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Sample records for molecular mechanics approach

  1. Vibrational spectrum at a water surface: a hybrid quantum mechanics/molecular mechanics molecular dynamics approach.

    PubMed

    Ishiyama, Tatsuya; Takahashi, Hideaki; Morita, Akihiro

    2012-03-28

    A hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulation is applied to the calculation of surface orientational structure and vibrational spectrum (second-order nonlinear susceptibility) at the vapor/water interface for the first time. The surface orientational structure of the QM water molecules is consistent with the previous MD studies, and the calculated susceptibility reproduces the experimentally reported one, supporting the previous results using the classical force field MD simulation. The present QM/MM MD simulation also demonstrates that the positive sign of the imaginary part of the second-order nonlinear susceptibility at the lower hydrogen bonding OH frequency region originates not from individual molecular orientational structure, but from cooperative electronic structure through the hydrogen bonding network.

  2. Molecular structure and elastic properties of thermotropic liquid crystals: integrated molecular dynamics--statistical mechanical theory vs molecular field approach.

    PubMed

    Ilk Capar, M; Nar, A; Ferrarini, A; Frezza, E; Greco, C; Zakharov, A V; Vakulenko, A A

    2013-03-21

    The connection between the molecular structure of liquid crystals and their elastic properties, which control the director deformations relevant for electro-optic applications, remains a challenging objective for theories and computations. Here, we compare two methods that have been proposed to this purpose, both characterized by a detailed molecular level description. One is an integrated molecular dynamics-statistical mechanical approach, where the bulk elastic constants of nematics are calculated from the direct correlation function (DCFs) and the single molecule orientational distribution function [D. A. McQuarrie, Statistical Mechanics (Harper & Row, New York, 1973)]. The latter is obtained from atomistic molecular dynamics trajectories, together with the radial distribution function, from which the DCF is then determined by solving the Ornstein-Zernike equation. The other approach is based on a molecular field theory, where the potential of mean torque experienced by a mesogen in the liquid crystal phase is parameterized according to its molecular surface. In this case, the calculation of elastic constants is combined with the Monte Carlo sampling of single molecule conformations. Using these different approaches, but the same description, at the level of molecular geometry and torsional potentials, we have investigated the elastic properties of the nematic phase of two typical mesogens, 4'-n-pentyloxy-4-cyanobiphenyl and 4'-n-heptyloxy-4-cyanobiphenyl. Both methods yield K3(bend) >K1 (splay) >K2 (twist), although there are some discrepancies in the average elastic constants and in their anisotropy. These are interpreted in terms of the different approximations and the different ways of accounting for the structural properties of molecules in the two approaches. In general, the results point to the role of the molecular shape, which is modulated by the conformational freedom and cannot be fully accounted for by a single descriptor such as the aspect ratio.

  3. Molecular structure and elastic properties of thermotropic liquid crystals: Integrated molecular dynamics—Statistical mechanical theory vs molecular field approach

    NASA Astrophysics Data System (ADS)

    Capar, M. Ilk; Nar, A.; Ferrarini, A.; Frezza, E.; Greco, C.; Zakharov, A. V.; Vakulenko, A. A.

    2013-03-01

    The connection between the molecular structure of liquid crystals and their elastic properties, which control the director deformations relevant for electro-optic applications, remains a challenging objective for theories and computations. Here, we compare two methods that have been proposed to this purpose, both characterized by a detailed molecular level description. One is an integrated molecular dynamics-statistical mechanical approach, where the bulk elastic constants of nematics are calculated from the direct correlation function (DCFs) and the single molecule orientational distribution function [D. A. McQuarrie, Statistical Mechanics (Harper & Row, New York, 1973)]. The latter is obtained from atomistic molecular dynamics trajectories, together with the radial distribution function, from which the DCF is then determined by solving the Ornstein-Zernike equation. The other approach is based on a molecular field theory, where the potential of mean torque experienced by a mesogen in the liquid crystal phase is parameterized according to its molecular surface. In this case, the calculation of elastic constants is combined with the Monte Carlo sampling of single molecule conformations. Using these different approaches, but the same description, at the level of molecular geometry and torsional potentials, we have investigated the elastic properties of the nematic phase of two typical mesogens, 4'-n-pentyloxy-4-cyanobiphenyl and 4'-n-heptyloxy-4-cyanobiphenyl. Both methods yield K3(bend) >K1 (splay) >K2 (twist), although there are some discrepancies in the average elastic constants and in their anisotropy. These are interpreted in terms of the different approximations and the different ways of accounting for the structural properties of molecules in the two approaches. In general, the results point to the role of the molecular shape, which is modulated by the conformational freedom and cannot be fully accounted for by a single descriptor such as the aspect ratio.

  4. Complement involvement in periodontitis: molecular mechanisms and rational therapeutic approaches

    PubMed Central

    Hajishengallis, George; Maekawa, Tomoki; Abe, Toshiharu; Hajishengallis, Evlambia; Lambris, John D.

    2015-01-01

    The complement system is a network of interacting fluid-phase and cell surface-associated molecules that trigger, amplify, and regulate immune and inflammatory signaling pathways. Dysregulation of this finely balanced network can destabilize host-microbe homeostasis and cause inflammatory tissue damage. Evidence from clinical and animal model-based studies suggests that complement is implicated in the pathogenesis of periodontitis, a polymicrobial community-induced chronic inflammatory disease that destroys the tooth-supporting tissues. This review discusses molecular mechanisms of complement involvement in the dysbiotic transformation of the periodontal microbiome and the resulting destructive inflammation, culminating in loss of periodontal bone support. These mechanistic studies have additionally identified potential therapeutic targets. In this regard, interventional studies in preclinical models have provided proof-of-concept for using complement inhibitors for the treatment of human periodontitis. PMID:26306443

  5. Ab initio quantum mechanical/molecular mechanical simulation of electron transfer process: fractional electron approach.

    PubMed

    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(2)O)(6)(2+/3+) and Ru(H(2)O)(6)(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.

  6. 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.

  7. A quantum mechanical/molecular mechanical approach to the investigation of particle-molecule interactions

    NASA Astrophysics Data System (ADS)

    Sloth, Marianne; Bilde, Merete; Mikkelsen, Kurt V.

    2003-06-01

    A quantum mechanical/molecular mechanical aerosol model is developed to describe the interaction between gas phase molecules and atmospheric particles. The model enables the calculation of interaction energies and time-dependent properties. We use the model to investigate how a succinic acid molecule interacts with an aqueous particle. We show how the interaction energies and linear response properties (excitation energies, transition moments, and polarizabilities) depend on the distance between aerosol particle and molecule and on their relative orientation. The results are compared with those obtained previously using a dielectric continuum model [Sloth et al., J. Phys. Chem. (submitted)].

  8. Molecular Mechanics

    PubMed Central

    Vanommeslaeghe, Kenno; Guvench, Olgun; MacKerell, Alexander D.

    2014-01-01

    Molecular Mechanics (MM) force fields are the methods of choice for protein simulations, which are essential in the study of conformational flexibility. Given the importance of protein flexibility in drug binding, MM is involved in most if not all Computational Structure-Based Drug Discovery (CSBDD) projects. This section introduces the reader to the fundamentals of MM, with a special emphasis on how the target data used in the parametrization of force fields determine their strengths and weaknesses. Variations and recent developments such as polarizable force fields are discussed. The section ends with a brief overview of common force fields in CSBDD. PMID:23947650

  9. [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.

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

    PubMed

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

    2016-07-01

    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. 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. 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. 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. Ruiz P, Perlina A, Mumtaz M, Fowler BA. 2016. A systems biology approach reveals converging molecular mechanisms that link different POPs to common metabolic diseases. Environ

  11. Genetic approaches to the molecular/neuronal mechanisms underlying learning and memory in the mouse.

    PubMed

    Nakajima, Akira; Tang, Ya-Ping

    2005-09-01

    Learning and memory is an essential component of human intelligence. To understand its underlying molecular and neuronal mechanisms is currently an extensive focus in the field of cognitive neuroscience. We have employed advanced mouse genetic approaches to analyze the molecular and neuronal bases for learning and memory, and our results showed that brain region-specific genetic manipulations (including transgenic and knockout), inducible/reversible knockout, genetic/chemical kinase inactivation, and neuronal-based genetic approach are very powerful tools for studying the involvements of various molecules or neuronal substrates in the processes of learning and memory. Studies using these techniques may eventually lead to the understanding of how new information is acquired and how learned information is memorized in the brain.

  12. Cellular and molecular mechanisms triggered by Deep Brain Stimulation in depression: A preclinical and clinical approach.

    PubMed

    Torres-Sanchez, S; Perez-Caballero, L; Berrocoso, E

    2017-02-06

    Deep Brain Stimulation (DBS) was originally developed as a therapeutic approach to manage movement disorders, in particular Parkinson's Disease. However, DBS also seems to be an effective treatment against refractory depression when patients fail to respond satisfactorily to conventional therapies. Thus, DBS targeting specific brain areas can produce an antidepressant response that improves depressive symptomatology, these areas including the subcallosal cingulate region, nucleus accumbens, ventral capsule/ventral striatum, medial forebrain bundle, the inferior thalamic peduncle and lateral habenula. Although the efficacy and safety of this therapy has been demonstrated in some clinical trials and preclinical studies, the intrinsic mechanisms underlying its antidepressant effect remain poorly understood. This review aims to provide a comprehensive overview of DBS, focusing on the molecular and cellular changes reported after its use that could shed light on the mechanisms underpinning its antidepressant effect. Several potential mechanisms of action of DBS are considered, including monoaminergic and glutamatergic neurotransmission, neurotrophic and neuroinflammatory mechanisms, as well as potential effects on certain intracellular signaling pathways. Although future studies will be necessary to determine the key molecular events underlying the antidepressant effect of DBS, the findings presented provide an insight into some of its possible modes of action.

  13. Aeromonas proteolytica aminopeptidase: an investigation of the mode of action using a quantum mechanical/molecular mechanical approach.

