    Llaurens, V; Joron, M; Billiard, S

    2015-12-01

    Natural selection acting on dominance between adaptive alleles at polymorphic loci can be sufficiently strong for dominance to evolve. However, the molecular mechanisms underlying such evolution are generally unknown. Here, using Müllerian mimicry as a case-study for adaptive morphological variation, we present a theoretical analysis of the invasion of dominance modifiers altering gene expression through different molecular mechanisms. Toxic species involved in Müllerian mimicry exhibit warning coloration, and converge morphologically with other toxic species of the local community, due to positive frequency-dependent selection acting on these colorations. Polymorphism in warning coloration may be maintained by migration-selection balance with fine scale spatial heterogeneity. We modeled a dominance modifier locus altering the expression of the warning coloration locus, targeting one or several alleles, acting in cis or trans, and either enhancing or repressing expression. We confirmed that dominance could evolve when balanced polymorphism was maintained at the color locus. Dominance evolution could result from modifiers enhancing one allele specifically, irrespective of their linkage with the targeted locus. Nonspecific enhancers could also persist in populations, at frequencies tightly depending on their linkage with the targeted locus. Altogether, our results identify which mechanisms of expression alteration could lead to dominance evolution in polymorphic mimicry.

  3. United polarizable multipole water model for molecular mechanics simulation

    NASA Astrophysics Data System (ADS)

    Qi, Rui; Wang, Lee-Ping; Wang, Qiantao; Pande, Vijay S.; Ren, Pengyu

    2015-07-01

    We report the development of a united AMOEBA (uAMOEBA) polarizable water model, which is computationally 3-5 times more efficient than the three-site AMOEBA03 model in molecular dynamics simulations while providing comparable accuracy for gas-phase and liquid properties. In this coarse-grained polarizable water model, both electrostatic (permanent and induced) and van der Waals representations have been reduced to a single site located at the oxygen atom. The permanent charge distribution is described via the molecular dipole and quadrupole moments and the many-body polarization via an isotropic molecular polarizability, all located at the oxygen center. Similarly, a single van der Waals interaction site is used for each water molecule. Hydrogen atoms are retained only for the purpose of defining local frames for the molecular multipole moments and intramolecular vibrational modes. The parameters have been derived based on a combination of ab initio quantum mechanical and experimental data set containing gas-phase cluster structures and energies, and liquid thermodynamic properties. For validation, additional properties including dimer interaction energy, liquid structures, self-diffusion coefficient, and shear viscosity have been evaluated. The results demonstrate good transferability from the gas to the liquid phase over a wide range of temperatures, and from nonpolar to polar environments, due to the presence of molecular polarizability. The water coordination, hydrogen-bonding structure, and dynamic properties given by uAMOEBA are similar to those derived from the all-atom AMOEBA03 model and experiments. Thus, the current model is an accurate and efficient alternative for modeling water.

  4. United polarizable multipole water model for molecular mechanics simulation.

    PubMed

    Qi, Rui; Wang, Lee-Ping; Wang, Qiantao; Pande, Vijay S; Ren, Pengyu

    2015-07-01

    We report the development of a united AMOEBA (uAMOEBA) polarizable water model, which is computationally 3-5 times more efficient than the three-site AMOEBA03 model in molecular dynamics simulations while providing comparable accuracy for gas-phase and liquid properties. In this coarse-grained polarizable water model, both electrostatic (permanent and induced) and van der Waals representations have been reduced to a single site located at the oxygen atom. The permanent charge distribution is described via the molecular dipole and quadrupole moments and the many-body polarization via an isotropic molecular polarizability, all located at the oxygen center. Similarly, a single van der Waals interaction site is used for each water molecule. Hydrogen atoms are retained only for the purpose of defining local frames for the molecular multipole moments and intramolecular vibrational modes. The parameters have been derived based on a combination of ab initio quantum mechanical and experimental data set containing gas-phase cluster structures and energies, and liquid thermodynamic properties. For validation, additional properties including dimer interaction energy, liquid structures, self-diffusion coefficient, and shear viscosity have been evaluated. The results demonstrate good transferability from the gas to the liquid phase over a wide range of temperatures, and from nonpolar to polar environments, due to the presence of molecular polarizability. The water coordination, hydrogen-bonding structure, and dynamic properties given by uAMOEBA are similar to those derived from the all-atom AMOEBA03 model and experiments. Thus, the current model is an accurate and efficient alternative for modeling water.

  5. United polarizable multipole water model for molecular mechanics simulation

    SciTech Connect

    Qi, Rui; Wang, Qiantao; Ren, Pengyu; Wang, Lee-Ping; Pande, Vijay S.

    2015-07-07

    We report the development of a united AMOEBA (uAMOEBA) polarizable water model, which is computationally 3–5 times more efficient than the three-site AMOEBA03 model in molecular dynamics simulations while providing comparable accuracy for gas-phase and liquid properties. In this coarse-grained polarizable water model, both electrostatic (permanent and induced) and van der Waals representations have been reduced to a single site located at the oxygen atom. The permanent charge distribution is described via the molecular dipole and quadrupole moments and the many-body polarization via an isotropic molecular polarizability, all located at the oxygen center. Similarly, a single van der Waals interaction site is used for each water molecule. Hydrogen atoms are retained only for the purpose of defining local frames for the molecular multipole moments and intramolecular vibrational modes. The parameters have been derived based on a combination of ab initio quantum mechanical and experimental data set containing gas-phase cluster structures and energies, and liquid thermodynamic properties. For validation, additional properties including dimer interaction energy, liquid structures, self-diffusion coefficient, and shear viscosity have been evaluated. The results demonstrate good transferability from the gas to the liquid phase over a wide range of temperatures, and from nonpolar to polar environments, due to the presence of molecular polarizability. The water coordination, hydrogen-bonding structure, and dynamic properties given by uAMOEBA are similar to those derived from the all-atom AMOEBA03 model and experiments. Thus, the current model is an accurate and efficient alternative for modeling water.

  6. Anti-Inflammatory Drug Design Using a Molecular Hybridization Approach

    PubMed Central

    Bosquesi, Priscila Longhin; Melo, Thais Regina Ferreira; Vizioli, Ednir Oliveira; dos Santos, Jean Leandro; Chung, Man Chin

    2011-01-01

    The design of new drugs with better physiochemical properties, adequate absorption, distribution, metabolism, and excretion, effective pharmacologic potency and lacking toxicity remains is a challenge. Inflammation is the initial trigger of several different diseases, such as Alzheimer's disease, asthma, atherosclerosis, colitis, rheumatoid arthritis, depression, cancer; and disorders such as obesity and sexual dysfunction. Although inflammation is not the direct cause of these disorders, inflammatory processes often increase related pain and suffering. New anti-inflammatory drugs developed using molecular hybridization techniques to obtain multiple-ligand drugs can act at one or multiple targets, allowing for synergic action and minimizing toxicity. This work is a review of new anti-inflammatory drugs developed using the molecular modification approach.

  7. Model-free simulation approach to molecular diffusion tensors.

    PubMed

    Chevrot, Guillaume; Hinsen, Konrad; Kneller, Gerald R

    2013-10-21

    In the present work, we propose a simple model-free approach for the computation of molecular diffusion tensors from molecular dynamics trajectories. The method uses a rigid body trajectory of the molecule under consideration, which is constructed a posteriori by an accumulation of quaternion-based superposition fits of consecutive conformations. From the rigid body trajectory, we compute the translational and angular velocities of the molecule and by integration of the latter also the corresponding angular trajectory. All quantities can be referred to the laboratory frame and a molecule-fixed frame. The 6 × 6 diffusion tensor is computed from the asymptotic slope of the tensorial mean square displacement and, for comparison, also from the Kubo integral of the velocity correlation tensor. The method is illustrated for two simple model systems - a water molecule and a lysozyme molecule in bulk water. We give estimations of the statistical accuracy of the calculations. PMID:24160503

  8. Model-free simulation approach to molecular diffusion tensors

    NASA Astrophysics Data System (ADS)

    Chevrot, Guillaume; Hinsen, Konrad; Kneller, Gerald R.

    2013-10-01

    In the present work, we propose a simple model-free approach for the computation of molecular diffusion tensors from molecular dynamics trajectories. The method uses a rigid body trajectory of the molecule under consideration, which is constructed a posteriori by an accumulation of quaternion-based superposition fits of consecutive conformations. From the rigid body trajectory, we compute the translational and angular velocities of the molecule and by integration of the latter also the corresponding angular trajectory. All quantities can be referred to the laboratory frame and a molecule-fixed frame. The 6 × 6 diffusion tensor is computed from the asymptotic slope of the tensorial mean square displacement and, for comparison, also from the Kubo integral of the velocity correlation tensor. The method is illustrated for two simple model systems - a water molecule and a lysozyme molecule in bulk water. We give estimations of the statistical accuracy of the calculations.

  9. Molecular mechanisms in autoimmune type 1 diabetes: a critical review.

    PubMed

    Xie, Zhiguo; Chang, Christopher; Zhou, Zhiguang

    2014-10-01

    Autoimmune type 1 diabetes is characterized by selective destruction of insulin-secreting beta cells in the pancreas of genetically susceptible individuals. The mechanisms underlying the development of type 1 diabetes are not fully understood. However, a widely accepted point is that type 1 diabetes is caused by a combination of genetic and environmental factors. Although most type 1 diabetes patients do not have a family history, genetic susceptibility does play a vital role in beta cell autoimmunity and destruction. Human leukocyte antigen (HLA) regions are the strongest genetic determinants, which can contribute 40-50 % of the genetic risk to type 1 diabetes. Other genes, including INS also contribute to disease risk. The mechanisms of the susceptible genes in type 1 diabetes may relate to their respective roles in antigen presentation, beta cell autoimmunity, immune tolerance, and autoreactive T cell response. Environmental susceptibility factors also contribute to the risk of developing type 1 diabetes. From an epigenetic standpoint, the pathologic mechanisms involved in the development of type 1 diabetes may include DNA methylation, histone modification, microRNA, and molecular mimicry. These mechanisms may act through regulating of gene expression, thereby affecting the immune system response toward islet beta cells. One of the characteristics of type 1 diabetes is the recognition of islet autoantigens by autoreactive CD4(+) and CD8(+) T cells and autoantibodies. Autoantibodies against islet autoantigens are involved in autoantigen processing and presentation by HLA molecules. This review will mainly focus on the molecular mechanism by which genetic, epigenetic, and environmental factors contribute to the risk of type 1 diabetes. PMID:24752371

  10. Molecular mechanisms in autoimmune type 1 diabetes: a critical review.

    PubMed

    Xie, Zhiguo; Chang, Christopher; Zhou, Zhiguang

    2014-10-01

    Autoimmune type 1 diabetes is characterized by selective destruction of insulin-secreting beta cells in the pancreas of genetically susceptible individuals. The mechanisms underlying the development of type 1 diabetes are not fully understood. However, a widely accepted point is that type 1 diabetes is caused by a combination of genetic and environmental factors. Although most type 1 diabetes patients do not have a family history, genetic susceptibility does play a vital role in beta cell autoimmunity and destruction. Human leukocyte antigen (HLA) regions are the strongest genetic determinants, which can contribute 40-50 % of the genetic risk to type 1 diabetes. Other genes, including INS also contribute to disease risk. The mechanisms of the susceptible genes in type 1 diabetes may relate to their respective roles in antigen presentation, beta cell autoimmunity, immune tolerance, and autoreactive T cell response. Environmental susceptibility factors also contribute to the risk of developing type 1 diabetes. From an epigenetic standpoint, the pathologic mechanisms involved in the development of type 1 diabetes may include DNA methylation, histone modification, microRNA, and molecular mimicry. These mechanisms may act through regulating of gene expression, thereby affecting the immune system response toward islet beta cells. One of the characteristics of type 1 diabetes is the recognition of islet autoantigens by autoreactive CD4(+) and CD8(+) T cells and autoantibodies. Autoantibodies against islet autoantigens are involved in autoantigen processing and presentation by HLA molecules. This review will mainly focus on the molecular mechanism by which genetic, epigenetic, and environmental factors contribute to the risk of type 1 diabetes.

  11. Molecular mechanisms underlying the onset of degenerative aortic valve disease.

    PubMed

    Hakuno, Daihiko; Kimura, Naritaka; Yoshioka, Masatoyo; Fukuda, Keiichi

    2009-01-01

    Morbidity from degenerative aortic valve disease is increasing worldwide, concomitant with the ageing of the general population and the habitual consumption of diets high in calories and cholesterol. Immunohistologic studies have suggested that the molecular mechanism occurring in the degenerate aortic valve resembles that of atherosclerosis, prompting the testing of HMG CoA reductase inhibitors (statins) for the prevention of progression of native and bioprosthetic aortic valve degeneration. However, the effects of these therapies remain controversial. Although the molecular mechanisms underlying the onset of aortic valve degeneration are largely unknown, research in this area is advancing rapidly. The signaling components involved in embryonic valvulogenesis, such as Wnt, TGF-beta(1), BMP, and Notch, are also involved in the onset of aortic valve degeneration. Furthermore, investigations into extracellular matrix remodeling, angiogenesis, and osteogenesis in the aortic valve have been reported. Having noted avascularity of normal cardiac valves, we recently identified chondromodulin-I (chm-I) as a crucial anti-angiogenic factor. The expression of chm-I is restricted to cardiac valves from late embryogenesis to adulthood in the mouse, rat, and human. In human degenerate atherosclerotic valves, the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases and angiogenesis is observed in the area of chm-I downregulation. Gene targeting of chm-I resulted in VEGF expression, angiogenesis, and calcification in the aortic valves of aged mice, and aortic stenosis is detected by echocardiography, indicating that chm-I is a crucial factor for maintaining normal cardiac valvular function by preventing angiogenesis. The present review focuses on the animal models of aortic valve degeneration and recent studies on the molecular mechanisms underlying the onset of degenerative aortic valve disease. PMID:18766323

  12. Quantum mechanics/molecular mechanics modeling of fatty acid amide hydrolase reactivation distinguishes substrate from irreversible covalent inhibitors.

    PubMed

    Lodola, Alessio; Capoferri, Luigi; Rivara, Silvia; Tarzia, Giorgio; Piomelli, Daniele; Mulholland, Adrian; Mor, Marco

    2013-03-28

    Carbamate and urea derivatives are important classes of fatty acid amide hydrolase (FAAH) inhibitors that carbamoylate the active-site nucleophile Ser241. In the present work, the reactivation mechanism of carbamoylated FAAH is investigated by means of a quantum mechanics/molecular mechanics (QM/MM) approach. The potential energy surfaces for decarbamoylation of FAAH covalent adducts, derived from the O-aryl carbamate URB597 and from the N-piperazinylurea JNJ1661610, were calculated and compared to that for deacylation of FAAH acylated by the substrate oleamide. Calculations show that a carbamic group bound to Ser241 prevents efficient stabilization of transition states of hydrolysis, leading to large increments in the activation barrier. Moreover, the energy barrier for the piperazine carboxylate was significantly lower than that for the cyclohexyl carbamate derived from URB597. This is consistent with experimental data showing slowly reversible FAAH inhibition for the N-piperazinylurea inhibitor and irreversible inhibition for URB597.

  13. Explaining the "Pulse of Protoplasm": the search for molecular mechanisms of protoplasmic streaming.

    PubMed

    Dietrich, Michael R

    2015-01-01

    Explanations for protoplasmic streaming began with appeals to contraction in the eighteenth century and ended with appeals to contraction in the twentieth. During the intervening years, biologists proposed a diverse array of mechanisms for streaming motions. This paper focuses on the re-emergence of contraction among the molecular mechanisms proposed for protoplasmic streaming during the twentieth century. The revival of contraction is a result of a broader transition from colloidal chemistry to a macromolecular approach to the chemistry of proteins, the recognition of the phenomena of shuttle streaming and the pulse of protoplasm, and the influential analogy between protoplasmic streaming and muscle contraction.

  14. A Structural and Molecular Approach for the Study Biomarkers

    NASA Technical Reports Server (NTRS)

    Thomas-Keprta, Kathie; Vali, Hojatollah; Sears, S. Kelly; Roh, Yul

    2001-01-01

    Investigation of the nucleation and growth of crystals in both abiotic and biotic systems is critical to seemingly diverse disciplines of geology, biology, environmental science, and astrobiology. While there are abundant studies devoted to the determination of the structure and composition of inorganic crystals, as well as to the development of thermodynamic and kinetic models, it is only recently that research efforts have been directed towards understanding mineralization in biological systems (i.e., biomineralization). Biomineralization refers to the processes by which living organisms form inorganic solids. Studies of the processes of biomineralization under low temperature aqueous conditions have focused primarily on magnetite forming bacteria and shell forming marine organisms. Many of the biological building materials consist of inorganic minerals (calcium carbonate, calcium phosphate, silica or iron oxide) intricately combined with organic polymers (like proteins). More recently, efforts have been undertaken to explore the nature of biological activities in ancient rocks. In the absence of well-preserved microorganisms or genetic material required for the polmerase chain reaction (PCR) method in molecular phylogenetic studies, using biominerals as biomarkers offers an alternative approach for the recognition of biogenic activity in both terrestrial and extraterrestrial environments. The primary driving force in biomineralization is the interaction between organic and inorganic phases. Thus, the investigation of the ultrastructure and the nature of reactions at the molecular level occurring at the interface between inorganic and organic phases is essential to understanding the processes leading to the nucleation and growth of crystals. It is recognized that crystal surfaces can serve as the substrate for the organization of organic molecules that lead to the formation of polymers and other complex organic molecules, and in discussions of the origins of life

  15. Molecular mechanisms of methicillin resistance in Staphylococcus aureus.

    PubMed

    Domínguez, M A; Liñares, J; Martín, R

    1997-09-01

    Methicillin-resistant Staphylococcus aureus (MRSA) strains are among the most common nosocomial pathogens. The most significant mechanism of resistance to methicillin in this-species is the acquisition of a genetic determinant (mecA gene). However, resistance seems to have a more complex molecular basis, since additional chromosomal material is involved in such resistance. Besides, overproduction of penicillinase and/or alterations in the PBPs can contribute to the formation of resistance phenotypes. Genetic and environmental factors leading to MRSA are reviewed.

  16. Molecular and Electrophysiological Mechanisms Underlying Cardiac Arrhythmogenesis in Diabetes Mellitus

    PubMed Central

    Tse, Vivian; Yeo, Jie Ming

    2016-01-01

    Diabetes is a common endocrine disorder with an ever increasing prevalence globally, placing significant burdens on our healthcare systems. It is associated with significant cardiovascular morbidities. One of the mechanisms by which it causes death is increasing the risk of cardiac arrhythmias. The aim of this article is to review the cardiac (ion channel abnormalities, electrophysiological and structural remodelling) and extracardiac factors (neural pathway remodelling) responsible for cardiac arrhythmogenesis in diabetes. It is concluded by an outline of molecular targets for future antiarrhythmic therapy for the diabetic population. PMID:27642609

  17. Buckling of microtubules: An insight by molecular and continuum mechanics

    SciTech Connect

    Zhang, Jin; Meguid, S. A.

    2014-10-27

    The molecular structural mechanics method has been extended to investigate the buckling of microtubules (MTs) with various configurations. The results indicate that for relative short MTs the shear deformation effect, rather than the nonlocal effect, is mainly responsible for the limitation of their widely used Euler beam description and the observed length-dependence of their bending stiffness. In addition, the configuration effect of MTs is also studied and considered as an explanation for the large scattering of the critical buckling force and bending stiffness observed in existing experiments. This configuration effect is also found to mainly originate from the geometry of the MTs and is mainly determined by the protofilament number.

  18. Molecular and Electrophysiological Mechanisms Underlying Cardiac Arrhythmogenesis in Diabetes Mellitus.

    PubMed

    Tse, Gary; Lai, Eric Tsz Him; Tse, Vivian; Yeo, Jie Ming

    2016-01-01

    Diabetes is a common endocrine disorder with an ever increasing prevalence globally, placing significant burdens on our healthcare systems. It is associated with significant cardiovascular morbidities. One of the mechanisms by which it causes death is increasing the risk of cardiac arrhythmias. The aim of this article is to review the cardiac (ion channel abnormalities, electrophysiological and structural remodelling) and extracardiac factors (neural pathway remodelling) responsible for cardiac arrhythmogenesis in diabetes. It is concluded by an outline of molecular targets for future antiarrhythmic therapy for the diabetic population. PMID:27642609

  19. Molecular mechanisms of cisplatin resistance in cervical cancer

    PubMed Central

    Zhu, Haiyan; Luo, Hui; Zhang, Wenwen; Shen, Zhaojun; Hu, Xiaoli; Zhu, Xueqiong

    2016-01-01

    Patients with advanced or recurrent cervical cancer have poor prognosis, and their 1-year survival is only 10%–20%. Chemotherapy is considered as the standard treatment for patients with advanced or recurrent cervical cancer, and cisplatin appears to treat the disease effectively. However, resistance to cisplatin may develop, thus substantially compromising the efficacy of cisplatin to treat advanced or recurrent cervical cancer. In this article, we systematically review the recent literature and summarize the recent advances in our understanding of the molecular mechanisms underlying cisplatin resistance in cervical cancer. PMID:27354763

  20. Molecular mechanisms associated with 46,XX disorders of sex development.

    PubMed

    Knarston, Ingrid; Ayers, Katie; Sinclair, Andrew

    2016-03-01

    In the female gonad, distinct signalling pathways activate ovarian differentiation while repressing the formation of testes. Human disorders of sex development (DSDs), such as 46,XX DSDs, can arise when this signalling is aberrant. Here we review the current understanding of the genetic mechanisms that control gonadal development, with particular emphasis on those that drive or inhibit ovarian differentiation. We discuss how disruption to these molecular pathways can lead to 46,XX disorders of ovarian development. Finally, we look at recently characterized novel genes and pathways that contribute and speculate how advances in technology will aid in further characterization of normal and disrupted human ovarian development.

  1. [Biochemistry, molecular mechanism of action and biological effects of endotoxin].

    PubMed

    Burgmann, H; Breyer, S

    1995-01-01

    This review is a brief attempt at providing an overview of a subject of enormous complexity-endotoxins and the mediators associated with its biological effects. More specifically it deals with biochemistry and biology of endotoxin, detection of endotoxin with the Limulus amebocyte lysate test, the molecular mechanisms and biological effects, and in the last part with future aspects of therapeutical strategies. It seems certain that the subject will become even more complex and possibly controversial as scientific knowledge further involves. However, because of the high mortality rate of patients suffering from gram-negative sepsis all efforts have to be made to find effective therapeutical strategies.

  2. The mechanism of selective molecular capture in carbon nanotube networks.

    PubMed

    Wan, Yu; Guan, Jun; Yang, Xudong; Zheng, Quanshui; Xu, Zhiping

    2014-07-28

    Recently, air pollution issues have drawn significant attention to the development of efficient air filters, and one of the most promising materials for this purpose is nanofibers. We explore here the mechanism of selective molecular capture of volatile organic compounds in carbon nanotube networks by performing atomistic simulations. The results are discussed with respect to the two key parameters that define the performance of nanofiltration, i.e. the capture efficiency and flow resistance, which demonstrate the advantages of carbon nanotube networks with high surface-to-volume ratio and atomistically smooth surfaces. We also reveal the important roles of interfacial adhesion and diffusion that govern selective gas transport through the network.

  3. Molecular and Electrophysiological Mechanisms Underlying Cardiac Arrhythmogenesis in Diabetes Mellitus

    PubMed Central

    Tse, Vivian; Yeo, Jie Ming

    2016-01-01

    Diabetes is a common endocrine disorder with an ever increasing prevalence globally, placing significant burdens on our healthcare systems. It is associated with significant cardiovascular morbidities. One of the mechanisms by which it causes death is increasing the risk of cardiac arrhythmias. The aim of this article is to review the cardiac (ion channel abnormalities, electrophysiological and structural remodelling) and extracardiac factors (neural pathway remodelling) responsible for cardiac arrhythmogenesis in diabetes. It is concluded by an outline of molecular targets for future antiarrhythmic therapy for the diabetic population.

  4. Anisotropy induced Kondo splitting in a mechanically stretched molecular junction: A first-principles based study.

    PubMed

    Wang, Xiaoli; Hou, Dong; Zheng, Xiao; Yan, YiJing

    2016-01-21

    The magnetic anisotropy and Kondo phenomena in a mechanically stretched magnetic molecular junction are investigated by combining the density functional theory (DFT) and hierarchical equations of motion (HEOM) approach. The system is comprised of a magnetic complex Co(tpy-SH)2 sandwiched between adjacent gold electrodes, which is mechanically stretched in experiments done by Parks et al. [Science 328, 1370 (2010)]. The electronic structure and mechanical property of the stretched system are investigated via the DFT calculations. The HEOM approach is then employed to characterize the Kondo resonance features, based on the Anderson impurity model parameterized from the DFT results. It is confirmed that the ground state prefers the S = 1 local spin state. The structural properties, the magnetic anisotropy, and corresponding Kondo peak splitting in the axial stretching process are systematically evaluated. The results reveal that the strong electron correlations and the local magnetic properties of the molecule magnet are very sensitive to structural distortion. This work demonstrates that the combined DFT+HEOM approach could be useful in understanding and designing mechanically controlled molecular junctions.

  5. Molecular and biochemical mechanisms of drug resistance in fungi.

    PubMed

    Yamaguchi, H

    1999-01-01

    This paper reviews the current status of our understanding of resistance mechanisms of three major classes of antifungal drugs for systemic use, amphotericin B (AMPH), flucytosine (5-FC) and several azole antifungals, in particular fluconazole (FLCZ), at the molecular and cellular levels. Although the number of reports of AMPH- or 5-FC-resistant fungal species and strains is limited, several mechanisms of resistance have been described. AMPH-resistant Candida have a marked decrease in ergosterol content compared with AMPH-susceptible control isolates. A lesion in the UMP-pyrophosphorylase is the most frequent determinant of 5-FC resistance in C. albicans. Recently resistance of C. albicans to azoles has become an increasing problem. Extensive biochemical studies have highlighted a significant diversity in mechanisms conferring resistance to FLCZ and other azoles, which include alterations in sterol biosynthesis, target site, uptake and efflux. Among them, the most important mechanism clinically is reduced access of the drug to the intracellular P450 14 DM target, probably because of the action of a multidrug resistance efflux pump, and overproduction of that target. However, other possible resistance mechanisms for azoles remain to be identified.

  6. Origin of microbial life: Nano- and molecular events, thermodynamics/entropy, quantum mechanisms and genetic instructions.

    PubMed

    Trevors, J T

    2011-03-01

    Currently, there are no agreed upon mechanisms and supporting evidence for the origin of the first microbial cells on the Earth. However, some hypotheses have been proposed with minimal supporting evidence and experimentation/observations. The approach taken in this article is that life originated at the nano- and molecular levels of biological organization, using quantum mechanic principles that became manifested as classical microbial cell(s), allowing the origin of microbial life on the Earth with a core or minimal, organic, genetic code containing the correct instructions for cell(s) for growth and division, in a micron dimension environment, with a local entropy range conducive to life (present about 4 billion years ago), and obeying the laws of thermodynamics. An integrated approach that explores all encompassing factors necessary for the origin of life, may bring forth plausible hypotheses (and mechanisms) with much needed supporting experimentation and observations for an origin of life theory.

  7. Supersymmetric Liouville theory: A statistical mechanical approach

    SciTech Connect

    Barrozo, M.C.; Belvedere, L.V.

    1996-02-01

    The statistical mechanical system associated with the two-dimensional supersymmetric Liouville theory is obtained through an infrared-finite perturbation expansion. Considering the system confined in a finite volume and in the presence of a uniform neutralizing background, we show that the grand-partition function of this system describes a one-component gas, in which the Boltzmann factor is weighted by an integration over the Grassmann variables. This weight function introduces the dimensional reduction phenomenon. After performing the thermodynamic limit, the resulting supersymmetric quantum theory is translationally invariant. {copyright} {ital 1996 The American Physical Society.}

  8. Statistical mechanical approach to human language

    NASA Astrophysics Data System (ADS)

    Kosmidis, Kosmas; Kalampokis, Alkiviadis; Argyrakis, Panos

    2006-07-01

    We use the formulation of equilibrium statistical mechanics in order to study some important characteristics of language. Using a simple expression for the Hamiltonian of a language system, which is directly implied by the Zipf law, we are able to explain several characteristic features of human language that seem completely unrelated, such as the universality of the Zipf exponent, the vocabulary size of children, the reduced communication abilities of people suffering from schizophrenia, etc. While several explanations are necessarily only qualitative at this stage, we have, nevertheless, been able to derive a formula for the vocabulary size of children as a function of age, which agrees rather well with experimental data.

  9. Transport in molecular states language: Generalized quantum master equation approach

    NASA Astrophysics Data System (ADS)

    Esposito, Massimiliano; Galperin, Michael

    2009-05-01

    A simple scheme, capable of treating transport in molecular junctions in the language of many-body states, is presented. By introducing an ansatz in Liouville space, similar to the generalized Kadanoff-Baym approximation, a quantum master equation (QME)-like expression is derived starting from the exact equation of motion for Hubbard operators. Using an effective Liouville space propagation, a dressing similar to the standard diagrammatic one is proposed. The scheme is compared to the standard QME approach and its applicability to transport calculations is discussed.

  10. A Structural and Molecular Approach for the Study Biomarkers

    NASA Technical Reports Server (NTRS)

    Thomas-Keprta, Kathie; Vali, Hojatollah; Sears, S. Kelly; Roh, Yul

    2001-01-01

    Investigation of the nucleation and growth of crystals in both abiotic and biotic systems is critical to seemingly diverse disciplines of geology, biology, environmental science, and astrobiology. While there are abundant studies devoted to the determination of the structure and composition of inorganic crystals, as well as to the development of thermodynamic and kinetic models, it is only recently that research efforts have been directed towards understanding mineralization in biological systems (i.e., biomineralization). Biomineralization refers to the processes by which living organisms form inorganic solids. Studies of the processes of biomineralization under low temperature aqueous conditions have focused primarily on magnetite forming bacteria and shell forming marine organisms. Many of the biological building materials consist of inorganic minerals (calcium carbonate, calcium phosphate, silica or iron oxide) intricately combined with organic polymers (like proteins). More recently, efforts have been undertaken to explore the nature of biological activities in ancient rocks. In the absence of well-preserved microorganisms or genetic material required for the polmerase chain reaction (PCR) method in molecular phylogenetic studies, using biominerals as biomarkers offers an alternative approach for the recognition of biogenic activity in both terrestrial and extraterrestrial environments. The primary driving force in biomineralization is the interaction between organic and inorganic phases. Thus, the investigation of the ultrastructure and the nature of reactions at the molecular level occurring at the interface between inorganic and organic phases is essential to understanding the processes leading to the nucleation and growth of crystals. It is recognized that crystal surfaces can serve as the substrate for the organization of organic molecules that lead to the formation of polymers and other complex organic molecules, and in discussions of the origins of life

  11. Using quantum mechanical approaches to study biological systems.

    PubMed

    Merz, Kenneth M

    2014-09-16

    Conspectus Quantum mechanics (QM) has revolutionized our understanding of the structure and reactivity of small molecular systems. Given the tremendous impact of QM in this research area, it is attractive to believe that this could also be brought into the biological realm where systems of a few thousand atoms and beyond are routine. Applying QM methods to biological problems brings an improved representation to these systems by the direct inclusion of inherently QM effects such as polarization and charge transfer. Because of the improved representation, novel insights can be gleaned from the application of QM tools to biomacromolecules in aqueous solution. To achieve this goal, the computational bottlenecks of QM methods had to be addressed. In semiempirical theory, matrix diagonalization is rate limiting, while in density functional theory or Hartree-Fock theory electron repulsion integral computation is rate-limiting. In this Account, we primarily focus on semiempirical models where the divide and conquer (D&C) approach linearizes the matrix diagonalization step with respect to the system size. Through the D&C approach, a number of applications to biological problems became tractable. Herein, we provide examples of QM studies on biological systems that focus on protein solvation as viewed by QM, QM enabled structure-based drug design, and NMR and X-ray biological structure refinement using QM derived restraints. Through the examples chosen, we show the power of QM to provide novel insights into biological systems, while also impacting practical applications such as structure refinement. While these methods can be more expensive than classical approaches, they make up for this deficiency by the more realistic modeling of the electronic nature of biological systems and in their ability to be broadly applied. Of the tools and applications discussed in this Account, X-ray structure refinement using QM models is now generally available to the community in the

  12. Molecular Mechanisms of Survival Strategies in Extreme Conditions

    PubMed Central

    Magazù, Salvatore; Migliardo, Federica; Gonzalez, Miguel A.; Mondelli, Claudia; Parker, Stewart F.; Vertessy, Beata G.

    2012-01-01

    Today, one of the major challenges in biophysics is to disclose the molecular mechanisms underlying biological processes. In such a frame, the understanding of the survival strategies in extreme conditions received a lot of attention both from the scientific and applicative points of view. Since nature provides precious suggestions to be applied for improving the quality of life, extremophiles are considered as useful model-systems. The main goal of this review is to present an overview of some systems, with a particular emphasis on trehalose playing a key role in several extremophile organisms. The attention is focused on the relation among the structural and dynamic properties of biomolecules and bioprotective mechanisms, as investigated by complementary spectroscopic techniques at low- and high-temperature values. PMID:25371270

  13. Anisotropic mechanical properties of graphene: a molecular dynamics study

    NASA Astrophysics Data System (ADS)

    Yu, Ming; Zeng, Anna; Zeng, Kevin

    2014-03-01

    The anisotropic mechanical properties of monolayer graphene with different shapes have been studied using an efficient quantum mechanics molecular dynamics scheme based on a semi-empirical Hamiltonian (refereed as SCED-LCAO) [PRB 74, 15540; PHYSE 42, 1]. We have found the anisotropic nature of the membrane stress. The stresses along the armchair direction are slightly stronger than that along the zigzag direction, showing strong direction selectivity. The graphene with the rectangular shape could sustain strong load (i . e ., 20%) in both armchair and zigzag directions. The graphene with the rhombus shape show large difference in the strain direction: it will quickly crack after 18 % of strain in armchair the direction, but slowly destroyed after 20% in the zigzag direction. The obtained 2D Young's modulus at infinitesimal strain and the third-order (effective nonlinear) elastic modulus are in good consistent with the experimental observation.

  14. RNA processing-associated molecular mechanisms of neurodegenerative diseases.

    PubMed

    Tang, Anna Y

    2016-08-01

    Dysfunctions of RNA processing and mutations of RNA binding proteins (RBPs) play a fundamental role in the pathogenesis of many neurodegenerative diseases. To elucidate the function of RNA processing and RBPs mutations in neuronal cells and to increase our understanding on the pathogenic mechanisms of neurodegeneration, I have reviewed recent advances on RNA processing-associated molecular mechanisms of neurodegenerative diseases, including RBPs-mediated dysfunction of RNA processing, dysfunctional microRNA (miRNA)-based regulation of gene expression, and oxidative RNA modification. I have focused on neurodegeneration induced by RBPs mutations, by dysfunction of miRNA regulation, and by the oxidized RNAs within neurons, and discuss how these dysfunctions have pathologically contributed to neurodegenerative diseases. The advances overviewed above will be valuable to basic investigation and clinical application of target diagnostic tests and therapies.

  15. Cellular and Molecular Mechanisms Underpinning Macrophage Activation during Remyelination

    PubMed Central

    Lloyd, Amy F.; Miron, Veronique E.

    2016-01-01

    Remyelination is an example of central nervous system (CNS) regeneration, whereby myelin is restored around demyelinated axons, re-establishing saltatory conduction and trophic/metabolic support. In progressive multiple sclerosis, remyelination is limited or fails altogether which is considered to contribute to axonal damage/loss and consequent disability. Macrophages have critical roles in both CNS damage and regeneration, such as remyelination. This diverse range in functions reflects the ability of macrophages to acquire tissue microenvironment-specific activation states. This activation is dynamically regulated during efficient regeneration, with a switch from pro-inflammatory to inflammation-resolution/pro-regenerative phenotypes. Although, some molecules and pathways have been implicated in the dynamic activation of macrophages, such as NFκB, the cellular and molecular mechanisms underpinning plasticity of macrophage activation are unclear. Identifying mechanisms regulating macrophage activation to pro-regenerative phenotypes may lead to novel therapeutic strategies to promote remyelination in multiple sclerosis. PMID:27446913

  16. Molecular Mechanisms of Two-Component Signal Transduction.

    PubMed

    Zschiedrich, Christopher P; Keidel, Victoria; Szurmant, Hendrik

    2016-09-25

    Two-component systems (TCS) comprising sensor histidine kinases and response regulator proteins are among the most important players in bacterial and archaeal signal transduction and also occur in reduced numbers in some eukaryotic organisms. Given their importance to cellular survival, virulence, and cellular development, these systems are among the most scrutinized bacterial proteins. In the recent years, a flurry of bioinformatics, genetic, biochemical, and structural studies have provided detailed insights into many molecular mechanisms that underlie the detection of signals and the generation of the appropriate response by TCS. Importantly, it has become clear that there is significant diversity in the mechanisms employed by individual systems. This review discusses the current knowledge on common themes and divergences from the paradigm of TCS signaling. An emphasis is on the information gained by a flurry of recent structural and bioinformatics studies.

  17. Molecular mechanism of resolving trinucleotide repeat hairpin by helicases.

    PubMed

    Qiu, Yupeng; Niu, Hengyao; Vukovic, Lela; Sung, Patrick; Myong, Sua

    2015-06-01

    Trinucleotide repeat (TNR) expansion is the root cause for many known congenital neurological and muscular disorders in human including Huntington's disease, fragile X syndrome, and Friedreich's ataxia. The stable secondary hairpin structures formed by TNR may trigger fork stalling during replication, causing DNA polymerase slippage and TNR expansion. Srs2 and Sgs1 are two helicases in yeast that resolve TNR hairpins during DNA replication and prevent genome expansion. Using single-molecule fluorescence, we investigated the unwinding mechanism by which Srs2 and Sgs1 resolves TNR hairpin and compared it with unwinding of duplex DNA. While Sgs1 unwinds both structures indiscriminately, Srs2 displays repetitive unfolding of TNR hairpin without fully unwinding it. Such activity of Srs2 shows dependence on the folding strength and the total length of TNR hairpin. Our results reveal a disparate molecular mechanism of Srs2 and Sgs1 that may contribute differently to efficient resolving of the TNR hairpin. PMID:26004439

  18. The molecular basis of mechanisms underlying polarization vision

    PubMed Central

    Roberts, Nicholas W.; Porter, Megan L.; Cronin, Thomas W.

    2011-01-01

    The underlying mechanisms of polarization sensitivity (PS) have long remained elusive. For rhabdomeric photoreceptors, questions remain over the high levels of PS measured experimentally. In ciliary photoreceptors, and specifically cones, little direct evidence supports any type of mechanism. In order to promote a greater interest in these fundamental aspects of polarization vision, we examined a varied collection of studies linking membrane biochemistry, protein–protein interactions, molecular ordering and membrane phase behaviour. While initially these studies may seem unrelated to polarization vision, a common narrative emerges. A surprising amount of evidence exists demonstrating the importance of protein–protein interactions in both rhabdomeric and ciliary photoreceptors, indicating the possible long-range ordering of the opsin protein for increased PS. Moreover, we extend this direction by considering how such protein paracrystalline organization arises in all cell types from controlled membrane phase behaviour and propose a universal pathway for PS to occur in both rhabdomeric and cone photoreceptors. PMID:21282166

  19. Molecular mechanism of size control in development and human diseases

    PubMed Central

    Yang, Xiaolong; Xu, Tian

    2011-01-01

    How multicellular organisms control their size is a fundamental question that fascinated generations of biologists. In the past 10 years, tremendous progress has been made toward our understanding of the molecular mechanism underlying size control. Original studies from Drosophila showed that in addition to extrinsic nutritional and hormonal cues, intrinsic mechanisms also play important roles in the control of organ size during development. Several novel signaling pathways such as insulin and Hippo-LATS signaling pathways have been identified that control organ size by regulating cell size and/or cell number through modulation of cell growth, cell division, and cell death. Later studies using mammalian cell and mouse models also demonstrated that the signaling pathways identified in flies are also conserved in mammals. Significantly, recent studies showed that dysregulation of size control plays important roles in the development of many human diseases such as cancer, diabetes, and hypertrophy. PMID:21483452

  20. High Cholesterol Deteriorates Bone Health: New Insights into Molecular Mechanisms

    PubMed Central

    Mandal, Chandi C.

    2015-01-01

    Many epidemiological studies show a positive connection between cardiovascular diseases and risk of osteoporosis, suggesting a role of hyperlipidemia and/or hypercholesterolemia in regulating osteoporosis. The majority of the studies indicated a correlation between high cholesterol and high LDL-cholesterol level with low bone mineral density, a strong predictor of osteoporosis. Similarly, bone metastasis is a serious complication of cancer for patients. Several epidemiological and basic studies have established that high cholesterol is associated with increased cancer risk. Moreover, osteoporotic bone environment predisposes the cancer cells for metastatic growth in the bone microenvironment. This review focuses on how cholesterol and cholesterol-lowering drugs (statins) regulate the functions of bone residential osteoblast and osteoclast cells to augment or to prevent bone deterioration. Moreover, this study provides an insight into molecular mechanisms of cholesterol-mediated bone deterioration. It also proposes a potential mechanism by which cellular cholesterol boosts cancer-induced bone metastasis. PMID:26557105

  1. Molecular Mechanisms of the Membrane Sculpting ESCRT Pathway

    PubMed Central

    Henne, William Mike; Stenmark, Harald; Emr, Scott D.