    PubMed

    Schürer, Gudrun; Lanig, Harald; Clark, Timothy

    2004-05-11

    The aminopeptidase of Aeromonas proteolytica (AAP) belongs to the group of metallo-hydrolases that require two divalent cations for full activity. Such binuclear metal centers are found in several aminopeptidases, raising the question whether a common mechanism, at least partly, is likely. We have used a quantum mechanical/molecular mechanical (QM/MM) approach to investigate the reaction mechanism of AAP. Among several possibilities, one reaction path was found to be clearly the most favorable. Beside the chemical transformation steps, effects of the enzyme environment and the influence of the solvent on the catalytic reaction were included in the study. The results are in good agreement with experimental studies and correspond to a high degree to our previous QM/MM calculations on the reaction mechanism of the related binuclear bovine lens leucine aminopeptidase (blLAP), which, although related to the AAP, has different Zn(2+)-coordination spheres and a different catalytic residue. The mechanisms of the two enzymes as suggested in the literature differ on the mode of coordination of the nucleophile and the identity of the general base. However, the results of this and our previous work on blLAP allow us to identify a common mechanism for the two enzymes. This mechanism is probably quite general for binuclear zinc enzymes.

  14. Elucidating Mechanisms of Molecular Recognition Between Human Argonaute and miRNA Using Computational Approaches.

    PubMed

    Jiang, Hanlun; Zhu, Lizhe; Héliou, Amélie; Gao, Xin; Bernauer, Julie; Huang, Xuhui

    2017-01-01

    MicroRNA (miRNA) and Argonaute (AGO) protein together form the RNA-induced silencing complex (RISC) that plays an essential role in the regulation of gene expression. Elucidating the underlying mechanism of AGO-miRNA recognition is thus of great importance not only for the in-depth understanding of miRNA function but also for inspiring new drugs targeting miRNAs. In this chapter we introduce a combined computational approach of molecular dynamics (MD) simulations, Markov state models (MSMs), and protein-RNA docking to investigate AGO-miRNA recognition. Constructed from MD simulations, MSMs can elucidate the conformational dynamics of AGO at biologically relevant timescales. Protein-RNA docking can then efficiently identify the AGO conformations that are geometrically accessible to miRNA. Using our recent work on human AGO2 as an example, we explain the rationale and the workflow of our method in details. This combined approach holds great promise to complement experiments in unraveling the mechanisms of molecular recognition between large, flexible, and complex biomolecules.

  15. Acceleration of Semiempirical Quantum Mechanical Calculations by Extended Lagrangian Molecular Dynamics Approach.

    PubMed

    Nam, Kwangho

    2013-08-13

    The implementation and performance of the atom-centered density matrix propagation (ADMP) [J. Chem. Phys. 2001, 114, 9758] and the curvy-steps (CURV) methods [J. Chem. Phys. 2004, 121, 1152] are described. These methods solve the electronic Schrödinger equation approximately by propagating the electronic degrees of freedom using the extended Lagrangian molecular dynamics (ELMD) simulation approach. The ADMP and CURV methods are implemented and parallelized to accelerate semiempirical quantum mechanical (QM) methods (such as the MNDO, AM1, PM3, MNDO/d, and AM1/d methods). Test calculations show that both the ADMP and the CURV methods are 2∼4 times faster than the Born-Oppenheimer molecular dynamics (BOMD) method and conserve the total energy well. The accuracy of the ADMP and CURV simulations is comparable to the BOMD simulations. The parallel implementation accelerates the MD simulation by up to 28 fold for the ADMP method and 25 fold for the CURV method, respectively, relative to the speed of the single core BOMD. In addition, a multiple time scale (MTS) approach is introduced to further speed up the semiempirical QM and QM/MM ELMD simulations. Since a larger integration time step is used for the propagation of the nuclear coordinates than that for the electronic degrees of freedom, the MTS approach allows the ELMD simulation to be carried out with a time step that is larger than the time step accessible by the original ADMP and CURV methods. It renders MD simulation to be carried out about 20 times faster than the BOMD simulation, and yields results that are comparable to the single time scale simulation results. The use of the methods introduced in the present work provides an efficient way to extend the length of the QM and QM/MM molecular dynamics simulations beyond the length accessible by BOMD simulation.

  16. Mechanical properties of particle systems using a molecular dynamics approach inspired by continuum homogenization

    NASA Astrophysics Data System (ADS)

    Andia, Pedro C.

    The topic of this dissertation is the study of the mechanical properties of solid material systems at the nanoscale. At such length scales, materials can be viewed as particle systems, and molecular dynamics (MD) simulations help one understand their behavior as well as quantify their properties. However, mechanical concepts such as strain, stress and moduli were originally developed in continuum models, which are typically applied in space scales that range from the microscopic to the macroscopic. For this reason, a careful translation of ideas from continuum scales to the nanoscale is necessary. In essence, this thesis reviews and refines the continuum notions of average mechanical properties, such as stress and strain, and the meaning of such notions when MD is used to compute them. A Lagrangian-based approach is utilized for the purpose of determining the stress-deformation behavior of continua as well as of particle systems. At the continuum level, the mentioned Lagrangian-based approach is applied within homogenization theory for developing a nonlinear continuum homogenization model, which includes a novel constitutive relation for the stress. At the nanoscale, an MD method is presented as the extension of the continuum homogenization model. This MD method is able to simulate the behavior of particle systems under a given type of deformation as well as to generate stress-strain curves. In the process of developing the MD method, some concepts and techniques commonly used in MD, such as the virial stress and the Parrinello-Rahman method, are clarified.

  17. Modelling the molecular mechanisms of synaptic plasticity using systems biology approaches.

    PubMed

    Kotaleski, Jeanette Hellgren; Blackwell, Kim T

    2010-04-01

    Synaptic plasticity is thought to underlie learning and memory, but the complexity of the interactions between the ion channels, enzymes and genes that are involved in synaptic plasticity impedes a deep understanding of this phenomenon. Computer modelling has been used to investigate the information processing that is performed by the signalling pathways involved in synaptic plasticity in principal neurons of the hippocampus, striatum and cerebellum. In the past few years, new software developments that combine computational neuroscience techniques with systems biology techniques have allowed large-scale, kinetic models of the molecular mechanisms underlying long-term potentiation and long-term depression. We highlight important advancements produced by these quantitative modelling efforts and introduce promising approaches that use advancements in live-cell imaging.

  18. 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

  19. 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

  20. 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.

  1. 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

  2. Elucidating the molecular mechanisms underlying cellular response to biophysical cues using synthetic biology approaches.

    PubMed

    Denning, Denise; Roos, Wouter H

    2016-09-02

    The use of synthetic surfaces and materials to influence and study cell behavior has vastly progressed our understanding of the underlying molecular mechanisms involved in cellular response to physicochemical and biophysical cues. Reconstituting cytoskeletal proteins and interfacing them with a defined microenvironment has also garnered deep insight into the engineering mechanisms existing within the cell. This review presents recent experimental findings on the influence of several parameters of the extracellular environment on cell behavior and fate, such as substrate topography, stiffness, chemistry and charge. In addition, the use of synthetic environments to measure physical properties of the reconstituted cytoskeleton and their interaction with intracellular proteins such as molecular motors is discussed, which is relevant for understanding cell migration, division and structural integrity, as well as intracellular transport. Insight is provided regarding the next steps to be taken in this interdisciplinary field, in order to achieve the global aim of artificially directing cellular response.

  3. Solvatochromic shift of phenol blue in water from a combined Car-Parrinello molecular dynamics hybrid quantum mechanics-molecular mechanics and ZINDO approach

    NASA Astrophysics Data System (ADS)

    Murugan, N. Arul; Jha, Prakash Chandra; Rinkevicius, Z.; Ruud, Kenneth; Ågren, Hans

    2010-06-01

    The present work addresses the solvatochromic shift of phenol blue (PB) dye. For this purpose the results of Car-Parrinello molecular dynamics (CPMD) simulations for PB in gas phase are compared with results obtained for PB in water from CPMD hybrid quantum mechanics-molecular mechanics (CPMD-QM/MM) calculations. The absorption spectra were obtained using the intermediate neglect of differential overlap/spectroscopic-configuration interaction (INDO/CIS) method and were calculated for a multitude of configurations of the trajectory. The calculated λmax for PB in gas phase was found to be about 535 nm, which is considerably lower than the λmax reported for PB in nonpolar solvents. Different solvation shells for PB in water have been defined based on the solute-all-atoms and solvent center of mass radial distribution function (g(rX-O)). The electronic excitation energies for PB computed in the presence of solvent molecules in an increasing number of solvation shells were calculated in a systematic way to evaluate their contributions to the solvatochrmic shift. The inclusion of solvent molecules in the hydration shell yields a λmax of 640 nm, which contributes to almost 78% of the solvatochromic shift. The inclusion of solvent molecules up to 10 Å in the g(rX-O) rdf yields a λmax of 670 nm which is in good agreement with the experimentally reported value of 654-684 nm. Overall, the present study suggests that the combined CPMD-QM/MM and INDO-CIS approach can be used successfully to model solvatochromic shifts of organic dye molecules.

  4. Solvatochromic shift of phenol blue in water from a combined Car-Parrinello molecular dynamics hybrid quantum mechanics-molecular mechanics and ZINDO approach.

    PubMed

    Murugan, N Arul; Jha, Prakash Chandra; Rinkevicius, Z; Ruud, Kenneth; Agren, Hans

    2010-06-21

    The present work addresses the solvatochromic shift of phenol blue (PB) dye. For this purpose the results of Car-Parrinello molecular dynamics (CPMD) simulations for PB in gas phase are compared with results obtained for PB in water from CPMD hybrid quantum mechanics-molecular mechanics (CPMD-QM/MM) calculations. The absorption spectra were obtained using the intermediate neglect of differential overlap/spectroscopic-configuration interaction (INDO/CIS) method and were calculated for a multitude of configurations of the trajectory. The calculated lambda(max) for PB in gas phase was found to be about 535 nm, which is considerably lower than the lambda(max) reported for PB in nonpolar solvents. Different solvation shells for PB in water have been defined based on the solute-all-atoms and solvent center of mass radial distribution function (g(r(X-O))). The electronic excitation energies for PB computed in the presence of solvent molecules in an increasing number of solvation shells were calculated in a systematic way to evaluate their contributions to the solvatochrmic shift. The inclusion of solvent molecules in the hydration shell yields a lambda(max) of 640 nm, which contributes to almost 78% of the solvatochromic shift. The inclusion of solvent molecules up to 10 A in the g(r(X-O)) rdf yields a lambda(max) of 670 nm which is in good agreement with the experimentally reported value of 654-684 nm. Overall, the present study suggests that the combined CPMD-QM/MM and INDO-CIS approach can be used successfully to model solvatochromic shifts of organic dye molecules.

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

    SciTech Connect

    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 the 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.

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

    NASA Astrophysics Data System (ADS)

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

    2016-02-01

    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.

  7. 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

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

    DOE PAGES

    Yoo, Brian; Jing, Benxin; Jones, Stuart E.; ...

    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

  9. An Estimation of Hybrid Quantum Mechanical Molecular Mechanical Polarization Energies for Small Molecules Using Polarizable Force-Field Approaches

    DOE PAGES

    Huang, Jing; Mei, Ye; König, Gerhard; ...

    2017-01-24

    Here in this work, we report two polarizable molecular mechanics (polMM) force field models for estimating the polarization energy in hybrid quantum mechanical molecular mechanical (QM/MM) calculations. These two models, named the potential of atomic charges (PAC) and potential of atomic dipoles (PAD), are formulated from the ab initio quantum mechanical (QM) response kernels for the prediction of the QM density response to an external molecular mechanical (MM) environment (as described by external point charges). The PAC model is similar to fluctuating charge (FQ) models because the energy depends on external electrostatic potential values at QM atomic sites; the PADmore » energy depends on external electrostatic field values at QM atomic sites, resembling induced dipole (ID) models. To demonstrate their uses, we apply the PAC and PAD models to 12 small molecules, which are solvated by TIP3P water. The PAC model reproduces the QM/MM polarization energy with a R2 value of 0.71 for aniline (in 10,000 TIP3P water configurations) and 0.87 or higher for other eleven solute molecules, while the PAD model has a much better performance with R2 values of 0.98 or higher. The PAC model reproduces reference QM/MM hydration free energies for 12 solute molecules with a RMSD of 0.59 kcal/mol. The PAD model is even more accurate, with a much smaller RMSD of 0.12 kcal/mol, with respect to the reference. Lastly, this suggests that polarization effects, including both local charge distortion and intramolecular charge transfer, can be well captured by induced dipole type models with proper parametrization.« less

  10. An Estimation of Hybrid Quantum Mechanical Molecular Mechanical Polarization Energies for Small Molecules Using Polarizable Force-Field Approaches.

    PubMed

    Huang, Jing; Mei, Ye; König, Gerhard; Simmonett, Andrew C; Pickard, Frank C; Wu, Qin; Wang, Lee-Ping; MacKerell, Alexander D; Brooks, Bernard R; Shao, Yihan

    2017-02-14

    In this work, we report two polarizable molecular mechanics (polMM) force field models for estimating the polarization energy in hybrid quantum mechanical molecular mechanical (QM/MM) calculations. These two models, named the potential of atomic charges (PAC) and potential of atomic dipoles (PAD), are formulated from the ab initio quantum mechanical (QM) response kernels for the prediction of the QM density response to an external molecular mechanical (MM) environment (as described by external point charges). The PAC model is similar to fluctuating charge (FQ) models because the energy depends on external electrostatic potential values at QM atomic sites; the PAD energy depends on external electrostatic field values at QM atomic sites, resembling induced dipole (ID) models. To demonstrate their uses, we apply the PAC and PAD models to 12 small molecules, which are solvated by TIP3P water. The PAC model reproduces the QM/MM polarization energy with a R(2) value of 0.71 for aniline (in 10,000 TIP3P water configurations) and 0.87 or higher for other 11 solute molecules, while the PAD model has a much better performance with R(2) values of 0.98 or higher. The PAC model reproduces reference QM/MM hydration free energies for 12 solute molecules with a RMSD of 0.59 kcal/mol. The PAD model is even more accurate, with a much smaller RMSD of 0.12 kcal/mol, with respect to the reference. This suggests that polarization effects, including both local charge distortion and intramolecular charge transfer, can be well captured by induced dipole type models with proper parametrization.

  11. New insight into the mechanism of Lonomia obliqua envenoming: toxin involvement and molecular approach.

    PubMed

    Alvarez Flores, M P; Zannin, M; Chudzinski-Tavassi, A M

    2010-01-01

    Despite the nearly worldwide distribution of Lepidoptera, there are few species with clear documentation of adverse reactions in humans. Most syndromes caused by Lepidoptera are consequences of direct contact with the hairs or setae of caterpillars. In most instances, the adverse effects caused by moth and caterpillars are self-limited and the treatment is based on the removal of hairs, application of topical antipruritics and, in some cases, the use of oral antihistamines. However, in the case of envenoming by South American Lonomiaobliqua caterpillars, the antilonomic serum produced at Instituto Butantan in Brazil is the only effective treatment to re-establish the physiological coagulation parameters in poisoned patients and to abolish the complications seen in severe cases (e.g. consumptive coagulopathy, intracerebral hemorrhage, and acute renal failure). Many studies have been carried out to understand the pathophysiological mechanism of envenoming by L. obliqua. Several toxic principles were found in bristle extract and the hemolymph, probably related to the envenoming. An interesting fact is that some toxins from the venom usually have more than one function. With the advent of molecular biology techniques it has become possible to analyze these processes at a molecular level, thus giving rise to hypotheses on the molecular basis of envenomation. This review contributes to enhance our understanding of the dramatic alterations that hemorrhagic syndrome causes in patients, current treatment, and the diversity of the molecules involved in this pathology. Copyright © 2010 S. Karger AG, Basel.

  12. Epigenetics, copy number variation, and other molecular mechanisms underlying neurodevelopmental disabilities: new insights and diagnostic approaches.

    PubMed

    Gropman, Andrea L; Batshaw, Mark L

    2010-09-01

    The diagnostic evaluation of children with intellectual disability (ID) and other neurodevelopmental disabilities (NDD) has become increasingly complex in recent years owing to a number of newly recognized genetic mechanisms and sophisticated methods to diagnose them. Previous studies have attempted to address the diagnostic yield of finding a genetic cause in ID. The results have varied widely from 10% to 81%, with the highest percentage being found in studies using new array comparative genomic hybridization methodology especially in autism. Although many cases of ID/NDD result from chromosomal aneuploidy or structural rearrangements, single gene disorders and new categories of genome modification, including epigenetics and copy number variation play an increasingly important role in diagnosis and testing. Epigenetic mechanisms, such as DNA methylation and modifications to histone proteins, regulate high-order DNA structure and gene expression. Aberrant epigenetic and copy number variation mechanisms are involved in several neurodevelopmental and neurodegenerative disorders including Rett syndrome, fragile X syndrome, and microdeletion syndromes. This review will describe a number of the molecular genetic mechanisms that play a role in disorders leading to ID/NDD and will discuss the categories and technologies for diagnostic testing of these conditions.

  13. 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.

  14. Deciphering the molecular mechanisms underlying sea urchin reversible adhesion: A quantitative proteomics approach.

    PubMed

    Lebesgue, Nicolas; da Costa, Gonçalo; Ribeiro, Raquel Mesquita; Ribeiro-Silva, Cristina; Martins, Gabriel G; Matranga, Valeria; Scholten, Arjen; Cordeiro, Carlos; Heck, Albert J R; Santos, Romana

    2016-04-14

    Marine bioadhesives have unmatched performances in wet environments, being an inspiration for biomedical applications. In sea urchins specialized adhesive organs, tube feet, mediate reversible adhesion, being composed by a disc, producing adhesive and de-adhesive secretions, and a motile stem. After tube foot detachment, the secreted adhesive remains bound to the substratum as a footprint. Sea urchin adhesive is composed by proteins and sugars, but so far only one protein, Nectin, was shown to be over-expressed as a transcript in tube feet discs, suggesting its involvement in sea urchin adhesion. Here we use high-resolution quantitative mass-spectrometry to perform the first study combining the analysis of the differential proteome of an adhesive organ, with the proteome of its secreted adhesive. This strategy allowed us to identify 163 highly over-expressed disc proteins, specifically involved in sea urchin reversible adhesion; to find that 70% of the secreted adhesive components fall within five protein groups, involved in exocytosis and microbial protection; and to provide evidences that Nectin is not only highly expressed in tube feet discs but is an actual component of the adhesive. These results give an unprecedented insight into the molecular mechanisms underlying sea urchin adhesion, and opening new doors to develop wet-reliable, reversible, and ecological biomimetic adhesives. Sea urchins attach strongly but in a reversible manner to substratum, being a valuable source of inspiration for industrial and biomedical applications. Yet, the molecular mechanisms governing reversible adhesion are still poorly studied delaying the engineering of biomimetic adhesives. We used the latest mass spectrometry techniques to analyze the differential proteome of an adhesive organ and the proteome of its secreted adhesive, allowing us to uncover the key players in sea urchin reversible adhesion. We demonstrate, that Nectin, a protein previously pointed out as potentially

  15. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2015-08-01

    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.

  17. Waterlogging Tolerance of Crops: Breeding, Mechanism of Tolerance, Molecular Approaches, and Future Prospects

    PubMed Central

    Ahmed, F.; Rafii, M. Y.; Ismail, M. R.; Juraimi, A. S.; Rahim, H. A.; Asfaliza, R.; Latif, M. A.