    2013-01-01

    The endosomal sorting complexes required for transport (ESCRT) drive multivesicular body (MVB) biogenesis and cytokinetic abscission. Originally identified through genetics and cell biology, more recent work has begun to elucidate the molecular mechanisms of ESCRT-mediated membrane remodeling, with special focus on the ESCRT-III complex. In particular, several light and electron microscopic studies provide high-resolution imaging of ESCRT-III rings and spirals that purportedly drive MVB morphogenesis and abscission. These studies highlight unifying principles to ESCRT-III function, in particular: (1) the ordered assembly of the ESCRT-III monomers into a heteropolymer, (2) ESCRT-III as a dynamic complex, and (3) the role of the AAA ATPase Vps4 as a contributing factor in membrane scission. Mechanistic comparisons of ESCRT-III function in MVB morphogenesis and cytokinesis suggest common mechanisms in membrane remodeling. PMID:24003212

  2. Huntington’s disease: underlying molecular mechanisms and emerging concepts

    PubMed Central

    Labbadia, John; Morimoto, Richard I.

    2013-01-01

    Huntington’s disease (HD) is a progressive neurodegenerative disorder for which no disease modifying treatments exist. Many molecular changes and cellular consequences that underlie HD are observed in other neurological disorders suggesting that common pathological mechanisms and pathways may exist. Recent findings have enhanced our understanding of the way cells regulate and respond to expanded polyglutamine proteins such as mutant huntingtin. These studies demonstrate that in addition to effects on folding, aggregation, and clearance pathways, a general transcriptional mechanism also dictates the expression of polyglutamine proteins. Here we summarize the key pathways and networks that are important in HD in the context of recent therapeutic advances and highlight how their interplay may be of relevance to other protein folding disorders. PMID:23768628

  3. Damage Mechanics Approach for Bearing Lifetime Prognostics

    NASA Astrophysics Data System (ADS)

    Qiu, Jing; Seth, Brij B.; Liang, Steven Y.; Zhang, Cheng

    2002-09-01

    The ability to achieve accurate bearing prognostics is critical to the optimal maintenance of rotating machinery in the interest of cost and productivity. However, techniques to real time predict the lifetime of a bearing under practical operating conditions have not been well developed. In this paper, a stiffness-based prognostic model for bearing systems based on vibration response analysis and damage mechanics is discussed. As the bearing system is considered as a single-degree-of-freedom vibratory system, its natural frequency and its acceleration amplitude at the natural frequency can be related to the system stiffness. On the other hand, the relationship between failure lifetime, running time and stiffness variation can be established from the damage mechanics. Combining the above two, the natural frequency and the acceleration amplitude of a bearing system can be related to its running time and failure lifetime. Thus, the failure lifetime of a bearing system can be predicted on-line based on vibration measurement. Experiments have been performed on a tapered roller bearing life testing stand under various operation conditions to calibrate and to validate the proposed model. The comparison between model-calculated data and experimental results indicates that this model can be used to effectively predict the failure lifetime and the remaining life of a bearing system.

  4. An atomistic approach to viral mechanical oscillations

    NASA Astrophysics Data System (ADS)

    Sankey, Otto F.

    2009-03-01

    Viruses are the simplest ``life'' form. These parasites reproduce by borrowing the machinery of their host cell. Many are pathogenic to plants, animals, and humans. Viruses possess an outer protein coat (capsid) that protects its genomic material that resides inside. We have developed a theoretical technique to model the very low frequency mechanical modes of the viral capsid with atomic resolution. The method uses empirical force fields and a mathematical framework borrowed from electronic structure theory for finding low energy states. The low frequency modes can be ``pinged'' with an ultra-short laser pulse and the aim of the light/vibrational coupling is to interfere with the viral life cycle. The theoretical work here is motivated by the recent work of Tsen et al. [2] who have used ultra-short pulsed laser scattering to inactivate viruses. The methodology can be applied to many systems, and the coupled mechanical oscillations of other floppy biomolecules such as a complete ATP binding cassette (ABC transporter) will also be discussed. Co-authors of this work are Dr. Eric Dykeman, Prof. K.-T. Tsen and Daryn Benson. [4pt] [1] E.C. Dykeman et al., Phys. Rev. Lett., 100, 028101 (2008). [0pt] [2] K-T. Tsen et al., J. of Physics -- Cond. Mat. 19, 472201 (2007).

  5. An approach to nonstandard quantum mechanics

    NASA Astrophysics Data System (ADS)

    Raab, A.

    2004-12-01

    We use nonstandard analysis to formulate quantum mechanics in hyperfinite-dimensional spaces. Self-adjoint operators on hyperfinite-dimensional spaces have complete eigensets, and bound states and continuum states of a Hamiltonian can thus be treated on an equal footing. We show that the formalism extends the standard formulation of quantum mechanics. To this end we develop the Loeb-function calculus in nonstandard hulls. The idea is to perform calculations in a hyperfinite-dimensional space, but to interpret expectation values in the corresponding nonstandard hull. We further apply the framework to nonrelativistic quantum scattering theory. For time-dependent scattering theory, we identify the starting time and the finishing time of a scattering experiment, and we obtain a natural separation of time scales on which the preparation process, the interaction process, and the detection process take place. For time-independent scattering theory, we derive rigorously explicit formulas for the Mo/ller wave operators and the S-matrix.

  6. Molecular mechanism of statin-mediated LOX-1 inhibition

    PubMed Central

    Biocca, Silvia; Iacovelli, Federico; Matarazzo, Sara; Vindigni, Giulia; Oteri, Francesco; Desideri, Alessandro; Falconi, Mattia

    2015-01-01

    Statins are largely used in clinics in the treatment of patients with cardiovascular diseases for their effect on lowering circulating cholesterol. Lectin-like oxidized low-density lipoprotein (LOX-1), the primary receptor for ox-LDL, plays a central role in the pathogenesis of atherosclerosis and cardiovascular disorders. We have recently shown that chronic exposure of cells to lovastatin disrupts LOX-1 receptor cluster distribution in plasma membranes, leading to a marked loss of LOX-1 function. Here we investigated the molecular mechanism of statin-mediated LOX-1 inhibition and we demonstrate that all tested statins are able to displace the binding of fluorescent ox-LDL to LOX-1 by a direct interaction with LOX-1 receptors in a cell-based binding assay. Molecular docking simulations confirm the interaction and indicate that statins completely fill the hydrophobic tunnel that crosses the C-type lectin-like (CTLD) recognition domain of LOX-1. Classical molecular dynamics simulation technique applied to the LOX-1 CTLD, considered in the entire receptor structure with or without a statin ligand inside the tunnel, indicates that the presence of a ligand largely increases the dimer stability. Electrophoretic separation and western blot confirm that different statins binding stabilize the dimer assembly of LOX-1 receptors in vivo. The simulative and experimental results allow us to propose a CTLD clamp motion, which enables the receptor-substrate coupling. These findings reveal a novel and significant functional effect of statins. PMID:25950192

  7. Probing the Molecular Mechanisms of the Fracture of Semicrystalline Polyethylene

    NASA Astrophysics Data System (ADS)

    Benkoski, J. J.; Flores, P.; Kramer, E. J.

    2003-03-01

    The effects of molecular architecture on the fracture properties of semicrystalline polymers were probed at diblock copolymer-reinforced interfaces between polystyrene (PS) and polyethylene (PE). The PE used for this study was a model ethylene-butene copolymer which was chosen for its compatibility with hydrogenated poly(styrene-b-1,4-tetradeuteriobutadiene). For a series of these diblock copolymers, the areal chain density (Σ) and the molecular weight of the PE block (M_n) were varied systematically to observe their effects on the interfacial fracture energy (G_c). At low Σ, Gc stayed relatively constant, and was roughly 1 J/m^2. Above a critical value of Σ, the fracture energy climbed rapidly. This critical value decreased with increasing M_n. The detection of deuterium on the fracture surfaces indicated that pullout of the PE block was the predominant failure mechanism when Mn <= 30 kg/mol. Since the entanglement molecular weight of PE is approximately 1 kg/mol, interfacial reinforcement does not appear to depend on the formation of entanglements for this system. The critical Mn coincides instead with the point at which the root-mean-square end-to-end length of the PE block exceeds the long period of the PE crystal lamellae (L).

  8. Lactobacilli as multifaceted probiotics with poorly disclosed molecular mechanisms.

    PubMed

    Turpin, Williams; Humblot, Christèle; Thomas, Muriel; Guyot, Jean-Pierre

    2010-10-15

    Lactic acid bacteria and more particularly lactobacilli have been used for the production of fermented foods for centuries. Several lactobacilli have been recognized as probiotics due to their wide range of health-promoting effects in humans. However, little is known about the molecular mechanisms underpinning their probiotic functions. Here we reviewed the main beneficial effects of lactobacilli and discussed, when the information is available, the molecular machinery involved in their probiotic function. Among the beneficial effects, lactobacilli can improve digestion, absorption and availability of nutrients. As an example, some strains are able to degrade carbohydrates such as lactose or α-galactosides that may cause abdominal pain. Furthermore, they can hydrolyze compounds that limit the bioavailability of minerals like tannin and phytate due to tannin acylhydrolase and phytase activities. In addition, it was shown that some lactobacilli strains can improve mineral absorption in Caco-2 cells. Lactobacilli can also contribute to improve the nutritional status of the host by producing B group vitamins. More recently, the role of lactobacilli in energy homeostasis, particularly in obese patients, is the object of an increased interest. Lactobacilli are also involved in the prevention of diseases. They have potential to prevent carcinogenesis through the modulation of enzymes involved in the xenobiotic pathway, and may prevent cardiovascular diseases such as hypertension through the production of a bioactive peptide that may have angiotensin converting enzyme inhibitor activity. Lactobacilli are increasingly studied for the treatment of inflammatory bowel diseases and exhibit interesting potential in the reduction of pain perception. The ability of some strains to bind to intestinal cells, their pathogen-associated molecular patterns and the metabolites they produce confer interesting immunomodulatory effects. Finally, pathogenic fungi, virus or bacteria can be

  9. Challenges and novel approaches for investigating molecular mediation

    PubMed Central

    Richmond, R.C.; Hemani, G.; Tilling, K.; Davey Smith, G.; Relton, C.L.

    2016-01-01

    Understanding mediation is useful for identifying intermediates lying between an exposure and an outcome which, when intervened upon, will block (some or all of) the causal pathway between the exposure and outcome. Mediation approaches used in conventional epidemiology have been adapted to understanding the role of molecular intermediates in situations of high-dimensional omics data with varying degrees of success. In particular, the limitations of observational epidemiological study including confounding, reverse causation and measurement error can afflict conventional mediation approaches and may lead to incorrect conclusions regarding causal effects. Solutions to analysing mediation which overcome these problems include the use of instrumental variable methods such as Mendelian randomization, which may be applied to evaluate causality in increasingly complex networks of omics data. PMID:27439390

  10. Phenomenological approach to mechanical damage growth analysis.

    PubMed

    Pugno, Nicola; Bosia, Federico; Gliozzi, Antonio S; Delsanto, Pier Paolo; Carpinteri, Alberto

    2008-10-01

    The problem of characterizing damage evolution in a generic material is addressed with the aim of tracing it back to existing growth models in other fields of research. Based on energetic considerations, a system evolution equation is derived for a generic damage indicator describing a material system subjected to an increasing external stress. The latter is found to fit into the framework of a recently developed phenomenological universality (PUN) approach and, more specifically, the so-called U2 class. Analytical results are confirmed by numerical simulations based on a fiber-bundle model and statistically assigned local strengths at the microscale. The fits with numerical data prove, with an excellent degree of reliability, that the typical evolution of the damage indicator belongs to the aforementioned PUN class. Applications of this result are briefly discussed and suggested. PMID:18999489

  11. Molecular Mechanisms of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

    PubMed Central

    Leopold, Jane A.; Maron, Bradley A.

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a devastating disease that is precipitated by hypertrophic pulmonary vascular remodeling of distal arterioles to increase pulmonary artery pressure and pulmonary vascular resistance in the absence of left heart, lung parenchymal, or thromboembolic disease. Despite available medical therapy, pulmonary artery remodeling and its attendant hemodynamic consequences result in right ventricular dysfunction, failure, and early death. To limit morbidity and mortality, attention has focused on identifying the cellular and molecular mechanisms underlying aberrant pulmonary artery remodeling to identify pathways for intervention. While there is a well-recognized heritable genetic component to PAH, there is also evidence of other genetic perturbations, including pulmonary vascular cell DNA damage, activation of the DNA damage response, and variations in microRNA expression. These findings likely contribute, in part, to dysregulation of proliferation and apoptosis signaling pathways akin to what is observed in cancer; changes in cellular metabolism, metabolic flux, and mitochondrial function; and endothelial-to-mesenchymal transition as key signaling pathways that promote pulmonary vascular remodeling. This review will highlight recent advances in the field with an emphasis on the aforementioned molecular mechanisms as contributors to the pulmonary vascular disease pathophenotype. PMID:27213345

  12. Molecular mechanisms of the plant heat stress response

    SciTech Connect

    Qu, Ai-Li; Ding, Yan-Fei; Jiang, Qiong; Zhu, Cheng

    2013-03-08

    Highlights: ► This review elaborates the response networks of heat stress in plants. ► It elaborates proteins responding to heat stress in special physiological period. ► The proteins and pathways have formed a basic network of the heat stress response. ► Achievements of the various technologies are also combined. -- Abstract: High temperature has become a global concern, which seriously affects the growth and production of plants, particularly crops. Thus, the molecular mechanism of the heat stress response and breeding of heat-tolerant plants is necessary to protect food production and ensure crop safety. This review elaborates on the response networks of heat stress in plants, including the Hsf and Hsp response pathways, the response of ROS and the network of the hormones. In addition, the production of heat stress response elements during particular physiological periods of the plant is described. We also discuss the existing problems and future prospects concerning the molecular mechanisms of the heat stress response in plants.

  13. Molecular Mechanisms of Phosphorus Metabolism and Transport during Leaf Senescence

    PubMed Central

    Stigter, Kyla A.; Plaxton, William C.

    2015-01-01

    Leaf senescence, being the final developmental stage of the leaf, signifies the transition from a mature, photosynthetically active organ to the attenuation of said function and eventual death of the leaf. During senescence, essential nutrients sequestered in the leaf, such as phosphorus (P), are mobilized and transported to sink tissues, particularly expanding leaves and developing seeds. Phosphorus recycling is crucial, as it helps to ensure that previously acquired P is not lost to the environment, particularly under the naturally occurring condition where most unfertilized soils contain low levels of soluble orthophosphate (Pi), the only form of P that roots can directly assimilate from the soil. Piecing together the molecular mechanisms that underpin the highly variable efficiencies of P remobilization from senescing leaves by different plant species may be critical for devising effective strategies for improving overall crop P-use efficiency. Maximizing Pi remobilization from senescing leaves using selective breeding and/or biotechnological strategies will help to generate P-efficient crops that would minimize the use of unsustainable and polluting Pi-containing fertilizers in agriculture. This review focuses on the molecular mechanisms whereby P is remobilized from senescing leaves and transported to sink tissues, which encompasses the action of hormones, transcription factors, Pi-scavenging enzymes, and Pi transporters. PMID:27135351

  14. Molecular Mechanisms of Biological Aging in Intervertebral Discs

    PubMed Central

    Vo, Nam V.; Hartman, Robert A.; Patil, Prashanti R.; Risbud, Makarand V.; Kletsas, Dimitris; Iatridis, James C.; Hoyland, Judith A.; Le Maitre, Christine L.; Sowa, Gwendolyn A.; Kang, James D.

    2016-01-01

    Advanced age is the greatest risk factor for the majority of human ailments, including spine-related chronic disability and back pain, which stem from age-associated intervertebral disc degeneration (IDD). Given the rapid global rise in the aging population, understanding the biology of intervertebral disc aging in order to develop effective therapeutic interventions to combat the adverse effects of aging on disc health is now imperative. Fortunately, recent advances in aging research have begun to shed light on the basic biological process of aging. Here we review some of these insights and organize the complex process of disc aging into three different phases to guide research efforts to understand the biology of disc aging. The objective of this review is to provide an overview of the current knowledge and the recent progress made to elucidate specific molecular mechanisms underlying disc aging. In particular, studies over the last few years have uncovered cellular senescence and genomic instability as important drivers of disc aging. Supporting evidence comes from DNA repair-deficient animal models that show increased disc cellular senescence and accelerated disc aging. Additionally, stress-induced senescent cells have now been well documented to secrete catabolic factors, which can negatively impact the physiology of neighboring cells and ECM. These along with other molecular drivers of aging are reviewed in depth to shed crucial insights into the underlying mechanisms of age-related disc degeneration. We also highlight molecular targets for novel therapies and emerging candidate therapeutics that may mitigate age-associated IDD. PMID:26890203

  15. MATCH: An Atom- Typing Toolset for Molecular Mechanics Force Fields

    PubMed Central

    Yesselman, Joseph D.; Price, Daniel J.; Knight, Jennifer L.; Brooks, Charles L.

    2011-01-01

    We introduce a toolset of program libraries collectively titled MATCH (Multipurpose Atom-Typer for CHARMM) for the automated assignment of atom types and force field parameters for molecular mechanics simulation of organic molecules. The toolset includes utilities for the conversion from multiple chemical structure file formats into a molecular graph. A general chemical pattern-matching engine using this graph has been implemented whereby assignment of molecular mechanics atom types, charges and force field parameters is achieved by comparison against a customizable list of chemical fragments. While initially designed to complement the CHARMM simulation package and force fields by generating the necessary input topology and atom-type data files, MATCH can be expanded to any force field and program, and has core functionality that makes it extendable to other applications such as fragment-based property prediction. In the present work, we demonstrate the accurate construction of atomic parameters of molecules within each force field included in CHARMM36 through exhaustive cross validation studies illustrating that bond increment rules derived from one force field can be transferred to another. In addition, using leave-one-out substitution it is shown that it is also possible to substitute missing intra and intermolecular parameters with ones included in a force field to complete the parameterization of novel molecules. Finally, to demonstrate the robustness of MATCH and the coverage of chemical space offered by the recent CHARMM CGENFF force field (Vanommeslaeghe, et al., JCC., 2010, 31, 671–690), one million molecules from the PubChem database of small molecules are typed, parameterized and minimized. PMID:22042689

  16. Towards identification of molecular mechanisms of short stature

    PubMed Central

    2013-01-01

    Growth evaluations are among the most common referrals to pediatric endocrinologists. Although a number of pathologies, both primary endocrine and non-endocrine, can present with short stature, an estimated 80% of evaluations fail to identify a clear etiology, leaving a default designation of idiopathic short stature (ISS). As a group, several features among children with ISS are suggestive of pathophysiology of the GH–IGF-1 axis, including low serum levels of IGF-1 despite normal GH secretion. Candidate gene analysis of rare cases has demonstrated that severe mutations of genes of the GH–IGF-1 axis can present with a profound height phenotype, leading to speculation that a collection of mild mutations or polymorphisms of these genes can explain poor growth in a larger proportion of patients. Recent genome-wide association studies have identified ~180 genomic loci associated with height that together account for approximately 10% of height variation. With only modest representation of the GH–IGF-1 axis, there is little support for the long-held hypothesis that common genetic variants of the hormone pathway provide the molecular mechanism for poor growth in a substantial proportion of individuals. The height-associated common variants are not observed in the anticipated frequency in the shortest individuals, suggesting rare genetic factors with large effect are more plausible in this group. As we advance towards establishing a molecular mechanism for poor growth in a greater percentage of those currently labeled ISS, we highlight two strategies that will likely be offered with increasing frequency: (1) unbiased genetic technologies including array analysis for copy number variation and whole exome/genome sequencing and (2) epigenetic alterations of key genomic loci. Ultimately data from subsets with similar molecular etiologies may emerge that will allow tailored interventions to achieve the best clinical outcome. PMID:24257104

  17. Towards identification of molecular mechanisms of short stature.

    PubMed

    Waldman, Lindsey A; Chia, Dennis J

    2013-11-20

    Growth evaluations are among the most common referrals to pediatric endocrinologists. Although a number of pathologies, both primary endocrine and non-endocrine, can present with short stature, an estimated 80% of evaluations fail to identify a clear etiology, leaving a default designation of idiopathic short stature (ISS). As a group, several features among children with ISS are suggestive of pathophysiology of the GH-IGF-1 axis, including low serum levels of IGF-1 despite normal GH secretion. Candidate gene analysis of rare cases has demonstrated that severe mutations of genes of the GH-IGF-1 axis can present with a profound height phenotype, leading to speculation that a collection of mild mutations or polymorphisms of these genes can explain poor growth in a larger proportion of patients. Recent genome-wide association studies have identified ~180 genomic loci associated with height that together account for approximately 10% of height variation. With only modest representation of the GH-IGF-1 axis, there is little support for the long-held hypothesis that common genetic variants of the hormone pathway provide the molecular mechanism for poor growth in a substantial proportion of individuals. The height-associated common variants are not observed in the anticipated frequency in the shortest individuals, suggesting rare genetic factors with large effect are more plausible in this group. As we advance towards establishing a molecular mechanism for poor growth in a greater percentage of those currently labeled ISS, we highlight two strategies that will likely be offered with increasing frequency: (1) unbiased genetic technologies including array analysis for copy number variation and whole exome/genome sequencing and (2) epigenetic alterations of key genomic loci. Ultimately data from subsets with similar molecular etiologies may emerge that will allow tailored interventions to achieve the best clinical outcome.