    2013-01-01

    Submergence or flood is one of the major harmful abiotic stresses in the low-lying countries and crop losses due to waterlogging are considerably high. Plant breeding techniques, conventional or genetic engineering, might be an effective and economic way of developing crops to grow successfully in waterlogged condition. Marker assisted selection (MAS) is a new and more effective approach which can identify genomic regions of crops under stress, which could not be done previously. The discovery of comprehensive molecular linkage maps enables us to do the pyramiding of desirable traits to improve in submergence tolerance through MAS. However, because of genetic and environmental interaction, too many genes encoding a trait, and using undesirable populations the mapping of QTL was hampered to ensure proper growth and yield under waterlogged conditions Steady advances in the field of genomics and proteomics over the years will be helpful to increase the breeding programs which will help to accomplish a significant progress in the field crop variety development and also improvement in near future. Waterlogging response of soybean and major cereal crops, as rice, wheat, barley, and maize and discovery of QTL related with tolerance of waterlogging, development of resistant variety, and, in addition, future prospects have also been discussed. PMID:23484164

  18. Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches

    PubMed Central

    Rosenbaum, Anton I.; Maxfield, Frederick R.

    2010-01-01

    Cholesterol is an important lipid of mammalian cells. Its unique physicochemical properties modulate membrane behavior and it serves as the precursor for steroid hormones, oxysterols and vitamin D. Cholesterol is effluxed from the late endosomes/lysosomes via the concerted action of at least two distinct proteins: Niemann-Pick C1 and Niemann-Pick C2. Mutations in these two proteins manifest as Niemann-Pick type C disease – a very rare, usually fatal, autosomal, recessive, neurovisceral, lysosomal storage disorder. In this review we discuss the possible mechanisms of action for NPC1 and NPC2 in mediating cholesterol efflux, as well as the different therapeutic approaches being pursued for the treatment of this lipid storage disorder. PMID:20807315

  19. Systematic analysis of molecular mechanisms for HCC metastasis via text mining approach.

    PubMed

    Zhen, Cheng; Zhu, Caizhong; Chen, Haoyang; Xiong, Yiru; Tan, Junyuan; Chen, Dong; Li, Jin

    2017-02-21

    To systematically explore the molecular mechanism for hepatocellular carcinoma (HCC) metastasis and identify regulatory genes with text mining methods. Genes with highest frequencies and significant pathways related to HCC metastasis were listed. A handful of proteins such as EGFR, MDM2, TP53 and APP, were identified as hub nodes in PPI (protein-protein interaction) network. Compared with unique genes for HBV-HCCs, genes particular to HCV-HCCs were less, but may participate in more extensive signaling processes. VEGFA, PI3KCA, MAPK1, MMP9 and other genes may play important roles in multiple phenotypes of metastasis. Genes in abstracts of HCC-metastasis literatures were identified. Word frequency analysis, KEGG pathway and PPI network analysis were performed. Then co-occurrence analysis between genes and metastasis-related phenotypes were carried out. Text mining is effective for revealing potential regulators or pathways, but the purpose of it should be specific, and the combination of various methods will be more useful.

  20. Insight into the molecular mechanism of P-glycoprotein mediated drug toxicity induced by bioflavonoids: an integrated computational approach.

    PubMed

    Wongrattanakamon, Pathomwat; Lee, Vannajan Sanghiran; Nimmanpipug, Piyarat; Sirithunyalug, Busaban; Chansakaow, Sunee; Jiranusornkul, Supat

    2017-05-01

    In this work, molecular docking, pharmacophore modeling and molecular dynamics (MD) simulation were rendered for the mouse P-glycoprotein (P-gp) (code: 4Q9H) and bioflavonoids; amorphigenin, chrysin, epigallocatechin, formononetin and rotenone including a positive control; verapamil to identify protein-ligand interaction features including binding affinities, interaction characteristics, hot-spot amino acid residues and complex stabilities. These flavonoids occupied the same binding site with high binding affinities and shared the same key residues for their binding interactions and the binding region of the flavonoids was revealed that overlapped the ATP binding region with hydrophobic and hydrophilic interactions suggesting a competitive inhibition mechanism of the compounds. Root mean square deviations (RMSDs) analysis of MD trajectories of the protein-ligand complexes and NBD2 residues, and ligands pointed out these residues were stable throughout the duration of MD simulations. Thus, the applied preliminary structure-based molecular modeling approach of interactions between NBD2 and flavonoids may be gainful to realize the intimate inhibition mechanism of P-gp at NBD2 level and on the basis of the obtained data, it can be concluded that these bioflavonoids have the potential to cause herb-drug interactions or be used as lead molecules for the inhibition of P-gp (as anti-multidrug resistance agents) via the NBD2 blocking mechanism in future.

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

    DOE PAGES

    Larsen, Peter E.; Sreedasyam, Avinash; Trivedi, Geetika; ...

    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

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

    SciTech Connect

    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 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 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.

  3. 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

  4. A hierarchical approach to accurate predictions of macroscopic thermodynamic behavior from quantum mechanics and molecular simulations

    NASA Astrophysics Data System (ADS)

    Garrison, Stephen L.

    2005-07-01

    The combination of molecular simulations and potentials obtained from quantum chemistry is shown to be able to provide reasonably accurate thermodynamic property predictions. Gibbs ensemble Monte Carlo simulations are used to understand the effects of small perturbations to various regions of the model Lennard-Jones 12-6 potential. However, when the phase behavior and second virial coefficient are scaled by the critical properties calculated for each potential, the results obey a corresponding states relation suggesting a non-uniqueness problem for interaction potentials fit to experimental phase behavior. Several variations of a procedure collectively referred to as quantum mechanical Hybrid Methods for Interaction Energies (HM-IE) are developed and used to accurately estimate interaction energies from CCSD(T) calculations with a large basis set in a computationally efficient manner for the neon-neon, acetylene-acetylene, and nitrogen-benzene systems. Using these results and methods, an ab initio, pairwise-additive, site-site potential for acetylene is determined and then improved using results from molecular simulations using this initial potential. The initial simulation results also indicate that a limited range of energies important for accurate phase behavior predictions. Second virial coefficients calculated from the improved potential indicate that one set of experimental data in the literature is likely erroneous. This prescription is then applied to methanethiol. Difficulties in modeling the effects of the lone pair electrons suggest that charges on the lone pair sites negatively impact the ability of the intermolecular potential to describe certain orientations, but that the lone pair sites may be necessary to reasonably duplicate the interaction energies for several orientations. Two possible methods for incorporating the effects of three-body interactions into simulations within the pairwise-additivity formulation are also developed. A low density

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

    PubMed

    Song, Jianglong; Zhang, Fangbo; Tang, Shihuan; Liu, Xi; Gao, Yibo; Lu, Peng; Wang, Yanping; Yang, Hongjun

    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.

  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. Holistic systems biology approaches to molecular mechanisms of human helper T cell differentiation to functionally distinct subsets.

    PubMed

    Chen, Z; Lönnberg, T; Lahesmaa, R

    2013-08-01

    Current knowledge of helper T cell differentiation largely relies on data generated from mouse studies. To develop therapeutical strategies combating human diseases, understanding the molecular mechanisms how human naïve T cells differentiate to functionally distinct T helper (Th) subsets as well as studies on human differentiated Th cell subsets is particularly valuable. Systems biology approaches provide a holistic view of the processes of T helper differentiation, enable discovery of new factors and pathways involved and generation of new hypotheses to be tested to improve our understanding of human Th cell differentiation and immune-mediated diseases. Here, we summarize studies where high-throughput systems biology approaches have been exploited to human primary T cells. These studies reveal new factors and signalling pathways influencing T cell differentiation towards distinct subsets, important for immune regulation. Such information provides new insights into T cell biology and into targeting immune system for therapeutic interventions.

  8. Cancer Cachexia: Traditional Therapies and Novel Molecular Mechanism-Based Approaches to Treatment

    PubMed Central

    Kazi, Aslam; Smith, Tiffany; Crocker, Theresa; Yu, Daohai; Reich, Richard R.; Reddy, Kiran; Hastings, Sally; Exterman, Martine; Balducci, Lodovico; Dalton, Kyle; Bepler, Gerold

    2010-01-01

    Opinion statement The complex syndrome of cancer cachexia (CC) that occurs in 50% to 80% cancer patients has been identified as an independent predictor of shorter survival and increased risk of treatment failure and toxicity, contributing to the mortality and morbidity in this population. CC is a pathological state including a symptom cluster of loss of muscle (skeletal and visceral) and fat, manifested in the cardinal feature of emaciation, weakness affecting functional status, impaired immune system, and metabolic dysfunction. The most prominent feature of CC is its non-responsiveness to traditional treatment approaches; randomized clinical trials with appetite stimulants, 5-HT3 antagonists, nutrient supplementation, and Cox-2 inhibitors all have failed to demonstrate success in reversing the metabolic abnormalities seen in CC. Interventions based on a clear understanding of the mechanism of CC, using validated markers relevant to the underlying metabolic abnormalities implicated in CC are much needed. Although the etiopathogenesis of CC is poorly understood, studies have proposed that NFkB is upregulated in CC, modulating immune and inflammatory responses induce the cellular breakdown of muscle, resulting in sarcopenia. Several recent laboratory studies have shown that n-3 fatty acid may attenuate protein degradation, potentially by preventing NFkB accumulation in the nucleus, preventing the degradation of muscle proteins. However, clinical trials to date have produced mixed results potentially attributed to timing of interventions (end stage) and utilizing outcome markers such as weight which is confounded by hydration, cytotoxic therapies, and serum cytokines. We propose that selective targeting of proteasome activity with a standardized dose of omega-3-acid ethyl esters, administered to cancer patients diagnosed with early stage CC, in addition to a standard intervention with nutritionally adequate diet and appetite stimulants, will alter metabolic

  9. Quantum Mechanical Molecular Interactions for Calculating the Excitation Energy in Molecular Environments: A First-Order Interacting Space Approach

    PubMed Central

    Hasegawa, Jun-ya; Yanai, Kazuma; Ishimura, Kazuya

    2015-01-01

    Intermolecular interactions regulate the molecular properties in proteins and solutions such as solvatochromic systems. Some of the interactions have to be described at an electronic-structure level. In this study, a commutator for calculating the excitation energy is used for deriving a first-order interacting space (FOIS) to describe the environmental response to solute excitation. The FOIS wave function for a solute-in-solvent cluster is solved by second-order perturbation theory. The contributions to the excitation energy are decomposed into each interaction and for each solvent. PMID:25393373

  10. a Variational Approach to Statistical Mechanics with Applications to Molecular Monolayer Assemblies.

    NASA Astrophysics Data System (ADS)

    MacCarthy, John Edward

    A new, versatile, theoretically self-consistent procedure is proposed for determining the thermodynamic properties of a classical system in the condensed fluid phase. The method of complementary variational principles, developed by A. M. Arthurs and his colleagues, is used to generate reference state (hard core) correlation function data via analysis of a well known (nonlinear) integral equation for the pair distribution function (namely, the Yvon-Born-Green equation). These data are then used within the context of the perturbation theory of classical fluids developed by Zwanzig, as implemented by Barker and Henderson, to investigate the role of attractive and repulsive perturbations in influencing the thermodynamics of the reference system. As a specific application of this procedure, one that leads to many new results, we focus on a classical system of particles whose effective interactions are confined to a space of two dimensions. We consider two classes of potential functions (the square well/square shoulder and linear well/linear shoulder potentials) and consider separately the effects of attractive and repulsive perturbations. Where possible, the predictions of the theory are compared against known results (specifically, the results obtained via molecular dynamics simulation); we find that the variational method accurately represents the thermodynamics of the reference state (the hard disc fluid) up to densities of (rho)(sigma)('2)(TURNEQ)0.8, and the variational method in tandem with perturbation theory adequately represents the thermodynamics of the square shoulder system over the same density range. The effects of increasing the strength and range parameters of the potential are explored in detail and quantified. Both for the case of attractive and repulsive perturbations, isotherms of the van der Waals type are found to develop below a certain critical temperature in the dense fluid regime. The possible significance of these mean field results to the

  11. Resistance mechanism of human immunodeficiency virus type-1 protease to inhibitors: A molecular dynamic approach

    PubMed Central

    Dayer, Mohammad Reza; Dayer, Mohammad Saaid

    2014-01-01

    Human immunodeficiency virus type 1 (HIV-1) protease inhibitors comprise an important class of drugs used in HIV treatments. However, mutations of protease genes accelerated by low fidelity of reverse transcriptase yield drug resistant mutants of reduced affinities for the inhibitors. This problem is considered to be a serious barrier against HIV treatment for the foreseeable future. In this study, molecular dynamic simulation method was used to examine the combinational and additive effects of all known mutations involved in drug resistance against FDA approved inhibitors. Results showed that drug resistant mutations are not randomly distributed along the protease sequence; instead, they are localized on flexible or hot points of the protein chain. Substitution of more hydrophobic residues in flexible points of protease chains tends to increase the folding, lower the flexibility and decrease the active site area of the protease. The reduced affinities of HIV-1 protease for inhibitors seemed to be due to substantial decrease in the size of the active site and flap mobility. A correlation was found between the binding energy of inhibitors and their affinities for each mutant suggesting the distortion of the active site geometry in drug resistance by preventing effective fitting of inhibitors into the enzymes' active site. To overcome the problem of drug resistance of HIV-1 protease, designing inhibitors of variable functional groups and configurations is proposed. PMID:27843989

  12. Charge sensitivity approach to mutual polarization of reactants: molecular mechanics perspective.

    PubMed

    Stachowicz, Anna; Rogalski, Marek; Korchowiec, Jacek

    2013-10-01

    Charge sensitivity analysis (CSA) in force-field atoms resolution was applied to describe the mutual polarization of reactants as well as charge-transfer (CT) effects. An inclusion complex of β-cyclodextrin with salicylic acid was used as a model system. Three CSA models were taken into account and verified on a Born-Oppenheimer molecular dynamics (BOMD) trajectory. The models differed in terms of the equilibrium conditions imposed on the system. It was demonstrated that mutual polarization is an important source of stabilization, in contrast to the results obtained from static charge calculations. The energy lowering induced by CT was small and comparable to the CT stabilization that occurs in hydrogen-bonded systems. All models correctly described the main topological features of the BOMD energy surface. CSA in force-field atoms resolution qualitatively reproduced the charge reorganization accompanying hydrogen-bond formation. It was shown that CSA parameters are very sensitive to the bond formation process, which suggests that they could be applied in reactive force fields as detectors of newly formed chemical bonds.

  13. Diabetic retinopathy: Proteomic approaches to help the differential diagnosis and to understand the underlying molecular mechanisms.

    PubMed

    Csősz, Éva; Deák, Eszter; Kalló, Gergő; Csutak, Adrienne; Tőzsér, József

    2017-01-06

    Diabetic retinopathy is the most common diabetic eye disease and a leading cause of blindness among patients with diabetes. The appearance and the severity of the symptoms correlate with the duration of diabetes and poor blood glucose level management. Diabetic retinopathy is also categorized as a chronic low-level inflammatory disease; the high blood glucose level promotes the accumulation of the advanced glycation end products and leads to the stimulation of monocytes and macrophages. Examination of protein level alterations in tears using state-of the art proteomics techniques have identified several proteins as possible biomarkers for the different stages of the diabetic retinopathy. Some of the differentially expressed tear proteins have a role in the barrier function of tears linking the diabetic retinopathy with another eye complication of diabetes, namely the diabetic keratopathy resulting in impaired wound healing. Understanding the molecular events leading to the eye complications caused by hyperglycemia may help the identification of novel biomarkers as well as therapeutic targets in order to improve quality of life of diabetic patients.

  14. Combining classical and molecular approaches elaborates on the complexity of mechanisms underpinning anterior regeneration.

    PubMed

    Evans, Deborah J; Owlarn, Suthira; Tejada Romero, Belen; Chen, Chen; Aboobaker, A Aziz

    2011-01-01

    The current model of planarian anterior regeneration evokes the establishment of low levels of Wnt signalling at anterior wounds, promoting anterior polarity and subsequent elaboration of anterior fate through the action of the TALE class homeodomain PREP. The classical observation that decapitations positioned anteriorly will regenerate heads more rapidly than posteriorly positioned decapitations was among the first to lead to the proposal of gradients along an anteroposterior (AP) axis in a developmental context. An explicit understanding of this phenomenon is not included in the current model of anterior regeneration. This raises the question what the underlying molecular and cellular basis of this temporal gradient is, whether it can be explained by current models and whether understanding the gradient will shed light on regenerative events. Differences in anterior regeneration rate are established very early after amputation and this gradient is dependent on the activity of Hedgehog (Hh) signalling. Animals induced to produce two tails by either Smed-APC-1(RNAi) or Smed-ptc(RNAi) lose anterior fate but form previously described ectopic anterior brain structures. Later these animals form peri-pharyngeal brain structures, which in Smed-ptc(RNAi) grow out of the body establishing a new A/P axis. Combining double amputation and hydroxyurea treatment with RNAi experiments indicates that early ectopic brain structures are formed by uncommitted stem cells that have progressed through S-phase of the cell cycle at the time of amputation. Our results elaborate on the current simplistic model of both AP axis and brain regeneration. We find evidence of a gradient of hedgehog signalling that promotes posterior fate and temporarily inhibits anterior regeneration. Our data supports a model for anterior brain regeneration with distinct early and later phases of regeneration. Together these insights start to delineate the interplay between discrete existing, new, and then

  15. Combining Classical and Molecular Approaches Elaborates on the Complexity of Mechanisms Underpinning Anterior Regeneration

    PubMed Central

    Evans, Deborah J.; Owlarn, Suthira; Tejada Romero, Belen; Chen, Chen; Aboobaker, A. Aziz

    2011-01-01

    The current model of planarian anterior regeneration evokes the establishment of low levels of Wnt signalling at anterior wounds, promoting anterior polarity and subsequent elaboration of anterior fate through the action of the TALE class homeodomain PREP. The classical observation that decapitations positioned anteriorly will regenerate heads more rapidly than posteriorly positioned decapitations was among the first to lead to the proposal of gradients along an anteroposterior (AP) axis in a developmental context. An explicit understanding of this phenomenon is not included in the current model of anterior regeneration. This raises the question what the underlying molecular and cellular basis of this temporal gradient is, whether it can be explained by current models and whether understanding the gradient will shed light on regenerative events. Differences in anterior regeneration rate are established very early after amputation and this gradient is dependent on the activity of Hedgehog (Hh) signalling. Animals induced to produce two tails by either Smed-APC-1(RNAi) or Smed-ptc(RNAi) lose anterior fate but form previously described ectopic anterior brain structures. Later these animals form peri-pharyngeal brain structures, which in Smed-ptc(RNAi) grow out of the body establishing a new A/P axis. Combining double amputation and hydroxyurea treatment with RNAi experiments indicates that early ectopic brain structures are formed by uncommitted stem cells that have progressed through S-phase of the cell cycle at the time of amputation. Our results elaborate on the current simplistic model of both AP axis and brain regeneration. We find evidence of a gradient of hedgehog signalling that promotes posterior fate and temporarily inhibits anterior regeneration. Our data supports a model for anterior brain regeneration with distinct early and later phases of regeneration. Together these insights start to delineate the interplay between discrete existing, new, and then

  16. Molecular Mechanism of Quorum-Sensing in Enterococcus faecalis: Its Role in Virulence and Therapeutic Approaches.

    PubMed

    Ali, Liaqat; Goraya, Mohsan Ullah; Arafat, Yasir; Ajmal, Muhammad; Chen, Ji-Long; Yu, Daojin

    2017-05-03

    Quorum-sensing systems control major virulence determinants in Enterococcusfaecalis, which causes nosocomial infections. The E. faecalis quorum-sensing systems include several virulence factors that are regulated by the cytolysin operon, which encodes the cytolysin toxin. In addition, the E. faecalis Fsr regulator system controls the expression of gelatinase, serine protease, and enterocin O16. The cytolysin and Fsr virulence factor systems are linked to enterococcal diseases that affect the health of humans and other host models. Therefore, there is substantial interest in understanding and targeting these regulatory pathways to develop novel therapies for enterococcal infection control. Quorum-sensing inhibitors could be potential therapeutic agents for attenuating the pathogenic effects of E. faecalis. Here, we discuss the regulation of cytolysin, the LuxS system, and the Fsr system, their role in E. faecalis-mediated infections, and possible therapeutic approaches to prevent E. faecalis infection.