  18. Molecular approaches to improve rice abiotic stress tolerance.

    PubMed

    Mizoi, Junya; Yamaguchi-Shinozaki, Kazuko

    2013-01-01

    Abiotic stress is a major factor limiting productivity of rice crops in large areas of the world. Because plants cannot avoid abiotic stress by moving, they have acquired various mechanisms for stress tolerance in the course of their evolution. Enhancing or introducing such mechanisms in rice is one effective way to develop stress-tolerant cultivars. Based on physiological studies on stress responses, recent progress in plant molecular biology has enabled discovery of many genes involved in stress tolerance. These genes include regulatory genes, which regulate stress response (e.g., transcription factors and protein kinases), and functional genes, which protect the cell (e.g., enzymes for generating protective metabolites and proteins). Both kinds of genes are used to increase stress tolerance in rice. In addition, several quantitative trait loci (QTLs) associated with higher stress tolerance have been cloned, contributing to the discovery of significantly important genes for stress tolerance.

  19. Molecular approaches in pig breeding to improve meat quality.

    PubMed

    Davoli, Roberta; Braglia, Silvia

    2007-12-01

    This article reviews the advances in molecular genetics that have led to the identification of genes and markers associated with meat quality in pig. The development of a considerable number of annotated livestock genome sequences represents an incredibly rich source of information that can be used to identify candidate genes responsible for complex traits and quantitative trait loci effects. In pig, the huge amount of information emerging from the study of the genome has helped in the acquisition of new knowledge concerning biological systems and it is opening new opportunities for the genetic selection of this specie. Among the new fields of genomics recently developed, functional genomics and proteomics that allow considering many genes and proteins at the same time are very useful tools for a better understanding of the function and regulation of genes, and how these participate in complex networks controlling the phenotypic characteristics of a trait. In particular, global gene expression profiling at the mRNA and protein level can provide a better understanding of gene regulation that underlies biological functions and physiology related to the delivery of a better pig meat quality. Moreover, the possibility to realize an integrated approach of genomics and proteomics with bioinformatics tools is essential to obtain a complete exploitation of the available molecular genetics information. The development of this knowledge will benefit scientists, industry and breeders considering that the efficiency and accuracy of the traditional pig selection schemes will be improved by the implementation of molecular data into breeding programs. PMID:18208864

  20. Molecular Targeted Approaches to Cancer Therapy and Prevention Using Chalcones

    PubMed Central

    Jandial, Danielle D.; Blair, Christopher A.; Zhang, Saiyang; Krill, Lauren S.; Zhang, Yan-Bing; Zi, Xiaolin

    2014-01-01

    There is an emerging paradigm shift in oncology that seeks to emphasize molecularly targeted approaches for cancer prevention and therapy. Chalcones (1,3-diphenyl-2-propen-1-ones), naturally-occurring compounds with widespread distribution in spices, tea, beer, fruits and vegetables, consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon α, β-unsaturated carbonyl system. Due to their structural diversity, relative ease of chemical manipulation and reaction of α, β-unsaturated carbonyl moiety with cysteine residues in proteins, some lead chalcones from both natural products and synthesis have been identified in a variety of screening assays for modulating important pathways or molecular targets in cancers. These pathways and targets that are affected by chalcones include MDM2/p53, tubulin, proteasome, NF-kappa B, TRIAL/death receptors and mitochondria mediated apoptotic pathways, cell cycle, STAT3, AP-1, NRF2, AR, ER, PPAR-γ and β-catenin/Wnt. Compared to current cancer targeted therapeutic drugs, chalcones have the advantages of being inexpensive, easily available and less toxic; the ease of synthesis of chalcones from substituted benzaldehydes and acetophenones also makes them an attractive drug scaffold. Therefore, this review is focused on molecular targets of chalcones and their potential implications in cancer prevention and therapy. PMID:24467530

  1. Characterization of molecular mechanisms of in vivo UVR induced cataract.

    PubMed

    Galichanin, Konstantin; Talebizadeh, Nooshin; Söderberg, Per

    2012-01-01

    Cataract is the leading cause of blindness in the world (1). The World Health Organization defines cataract as a clouding of the lens of the eye which impedes the transfer of light. Cataract is a multi-factorial disease associated with diabetes, smoking, ultraviolet radiation (UVR), alcohol, ionizing radiation, steroids and hypertension. There is strong experimental (2-4) and epidemiological evidence (5,6) that UVR causes cataract. We developed an animal model for UVR B induced cataract in both anesthetized (7) and non-anesthetized animals (8). The only cure for cataract is surgery but this treatment is not accessible to all. It has been estimated that a delay of onset of cataract for 10 years could reduce the need for cataract surgery by 50% (9). To delay the incidence of cataract, it is needed to understand the mechanisms of cataract formation and find effective prevention strategies. Among the mechanisms for cataract development, apoptosis plays a crucial role in initiation of cataract in humans and animals (10). Our focus has recently been apoptosis in the lens as the mechanism for cataract development (8,11,12). It is anticipated that a better understanding of the effect of UVR on the apoptosis pathway will provide possibilities for discovery of new pharmaceuticals to prevent cataract. In this article, we describe how cataract can be experimentally induced by in vivo exposure to UVR-B. Further RT-PCR and immunohistochemistry are presented as tools to study molecular mechanisms of UVR-B induced cataract. PMID:23222480

  2. Mechanisms of esophageal adenocarcinoma formation and approaches to chemopreventive intervention.

    PubMed

    Richmond, Ellen; Umar, Asad

    2016-02-01

    The incidence of esophageal adenocarcinoma (EAC), a debilitating and highly lethal malignancy, has risen dramatically over the past 40 years in the United States and other Western countries. To reverse this trend, EAC prevention and early detection efforts by clinicians, academic researchers and endoscope manufacturers have targeted Barrett's esophagus (BE), the widely accepted EAC precursor lesion. Data from surgical, endoscopic and pre-clinical investigations strongly support the malignant potential of BE. For patients with BE, the risk of developing EAC has been estimated at 11- to 125-fold greater than that of the individual at average risk. Nevertheless, screening for BE in symptomatic patients (ie, with symptoms of reflux) and surveillance in patients diagnosed with BE have not had a substantial impact on the incidence, morbidity or mortality of EAC; the overwhelming majority of EAC patients are diagnosed without a pre-operative diagnosis of BE. This article will discuss the current state of the science of esophageal adenocarcinoma prevention, including ideas about carcinogenesis and its underlying genomic and molecular level mechanisms, and suggest strategies for a systems approach to targeted preventive management. PMID:26970126

  3. Disease Mechanisms and Therapeutic Approaches in Spinal Muscular Atrophy

    PubMed Central

    Tisdale, Sarah

    2015-01-01

    Motor neuron diseases are neurological disorders characterized primarily by the degeneration of spinal motor neurons, skeletal muscle atrophy, and debilitating and often fatal motor dysfunction. Spinal muscular atrophy (SMA) is an autosomal-recessive motor neuron disease of high incidence and severity and the most common genetic cause of infant mortality. SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene and retention of at least one copy of the hypomorphic gene paralog SMN2. Early studies established a loss-of-function disease mechanism involving ubiquitous SMN deficiency and suggested SMN upregulation as a possible therapeutic approach. In recent years, greater knowledge of the central role of SMN in RNA processing combined with deep characterization of animal models of SMA has significantly advanced our understanding of the cellular and molecular basis of the disease. SMA is emerging as an RNA disease not limited to motor neurons, but one that involves dysfunction of motor circuits that comprise multiple neuronal subpopulations and possibly other cell types. Advances in SMA research have also led to the development of several potential therapeutics shown to be effective in animal models of SMA that are now in clinical trials. These agents offer unprecedented promise for the treatment of this still incurable neurodegenerative disease. PMID:26063904

  4. New Approaches to Sepsis: Molecular Diagnostics and Biomarkers

    PubMed Central

    Bauer, Michael; Riedemann, Niels C.; Hartog, Christiane S.

    2012-01-01

    Summary: Sepsis is among the most common causes of death in hospitals. It arises from the host response to infection. Currently, diagnosis relies on nonspecific physiological criteria and culture-based pathogen detection. This results in diagnostic uncertainty, therapeutic delays, the mis- and overuse of antibiotics, and the failure to identify patients who might benefit from immunomodulatory therapies. There is a need for new sepsis biomarkers that can aid in therapeutic decision making and add information about screening, diagnosis, risk stratification, and monitoring of the response to therapy. The host response involves hundreds of mediators and single molecules, many of which have been proposed as biomarkers. It is, however, unlikely that one single biomarker is able to satisfy all the needs and expectations for sepsis research and management. Among biomarkers that are measurable by assays approved for clinical use, procalcitonin (PCT) has shown some usefulness as an infection marker and for antibiotic stewardship. Other possible new approaches consist of molecular strategies to improve pathogen detection and molecular diagnostics and prognostics based on transcriptomic, proteomic, or metabolic profiling. Novel approaches to sepsis promise to transform sepsis from a physiologic syndrome into a group of distinct biochemical disorders and help in the development of better diagnostic tools and effective adjunctive sepsis therapies. PMID:23034322

  5. DommiMOE: an implementation of ligand field molecular mechanics in the molecular operating environment.

    PubMed

    Deeth, Robert J; Fey, Natalie; Williams-Hubbard, Benjamin

    2005-01-30

    The ligand field molecular mechanics (LFMM) model, which incorporates the ligand field stabilization energy (LFSE) directly into the potential energy expression of molecular mechanics (MM), has been implemented in the "chemically aware" molecular operating environment (MOE) software package. The new program, christened DommiMOE, is derived from our original in-house code that has been linked to MOE via its applications programming interface and a number of other routines written in MOE's native scientific vector language (SVL). DommiMOE automates the assignment of atom types and their associated parameters and popular force fields available in MOE such as MMFF94, AMBER, and CHARMM can be easily extended to provide a transition metal simulation capability. Some of the unique features of the LFMM are illustrated using MMFF94 and some simple [MCl)]2- and [Ni(NH3)n]2+ species. These studies also demonstrate how density functional theory calculations, especially on experimentally inaccessible systems, provide important data for designing improved LFMM parameters. DommiMOE treats Jahn-Teller distortions automatically, and can compute the relative energies of different spin states for Ni(II) complexes using a single set of LFMM parameters.

  6. Intelligence and embodiment: a statistical mechanics approach.

    PubMed

    Chinea, Alejandro; Korutcheva, Elka

    2013-04-01

    Evolutionary neuroscience has been mainly dominated by the principle of phylogenetic conservation, specifically, by the search for similarities in brain organization. This principle states that closely related species tend to be similar because they have a common ancestor. However, explaining, for instance, behavioral differences between humans and chimpanzees, has been revealed to be notoriously difficult. In this paper, the hypothesis of a common information-processing principle exploited by the brains evolved through natural evolution is explored. A model combining recent advances in cognitive psychology and evolutionary neuroscience is presented. The macroscopic effects associated with the intelligence-like structures postulated by the model are analyzed from a statistical mechanics point of view. As a result of this analysis, some plausible explanations are put forward concerning the disparities and similarities in cognitive capacities which are observed in nature across species. Furthermore, an interpretation on the efficiency of brain's computations is also provided. These theoretical results and their implications against modern theories of intelligence are shown to be consistent with the formulated hypothesis. PMID:23454920

  7. MOLECULAR MECHANISM OF MICROBIAL TECHNETIUM REDUCTION FINAL REPORT

    SciTech Connect

    DiChristina, Thomas J.

    2013-04-30

    Microbial Tc(VII) reduction is an attractive alternative strategy for bioremediation of technetium-contaminated subsurface environments. Traditional ex situ remediation processes (e.g., adsorption or ion exchange) are often limited by poor extraction efficiency, inhibition by competing ions and production of large volumes of produced waste. Microbial Tc(VII) reduction provides an attractive alternative in situ remediation strategy since the reduced end-product Tc(IV) precipitates as TcO2, a highly insoluble hydrous oxide. Despite its potential benefits, the molecular mechanism of microbial Tc(VII) reduction remains poorly understood. The main goal of the proposed DOENABIR research project is to determine the molecular mechanism of microbial Tc(VII) reduction. Random mutagenesis studies in our lab have resulted in generation of a set of six Tc(VII) reduction-deficient mutants of Shewanella oneidensis. The anaerobic respiratory deficiencies of each Tc(VII) reduction-deficient mutant was determined by anaerobic growth on various combinations of three electron donors and 14 terminal electron acceptors. Results indicated that the electron transport pathways to Tc(VII), NO3 -, Mn(III) and U(VI) share common structural or regulatory components. In addition, we have recently found that wild-type Shewanella are also able to reduce Tc(IV) as electron acceptor, producing Tc(III) as an end-product. The recent genome sequencing of a variety of technetium-reducing bacteria and the anticipated release of several additional genome sequences in the coming year, provides us with an unprecedented opportunity to determine the mechanism of microbial technetium reduction across species and genus lines.

  8. Molecular mechanisms of asbestos-induced lung epithelial cell apoptosis.

    PubMed

    Liu, Gang; Beri, Rohinee; Mueller, Amanda; Kamp, David W

    2010-11-01

    Asbestos causes pulmonary fibrosis (asbestosis) and malignancies (bronchogenic lung cancer and mesothelioma) by mechanisms that are not fully elucidated. Accumulating evidence show that alveolar epithelial cell (AEC) apoptosis is a crucial initiating and perpetuating event in the development of pulmonary fibrosis following exposure to a wide variety of noxious stimuli, including asbestos. We review the important molecular mechanisms underlying asbestos-induced AEC apoptosis. Specifically, we focus on the role of asbestos in augmenting AEC apoptosis by the mitochondria- and p53-regulated death pathways that result from the production of iron-derived reactive oxygen species (ROS) and DNA damage. We summarize emerging evidence implicating the endoplasmic reticulum (ER) stress response in AEC apoptosis in patients with idiopathic pulmonary fibrosis (IPF), a disease with similarities to asbestosis. Finally, we discuss a recent finding that a mitochondrial oxidative DNA repair enzyme (8-oxoguanine DNA glycosylase; Ogg1) acts as a mitochondrial aconitase chaperone protein to prevent oxidant (asbestos and H(2)O(2))-induced AEC mitochondrial dysfunction and intrinsic apoptosis. The coupling of mitochondrial Ogg1 to mitochondrial aconitase is a novel mechanism linking metabolism to mitochondrial DNA that may be important in the pathophysiologic events resulting in oxidant-induced toxicity as seen in tumors, aging, and respiratory disorders (e.g. asbestosis, IPF). Collectively, these studies are illuminating the molecular basis of AEC apoptosis following asbestos exposure that may prove useful for developing novel therapeutic strategies. Importantly, the asbestos paradigm is elucidating pathophysiologic insights into other more common pulmonary diseases, such as IPF and lung cancer, for which better therapy is required. PMID:20380827

  9. Aftershock Energy Distribution by Statistical Mechanics Approach

    NASA Astrophysics Data System (ADS)

    Daminelli, R.; Marcellini, A.

    2015-12-01

    The aim of our work is to research the most probable distribution of the energy of aftershocks. We started by applying one of the fundamental principles of statistical mechanics that, in case of aftershock sequences, it could be expressed as: the greater the number of different ways in which the energy of aftershocks can be arranged among the energy cells in phase space the more probable the distribution. We assume that each cell in phase space has the same possibility to be occupied, and that more than one cell in the phase space can have the same energy. Seeing that seismic energy is proportional to products of different parameters, a number of different combinations of parameters can produce different energies (e.g., different combination of stress drop and fault area can release the same seismic energy). Let us assume that there are gi cells in the aftershock phase space characterised by the same energy released ɛi. Therefore we can assume that the Maxwell-Boltzmann statistics can be applied to aftershock sequences with the proviso that the judgment on the validity of this hypothesis is the agreement with the data. The aftershock energy distribution can therefore be written as follow: n(ɛ)=Ag(ɛ)exp(-βɛ)where n(ɛ) is the number of aftershocks with energy, ɛ, A and β are constants. Considering the above hypothesis, we can assume g(ɛ) is proportional to ɛ. We selected and analysed different aftershock sequences (data extracted from Earthquake Catalogs of SCEC, of INGV-CNT and other institutions) with a minimum magnitude retained ML=2 (in some cases ML=2.6) and a time window of 35 days. The results of our model are in agreement with the data, except in the very low energy band, where our model resulted in a moderate overestimation.

  10. Statistical mechanics approach to lock-key supramolecular chemistry interactions.

    PubMed

    Odriozola, Gerardo; Lozada-Cassou, Marcelo

    2013-03-01

    In the supramolecular chemistry field, intuitive concepts such as molecular complementarity and molecular recognition are used to explain the mechanism of lock-key associations. However, these concepts lack a precise definition, and consequently this mechanism is not well defined and understood. Here we address the physical basis of this mechanism, based on formal statistical mechanics, through Monte Carlo simulation and compare our results with recent experimental data for charged or uncharged lock-key colloids. We find that, given the size range of the molecules involved in these associations, the entropy contribution, driven by the solvent, rules the interaction, over that of the enthalpy. A universal behavior for the uncharged lock-key association is found. Based on our results, we propose a supramolecular chemistry definition.

  11. A systematic molecular genetic approach to study mammalian germline development

    PubMed Central

    Abe, Kuniya; Ko, Minoru S. H.; MacGregor, Grant R.

    2011-01-01

    It is difficult to study gene expression in mammalian embryonic germ cells as PGCs constitute only a minor proportion of the mouse embryo. We have overcome this problem by using a novel combination of established molecular and transgenic approaches. A line of mice has been generated in which the cells of the germ lineage express the β-galactosidase reporter gene during embryogenesis. Using this line, germ cells have been purified to near homogeneity from embryos at discrete stages during germline development by use of a stain for β-gal activity and a fluorescence activated cell sorter. Subsequently, cDNA libraries have been constructed from each germ cell population using a modified lone-linker PCR strategy. These combined cDNA libraries represent genes expressed in PGCs during mammalian germline development. To facilitate a molecular genetic approach to studying mammalian germline development, these cDNA libraries will be pooled to form an arrayed, addressed reference embryonic germ cell cDNA library. In parallel with large-scale cDNA sequencing efforts, genes that are differentially expressed in germ cells will be identified by screening the reference library with probes generated by subtractive hybridization. Complementary DNAs identified using this approach will be analyzed by sequencing, database comparison, genomic mapping and in situ hybridization to ascertain the potential functional importance of each gene to germline development. In addition to providing a wealth of novel information regarding patterns of gene expression during mammalian germline development, these results will form the basis for future experiments to determine the function of these genes in this process. PMID:9853837

  12. A density-based adaptive quantum mechanical/molecular mechanical method.

    PubMed

    Waller, Mark P; Kumbhar, Sadhana; Yang, Jack

    2014-10-20

    We present a density-based adaptive quantum mechanical/molecular mechanical (DBA-QM/MM) method, whereby molecules can switch layers from the QM to the MM region and vice versa. The adaptive partitioning of the molecular system ensures that the layer assignment can change during the optimization procedure, that is, on the fly. The switch from a QM molecule to a MM molecule is determined if there is an absence of noncovalent interactions to any atom of the QM core region. The presence/absence of noncovalent interactions is determined by analysis of the reduced density gradient. Therefore, the location of the QM/MM boundary is based on physical arguments, and this neatly removes some empiricism inherent in previous adaptive QM/MM partitioning schemes. The DBA-QM/MM method is validated by using a water-in-water setup and an explicitly solvated L-alanyl-L-alanine dipeptide. PMID:24954803

  13. A density-based adaptive quantum mechanical/molecular mechanical method.

    PubMed

    Waller, Mark P; Kumbhar, Sadhana; Yang, Jack

    2014-10-20

    We present a density-based adaptive quantum mechanical/molecular mechanical (DBA-QM/MM) method, whereby molecules can switch layers from the QM to the MM region and vice versa. The adaptive partitioning of the molecular system ensures that the layer assignment can change during the optimization procedure, that is, on the fly. The switch from a QM molecule to a MM molecule is determined if there is an absence of noncovalent interactions to any atom of the QM core region. The presence/absence of noncovalent interactions is determined by analysis of the reduced density gradient. Therefore, the location of the QM/MM boundary is based on physical arguments, and this neatly removes some empiricism inherent in previous adaptive QM/MM partitioning schemes. The DBA-QM/MM method is validated by using a water-in-water setup and an explicitly solvated L-alanyl-L-alanine dipeptide.

  14. Mechanical properties of borophene films: a reactive molecular dynamics investigation

    NASA Astrophysics Data System (ADS)

    Quy Le, Minh; Mortazavi, Bohayra; Rabczuk, Timon

    2016-11-01

    The most recent experimental advances could provide ways for the fabrication of several atomic thick and planar forms of boron atoms. For the first time, we explore the mechanical properties of five types of boron films with various vacancy ratios ranging from 0.1–0.15, using molecular dynamics simulations with ReaxFF force field. It is found that the Young’s modulus and tensile strength decrease with increasing the temperature. We found that boron sheets exhibit an anisotropic mechanical response due to the different arrangement of atoms along the armchair and zigzag directions. At room temperature, 2D Young’s modulus and fracture stress of these five sheets appear in the range 63–136 N m‑1 and 12–19 N m‑1, respectively. In addition, the strains at tensile strength are in the ranges of 9%–14%, 11%–19%, and 10%–16% at 1, 300, and 600 K, respectively. This investigation not only reveals the remarkable stiffness of 2D boron, but establishes relations between the mechanical properties of the boron sheets to the loading direction, temperature and atomic structures.

  15. Aging and Immune Function: Molecular Mechanisms to Interventions

    PubMed Central

    Ponnappan, Subramaniam

    2011-01-01

    Abstract The immune system of an organism is an essential component of the defense mechanism aimed at combating pathogenic stress. Age-associated immune dysfunction, also dubbed “immune senescence,” manifests as increased susceptibility to infections, increased onset and progression of autoimmune diseases, and onset of neoplasia. Over the years, extensive research has generated consensus in terms of the phenotypic and functional defects within the immune system in various organisms, including humans. Indeed, age-associated alterations such as thymic involution, T cell repertoire skewing, decreased ability to activate naïve T cells and to generate robust memory responses, have been shown to have a causative role in immune decline. Further, understanding the molecular mechanisms underlying the generation of proteotoxic stress, DNA damage response, modulation of ubiquitin proteasome pathway, and regulation of transcription factor NFκB activation, in immune decline, have paved the way to delineating signaling pathways that cross-talk and impact immune senescence. Given the role of the immune system in combating infections, its effectiveness with age may well be a marker of health and a predictor of longevity. It is therefore believed that a better understanding of the mechanisms underlying immune senescence will lead to an effective interventional strategy aimed at improving the health span of individuals. Antioxid. Redox Signal. 14, 1551–1585. PMID:20812785

  16. Tea and cancer prevention: Molecular mechanisms and human relevance

    SciTech Connect

    Yang, Chung S. Lambert, Joshua D.; Ju Jihyeung; Lu Gang; Sang Shengmin

    2007-11-01

    Tea made from the leaves of the plant Camellia sinensis is a popular beverage. The possible cancer-preventive activity of tea and tea polyphenols has been studied extensively. This article briefly reviews studies in animal models, cell lines, and possible relevance of these studies to the prevention of human cancer. The cancer-preventive activity of tea constituents have been demonstrated in many animal models including cancer of the skin, lung, oral cavity, esophagus, stomach, liver, pancreas, small intestine, colon, bladder, prostate, and mammary gland. The major active constituents are polyphenols, of which (-)-epigallocatechin-3-gallate (EGCG) is most abundant, most active, and most studied, and caffeine. The molecular mechanisms of the cancer-preventive action, however, are just beginning to be understood. Studies in cell lines led to the proposal of many mechanisms on the action of EGCG. However, mechanisms based on studies with very high concentrations of EGCG may not be relevant to cancer prevention in vivo. The autooxidation of EGCG in cell culture may also produce activities that do not occur in many internal organs. In contrast to the cancer prevention activity demonstrated in different animal models, no such conclusion can be convincingly drawn from epidemiological studies on tea consumption and human cancers. Even though the human data are inconclusive, tea constituents may still be used for the prevention of cancer at selected organ sites if sufficient concentrations of the agent can be delivered to these organs. Some interesting examples in this area are discussed.

  17. Mechanical properties of borophene films: a reactive molecular dynamics investigation.

    PubMed

    Le, Minh Quy; Mortazavi, Bohayra; Rabczuk, Timon

    2016-11-01

    The most recent experimental advances could provide ways for the fabrication of several atomic thick and planar forms of boron atoms. For the first time, we explore the mechanical properties of five types of boron films with various vacancy ratios ranging from 0.1-0.15, using molecular dynamics simulations with ReaxFF force field. It is found that the Young's modulus and tensile strength decrease with increasing the temperature. We found that boron sheets exhibit an anisotropic mechanical response due to the different arrangement of atoms along the armchair and zigzag directions. At room temperature, 2D Young's modulus and fracture stress of these five sheets appear in the range 63-136 N m(-1) and 12-19 N m(-1), respectively. In addition, the strains at tensile strength are in the ranges of 9%-14%, 11%-19%, and 10%-16% at 1, 300, and 600 K, respectively. This investigation not only reveals the remarkable stiffness of 2D boron, but establishes relations between the mechanical properties of the boron sheets to the loading direction, temperature and atomic structures. PMID:27678335

  18. Molecular mechanisms of angioimmunoblastic T-cell lymphoma development.

    PubMed

    Sakata-Yanagimoto, Mamiko; Chiba, Shigeru

    2016-08-01

    The molecular pathogenesis of peripheral T-cell lymphoma (PTCL) has gradually been clarified in terms of genomic abnormalities. Insights into these genomic abnormalities have provided clues to understanding the pathogenesis of PTCL. Furthermore, the origins of lymphoma cells have been clarified by investigating the distribution of genomic abnormalities in tumor cells and non-tumor blood cells. Multistep tumorigenesis has been suggested to be a fundamental mechanism underlying the development of angioimmunoblastic T-cell lymphoma (AITL), a distinct subtype of PTCL: premalignant cells evolve from hematopoietic progenitors via mutations in epigenetic regulators. These cells then further differentiate into tumor cells via the addition of tumor-specific G17V RHOA mutations. Meanwhile, AITL are composed of various infiltrating cells as well as tumor cells. Most notably, AITL tissues are characterized by massive infiltration of B cells partially infected by Epstein-Barr virus, follicular dendritic cells, and high endothelial venules. Infiltration of these cell types has been thought to be a reactive process, promoted by cytokines and chemokines released from tumor cells. Considering the multistep mechanisms of AITL allows us to analyze whether these infiltrating cells are also derived from premalignant cells. Indeed, the mechanisms underlying massive infiltration of bystander cells might be more complicated than previously imagined. PMID:27599421

  19. Mechanical properties of borophene films: a reactive molecular dynamics investigation.

    PubMed

    Le, Minh Quy; Mortazavi, Bohayra; Rabczuk, Timon

    2016-11-01

    The most recent experimental advances could provide ways for the fabrication of several atomic thick and planar forms of boron atoms. For the first time, we explore the mechanical properties of five types of boron films with various vacancy ratios ranging from 0.1-0.15, using molecular dynamics simulations with ReaxFF force field. It is found that the Young's modulus and tensile strength decrease with increasing the temperature. We found that boron sheets exhibit an anisotropic mechanical response due to the different arrangement of atoms along the armchair and zigzag directions. At room temperature, 2D Young's modulus and fracture stress of these five sheets appear in the range 63-136 N m(-1) and 12-19 N m(-1), respectively. In addition, the strains at tensile strength are in the ranges of 9%-14%, 11%-19%, and 10%-16% at 1, 300, and 600 K, respectively. This investigation not only reveals the remarkable stiffness of 2D boron, but establishes relations between the mechanical properties of the boron sheets to the loading direction, temperature and atomic structures.

  20. Garlic and cardioprotection: insights into the molecular mechanisms.

    PubMed

    Khatua, Tarak Nath; Adela, Ramu; Banerjee, Sanjay K

    2013-06-01

    Garlic is widely recognized for its immense therapeutic potential. Garlic has been shown to exert its beneficial effects against a wide spectrum of diseases, including cancer, diabetes, and microbial infections, as well as immunological and cardiovascular disorders. Most of the research on garlic has indicated that garlic and its active compounds are effective in reducing cardiovascular and metabolic risk by normalizing abnormal plasma lipids, oxidized low density lipoproteins, abnormal platelet aggregation, high blood pressure, and cardiac injury. Some of the beneficial effects of dietary garlic against cardiovascular disorders are mediated via the generation of hydrogen sulfide and nitric oxide in cardiomyocytes and endothelial cells. Garlic has the potential to protect the heart against myocardial infarction, doxorubicin-induced cardiotoxicity, arrhythmia, hypertrophy, and ischemia-reperfusion injury. The induction of cardiac endogenous antioxidants and the reduction of lipid peroxidation by garlic has been reported by several different groups. Other mechanisms, such as regulating ion channels, modulating Akt signaling pathways, histone deacetylase inhibition, and cytochrome P450 inhibition, could be responsible for the cardioprotective effect of garlic. Although several mechanisms have been identified for the cardioprotective effect of garlic, there is a need for further research to identify the specific molecular mechanism of cardioprotection in different cardiac diseases.

  1. Mechanical Properties of Nanostructured Materials Determined Through Molecular Modeling Techniques

    NASA Technical Reports Server (NTRS)

    Clancy, Thomas C.; Gates, Thomas S.

    2005-01-01

    The potential for gains in material properties over conventional materials has motivated an effort to develop novel nanostructured materials for aerospace applications. These novel materials typically consist of a polymer matrix reinforced with particles on the nanometer length scale. In this study, molecular modeling is used to construct fully atomistic models of a carbon nanotube embedded in an epoxy polymer matrix. Functionalization of the nanotube which consists of the introduction of direct chemical bonding between the polymer matrix and the nanotube, hence providing a load transfer mechanism, is systematically varied. The relative effectiveness of functionalization in a nanostructured material may depend on a variety of factors related to the details of the chemical bonding and the polymer structure at the nanotube-polymer interface. The objective of this modeling is to determine what influence the details of functionalization of the carbon nanotube with the polymer matrix has on the resulting mechanical properties. By considering a range of degree of functionalization, the structure-property relationships of these materials is examined and mechanical properties of these models are calculated using standard techniques.

  2. Molecular mechanisms linking sodium to hypertension: report of a symposium.

    PubMed

    Hamilton, Bruce P; Blaustein, Mordecai P

    2006-03-01

    There is abundant clinical and epidemiologic data linking excess body sodium with hypertension. The mechanism(s) at the molecular level to explain this relationship are unknown. Recent studies by multiple investigators, have identified several ion transport mechanisms in the vascular wall that interact to control vascular tone and contractility. These new data include 1) biochemical, pharmacologic, and molecule structural studies, 2) experiments in transgenic and knockout mice, and 3) results in clinical hypertension. The overall results provide compelling evidence for the concept that salt-dependent hypertension involves the secretion of endogenous ouabain (EO), an adrenal steroid synthesized with the same initial steps as aldosterone and secreted by the zona glomerulosa. Circulating EO inhibits arterial smooth muscle Na+ pumps with alpha 2 subunits. These are functionally coupled to the type 1 Na/Ca exchanger (NCX1). Thus when a2 Na pumps are inhibited in arterial smooth muscle, the resulting subplasma membrane increase in Na+ concentration triggers, via NCX1 Ca2+ entry, a rise in cytosolic Ca2+ concentration and increased myogenic tone and contractility. The ultimate result is a rise in peripheral vascular resistance-the hemodynamic hallmark of hypertension. The elucidation of this pathway has facilitated the development of pharmacologic agents that have therapeutic potential for hypertension and other cardiovascular diseases. These include agents that compete with EO for binding to the Na+ pump and inhibitors of NCX1. PMID:16472478

  3. Causes, effects and molecular mechanisms of testicular heat stress.

    PubMed

    Durairajanayagam, Damayanthi; Agarwal, Ashok; Ong, Chloe

    2015-01-01

    The process of spermatogenesis is temperature-dependent and occurs optimally at temperatures slightly lower than that of the body. Adequate thermoregulation is imperative to maintain testicular temperatures at levels lower than that of the body core. Raised testicular temperature has a detrimental effect on mammalian spermatogenesis and the resultant spermatozoa. Therefore, thermoregulatory failure leading to heat stress can compromise sperm quality and increase the risk of infertility. In this paper, several different types of external and internal factors that may contribute towards testicular heat stress are reviewed. The effects of heat stress on the process of spermatogenesis, the resultant epididymal spermatozoa and on germ cells, and the consequent changes in the testis are elaborated upon. We also discuss the molecular response of germ cells to heat exposure and the possible mechanisms involved in heat-induced germ cell damage, including apoptosis, DNA damage and autophagy. Further, the intrinsic and extrinsic pathways that are involved in the intricate mechanism of germ cell apoptosis are explained. Ultimately, these complex mechanisms of apoptosis lead to germ cell death.

  4. Molecular Mechanisms of Signaling in Myxococcus xanthus Development.

    PubMed

    Bretl, Daniel J; Kirby, John R

    2016-09-25

    Myxococcus xanthus is an environmental bacterium that displays a complex life cycle that includes motility, predation, multicellular fruiting body development, and sporulation. Given the elaborate fruiting body development of this bacterial species, M. xanthus has served as a model organism for the study of multicellular development of bacteria, and a remarkable number of genes have been identified that contribute to the regulation of this highly dynamic process. Included among these developmental factors is a robust repertoire of signaling proteins, which have arisen from extensive gene duplication in M. xanthus and related species. In this review, we explore several aspects of the molecular mechanisms of signaling in M. xanthus development. This includes mechanisms of kin selection, single-cell sensing of nutrient depletion and the stringent response, the production of and response to extracellular population cues, and the contribution of several two-component signaling systems regulating developmental transcriptional programs. Collectively, these signaling mechanisms function to tightly regulate the sensing of nutrient depletion, the aggregation of populations of cells, and the temporal and spatial formation of complex fruiting bodies and sporulation of M. xanthus. PMID:27430596

  5. Cellular and molecular mechanisms for the bone response to mechanical loading

    NASA Technical Reports Server (NTRS)

    Bloomfield, S. A.

    2001-01-01

    To define the cellular and molecular mechanisms for the osteogenic response of bone to increased loading, several key steps must be defined: sensing of the mechanical signal by cells in bone, transduction of the mechanical signal to a biochemical one, and transmission of that biochemical signal to effector cells. Osteocytes are likely to serve as sensors of loading, probably via interstitial fluid flow produced during loading. Evidence is presented for the role of integrins, the cell's actin cytoskeleton, G proteins, and various intracellular signaling pathways in transducing that mechanical signal to a biochemical one. Nitric oxide, prostaglandins, and insulin-like growth factors all play important roles in these pathways. There is growing evidence for modulation of these mechanotransduction steps by endocrine factors, particularly parathyroid hormone and estrogen. The efficiency of this process is also impaired in the aged animal, yet what remains undefined is at what step mechanotransduction is affected.

  6. Probabilistic Approach to Teaching the Principles of Quantum Mechanics

    ERIC Educational Resources Information Center

    Santos, Emilio

    1976-01-01

    Approaches the representation of quantum mechanics through Hilbert space postulates. Demonstrates that if the representation is to be accurate, an evolution operator of the form of a Hamiltonian must be used. (CP)

  7. A multilayered representation, quantum mechanical and molecular mechanics study of the CH3 F + OH(-) reaction in water.

    PubMed

    Chen, Jie; Xu, Yulong; Wang, Dunyou

    2014-03-01

    The bimolecular nucleophilic substitution (SN 2) reaction of CH3 F + OH(-) in aqueous solution was investigated using a combined quantum mechanical and molecular mechanics approach. Reactant complex, transition state, and product complex along the reaction pathway were analyzed in water. The potentials of mean force were calculated using a multilayered representation with the DFT and CCSD(T) level of theory for the reactive region. The obtained free energy activation barrier for this reaction at the CCSD(T)/MM representation is 18.3 kcal/mol which agrees well with the experimental value at ∼21.6 kcal/mol. Both the solvation effect and solute polarization effect play key roles on raising the activation barrier height in aqueous solution, with the former raising the barrier height by 3.1 kcal/mol, the latter 1.5 kcal/mol.

  8. Molecular mechanisms responsible for hydrate anti-agglomerant performance.

    PubMed

    Phan, Anh; Bui, Tai; Acosta, Erick; Krishnamurthy, Pushkala; Striolo, Alberto

    2016-09-28

    Steered and equilibrium molecular dynamics simulations were employed to study the coalescence of a sI hydrate particle and a water droplet within a hydrocarbon mixture. The size of both the hydrate particle and the water droplet is comparable to that of the aqueous core in reverse micelles. The simulations were repeated in the presence of various quaternary ammonium chloride surfactants. We investigated the effects due to different groups on the quaternary head group (e.g. methyl vs. butyl groups), as well as different hydrophobic tail lengths (e.g. n-hexadecyl vs. n-dodecyl tails) on the surfactants' ability to prevent coalescence. Visual inspection of sequences of simulation snapshots indicates that when the water droplet is not covered by surfactants it is more likely to approach the hydrate particle, penetrate the protective surfactant film, reach the hydrate surface, and coalesce with the hydrate than when surfactants are present on both surfaces. Force-distance profiles obtained from steered molecular dynamics simulations and free energy profiles obtained from umbrella sampling suggest that surfactants with butyl tripods on the quaternary head group and hydrophobic tails with size similar to the solvent molecules can act as effective anti-agglomerants. These results qualitatively agree with macroscopic experimental observations. The simulation results provide additional insights, which could be useful in flow assurance applications: the butyl tripod provides adhesion between surfactants and hydrates; when the length of the surfactant tail is compatible with that of the hydrocarbon in the liquid phase a protective film can form on the hydrate; however, once a molecularly thin chain of water molecules forms through the anti-agglomerant film, connecting the water droplet and the hydrate, water flows to the hydrate and coalescence is inevitable. PMID:27436688

  9. Cellular and molecular investigations of the adhesion and mechanics of Listeria monocytogenes

    NASA Astrophysics Data System (ADS)

    Eskhan, Asma Omar

    Atomic force microscopy has been used to quantify the adherence and mechanical properties of an array of L. monocytogenes strains and their surface biopolymers. First, eight L. monocytogenes strains that represented the two major lineages of the species were compared for their adherence and mechanics at cellular and molecular levels. Our results indicated that strains of lineage' II were characterized by higher adhesion and Young's moduli, longer and more rigid surface biopolymers and lower specific and nonspecific forces when compared to lineage' I strains. Additionally, adherence and mechanical properties of eight L. monocytogenes epidemic and environmental strains were probed. Our results pointed to that environmental and epidemic strains representative of a given lineage were similar in their adherence and mechanical properties when investigated at a cellular level. However, when the molecular properties of the strains were considered, epidemic strains were characterized by higher specific and nonspecific forces, shorter, denser and more flexible biopolymers compared to environmental strains. Second, the role of environmental pH conditions of growth on the adhesion and mechanics of a pathogenic L. monocytogenes EGDe was investigated. Our results pointed to a transition in the adhesion energies for cells cultured at pH 7. In addition, when the types of molecular forces that govern the adhesion were quantified using Poisson statistical approach and using a new proposed method, specific hydrogen-bond energies dominated the bacterial adhesion process. Such a finding is instrumental to researchers designing methods to control bacterial adhesion. Similarly, bacterial cells underwent a transition in their mechanical properties. We have shown that cells cultured at pH 7 were the most rigid compared to those cultured in lower or higher pH conditions of growth. Due to transitions observed in adherence and mechanics when cells were cultured at pH 7, we hypothesized that

  10. Ethanol-Induced Cerebellar Ataxia: Cellular and Molecular Mechanisms.

    PubMed

    Dar, M Saeed

    2015-08-01

    The cerebellum is an important target of ethanol toxicity given that cerebellar ataxia is the most consistent physical manifestation of acute ethanol consumption. Despite the significance of the cerebellum in ethanol-induced cerebellar ataxia (EICA), the cellular and molecular mechanisms underlying EICA are incompletely understood. However, two important findings have shed greater light on this phenomenon. First, ethanol-induced blockade of cerebellar adenosine uptake in rodent models points to a role for adenosinergic A1 modulation of EICA. Second, the consistent observation that intracerebellar administration of nicotine in mice leads to antagonism of EICA provides evidence for a critical role of cerebellar nitric oxide (NO) in EICA reversal. Based on these two important findings, this review discusses the potential molecular events at two key synaptic sites (mossy fiber-granule cell-Golgi cell (MGG synaptic site) and granule cell parallel fiber-Purkinje cell (GPP synaptic site) that lead to EICA. Specifically, ethanol-induced neuronal NOS inhibition at the MGG synaptic site acts as a critical trigger for Golgi cell activation which leads to granule cell deafferentation. Concurrently, ethanol-induced inhibition of adenosine uptake at the GPP synaptic site produces adenosine accumulation which decreases glutamate release and leads to the profound activation of Purkinje cells (PCs). These molecular events at the MGG and GPP synaptic sites are mutually reinforcing and lead to cerebellar dysfunction, decreased excitatory output of deep cerebellar nuclei, and EICA. The critical importance of PCs as the sole output of the cerebellar cortex suggests normalization of PC function could have important therapeutic implications.