  17. Molecular Mechanism of Quorum-Sensing in Enterococcus faecalis: Its Role in Virulence and Therapeutic Approaches

    PubMed Central

    Ali, Liaqat; Goraya, Mohsan Ullah; Arafat, Yasir; Ajmal, Muhammad; Chen, Ji-Long; Yu, Daojin

    2017-01-01

    Quorum-sensing systems control major virulence determinants in Enterococcus faecalis, which causes nosocomial infections. The E. faecalis quorum-sensing systems include several virulence factors that are regulated by the cytolysin operon, which encodes the cytolysin toxin. In addition, the E. faecalis Fsr regulator system controls the expression of gelatinase, serine protease, and enterocin O16. The cytolysin and Fsr virulence factor systems are linked to enterococcal diseases that affect the health of humans and other host models. Therefore, there is substantial interest in understanding and targeting these regulatory pathways to develop novel therapies for enterococcal infection control. Quorum-sensing inhibitors could be potential therapeutic agents for attenuating the pathogenic effects of E. faecalis. Here, we discuss the regulation of cytolysin, the LuxS system, and the Fsr system, their role in E. faecalis-mediated infections, and possible therapeutic approaches to prevent E. faecalis infection. PMID:28467378

  18. 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

  19. Ecotoxicogenomic approaches for understanding molecular mechanisms of environmental chemical toxicity using aquatic invertebrate, Daphnia model organism.

    PubMed

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

    2015-05-29

    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.

  20. Molecular mechanism aspect of ER stress in Alzheimer's disease: current approaches and future strategies.

    PubMed

    Ansari, Niloufar; Khodagholi, Fariba

    2013-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by progressive loss of memory and cognitive impairment. Aggregation of amyloid-β (Aβ) peptides is the crucial factor in the onset of AD. The toxic Aβ peptides Aβ40 and Aβ42 are produced from the Aβ precursor protein (APP), a transmembrane protein which is folded and modified in endoplasmic reticulum (ER). ER is the main organelle for the synthesis and processing of nearly all proteins as well as the main cellular source of Ca2+. Under stress conditions, three main ER pathways including inositol-requiring enzyme 1, protein kinase RNA-like ER kinase, and activating transcription factor 6 become activated causing the accumulation of unfolded or misfolded proteins within ER lumen. These pathways manage the stress by regulating the expression of chaperones and enzymes involved in protein folding. Several studies have reported the dysfunction of these stress-sensing pathways in pathological conditions, including neurodegenerative diseases. Recent studies have proposed that neuronal death in AD arises from dysfunction of the ER. Here, we will review recent research findings on the interaction between ER and mitochondria, and its effect on apoptotic pathways. We further provide insights into studies which suggest the role of ER in animal and/or cellular models of AD. Therapeutic strategies that modulate ER could represent a promising approach for prevention or treatment of AD.

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

    PubMed

    Archer, A J

    2009-01-07

    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.

  2. Molecular mechanisms in gliomagenesis.

    PubMed

    Hulleman, Esther; Helin, Kristian

    2005-01-01

    Glioma, and in particular high-grade astrocytoma termed glioblastoma multiforme (GBM), is the most common primary tumor of the brain. Primarily because of its diffuse nature, there is no effective treatment for GBM, and relatively little is known about the processes by which it develops. Therefore, in order to design novel therapies and treatments for GBM, research has recently intensified to identify the cellular and molecular mechanisms leading to GBM formation. Modeling of astrocytomas by genetic manipulation of mice suggests that deregulation of the pathways that control gliogenesis during normal brain development, such as the differentiation of neural stem cells (NSCs) into astrocytes, might contribute to GBM formation. These pathways include growth factor-induced signal transduction routes and processes that control cell cycle progression, such as the p16-CDK4-RB and the ARF-MDM2-p53 pathways. The expression of several of the components of these signaling cascades has been found altered in GBM, and recent data indicate that combinations of mutations in these pathways may contribute to GBM formation, although the exact mechanisms are still to be uncovered. Use of novel techniques including large-scale genomics and proteomics in combination with relevant mouse models will most likely provide novel insights into the molecular mechanisms underlying glioma formation and will hopefully lead to development of treatment modalities for GBM.

  3. 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

  4. Variational Approach to Molecular Kinetics.

    PubMed

    Nüske, Feliks; Keller, Bettina G; Pérez-Hernández, Guillermo; Mey, Antonia S J S; Noé, Frank

    2014-04-08

    The eigenvalues and eigenvectors of the molecular dynamics propagator (or transfer operator) contain the essential information about the molecular thermodynamics and kinetics. This includes the stationary distribution, the metastable states, and state-to-state transition rates. Here, we present a variational approach for computing these dominant eigenvalues and eigenvectors. This approach is analogous to the variational approach used for computing stationary states in quantum mechanics. A corresponding method of linear variation is formulated. It is shown that the matrices needed for the linear variation method are correlation matrices that can be estimated from simple MD simulations for a given basis set. The method proposed here is thus to first define a basis set able to capture the relevant conformational transitions, then compute the respective correlation matrices, and then to compute their dominant eigenvalues and eigenvectors, thus obtaining the key ingredients of the slow kinetics.

  5. 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.

  6. Simple and exact approach to the electronic polarization effect on the solvation free energy: formulation for quantum-mechanical/molecular-mechanical system and its applications to aqueous solutions.

    PubMed

    Takahashi, Hideaki; Omi, Atsushi; Morita, Akihiro; Matubayasi, Nobuyuki

    2012-06-07

    We present a simple and exact numerical approach to compute the free energy contribution δμ in solvation due to the electron density polarization and fluctuation of a quantum-mechanical solute in the quantum-mechanical/molecular-mechanical (QM/MM) simulation combined with the theory of the energy representation (QM/MM-ER). Since the electron density fluctuation is responsible for the many-body QM-MM interactions, the standard version of the energy representation method cannot be applied directly. Instead of decomposing the QM-MM polarization energy into the pairwise additive and non-additive contributions, we take sum of the polarization energies in the QM-MM interaction and adopt it as a new energy coordinate for the method of energy representation. Then, it is demonstrated that the free energy δμ can be exactly formulated in terms of the energy distribution functions for the solution and reference systems with respect to this energy coordinate. The benchmark tests were performed to examine the numerical efficiency of the method with respect to the changes in the individual properties of the solvent and the solute. Explicitly, we computed the solvation free energy of a QM water molecule in ambient and supercritical water, and also the free-energy change associated with the isomerization reaction of glycine from neutral to zwitterionic structure in aqueous solution. In all the systems examined, it was demonstrated that the computed free energy δμ agrees with the experimental value, irrespective of the choice of the reference electron density of the QM solute. The present method was also applied to a prototype reaction of adenosine 5'-triphosphate hydrolysis where the effect of the electron density fluctuation is substantial due to the excess charge. It was demonstrated that the experimental free energy of the reaction has been accurately reproduced with the present approach.

  7. Cisplatin nephrotoxicity: molecular mechanisms

    PubMed Central

    Hanigan, Marie H.; Devarajan, Prasad

    2007-01-01

    Summary Cisplatin is one of the most widely used chemotherapeutic agents for the treatment of several human malignancies. The efficacy of cisplatin is dose dependent, but the significant risk of nephrotoxicity frequently hinders the use of higher doses to maximize its antineoplastic effects. Several advances in our understanding of the biochemical and molecular mechanisms underlying cisplatin nephrotoxicity have recently emerged, and are reviewed in this article. Evidence is presented for distinct mechanisms of cisplatin toxicity in actively dividing tumor cells versus the normally quiescent renal proximal tubular epithelial cells. The unexpected role of gamma-glutamyl transpeptidase in cisplatin nephrotoxicity is elucidated. Recent studies demonstrating the ability of proximal tubular cells to metabolize cisplatin to a nephrotoxin are reviewed. The evidence for apoptosis as a major mechanism underlying cisplatin-induced renal cell injury is presented, along with the data exploring the role of specific intracellular pathways that may mediate the programmed cell death. The information gleaned from this review may provide critical clues to novel therapeutic interventions aimed at minimizing cisplatin-induced nephrotoxicity while enhancing its antineoplastic efficacy. PMID:18185852

  8. Molecular mechanisms in cardiomyopathy.

    PubMed

    Dadson, Keith; Hauck, Ludger; Billia, Filio

    2017-07-01

    Cardiomyopathies represent a heterogeneous group of diseases that negatively affect heart function. Primary cardiomyopathies specifically target the myocardium, and may arise from genetic [hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), mitochondrial cardiomyopathy] or genetic and acquired [dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM)] etiology. Modern genomics has identified mutations that are common in these populations, while in vitro and in vivo experimentation with these mutations have provided invaluable insight into the molecular mechanisms native to these diseases. For example, increased myosin heavy chain (MHC) binding and ATP utilization lead to the hypercontractile sarcomere in HCM, while abnormal protein-protein interaction and impaired Ca(2+) flux underlie the relaxed sarcomere of DCM. Furthermore, expanded access to genetic testing has facilitated identification of potential risk factors that appear through inheritance and manifest sometimes only in the advanced stages of the disease. In this review, we discuss the genetic and molecular abnormalities unique to and shared between these primary cardiomyopathies and discuss some of the important advances made using more traditional basic science experimentation. © 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  9. Insights into the molecular mechanisms of Polygonum multiflorum Thunb-induced liver injury: a computational systems toxicology approach.