  11. EGFR gene deregulation mechanisms in lung adenocarcinoma: A molecular review.

    PubMed

    Tsiambas, Evangelos; Lefas, Alicia Y; Georgiannos, Stavros N; Ragos, Vasileios; Fotiades, Panagiotis P; Grapsa, Dimitra; Stamatelopoulos, Athanasios; Kavantzas, Nikolaos; Patsouris, Efstratios; Syrigos, Konstantinos

    2016-08-01

    For the last two decades, evolution in molecular biology has expanded our knowledge in decoding a broad spectrum of genomic imbalances that progressively lead normal cells to a neoplastic state and finally to complete malignant transformation. Concerning oncogenes and signaling transduction pathways mediated by them, identification of specific gene alterations remains a critical process for handling patients by applying targeted therapeutic regimens. The epidermal growth factor receptor (EGFR) signaling pathway plays a crucial role in regulating cell proliferation, differentiation and apoptosis in normal cells. EGFR mutations and amplification represent the gene's main deregulation mechanisms in cancers of different histo-genetic origin. Furthermore, intra-cancer molecular heterogeneity due to clonal rise and expansion mainly explains the variable resistance to novel anti-EGFR monoclonal antibody (mAb), and also tyrosine kinase inhibitors (TKIs). According to recently published 2015 WHO new classification, lung cancer is the leading cause of death related to cancer and its incidence is still on the increase worldwide. The majority of patients suffering from lung cancer are diagnosed with epithelial tumors (adenocarcinoma predominantly and squamous cell carcinoma represent ∼85% of all pathologically defined lung cancer cases). In those patients, EGFR-activating somatic mutations in exons 18/19/20/21 modify patients' sensitivity (i.e. exon 21 L858R, exon 19 LREA deletion) or resistance (ie exon 20 T790M and/or insertion) to TKI mediated targeted therapeutic strategies. Additionally, the role of specific micro-RNAs that affect EGFR regulation is under investigation. In the current review, we focused on EGFR gene/protein structural and functional aspects and the corresponding alterations that occur mainly in lung adenocarcinoma to critically modify its molecular landscape. PMID:27461822

  12. Cellular and molecular mechanisms of chemical synaptic transmission.

    PubMed

    Millhorn, D E; Bayliss, D A; Erickson, J T; Gallman, E A; Szymeczek, C L; Czyzyk-Krzeska, M; Dean, J B

    1989-12-01

    During the last decade much progress has been made in understanding the cellular and molecular mechanisms by which nerve cells communicate with each other and nonneural (e.g., muscle) target tissue. This review is intended to provide the reader with an account of this work. We begin with an historical overview of research on cell-to-cell communication and then discuss recent developments that, in some instances, have led to dramatic changes in the concept of synaptic transmission. For instance, the finding that single neurons often contain multiple messengers (i.e., neurotransmitters) invalidated the long-held theory (i.e., Dale's Law) that individual neurons contain and release one and only one type of neurotransmitter. Moreover, the last decade witnessed the inclusion of an entire group of compounds, the neuropeptides, as messenger molecules. Enormous progress has also been made in elucidating postsynaptic receptor complexes and biochemical intermediaries involved in synaptic transmission. Here the development of recombinant DNA technology has made it possible to clone and determine the molecular structure for a number of receptors. This information has been used to gain insight into how these receptors function either as a ligand-gated channel or as a G protein-linked ligand recognition molecule. Perhaps the most progress made during this era was in understanding the molecular linkage of G protein-linked receptors to intramembranous and cytoplasmic macromolecules involved in signal amplification and transduction. We conclude with a brief discussion of how synaptic transmission leads to immediate alterations in the electrical activity and, in some cases, to a change in phenotype by altering gene expression. These alterations in cellular behavior are believed to be mediated by phosphoproteins, the final biochemical product of signal transduction. PMID:2575357

  13. Molecular mechanics work station for protein conformational studies

    SciTech Connect

    Fine, R.; Levinthal, C.; Schoenborn, B.; Dimmier, G.; Rankowitz, C.

    1984-01-01

    Interest in computational problems in Biology has intensified over the last few years, partly due to the development of techniques for the rapid cloning, sequencing, and mutagenesis of genes from organisims ranging from E. coli to Man. The central dogma of molecular biology; that DNA codes for mRNA which codes for protein, has been understood in a linear programming sense since the genetic code was cracked. But what is not understood at present is how a protein, once assembled as a long sequence of amino acids, folds back on itself to produce a three-dimensional structure which is unique to that protein and which dictates its chemical and biological activity. This folding process is purely physics, and involves the time evolution of a system of several thousand atoms which interact with each other and with atoms from the surrounding solvent. Molecular dynamics simulations on smaller molecules suggest that approaches which treat the protein as a classical ensemble of atoms interacting with each other via an empirical Hamiltonian can yield the kind of predictive results one would like when applied to proteins.

  14. Molecular mechanisms of hepcidin regulation in sea bass (Dicentrarchus labrax).

    PubMed

    Neves, J V; Caldas, C; Wilson, J M; Rodrigues, P N S

    2011-12-01

    Hepcidin, an antimicrobial peptide described as a key regulator of iron metabolism, is known to respond in mammals to several stimuli, including iron overload, anemia, hypoxia and inflammation, through a number of molecular pathways. In order to understand the molecular pathways involved in the regulation of hepcidin expression in teleost fish, we have isolated for European sea bass (Dicentrarchus labrax) several coding sequences of known molecules involved on these pathways in mammals, namely jak3, stat3, tmprss6, bmp6, bmpr2, hjv, smad4, smad5, tfr1 and tfr2. The transcription levels of the isolated genes were evaluated by real-time PCR on fish subjected to experimental iron modulation (overload/deficiency) or infection with Photobacterium damsela. Results show that genes associated with the major pathway of the inflammatory response (IL6/JAK/STAT pathway) in mammals are also modulated in sea bass, being up-regulated during infection. Similarly, genes of the pathways classically associated with the response to variations in iron status (the HJV/BMP/SMAD and HFE/TfR pathways) are also modulated, mostly through down-regulation in iron deficiency and up-regulation during iron overload. Interestingly, many of these genes are also found to be up-regulated during infection, which may indicate a crosstalk between the known pathways of hepcidin regulation. These observations suggest the evolutionary conservation of the mechanisms of hepcidin regulation in teleost fish.

  15. Redox Control of Leukemia: From Molecular Mechanisms to Therapeutic Opportunities

    PubMed Central

    Irwin, Mary E.; Rivera-Del Valle, Nilsa

    2013-01-01

    Abstract Reactive oxygen species (ROS) play both positive and negative roles in the proliferation and survival of a cell. This dual nature has been exploited by leukemia cells to promote growth, survival, and genomic instability—some of the hallmarks of the cancer phenotype. In addition to altered ROS levels, many antioxidants are dysregulated in leukemia cells. Together, the production of ROS and the expression and activity of antioxidant enzymes make up the primary redox control of leukemia cells. By manipulating this system, leukemia cells gain proliferative and survival advantages, even in the face of therapeutic insults. Standard treatment options have improved leukemia patient survival rates in recent years, although relapse and the development of resistance are persistent challenges. Therapies targeting the redox environment show promise for these cases. This review highlights the molecular mechanisms that control the redox milieu of leukemia cells. In particular, ROS production by the mitochondrial electron transport chain, NADPH oxidase, xanthine oxidoreductase, and cytochrome P450 will be addressed. Expression and activation of antioxidant enzymes such as superoxide dismutase, catalase, heme oxygenase, glutathione, thioredoxin, and peroxiredoxin are perturbed in leukemia cells, and the functional consequences of these molecular alterations will be described. Lastly, we delve into how these pathways can be potentially exploited therapeutically to improve treatment regimens and promote better outcomes for leukemia patients. Antioxid. Redox Signal. 18, 1349–1383. PMID:22900756

  16. Molecular mechanisms underlying genotype-dependent responses to dietary restriction

    PubMed Central

    Schleit, Jennifer; Johnson, Simon C.; Bennett, Christopher F.; Simko, Marissa; Trongtham, Natalie; Castanza, Anthony; Hsieh, Edward J.; Moller, Richard M.; Wasko, Brian M.; Delaney, Joe R.; Sutphin, George L.; Carr, Daniel; Murakami, Christopher J.; Tocchi, Autumn; Xian, Bo; Chen, Weiyang; Yu, Tao; Goswami, Sarani; Higgins, Sean; Holmberg, Mollie; Jeong, Ki-Soo; Kim, Jin R.; Klum, Shannon; Liao, Eric; Lin, Michael S.; Lo, Winston; Miller, Hillary; Olsen, Brady; Peng, Zhao J.; Pollard, Tom; Pradeep, Prarthana; Pruett, Dillon; Rai, Dilreet; Ros, Vanessa; Singh, Minnie; Spector, Benjamin L.; Wende, Helen Vander; An, Elroy H.; Fletcher, Marissa; Jelic, Monika; Rabinovitch, Peter S.; MacCoss, Michael J.; Han, Jing-Dong J.; Kennedy, Brian K.; Kaeberlein, Matt

    2013-01-01

    Summary Dietary restriction (DR) increases lifespan and attenuates age-related phenotypes in many organisms; however, the effect of DR on longevity of individuals in genetically heterogeneous populations is not well characterized. Here we describe a large-scale effort to define molecular mechanisms that underlie genotype-specific responses to DR. The effect of DR on lifespan was determined for 166 single-gene deletion strains in Saccharomyces cerevisiae. Resulting changes in mean lifespan ranged from a reduction of 79% to an increase of 103%. Vacuolar pH homeostasis, superoxide dismutase activity, and mitochondrial proteostasis were found to be strong determinants of the response to DR. Proteomic analysis of cells deficient in prohibitins revealed induction of a mitochondrial unfolded protein response (mtUPR) which has not previously been described in yeast. Mitochondrial proteotoxic stress in prohibitin mutants was suppressed by DR via reduced cytoplasmic mRNA translation. A similar relationship between prohibitins, the mtUPR, and longevity was also observed in Caenorhabditis elegans. These observations define conserved molecular processes that underlie genotype-dependent effects of DR that may be important modulators of DR in higher organisms. PMID:23837470

  17. Molecular Mechanisms of Inflammasome Activation during Microbial Infections

    PubMed Central

    Broz, Petr; Monack, Denise M.

    2011-01-01

    Summary The innate immune system plays a crucial role in the rapid recognition and elimination of invading microbes. Detection of microbes relies on germ-line encoded pattern recognition receptors (PRRs) that recognize essential bacterial molecules, so-called pathogen-associated molecular patterns (PAMPs). A subset of PRRs, belonging to the NOD-like receptor (NLR) and the PYHIN protein families, detects viral and bacterial pathogens in the cytosol of host cells and induces the assembly of a multi-protein signaling platform called the inflammasome. The inflammasome serves as an activation platform for the mammalian cysteine protease caspase-1, a central mediator of innate immunity. Active caspase-1 promotes the maturation and release of interleukin-1β (IL-1β) and IL-18 as well as protein involved in cytoprotection and tissue repair. In addition, caspase-1 initiates a novel form of cell death called pyroptosis. Here we discuss latest advances and our insights on inflammasome stimulation by two model intracellular pathogens, Francisella tularensis and Salmonella typhimurium. Recent studies on these pathogens have significantly shaped our understanding of the molecular mechanisms of inflammasome activation and how microbes can evade or manipulate inflammasome activity. In addition, we review the role of the inflammasome adapter ASC in the caspase-1 autoproteolysis and new insights into the structure of the inflammasome complex. PMID:21884176

  18. Integration of Ligand Field Molecular Mechanics in Tinker.

    PubMed

    Foscato, Marco; Deeth, Robert J; Jensen, Vidar R

    2015-06-22

    The ligand field molecular mechanics (LFMM) method for transition-metal complexes has been integrated in Tinker, an easily available and popular molecular modeling software package. The capability to calculate LFMM potentials has been provided by extending the functional forms of the Tinker package as well as by integrating routines for calculating the ligand field stabilization energy (LFSE), which is central to LFMM. The capabilities of the implementation are illustrated by both static calculations on the two spin states of [Fe(NH3)6](2+) and on [Cu(NH3)m](2+) (m = 4, 5, 6) and dynamic (LFMD) simulations of an FeN6-type spin-crossover compound. In addition to showing that results obtained with the Tinker-LFMM implementation are consistent with those of experiment and other computational methods and programs, we note that whereas LFMM is able to handle the conventional tetragonal Jahn-Teller distortion of the bond distances in [Cu(NH3)6](2+), the LFSE term is also necessary in order to obtain even qualitatively correct coordination geometries for the two lower-coordinate copper complexes. PMID:25970002

  19. Molecular spectroscopic study for suggested mechanism of chrome tanned leather

    NASA Astrophysics Data System (ADS)

    Nashy, Elshahat H. A.; Osman, Osama; Mahmoud, Abdel Aziz; Ibrahim, Medhat

    2012-03-01

    Collagen represents the structural protein of the extracellular matrix, which gives strength of hides and/or skin under tanning process. Chrome tan is the most important tanning agent all over the world. The methods for production of leather evolved over several centuries as art and engineering with little understanding of the underlying science. The present work is devoted to suggest the most probable mechanistic action of chrome tan on hide proteins. First the affect of Cr upon hide protein is indicated by the studied mechanical properties. Then the spectroscopic characterization of the hide protein as well as chrome tanned leather was carried out with Horizontal Attenuated Total Reflection (HATR) FT-IR. The obtained results indicate how the chromium can attached with the active sites of collagen. Molecular modeling confirms that chromium can react with amino as well as carboxylate groups. Four schemes were obtained to describe the possible interactions of chrome tan with hide proteins.

  20. Molecular mechanism of respiratory syncytial virus fusion inhibitors.

    PubMed

    Battles, Michael B; Langedijk, Johannes P; Furmanova-Hollenstein, Polina; Chaiwatpongsakorn, Supranee; Costello, Heather M; Kwanten, Leen; Vranckx, Luc; Vink, Paul; Jaensch, Steffen; Jonckers, Tim H M; Koul, Anil; Arnoult, Eric; Peeples, Mark E; Roymans, Dirk; McLellan, Jason S

    2016-02-01

    Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. Here we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.

  1. [Biodegradation mechanism of DDT and chlorpyrifos using molecular simulation].

    PubMed

    Lin, Yu-Zhen; Zeng, Guang-Ming; Zhang, Yu; Chen, Ming; Jiang, Min; Zhang, Jia-Chao; Lu, Lun-Hui; Liu, Li-Feng

    2012-03-01

    In order to explore the microscopic degradation mechanism of organic pesticides degrading enzymes, we used molecular docking method to investigate the binding modes of DDT to laccase and chlorpyrifos to organophosphorus hydrolase, and obtained the corresponding complex structures. According to the principle of minimum scoring, the results showed that the MolDock scores were -103.134 and -111.626, re-rank scores were -72.858 and -80.261, respectively. And we used LPC/CSU server search the interactions between organic pesticides and their degrading enzymes. Our results showed that hydrophobic interaction was the strongest contacts in DDT-laccase complex, and both hydrogen bonds and hydrophobic interactions were the strongest contacts when chlorpyrifos-organophosphorus hydrolase complex. The amino acid residues Tyr224 in laccase and Arg254 in organophosphorus hydrolase were detected to play significant roles in catalytic processes.

  2. Molecular Mechanisms of Opioid Receptor-Dependent Signaling and Behavior

    PubMed Central

    Al-Hasani, Ream; Bruchas, Michael R.

    2013-01-01

    Opioid receptors have been targeted for the treatment of pain and related disorders for thousands of years, and remain the most widely used analgesics in the clinic. Mu (μ), kappa (κ), and delta (δ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized. All four receptors are G-protein coupled, and activate inhibitory G-proteins. These receptors form homo- and hetereodimeric complexes, signal to kinase cascades, and scaffold a variety of proteins. In this review, we discuss classical mechanisms and developments in understanding opioid tolerance, opioid receptor signaling, and highlight advances in opioid molecular pharmacology, behavioral pharmacology, and human genetics. We put into context how opioid receptor signaling leads to the modulation of behavior with the potential for therapeutic intervention. Finally, we conclude that there is a continued need for more translational work on opioid receptors in vivo. PMID:22020140

  3. Recent Advances in Methamphetamine Neurotoxicity Mechanisms and Its Molecular Pathophysiology

    PubMed Central

    Yu, Shaobin; Zhu, Ling; Shen, Qiang; Bai, Xue; Di, Xuhui

    2015-01-01

    Methamphetamine (METH) is a sympathomimetic amine that belongs to phenethylamine and amphetamine class of psychoactive drugs, which are widely abused for their stimulant, euphoric, empathogenic, and hallucinogenic properties. Many of these effects result from acute increases in dopamine and serotonin neurotransmission. Subsequent to these acute effects, METH produces persistent damage to dopamine and serotonin release in nerve terminals, gliosis, and apoptosis. This review summarized the numerous interdependent mechanisms including excessive dopamine, ubiquitin-proteasome system dysfunction, protein nitration, endoplasmic reticulum stress, p53 expression, inflammatory molecular, D3 receptor, microtubule deacetylation, and HIV-1 Tat protein that have been demonstrated to contribute to this damage. In addition, the feasible therapeutic strategies according to recent studies were also summarized ranging from drug and protein to gene level. PMID:25861156

  4. Mechanochromism, Shear Force Anisotropy, and Molecular Mechanics in Polydiacetylene Monolayers

    SciTech Connect

    BURNS,ALAN R.; CARPICK,R.W.; SASAKI,DARRYL Y.; SHELNUTT,JOHN A.; HADDAD,R.

    2000-08-14

    The authors use scanning probe microscopy to actuate and characterize the nanoscale mechanochromism of polydiacetylene monolayer on atomically-flat silicon oxide substrates. They find explicit evidence that the irreversible blue-to-red transformation is caused by shear forces exerted normal to the polydiacetylene polymer backbone. The anisotropic probe-induced transformation is characterized by a significant change in the tilt orientation of the side chains with respect to the surface normal. They also describe a new technique, based on shear force microscopy, that allows them to image friction anisotropy of polydiacetylene monolayer independent of scan direction. Finally, they discuss preliminary molecular mechanics modeling and electronic structure calculations that allow them to understand the correlation of mechanochromism with bond-angle changes in the conjugated polymer backbone.

  5. Molecular organization and force-generating mechanism of dynein.

    PubMed

    Sakakibara, Hitoshi; Oiwa, Kazuhiro

    2011-09-01

    Dynein, which is a minus-end-directed microtubule motor, is crucial to a range of cellular processes. The mass of its motor domain is about 10 times that of kinesin, the other microtubule motor. Its large size and the difficulty of expressing and purifying mutants have hampered progress in dynein research. Recently, however, electron microscopy, X-ray crystallography and single-molecule nanometry have shed light on several key unsolved questions concerning how the dynein molecule is organized, what conformational changes in the molecule accompany ATP hydrolysis, and whether two or three motor domains are coordinated in the movements of dynein. This minireview describes our current knowledge of the molecular organization and the force-generating mechanism of dynein, with emphasis on findings from electron microscopy and single-molecule nanometry.

  6. Molecular Mechanisms of Floral Boundary Formation in Arabidopsis

    PubMed Central

    Yu, Hongyang; Huang, Tengbo

    2016-01-01

    Boundary formation is a crucial developmental process in plant organogenesis. Boundaries separate cells with distinct identities and act as organizing centers to control the development of adjacent organs. In flower development, initiation of floral primordia requires the formation of the meristem-to-organ (M–O) boundaries and floral organ development depends on the establishment of organ-to-organ (O–O) boundaries. Studies in this field have revealed a suite of genes and regulatory pathways controlling floral boundary formation. Many of these genes are transcription factors that interact with phytohormone pathways. This review will focus on the functions and interactions of the genes that play important roles in the floral boundaries and discuss the molecular mechanisms that integrate these regulatory pathways to control the floral boundary formation. PMID:26950117

  7. Recent Advances in Molecular Mechanisms of Taste Signaling and Modifying.

    PubMed

    Shigemura, Noriatsu; Ninomiya, Yuzo

    2016-01-01

    The sense of taste conveys crucial information about the quality and nutritional value of foods before it is ingested. Taste signaling begins with taste cells via taste receptors in oral cavity. Activation of these receptors drives the transduction systems in taste receptor cells. Then particular transmitters are released from the taste cells and activate corresponding afferent gustatory nerve fibers. Recent studies have revealed that taste sensitivities are defined by distinct taste receptors and modulated by endogenous humoral factors in a specific group of taste cells. Such peripheral taste generations and modifications would directly influence intake of nutritive substances. This review will highlight current understanding of molecular mechanisms for taste reception, signal transduction in taste bud cells, transmission between taste cells and nerves, regeneration from taste stem cells, and modification by humoral factors at peripheral taste organs. PMID:26944619

  8. Obstructive renal injury: from fluid mechanics to molecular cell biology.

    PubMed

    Ucero, Alvaro C; Gonçalves, Sara; Benito-Martin, Alberto; Santamaría, Beatriz; Ramos, Adrian M; Berzal, Sergio; Ruiz-Ortega, Marta; Egido, Jesus; Ortiz, Alberto

    2010-04-22

    Urinary tract obstruction is a frequent cause of renal impairment. The physiopathology of obstructive nephropathy has long been viewed as a mere mechanical problem. However, recent advances in cell and systems biology have disclosed a complex physiopathology involving a high number of molecular mediators of injury that lead to cellular processes of apoptotic cell death, cell injury leading to inflammation and resultant fibrosis. Functional studies in animal models of ureteral obstruction using a variety of techniques that include genetically modified animals have disclosed an important role for the renin-angiotensin system, transforming growth factor-β1 (TGF-β1) and other mediators of inflammation in this process. In addition, high throughput techniques such as proteomics and transcriptomics have identified potential biomarkers that may guide clinical decision-making.

  9. Molecular mechanisms underlying progesterone-enhanced breast cancer cell migration

    PubMed Central

    Wang, Hui-Chen; Lee, Wen-Sen

    2016-01-01

    Progesterone (P4) was demonstrated to inhibit migration in vascular smooth muscle cells (VSMCs), but to enhance migration in T47D breast cancer cells. To investigate the mechanism responsible for this switch in P4 action, we examined the signaling pathway responsible for the P4-induced migration enhancement in breast cancer cell lines, T47D and MCF-7. Here, we demonstrated that P4 activated the cSrc/AKT signaling pathway, subsequently inducing RSK1 activation, which in turn increased phosphorylation of p27 at T198 and formation of the p27pT198-RhoA complex in the cytosol, thereby preventing RhoA degradation, and eventually enhanced migration in T47D cells. These findings were confirmed in the P4-treated MCF-7. Comparing the P4-induced molecular events in between breast cancer cells and VSMCs, we found that P4 increased p27 phosphorylation at T198 in breast cancer cells through RSK1 activation, while P4 increased p27 phosphorlation at Ser10 in VSMCs through KIS activation. P27pT198 formed the complex with RhoA and prevented RhoA degradation in T47D cells, whereas p-p27Ser10 formed the complex with RhoA and caused RhoA degradation in VSMCs. The results of this study highlight the molecular mechanism underlying P4-enhanced breast cancer cell migration, and suggest that RSK1 activation is responsible for the P4-induced migration enhancement in breast cancer cells. PMID:27510838

  10. Recent advances in the molecular mechanisms causing primary generalized glucocorticoid resistance.

    PubMed

    Nicolaides, Nicolas; Lamprokostopoulou, Agaristi; Sertedaki, Amalia; Charmandari, Evangelia

    2016-01-01

    Primary Generalized Glucocorticoid Resistance is a rare condition characterized by generalized, partial, target tissue insensitivity to glucocorticoids owing to inactivating mutations, insertions or deletions in the human glucocorticoid receptor (hGR) gene (NR3C1). Recent advances in molecular and structural biology have enabled us to elucidate the molecular mechanisms of action of the mutant receptors and to understand how certain conformational alterations of the defective hGRs result in generalized glucocorticoid resistance. Furthermore, our ever-increasing understanding of the molecular mechanisms of glucocorticoid action indicates that the glucocorticoid signaling pathway is a stochastic system that plays a fundamental role in maintaining both basal and stress-related homeostasis. In this review, we summarize the clinical manifestations and molecular pathogenesis of Primary Generalized Glucocorticoid Resistance, we present our recent findings from the functional characterization of three novel heterozygous point mutations in the NR3C1 gene, and we discuss the diagnostic approach and therapeutic management of the condition. When the condition is suspected, we recommend sequencing analysis of the NR3C1 gene as well as of other genes encoding proteins involved in the glucocorticoid signal transduction. The tremendous progress of next-generation sequencing will undoubtedly uncover novel hGR partners or cofactors.

  11. Molecular Mechanisms of Aldehyde Toxicity: A Chemical Perspective

    PubMed Central

    2015-01-01

    Aldehydes are electrophilic compounds to which humans are pervasively exposed. Despite a significant health risk due to exposure, the mechanisms of aldehyde toxicity are poorly understood. This ambiguity is likely due to the structural diversity of aldehyde derivatives and corresponding differences in chemical reactions and biological targets. To gain mechanistic insight, we have used parameters based on the hard and soft, acids and bases (HSAB) theory to profile the different aldehyde subclasses with respect to electronic character (softness, hardness), electrophilic reactivity (electrophilic index), and biological nucleophilic targets. Our analyses indicate that short chain aldehydes and longer chain saturated alkanals are hard electrophiles that cause toxicity by forming adducts with hard biological nucleophiles, e.g., primary nitrogen groups on lysine residues. In contrast, α,β-unsaturated carbonyl derivatives, alkenals, and the α-oxoaldehydes are soft electrophiles that preferentially react with soft nucleophilic thiolate groups on cysteine residues. The aldehydes can therefore be grouped into subclasses according to common electronic characteristics (softness/hardness) and molecular mechanisms of toxicity. As we will discuss, the toxic potencies of these subgroups are generally related to corresponding electrophilicities. For some aldehydes, however, predictions of toxicity based on electrophilicity are less accurate due to inherent physicochemical variables that limit target accessibility, e.g., steric hindrance and solubility. The unsaturated aldehydes are also members of the conjugated type-2 alkene chemical class that includes α,β-unsaturated amide, ketone, and ester derivatives. Type-2 alkenes are electrophiles of varying softness and electrophilicity that share a common mechanism of toxicity. Therefore, exposure to an environmental mixture of unsaturated carbonyl derivatives could cause “type-2 alkene toxicity” through additive interactions

  12. Molecular Mechanism for LAMP1 Recognition by Lassa Virus

    PubMed Central

    Cohen-Dvashi, Hadas; Cohen, Nadav; Israeli, Hadar

    2015-01-01

    ABSTRACT Lassa virus is a notorious human pathogen that infects many thousands of people each year in West Africa, causing severe viral hemorrhagic fevers and significant mortality. The surface glycoprotein of Lassa virus mediates receptor recognition through its GP1 subunit. Here we report the crystal structure of GP1 from Lassa virus, which is the first representative GP1 structure for Old World arenaviruses. We identify a unique triad of histidines that forms a binding site for LAMP1, a known lysosomal protein recently discovered to be a critical receptor for internalized Lassa virus at acidic pH. We demonstrate that mutation of this histidine triad, which is highly conserved among Old World arenaviruses, impairs LAMP1 recognition. Our biochemical and structural data further suggest that GP1 from Lassa virus may undergo irreversible conformational changes that could serve as an immunological decoy mechanism. Together with a variable region that we identify on the surface of GP1, those could be two distinct mechanisms that Lassa virus utilizes to avoid antibody-based immune response. IMPORTANCE Structural data at atomic resolution for viral proteins is key for understanding their function at the molecular level and can facilitate novel avenues for combating viral infections. Here we used X-ray protein crystallography to decipher the crystal structure of the receptor-binding domain (GP1) from Lassa virus. This is a pathogenic virus that causes significant illness and mortality in West Africa. This structure reveals the overall architecture of GP1 domains from the group of viruses known as the Old World arenaviruses. Using this structural information, we elucidated the mechanisms for pH switch and binding of Lassa virus to LAMP1, a recently identified host receptor that is critical for successful infection. Lastly, our structural analysis suggests two novel immune evasion mechanisms that Lassa virus may utilize to escape antibody-based immune response. PMID

  13. Molecular mechanisms of aldehyde toxicity: a chemical perspective.

    PubMed

    LoPachin, Richard M; Gavin, Terrence

    2014-07-21

    Aldehydes are electrophilic compounds to which humans are pervasively exposed. Despite a significant health risk due to exposure, the mechanisms of aldehyde toxicity are poorly understood. This ambiguity is likely due to the structural diversity of aldehyde derivatives and corresponding differences in chemical reactions and biological targets. To gain mechanistic insight, we have used parameters based on the hard and soft, acids and bases (HSAB) theory to profile the different aldehyde subclasses with respect to electronic character (softness, hardness), electrophilic reactivity (electrophilic index), and biological nucleophilic targets. Our analyses indicate that short chain aldehydes and longer chain saturated alkanals are hard electrophiles that cause toxicity by forming adducts with hard biological nucleophiles, e.g., primary nitrogen groups on lysine residues. In contrast, α,β-unsaturated carbonyl derivatives, alkenals, and the α-oxoaldehydes are soft electrophiles that preferentially react with soft nucleophilic thiolate groups on cysteine residues. The aldehydes can therefore be grouped into subclasses according to common electronic characteristics (softness/hardness) and molecular mechanisms of toxicity. As we will discuss, the toxic potencies of these subgroups are generally related to corresponding electrophilicities. For some aldehydes, however, predictions of toxicity based on electrophilicity are less accurate due to inherent physicochemical variables that limit target accessibility, e.g., steric hindrance and solubility. The unsaturated aldehydes are also members of the conjugated type-2 alkene chemical class that includes α,β-unsaturated amide, ketone, and ester derivatives. Type-2 alkenes are electrophiles of varying softness and electrophilicity that share a common mechanism of toxicity. Therefore, exposure to an environmental mixture of unsaturated carbonyl derivatives could cause "type-2 alkene toxicity" through additive interactions

  14. A computational kinematics and evolutionary approach to model molecular flexibility for bionanotechnology

    NASA Astrophysics Data System (ADS)

    Brintaki, Athina N.

    Modeling molecular structures is critical for understanding the principles that govern the behavior of molecules and for facilitating the exploration of potential pharmaceutical drugs and nanoscale designs. Biological molecules are flexible bodies that can adopt many different shapes (or conformations) until they reach a stable molecular state that is usually described by the minimum internal energy. A major challenge in modeling flexible molecules is the exponential explosion in computational complexity as the molecular size increases and many degrees of freedom are considered to represent the molecules' flexibility. This research work proposes a novel generic computational geometric approach called enhanced BioGeoFilter (g.eBGF) that geometrically interprets inter-atomic interactions to impose geometric constraints during molecular conformational search to reduce the time for identifying chemically-feasible conformations. Two new methods called Kinematics-Based Differential Evolution ( kDE) and Biological Differential Evolution ( BioDE) are also introduced to direct the molecular conformational search towards low energy (stable) conformations. The proposed kDE method kinematically describes a molecule's deformation mechanism while it uses differential evolution to minimize the intra-molecular energy. On the other hand, the proposed BioDE utilizes our developed g.eBGF data structure as a surrogate approximation model to reduce the number of exact evaluations and to speed the molecular conformational search. This research work will be extremely useful in enabling the modeling of flexible molecules and in facilitating the exploration of nanoscale designs through the virtual assembly of molecules. Our research work can also be used in areas such as molecular docking, protein folding, and nanoscale computer-aided design where rapid collision detection scheme for highly deformable objects is essential.

  15. Exactly Solvable Quantum Mechanical Potentials: An Alternative Approach.

    ERIC Educational Resources Information Center

    Pronchik, Jeremy N.; Williams, Brian W.

    2003-01-01

    Describes an alternative approach to finding exactly solvable, one-dimensional quantum mechanical potentials. Differs from the usual approach in that instead of starting with a particular potential and seeking solutions to the related Schrodinger equations, it begins with known solutions to second-order ordinary differential equations and seeks to…

  16. Molecular and genetic ecotoxicologic approaches to aquatic environmental bioreporting.

    PubMed Central

    Beaty, B J; Black, W C; Carlson, J O; Clements, W H; DuTeau, N; Harrahy, E; Nuckols, J; Kenneth, E; Olson, K E; Rayms-Keller, A

    1998-01-01

    Molecular and population genetic ecotoxicologic approaches are being developed for the utilization of arthropods as bioreporters of heavy metal mixtures in the environment. The explosion of knowledge in molecular biology, molecular genetics, and biotechnology provides an unparalleled opportunity to use arthropods as bioreporter organisms. Interspecific differences in aquatic arthropod populations have been previously demonstrated in response to heavy metal insult in the Arkansas River (AR) California Gulch Superfund site (CGSS). Population genetic analyses were conducted on the mayfly Baetis tricaudatus. Genetic polymorphisms were detected in polymerase chain reaction amplified 16S mitochondrial rDNA (a selectively neutral gene) of B tricaudatus using single-strand conformation polymorphism analysis. Genetic differences may have resulted from impediments to gene flow in the population caused by mortality arising from exposure to heavy metal mixture pollution. In laboratory studies a candidate metal-responsive mucinlike gene, which is metal and dose specific, has been identified in Chironomus tentans and other potential AR-CGSS bioreporter species. Population genetic analyses using the mucinlike gene may provide insight into the role of this selectable gene in determining the breeding structure of B. tricaudatus in the AR-CGSS and may provide mechanistic insight into determinants of aquatic arthropod response to heavy metal insult. Metal-responsive (MR) genes and regulatory sequences are being isolated, characterized, and assayed for differential gene expression in response to heavy metal mixture pollution in the AR-CGSS. Identified promoter sequences can then be engineered into previously developed MR constructs to provide sensitive in vitro assays for environmental bioreporting of heavy metal mixtures. The results of the population genetic studies are being entered into an AR geographic information system that contains substantial biological, chemical, and

  17. Novel Molecular Imaging Approaches to Abdominal Aortic Aneurysm Risk Stratification

    PubMed Central

    Toczek, Jakub; Meadows, Judith L.; Sadeghi, Mehran M.

    2015-01-01

    Selection of patients for abdominal aortic aneurysm (AAA) repair is currently based on aneurysm size, growth rate and symptoms. Molecular imaging of biological processes associated with aneurysm growth and rupture, e.g., inflammation and matrix remodeling, could improve patient risk stratification and lead to a reduction in AAA morbidity and mortality. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and ultrasmall superparamagnetic particles of iron oxide (USPIO) magnetic resonance imaging are two novel approaches to AAA imaging evaluated in clinical trials. A variety of other tracers, including those that target inflammatory cells and proteolytic enzymes (e.g., integrin αvβ3 and matrix metalloproteinases), have proven effective in preclinical models of AAA and show great potential for clinical translation. PMID:26763279

  18. Rapid Molecular Identification of Human Taeniid Cestodes by Pyrosequencing Approach

    PubMed Central

    Thanchomnang, Tongjit; Tantrawatpan, Chairat; Intapan, Pewpan M.; Sanpool, Oranuch; Janwan, Penchom; Lulitanond, Viraphong; Tourtip, Somjintana; Yamasaki, Hiroshi; Maleewong, Wanchai

    2014-01-01

    Taenia saginata, T. solium, and T. asiatica are causative agents of taeniasis in humans. The difficulty of morphological identification of human taeniids can lead to misdiagnosis or confusion. To overcome this problem, several molecular methods have been developed, but use of these tends to be time-consuming. Here, a rapid and high-throughput pyrosequencing approach was developed for the identification of three human taeniids originating from various countries. Primers targeting the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene of the three Taenia species were designed. Variations in a 26-nucleotide target region were used for identification. The reproducibility and accuracy of the pyrosequencing technology was confirmed by Sanger sequencing. This technique will be a valuable tool to distinguish between sympatric human taeniids that occur in Thailand, Asia and Pacific countries. This method could potentially be used for the molecular identification of the taeniid species that might be associated with suspicious cysts and lesions, or cyst residues in humans or livestock at the slaughterhouse. PMID:24945530

  19. Rapid molecular identification of human taeniid cestodes by pyrosequencing approach.

    PubMed

    Thanchomnang, Tongjit; Tantrawatpan, Chairat; Intapan, Pewpan M; Sanpool, Oranuch; Janwan, Penchom; Lulitanond, Viraphong; Tourtip, Somjintana; Yamasaki, Hiroshi; Maleewong, Wanchai

    2014-01-01

    Taenia saginata, T. solium, and T. asiatica are causative agents of taeniasis in humans. The difficulty of morphological identification of human taeniids can lead to misdiagnosis or confusion. To overcome this problem, several molecular methods have been developed, but use of these tends to be time-consuming. Here, a rapid and high-throughput pyrosequencing approach was developed for the identification of three human taeniids originating from various countries. Primers targeting the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene of the three Taenia species were designed. Variations in a 26-nucleotide target region were used for identification. The reproducibility and accuracy of the pyrosequencing technology was confirmed by Sanger sequencing. This technique will be a valuable tool to distinguish between sympatric human taeniids that occur in Thailand, Asia and Pacific countries. This method could potentially be used for the molecular identification of the taeniid species that might be associated with suspicious cysts and lesions, or cyst residues in humans or livestock at the slaughterhouse. PMID:24945530

  20. Genetic variants in Alzheimer disease - molecular and brain network approaches.

    PubMed

    Gaiteri, Chris; Mostafavi, Sara; Honey, Christopher J; De Jager, Philip L; Bennett, David A

    2016-07-01

    Genetic studies in late-onset Alzheimer disease (LOAD) are aimed at identifying core disease mechanisms and providing potential biomarkers and drug candidates to improve clinical care of AD. However, owing to the complexity of LOAD, including pathological heterogeneity and disease polygenicity, extraction of actionable guidance from LOAD genetics has been challenging. Past attempts to summarize the effects of LOAD-associated genetic variants have used pathway analysis and collections of small-scale experiments to hypothesize functional convergence across several variants. In this Review, we discuss how the study of molecular, cellular and brain networks provides additional information on the effects of LOAD-associated genetic variants. We then discuss emerging combinations of these omic data sets into multiscale models, which provide a more comprehensive representation of the effects of LOAD-associated genetic variants at multiple biophysical scales. Furthermore, we highlight the clinical potential of mechanistically coupling genetic variants and disease phenotypes with multiscale brain models. PMID:27282653

  1. Modeling thermal decomposition mechanisms in gaseous and crystalline molecular materials: application to β-HMX.

    PubMed

    Sharia, Onise; Kuklja, Maija M

    2011-11-10

    Exploration of initiation of chemistry in materials is especially challenging when several coexisting chemical mechanisms are possible and many reactions' products are produced. It is even more difficult for complex materials, such as molecular, supramolecular, and hierarchical materials and systems. A strategy to draw a complete picture of the earliest stages of rapid decomposition reactions in molecular materials is presented in this study. The strategy is based on theoretical and computational modeling of chemical decomposition reactions in the gaseous and crystalline molecular material that has been performed by means of combined density functional theory and transition state theory. This study reveals how a crystalline field affects materials chemical degradation. We also demonstrate how incomplete results, which are often used due to difficulties in obtaining comprehensive data, can lead to erroneous conclusions and predictions. We discuss our approach in the context of the obtained reaction energies, activation barriers, structures of transition states, and reaction rates with the example of a representative molecular material, β-HMX, which tends to decompose violently with large energy release upon an external perturbation. The performed analysis helps to provide a consistent interpretation of available experimental data. The article illustrates that the complete picture of decomposition reactions of complex molecular materials, while theoretically challenging and computationally demanding, is possible and even practical at this point in time. PMID:21942331

  2. Mechanical behavior of linear amorphous polymers: Comparison between molecular dynamics and finite-element simulations

    NASA Astrophysics Data System (ADS)

    Solar, Mathieu; Meyer, Hendrik; Gauthier, Christian; Fond, Christophe; Benzerara, Olivier; Schirrer, Robert; Baschnagel, Jörg

    2012-02-01

    This paper studies the rheology of weakly entangled polymer melts and films in the glassy domain and near the rubbery domain using two different methods: molecular dynamics (MD) and finite element (FE) simulations. In a first step, the uniaxial mechanical behavior of a bulk polymer sample is studied by means of particle-based MD simulations. The results are in good agreement with experimental data, and mechanical properties may be computed from the simulations. This uniaxial mechanical behavior is then implemented in FE simulations using an elasto-viscoelasto-viscoplastic constitutive law in a continuum mechanics (CM) approach. In a second step, the mechanical response of a polymer film during an indentation test is modeled with the MD method and with the FE simulations using the same constitutive law. Good agreement is found between the MD and CM results. This work provides evidence in favor of using MD simulations to investigate the local physics of contact mechanics, since the volume elements studied are representative and thus contain enough information about the microstructure of the polymer model, while surface phenomena (adhesion and surface tension) are naturally included in the MD approach.

  3. Mechanical behavior of linear amorphous polymers: comparison between molecular dynamics and finite-element simulations.