    PubMed

    Wang, Yin-Yin; Li, Jie; Wu, Zeng-Rui; Zhang, Bo; Yang, Hong-Bin; Wang, Qin; Cai, Ying-Chun; Liu, Gui-Xia; Li, Wei-Hua; Tang, Yun

    2017-02-27

    An increasing number of cases of herb-induced liver injury (HILI) have been reported, presenting new clinical challenges. In this study, taking Polygonum multiflorum Thunb (PmT) as an example, we proposed a computational systems toxicology approach to explore the molecular mechanisms of HILI. First, the chemical components of PmT were extracted from 3 main TCM databases as well as the literature related to natural products. Then, the known targets were collected through data integration, and the potential compound-target interactions (CTIs) were predicted using our substructure-drug-target network-based inference (SDTNBI) method. After screening for hepatotoxicity-related genes by assessing the symptoms of HILI, a compound-target interaction network was constructed. A scoring function, namely, Ascore, was developed to estimate the toxicity of chemicals in the liver. We conducted network analysis to determine the possible mechanisms of the biphasic effects using the analysis tools, including BiNGO, pathway enrichment, organ distribution analysis and predictions of interactions with CYP450 enzymes. Among the chemical components of PmT, 54 components with good intestinal absorption were used for analysis, and 2939 CTIs were obtained. After analyzing the mRNA expression data in the BioGPS database, 1599 CTIs and 125 targets related to liver diseases were identified. In the top 15 compounds, seven with Ascore values >3000 (emodin, quercetin, apigenin, resveratrol, gallic acid, kaempferol and luteolin) were obviously associated with hepatotoxicity. The results from the pathway enrichment analysis suggest that multiple interactions between apoptosis and metabolism may underlie PmT-induced liver injury. Many of the pathways have been verified in specific compounds, such as glutathione metabolism, cytochrome P450 metabolism, and the p53 pathway, among others. Hepatitis symptoms, the perturbation of nine bile acids and yellow or tawny urine also had corresponding pathways

  10. Investigation of mechanical strength of 2D nanoscale structures using a molecular dynamics based computational intelligence approach

    NASA Astrophysics Data System (ADS)

    Garg, A.; Vijayaraghavan, V.; Wong, C. H.; Tai, K.; Singru, Pravin M.; Mahapatra, S. S.; Sangwan, K. S.

    2015-09-01

    A molecular dynamics (MD) based computational intelligence (CI) approach is proposed to investigate the Young modulus of two graphene sheets: Armchair and Zigzag. In this approach, the effect of aspect ratio, the temperature, the number of atomic planes and the vacancy defects on the Young modulus of two graphene sheets are first analyzed using the MD simulation. The data obtained using the MD simulation is then fed into the paradigm of a CI cluster comprising of genetic programming, which was specifically designed to formulate the explicit relationship of Young modulus of two graphene structures. We find that the MD-based-CI model is able to model the Young modulus of two graphene structures very well, which compiles in good agreement with that of experimental results obtained from the literature. Additionally, we also conducted sensitivity and parametric analysis and found that the number of defects has the most dominating influence on the Young modulus of two graphene structures.

  11. Genomic, transcriptomic, and proteomic approaches towards understanding the molecular mechanisms of salt tolerance in Frankia strains isolated from Casuarina trees.

    PubMed

    Oshone, Rediet; Ngom, Mariama; Chu, Feixia; Mansour, Samira; Sy, Mame Ourèye; Champion, Antony; Tisa, Louis S

    2017-08-18

    Soil salinization is a worldwide problem that is intensifying because of the effects of climate change. An effective method for the reclamation of salt-affected soils involves initiating plant succession using fast growing, nitrogen fixing actinorhizal trees such as the Casuarina. The salt tolerance of Casuarina is enhanced by the nitrogen-fixing symbiosis that they form with the actinobacterium Frankia. Identification and molecular characterization of salt-tolerant Casuarina species and associated Frankia is imperative for the successful utilization of Casuarina trees in saline soil reclamation efforts. In this study, salt-tolerant and salt-sensitive Casuarina associated Frankia strains were identified and comparative genomics, transcriptome profiling, and proteomics were employed to elucidate the molecular mechanisms of salt and osmotic stress tolerance. Salt-tolerant Frankia strains (CcI6 and Allo2) that could withstand up to 1000 mM NaCl and a salt-sensitive Frankia strain (CcI3) which could withstand only up to 475 mM NaCl were identified. The remaining isolates had intermediate levels of salt tolerance with MIC values ranging from 650 mM to 750 mM. Comparative genomic analysis showed that all of the Frankia isolates from Casuarina belonged to the same species (Frankia casuarinae). Pangenome analysis revealed a high abundance of singletons among all Casuarina isolates. The two salt-tolerant strains contained 153 shared single copy genes (most of which code for hypothetical proteins) that were not found in the salt-sensitive(CcI3) and moderately salt-tolerant (CeD) strains. RNA-seq analysis of one of the two salt-tolerant strains (Frankia sp. strain CcI6) revealed hundreds of genes differentially expressed under salt and/or osmotic stress. Among the 153 genes, 7 and 7 were responsive to salt and osmotic stress, respectively. Proteomic profiling confirmed the transcriptome results and identified 19 and 8 salt and/or osmotic stress-responsive proteins in the

  12. 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

  13. Molecular Mechanisms of Preeclampsia

    PubMed Central

    Hod, Tammy; Cerdeira, Ana Sofia; Karumanchi, S. Ananth

    2015-01-01

    Preeclampsia is a pregnancy-specific disease characterized by new onset hypertension and proteinuria after 20 wk of gestation. It is a leading cause of maternal and fetal morbidity and mortality worldwide. Exciting discoveries in the last decade have contributed to a better understanding of the molecular basis of this disease. Epidemiological, experimental, and therapeutic studies from several laboratories have provided compelling evidence that an antiangiogenic state owing to alterations in circulating angiogenic factors leads to preeclampsia. In this review, we highlight the role of key circulating antiangiogenic factors as pathogenic biomarkers and in the development of novel therapies for preeclampsia. PMID:26292986

  14. 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.

  15. 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

  16. A Novel Perspective and Approach to Intestinal Octreotide Absorption: Sinomenine-Mediated Reversible Tight Junction Opening and Its Molecular Mechanism

    PubMed Central

    Li, Yuling; Duan, Zhijun; Tian, Yan; Liu, Zhen; Wang, Qiuming

    2013-01-01

    In this work, we assessed the effects of sinomenine (SN) on intestinal octreotide (OCT) absorption both in Caco-2 cell monolayers and in rats. We also investigated the molecular mechanisms of tight junction (TJ) disruption and recovery by SN-mediated changes in the claudin-1 and protein kinase C (PKC) signaling pathway. The data showed that exposure to SN resulted in a significant decrease in the expression of claudin-1, which represented TJ weakening and paracellular permeability enhancement. Then, the recovery of TJ after SN removal required an increase in claudin-1, which demonstrated the transient and reversible opening for TJ. Meanwhile, the SN-mediated translocation of PKC-α from the cytosol to the membrane was found to prove PKC activation. Finally, SN significantly improved the absolute OCT bioavailability in rats and the transport rate in Caco-2 cell monolayers. We conclude that SN has the ability to enhance intestinal OCT absorption and that these mechanisms are related at least in part to the important role of claudin-1 in SN-mediated, reversible TJ opening via PKC activation. PMID:23787475

  17. Molecular Mechanisms of Antisense Oligonucleotides.

    PubMed

    Crooke, Stanley T

    2017-04-01

    In 1987, when I became interested in the notion of antisense technology, I returned to my roots in RNA biochemistry and began work to understand how oligonucleotides behave in biological systems. Since 1989, my research has focused primarily on this topic, although I have been involved in most areas of research in antisense technology. I believe that the art of excellent science is to frame large important questions that are perhaps not immediately answerable with existing knowledge and methods, and then conceive a long-term (multiyear) research strategy that begins by answering the most pressing answerable questions on the path to the long-term goals. Then, a step-by-step research pathway that will address the strategic questions posed must be implemented, adjusting the plan as new things are learned. This is the approach we have taken at Ionis. Obviously, to create antisense technology, we have had to address a wide array of strategic questions, for example, the medicinal chemistry of oligonucleotides, manufacturing and analytical methods, pharmacokinetics and toxicology, as well as questions about the molecular pharmacology of antisense oligonucleotides (ASOs). Each of these endeavors has consumed nearly three decades of scientific effort, is still very much a work-in-progress, and has resulted in hundreds of publications. As a recipient of the Lifetime Achievement Award 2016 granted by the Oligonucleotide Therapeutic Society, in this note, my goal is to summarize the contributions of my group to the efforts to understand the molecular mechanisms of ASOs.

  18. Molecular Mechanisms of Antisense Oligonucleotides

    PubMed Central

    2017-01-01

    In 1987, when I became interested in the notion of antisense technology, I returned to my roots in RNA biochemistry and began work to understand how oligonucleotides behave in biological systems. Since 1989, my research has focused primarily on this topic, although I have been involved in most areas of research in antisense technology. I believe that the art of excellent science is to frame large important questions that are perhaps not immediately answerable with existing knowledge and methods, and then conceive a long-term (multiyear) research strategy that begins by answering the most pressing answerable questions on the path to the long-term goals. Then, a step-by-step research pathway that will address the strategic questions posed must be implemented, adjusting the plan as new things are learned. This is the approach we have taken at Ionis. Obviously, to create antisense technology, we have had to address a wide array of strategic questions, for example, the medicinal chemistry of oligonucleotides, manufacturing and analytical methods, pharmacokinetics and toxicology, as well as questions about the molecular pharmacology of antisense oligonucleotides (ASOs). Each of these endeavors has consumed nearly three decades of scientific effort, is still very much a work-in-progress, and has resulted in hundreds of publications. As a recipient of the Lifetime Achievement Award 2016 granted by the Oligonucleotide Therapeutic Society, in this note, my goal is to summarize the contributions of my group to the efforts to understand the molecular mechanisms of ASOs. PMID:28080221

  19. Molecular mechanisms underlying the Arabidopsis circadian clock.

    PubMed

    Nakamichi, Norihito

    2011-10-01

    A wide range of biological processes exhibit circadian rhythm, enabling plants to adapt to the environmental day-night cycle. This rhythm is generated by the so-called 'circadian clock'. Although a number of genetic approaches have identified >25 clock-associated genes involved in the Arabidopsis clock mechanism, the molecular functions of a large part of these genes are not known. Recent comprehensive studies have revealed the molecular functions of several key clock-associated proteins. This progress has provided mechanistic insights into how key clock-associated proteins are integrated, and may help in understanding the essence of the clock's molecular mechanisms.