    PubMed

    Solar, Mathieu; Meyer, Hendrik; Gauthier, Christian; Fond, Christophe; Benzerara, Olivier; Schirrer, Robert; Baschnagel, Jörg

    2012-02-01

    This paper studies the rheology of weakly entangled polymer melts and films in the glassy domain and near the rubbery domain using two different methods: molecular dynamics (MD) and finite element (FE) simulations. In a first step, the uniaxial mechanical behavior of a bulk polymer sample is studied by means of particle-based MD simulations. The results are in good agreement with experimental data, and mechanical properties may be computed from the simulations. This uniaxial mechanical behavior is then implemented in FE simulations using an elasto-viscoelasto-viscoplastic constitutive law in a continuum mechanics (CM) approach. In a second step, the mechanical response of a polymer film during an indentation test is modeled with the MD method and with the FE simulations using the same constitutive law. Good agreement is found between the MD and CM results. This work provides evidence in favor of using MD simulations to investigate the local physics of contact mechanics, since the volume elements studied are representative and thus contain enough information about the microstructure of the polymer model, while surface phenomena (adhesion and surface tension) are naturally included in the MD approach. PMID:22463237

  4. Role of soluble guanylate cyclase in the molecular mechanism underlying the physiological effects of nitric oxide.

    PubMed

    Severina, I S

    1998-07-01

    In this review the molecular mechanisms underlying the antihypertensive and antiaggregatory actions of nitric oxide (NO) are discussed. It has been shown that these effects are directly connected with the activation of soluble guanylate cyclase and the accumulation of cyclic 3;,5;-guanosine monophosphate (cGMP). The mechanism of guanylate cyclase activation by NO is analyzed, especially the role and biological significance of the nitrosyl--heme complex formed as a result of interaction of guanylate cyclase heme with NO and the role of sulfhydryl groups of the enzyme in this process. Using new approaches for studying the antihypertensive and antiaggregatory actions of nitric oxide in combination with the newly obtained data on the regulatory role of guanylate cyclase in the platelet aggregation process, the most important results were obtained regarding the molecular bases providing for a directed search for and creation of new effective antihypertensive and antiaggregatory preparations. In studying the molecular mechanism for directed activation of soluble guanylate cyclase by new NO donors, a series of hitherto unknown enzyme activators generating NO and involved in the regulation of hemostasis and vascular tone were revealed. PMID:9721331

  5. Features of Knowledge Building in Biology: Understanding Undergraduate Students' Ideas about Molecular Mechanisms.

    PubMed

    Southard, Katelyn; Wince, Tyler; Meddleton, Shanice; Bolger, Molly S

    2016-01-01

    Research has suggested that teaching and learning in molecular and cellular biology (MCB) is difficult. We used a new lens to understand undergraduate reasoning about molecular mechanisms: the knowledge-integration approach to conceptual change. Knowledge integration is the dynamic process by which learners acquire new ideas, develop connections between ideas, and reorganize and restructure prior knowledge. Semistructured, clinical think-aloud interviews were conducted with introductory and upper-division MCB students. Interviews included a written conceptual assessment, a concept-mapping activity, and an opportunity to explain the biomechanisms of DNA replication, transcription, and translation. Student reasoning patterns were explored through mixed-method analyses. Results suggested that students must sort mechanistic entities into appropriate mental categories that reflect the nature of MCB mechanisms and that conflation between these categories is common. We also showed how connections between molecular mechanisms and their biological roles are part of building an integrated knowledge network as students develop expertise. We observed differences in the nature of connections between ideas related to different forms of reasoning. Finally, we provide a tentative model for MCB knowledge integration and suggest its implications for undergraduate learning.

  6. Features of Knowledge Building in Biology: Understanding Undergraduate Students’ Ideas about Molecular Mechanisms

    PubMed Central

    Southard, Katelyn; Wince, Tyler; Meddleton, Shanice; Bolger, Molly S.

    2016-01-01

    Research has suggested that teaching and learning in molecular and cellular biology (MCB) is difficult. We used a new lens to understand undergraduate reasoning about molecular mechanisms: the knowledge-integration approach to conceptual change. Knowledge integration is the dynamic process by which learners acquire new ideas, develop connections between ideas, and reorganize and restructure prior knowledge. Semistructured, clinical think-aloud interviews were conducted with introductory and upper-division MCB students. Interviews included a written conceptual assessment, a concept-mapping activity, and an opportunity to explain the biomechanisms of DNA replication, transcription, and translation. Student reasoning patterns were explored through mixed-method analyses. Results suggested that students must sort mechanistic entities into appropriate mental categories that reflect the nature of MCB mechanisms and that conflation between these categories is common. We also showed how connections between molecular mechanisms and their biological roles are part of building an integrated knowledge network as students develop expertise. We observed differences in the nature of connections between ideas related to different forms of reasoning. Finally, we provide a tentative model for MCB knowledge integration and suggest its implications for undergraduate learning. PMID:26931398

  7. An approximate approach to quantum mechanical study of biomacromolecules

    NASA Astrophysics Data System (ADS)

    Chen, Xihua

    This thesis summarizes the author's major work in Prof. John Z.H. Zhang's Threoretical Chemistry research group. In Chapter 1, we present a general description of MFCC (molecular fractionation with conjugated caps) method that has been developed in this group to treat biomacromolecules in a divide-and-conquer fashion. Then we give in detail a computational study of MFCC application to peptide/protein that contains disulfide bonds. Continued on the basis of previous MFCC tests, this study provides another numerical support for the accuracy of the MFCC approach to full quantum mechanical calculation of protein/peptide-small molecule interaction. In Chapter 2, we further develop the MFCC scheme for quantum mechanical computation of DNA-ligand interaction energy. We study three oligonuclear acid interaction systems: dinucleotide dCG/water, trinucleotide dCGT/water and a Watson-Crick paired DNA segment dCGT/dGCA. The MFCC interaction energies are found to be in excellent agreement with the corresponding results obtained from the full system ab initio calculations. This study is an exemplification of the application of the general MFCC approach to biomacromolecules. In Chapter 3, firstly, a MFCC-downhill simplex method is proposed to study binding structures of ligands (atoms, ions, or small molecules) in large molecular complex systems. This method employs the MFCC approach to compute the interaction energy-structure relation of the system and implements the downhill simplex algorithm for structural optimization. Secondly, this method is numerically tested on a system of [KCp(18-crown-6)], as a simplest monatomic case study, to optimize the binding position of the potassium cation in a fixed coordination Cp and 18-crown-6 coordinating sphere. The result of the MFCC-downhill simplex optimization shows good agreement with both the crystal structure and with the full-system downhill simplex optimized structure. The effects of the initial structure of the simplex and of the

  8. Molecular mechanisms of autophagy in the cardiovascular system.

    PubMed

    Gatica, Damián; Chiong, Mario; Lavandero, Sergio; Klionsky, Daniel J

    2015-01-30

    Autophagy is a catabolic recycling pathway triggered by various intra- or extracellular stimuli that is conserved from yeast to mammals. During autophagy, diverse cytosolic constituents are enveloped by double-membrane vesicles, autophagosomes, which later fuse with lysosomes or the vacuole to degrade their cargo. Dysregulation in autophagy is associated with a diverse range of pathologies including cardiovascular disease, the leading cause of death in the world. As such, there is great interest in identifying novel mechanisms that govern the cardiovascular response to disease-related stress. First described in failing hearts, autophagy within the cardiovascular system has been characterized widely in cardiomyocytes, cardiac fibroblasts, endothelial cells, and vascular smooth muscle cells. In all cases, a window of optimal autophagic activity seems to be critical to the maintenance of cardiovascular homeostasis and function; excessive or insufficient levels of autophagic flux can each contribute to heart disease pathogenesis. Here, we review the molecular mechanisms that govern autophagosome formation and analyze the link between autophagy and cardiovascular disease.

  9. Cellular and molecular mechanisms of metformin: an overview

    PubMed Central

    Viollet, Benoit; Guigas, Bruno; Sanz Garcia, Nieves; Leclerc, Jocelyne; Foretz, Marc; Andreelli, Fabrizio

    2012-01-01

    Considerable efforts have been made since the 1950s to better understand the cellular and molecular mechanisms of action of metformin, a potent antihyperglycemic agent now recommended as the first line oral therapy for type 2 diabetes (T2D). The main effect of this drug from the biguanide family is to acutely decrease hepatic glucose production, mostly through a mild and transient inhibition of the mitochondrial respiratory-chain complex 1. In addition, the resulting decrease in hepatic energy status activates the AMP-activated protein kinase (AMPK), a cellular metabolic sensor, providing a generally accepted mechanism for metformin action on hepatic gluconeogenic program. The demonstration that the respiratory-chain complex 1, but not AMPK, is the primary target of metformin was recently strengthened by showing that the metabolic effect of the drug is preserved in liver-specific AMPK-deficient mice. Beyond its effect on glucose metabolism, metformin was reported to restore ovarian function in polycystic ovary syndrome, reduce fatty liver and to lower microvascular and macrovascular complications associated with T2D. Its use was also recently suggested as an adjuvant treatment for cancer or gestational diabetes, and for the prevention in pre-diabetic populations. These emerging new therapeutic areas for metformin will be reviewed together with recent data from pharmacogenetic studies linking genetic variations to drug response, a promising new step towards personalized medicine in the treatment of T2D. PMID:22117616

  10. Molecular mechanisms of CRISPR-mediated microbial immunity.

    PubMed

    Gasiunas, Giedrius; Sinkunas, Tomas; Siksnys, Virginijus

    2014-02-01

    Bacteriophages (phages) infect bacteria in order to replicate and burst out of the host, killing the cell, when reproduction is completed. Thus, from a bacterial perspective, phages pose a persistent lethal threat to bacterial populations. Not surprisingly, bacteria evolved multiple defense barriers to interfere with nearly every step of phage life cycles. Phages respond to this selection pressure by counter-evolving their genomes to evade bacterial resistance. The antagonistic interaction between bacteria and rapidly diversifying viruses promotes the evolution and dissemination of bacteriophage-resistance mechanisms in bacteria. Recently, an adaptive microbial immune system, named clustered regularly interspaced short palindromic repeats (CRISPR) and which provides acquired immunity against viruses and plasmids, has been identified. Unlike the restriction–modification anti-phage barrier that subjects to cleavage any foreign DNA lacking a protective methyl-tag in the target site, the CRISPR–Cas systems are invader-specific, adaptive, and heritable. In this review, we focus on the molecular mechanisms of interference/immunity provided by different CRISPR–Cas systems. PMID:23959171

  11. Plasticity of oxidative metabolism in variable climates: molecular mechanisms.

    PubMed

    Seebacher, Frank; Brand, Martin D; Else, Paul L; Guderley, Helga; Hulbert, Anthony J; Moyes, Christopher D

    2010-01-01

    Converting food to chemical energy (ATP) that is usable by cells is a principal requirement to sustain life. The rate of ATP production has to be sufficient for housekeeping functions, such as protein synthesis and maintaining membrane potentials, as well as for growth and locomotion. Energy metabolism is temperature sensitive, and animals respond to environmental variability at different temporal levels, from within-individual to evolutionary timescales. Here we review principal molecular mechanisms that underlie control of oxidative ATP production in response to climate variability. Nuclear transcription factors and coactivators control expression of mitochondrial proteins and abundance of mitochondria. Fatty acid and phospholipid concentrations of membranes influence the activity of membrane-bound proteins as well as the passive leak of protons across the mitochondrial membrane. Passive proton leak as well as protein-mediated proton leak across the inner mitochondrial membrane determine the efficacy of ATP production but are also instrumental in endothermic heat production and as a defense against reactive oxygen species. Both transcriptional mechanisms and membrane composition interact with environmental temperature and diet, and this interaction between diet and temperature in determining mitochondrial function links the two major environmental variables that are affected by changing climates. The limits to metabolic plasticity could be set by the production of reactive oxygen species leading to cellular damage, limits to substrate availability in mitochondria, and a disproportionally large increase in proton leak over ATP production. PMID:20586603

  12. Molecular mechanisms of CRISPR-mediated microbial immunity.

    PubMed

    Gasiunas, Giedrius; Sinkunas, Tomas; Siksnys, Virginijus

    2014-02-01

    Bacteriophages (phages) infect bacteria in order to replicate and burst out of the host, killing the cell, when reproduction is completed. Thus, from a bacterial perspective, phages pose a persistent lethal threat to bacterial populations. Not surprisingly, bacteria evolved multiple defense barriers to interfere with nearly every step of phage life cycles. Phages respond to this selection pressure by counter-evolving their genomes to evade bacterial resistance. The antagonistic interaction between bacteria and rapidly diversifying viruses promotes the evolution and dissemination of bacteriophage-resistance mechanisms in bacteria. Recently, an adaptive microbial immune system, named clustered regularly interspaced short palindromic repeats (CRISPR) and which provides acquired immunity against viruses and plasmids, has been identified. Unlike the restriction–modification anti-phage barrier that subjects to cleavage any foreign DNA lacking a protective methyl-tag in the target site, the CRISPR–Cas systems are invader-specific, adaptive, and heritable. In this review, we focus on the molecular mechanisms of interference/immunity provided by different CRISPR–Cas systems.

  13. Molecular mechanisms of Tetranychus urticae chemical adaptation in hop fields

    PubMed Central

    Piraneo, Tara G.; Bull, Jon; Morales, Mariany A.; Lavine, Laura C.; Walsh, Douglas B.; Zhu, Fang

    2015-01-01

    The two-spotted spider mite, Tetranychus urticae Koch is a major pest that feeds on >1,100 plant species. Many perennial crops including hop (Humulus lupulus) are routinely plagued by T. urticae infestations. Hop is a specialty crop in Pacific Northwest states, where 99% of all U.S. hops are produced. To suppress T. urticae, growers often apply various acaricides. Unfortunately T. urticae has been documented to quickly develop resistance to these acaricides which directly cause control failures. Here, we investigated resistance ratios and distribution of multiple resistance-associated mutations in field collected T. urticae samples compared with a susceptible population. Our research revealed that a mutation in the cytochrome b gene (G126S) in 35% tested T. urticae populations and a mutation in the voltage-gated sodium channel gene (F1538I) in 66.7% populations may contribute resistance to bifenazate and bifenthrin, respectively. No mutations were detected in Glutamate-gated chloride channel subunits tested, suggesting target site insensitivity may not be important in our hop T. urticae resistance to abamectin. However, P450-mediated detoxification was observed and is a putative mechanism for abamectin resistance. Molecular mechanisms of T. urticae chemical adaptation in hopyards is imperative new information that will help growers develop effective and sustainable management strategies. PMID:26621458

  14. Molecular mechanisms of Tetranychus urticae chemical adaptation in hop fields.

    PubMed

    Piraneo, Tara G; Bull, Jon; Morales, Mariany A; Lavine, Laura C; Walsh, Douglas B; Zhu, Fang

    2015-01-01

    The two-spotted spider mite, Tetranychus urticae Koch is a major pest that feeds on >1,100 plant species. Many perennial crops including hop (Humulus lupulus) are routinely plagued by T. urticae infestations. Hop is a specialty crop in Pacific Northwest states, where 99% of all U.S. hops are produced. To suppress T. urticae, growers often apply various acaricides. Unfortunately T. urticae has been documented to quickly develop resistance to these acaricides which directly cause control failures. Here, we investigated resistance ratios and distribution of multiple resistance-associated mutations in field collected T. urticae samples compared with a susceptible population. Our research revealed that a mutation in the cytochrome b gene (G126S) in 35% tested T. urticae populations and a mutation in the voltage-gated sodium channel gene (F1538I) in 66.7% populations may contribute resistance to bifenazate and bifenthrin, respectively. No mutations were detected in Glutamate-gated chloride channel subunits tested, suggesting target site insensitivity may not be important in our hop T. urticae resistance to abamectin. However, P450-mediated detoxification was observed and is a putative mechanism for abamectin resistance. Molecular mechanisms of T. urticae chemical adaptation in hopyards is imperative new information that will help growers develop effective and sustainable management strategies. PMID:26621458

  15. Autoinhibitory mechanisms of ERG studied by molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Lu, Yan; Salsbury, Freddie R.

    2015-01-01

    ERG, an ETS-family transcription factor, acts as a regulator of differentiation of early hematopoietic cells. It contains an autoinhibitory domain, which negatively regulates DNA-binding. The mechanism of autoinhibitory is still illusive. To understand the mechanism, we study the dynamical properties of ERG protein by molecular dynamics simulations. These simulations suggest that DNA binding autoinhibition associates with the internal dynamics of ERG. Specifically, we find that (1), The N-C terminal correlation in the inhibited ERG is larger than that in uninhibited ERG that contributes to the autoinhibition of DNA-binding. (2), DNA-binding changes the property of the N-C terminal correlation from being anti-correlated to correlated, that is, changing the relative direction of the correlated motions and (3), For the Ets-domain specifically, the inhibited and uninhibited forms exhibit essentially the same dynamics, but the binding of the DNA decreases the fluctuation of the Ets-domain. We also find from PCA analysis that the three systems, even with quite different dynamics, do have highly similar free energy surfaces, indicating that they share similar conformations.

  16. [Molecular mechanism of morphogenesis: a theory of locational DNA].

    PubMed

    Olovnikov, A M

    1996-11-01

    A molecular mechanism of reading of positional information by cells in morphogenesis and regeneration is proposed. It permits to translate the genome information into three-dimensional form of an organism. In the mechanism, a new fraction of DNA, so called "location DNA" is used which is suggested as a substitution instead of a former "egoistic" DNA. Domains, that are formed by this DNA and packed by lipid-containing bridges, are selectively unpacking in the gradient of inductor, the concentration of which positively correlates with the production of free radicals in the cells. Free radicals induce a selective destruction of lipid bridges which are variable in their resistance to the oxidative destruction. Hence the domains of location DNA are selectively decomactizing and activiting after bridge's elimination. In this way, a reading of positional information is performed. An epigenetic memory concerning the cellular determination state, that was already achieved, is based on the so called process of triplexation, the essence of which is a triplex formation, between signal RNA molecule and nascent double stranded DNA. A triplex is formed during the lagging strand synthesis or in the course of DNA repair synthesis. A telomeric element of postmitotic neurons, so called chronomere, assists to the organism in measuring of the flow of biological time, while chronomere length is an indicator of biological age of the organism.

  17. Molecular mechanisms of antibody-mediated neutralisation of flavivirus infection.

    PubMed

    Pierson, Theodore C; Diamond, Michael S

    2008-01-01

    Flaviviruses are a group of positive-stranded RNA viruses that cause a spectrum of severe illnesses globally in more than 50 million individuals each year. While effective vaccines exist for three members of this group (yellow fever, Japanese encephalitis, and tick-borne encephalitis viruses), safe and effective vaccines for several other flaviviruses of clinical importance, including West Nile and dengue viruses, remain in development. An effective humoral immune response is critical for protection against flaviviruses and an essential goal of vaccine development. The effectiveness of virus-specific antibodies in vivo reflects their capacity to inhibit virus entry and spread through several mechanisms, including the direct neutralisation of virus infection. Recent advances in our understanding of the structural biology of flaviviruses, coupled with the use of small-animal models of flavivirus infection, have promoted significant advances in our appreciation of the factors that govern antibody recognition and inhibition of flaviviruses in vitro and in vivo. In this review, we discuss the properties that define the potency of neutralising antibodies and the molecular mechanisms by which they inhibit virus infection. How recent advances in this area have the potential to improve the development of safe and effective vaccines and immunotherapeutics is also addressed. PMID:18471342

  18. Categorical prototyping: incorporating molecular mechanisms into 3D printing.

    PubMed

    Brommer, Dieter B; Giesa, Tristan; Spivak, David I; Buehler, Markus J

    2016-01-15

    We apply the mathematical framework of category theory to articulate the precise relation between the structure and mechanics of a nanoscale system in a macroscopic domain. We maintain the chosen molecular mechanical properties from the nanoscale to the continuum scale. Therein we demonstrate a procedure to 'protoype a model', as category theory enables us to maintain certain information across disparate fields of study, distinct scales, or physical realizations. This process fits naturally with prototyping, as a prototype is not a complete product but rather a reduction to test a subset of properties. To illustrate this point, we use large-scale multi-material printing to examine the scaling of the elastic modulus of 2D carbon allotropes at the macroscale and validate our printed model using experimental testing. The resulting hand-held materials can be examined more readily, and yield insights beyond those available in the original digital representations. We demonstrate this concept by twisting the material, a test beyond the scope of the original model. The method developed can be extended to other methods of additive manufacturing.

  19. Categorical prototyping: incorporating molecular mechanisms into 3D printing

    NASA Astrophysics Data System (ADS)

    Brommer, Dieter B.; Giesa, Tristan; Spivak, David I.; Buehler, Markus J.

    2016-01-01

    We apply the mathematical framework of category theory to articulate the precise relation between the structure and mechanics of a nanoscale system in a macroscopic domain. We maintain the chosen molecular mechanical properties from the nanoscale to the continuum scale. Therein we demonstrate a procedure to ‘protoype a model’, as category theory enables us to maintain certain information across disparate fields of study, distinct scales, or physical realizations. This process fits naturally with prototyping, as a prototype is not a complete product but rather a reduction to test a subset of properties. To illustrate this point, we use large-scale multi-material printing to examine the scaling of the elastic modulus of 2D carbon allotropes at the macroscale and validate our printed model using experimental testing. The resulting hand-held materials can be examined more readily, and yield insights beyond those available in the original digital representations. We demonstrate this concept by twisting the material, a test beyond the scope of the original model. The method developed can be extended to other methods of additive manufacturing.

  20. Molecular mechanisms of antibody-mediated neutralisation of flavivirus infection.

    PubMed

    Pierson, Theodore C; Diamond, Michael S

    2008-01-01

    Flaviviruses are a group of positive-stranded RNA viruses that cause a spectrum of severe illnesses globally in more than 50 million individuals each year. While effective vaccines exist for three members of this group (yellow fever, Japanese encephalitis, and tick-borne encephalitis viruses), safe and effective vaccines for several other flaviviruses of clinical importance, including West Nile and dengue viruses, remain in development. An effective humoral immune response is critical for protection against flaviviruses and an essential goal of vaccine development. The effectiveness of virus-specific antibodies in vivo reflects their capacity to inhibit virus entry and spread through several mechanisms, including the direct neutralisation of virus infection. Recent advances in our understanding of the structural biology of flaviviruses, coupled with the use of small-animal models of flavivirus infection, have promoted significant advances in our appreciation of the factors that govern antibody recognition and inhibition of flaviviruses in vitro and in vivo. In this review, we discuss the properties that define the potency of neutralising antibodies and the molecular mechanisms by which they inhibit virus infection. How recent advances in this area have the potential to improve the development of safe and effective vaccines and immunotherapeutics is also addressed.