  20. Molecular mechanisms of carcinogenesis

    SciTech Connect

    Hall, E.J.

    1997-03-01

    The possibility that chromosomal changes are responsible for neoplasia was proposed in the early years of this century. A combination of improved cytogenetics and the advent of recombinant technology has settled the issue. As recently as 20 years ago, however, the genetic and molecular basis of familiar predisposition to cancer were a mystery, and it is only in the last few years that light has been shed on a few specific types of malignancies. As the genetic basis of human cancer had been documented, a number of genes have been identified as functioning either as oncogenes which act in a dominant fashion to promote tumor growth when mutated, or as tumor suppressor genes which act in a recessive fashion.

  1. 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

  2. A Systems Biology Approach to Understanding Alcoholic Liver Disease Molecular Mechanism: The Development of Static and Dynamic Models.

    PubMed

    Shafaghati, Leila; Razaghi-Moghadam, Zahra; Mohammadnejad, Javad

    2017-08-28

    Alcoholic liver disease (ALD) is a complex disease characterized by damages to the liver and is the consequence of excessive alcohol consumption over years. Since this disease is associated with several pathway failures, pathway reconstruction and network analysis are likely to explicit the molecular basis of the disease. To this aim, in this paper, a network medicine approach was employed to integrate interactome (protein-protein interaction and signaling pathways) and transcriptome data to reconstruct both a static network of ALD and a dynamic model for it. Several data sources were exploited to assemble a set of ALD-associated genes which further was used for network reconstruction. Moreover, a comprehensive literature mining reveals that there are four signaling pathways with crosstalk (TLR4, NF- [Formula: see text]B, MAPK and Apoptosis) which play a major role in ALD. These four pathways were exploited to reconstruct a dynamic model of ALD. The results assure that these two models are consistent with a number of experimental observations. The static network of ALD and its dynamic model are the first models provided for ALD which offer potentially valuable information for researchers in this field.

  3. 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.

  4. A Systems Genetics Approach Identified GPD1L and its Molecular Mechanism for Obesity in Human Adipose Tissue.

    PubMed

    He, Hao; Sun, Dianjianyi; Zeng, Yong; Wang, Ruifeng; Zhu, Wei; Cao, Shaolong; Bray, George A; Chen, Wei; Shen, Hui; Sacks, Frank M; Qi, Lu; Deng, Hong-Wen

    2017-05-11

    To explore novel molecular mechanisms underlying obesity, we applied a systems genetics framework to integrate risk genetic loci from the largest body mass index (BMI) genome-wide association studies (GWAS) meta-analysis with mRNA and microRNA profiling in adipose tissue from 200 subjects. One module was identified to be most significantly associated with obesity and other metabolic traits. We identified eight hub genes which likely play important roles in obesity metabolism and identified microRNAs that significantly negatively correlated with hub genes. This module was preserved in other three test gene expression datasets, and all hub genes were consistently downregulated in obese subjects through the meta-analysis. Gene GPD1L had the highest connectivity and was identified a key causal regulator in the module. Gene GPD1L was significantly negatively correlated with the expression of miR-210, which was experimentally validated that miR-210 regulated GPD1L protein level through direct interaction with its mRNA three prime untranslated region (3'-UTR). GPD1L was found to be upregulated during weight loss and weight maintenance induced by low calorie diet (LCD), while downregulated during weight gain induced by high-fat diet (HFD). The results indicated that increased GPD1L in adipose tissue may have a significant therapeutic potential in reducing obesity and insulin resistance.

  5. 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.

  6. 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

  7. Potential Molecular Mechanism of Retrograde Aortic Arch Stenosis in the Hybrid Approach to Hypoplastic Left Heart Syndrome

    PubMed Central

    Hibino, Narutoshi; Cismowski, Mary J.; Lilly, Brenda J.; McConnell, Patrick I.; Shinoka, Toshiharu; Cheatham, John P.; Lucchesi, Pamela A.; Galantowicz, Mark E.; Trask, Aaron J.

    2015-01-01

    Background The hybrid palliation for hypoplastic left heart syndrome (HLHS) has emerged as an alternative approach to the Norwood procedure. The development of patent ductus arteriosus (PDA) in-stent stenosis can cause retrograde aortic arch stenosis (RAAS), leading to significant morbidity. This study aimed to identify potential mechanisms of PDA in-stent stenosis contributing to RAAS. METHODS Tissues from stented PDA were collected from 17 patients undergoing comprehensive stage 2 repair between 2009 and 2014. Patients requiring RAAS intervention based on cardiology–surgery consensus were defined as RAAS (+) (n=10), whereas patients without any RAAS intervention were defined as RAAS (−) (n=7). Tissues were examined by qPCR analysis for vascular smooth muscle cell (VSMC) differentiation and proliferation markers. RESULTS Patient characteristics were: HLHS with aortic atresia: 6; HLHS with aortic stenosis: 3; unbalanced AVC: 3; DILV/TGA: 3; DORV: 2. VSMC differentiation markers (β–actin, SM22, and calponin) and signaling pathways for VSMC modulation (TGFβ1, Notch, and PDGF-BB) were significantly higher in the RAAS (+) than in RAAS (−). The proliferation marker Ki67 was increased in RAAS (+). Cell cycle markers were comparable in both groups. CONCLUSION Increased VSMC differentiation and proliferation markers suggest a mechanism for inward neointima formation of the PDA in RAAS. The apparent lack of change in cell cycle markers is contrary to coronary artery in-stent stenosis, suggesting further targets should be examined. Combined primary in vitro PDA cell culture and proteomics can be strong tools to elucidate targets to reduce PDA in-stent stenosis for RAAS in the future. PMID:26163359

  8. Molecular Mechanisms of Neuronal Responsivity.

    DTIC Science & Technology

    1987-07-10

    O-A187 061 MOLECULAR MECHANISMS OF NEURONAL RESPONSIVITY(U) / VERMONT UNIV BURLINGTON COIL OF MEDICINE V EHRLICH 7 UwKL7RS1S1 IS1 JUL 87 RFOSR-TR-87...The grant was awarded to support the organization of a scientific conference entitled: "Molecular Mechanisms of Neuronal Responsivity." This...from the University of New York, on: "Synaptic Transmission and Neuronal Integration." It should be mentioned that this presentation emerged as a most

  9. New quantum mechanics-based three-dimensional molecular descriptors for use in QSSR approaches: application to asymmetric catalysis.

    PubMed

    Urbano-Cuadrado, Manuel; Carbó, Jorge J; Maldonado, Ana G; Bo, Carles

    2007-01-01

    This paper presents a new protocol based on 3D molecular descriptors using QM calculations for use in CoMFA-like 3D-QSSR. The new method was developed and then applied to predict catalytic selectivity in the asymmetric alkylation of aldehydes catalyzed by Zn-aminoalcohols. The molecular descriptors are obtained straightforwardly from the electronic charge density function, rho(r), and the molecular electrostatic potential (MEP) distributions. The chemically meaningful Molecular Shape Field (MSF) descriptor that accounts for the shape properties of the catalyst is defined from rho(r). Alignment independence was achieved by computing the product of the MSF and MEP values of pairs of points over a given distance range on a molecular isosurface and then selecting the product with the highest value. The new QSSR method demonstrated good predictive ability (q2 = 0.79) when full cross-validation procedures were carried out. Accurate predictions were made for a larger data set, although some deviations occurred in the predictions for catalytic systems with low enantiodiscrimination. Analysis of this QSSR model allows for the following: (1) evaluation of the contribution of each functional group to enantioselectivity and (2) the molecular descriptors to be related to previously proposed stereochemical models for the reaction under study.

  10. Understanding the adsorptive interactions of arsenate-iron nanoparticles with curved fullerene-like sheets in activated carbon using a quantum mechanics/molecular mechanics computational approach.

    PubMed

    Ha, Nguyen Ngoc; Cam, Le Minh; Ha, Nguyen Thi Thu; Goh, Bee-Min; Saunders, Martin; Jiang, Zhong-Tao; Altarawneh, Mohammednoor; Dlugogorski, Bogdan Z; El-Harbawi, Mohanad; Yin, Chun-Yang

    2017-06-07

    The prevalence of global arsenic groundwater contamination has driven widespread research on developing effective treatment systems including adsorption using various sorbents. The uptake of arsenic-based contaminants onto established sorbents such as activated carbon (AC) can be effectively enhanced via immobilization/impregnation of iron-based elements on the porous AC surface. Recent suggestions that AC pores structurally consist of an eclectic mix of curved fullerene-like sheets may affect the arsenic adsorption dynamics within the AC pores and is further complicated by the presence of nano-sized iron-based elements. We have therefore, attempted to shed light on the adsorptive interactions of arsenate-iron nanoparticles with curved fullerene-like sheets by using hybridized quantum mechanics/molecular mechanics (QMMM) calculations and microscopy characterization. It is found that, subsequent to optimization, chemisorption between HAsO4(2-) and the AC carbon sheet (endothermic process) is virtually non-existent - this observation is supported by experimental results. Conversely, the incorporation of iron nanoparticles (FeNPs) into the AC carbon sheet greatly facilitates chemisorption of HAsO4(2-). Our calculation implies that iron carbide is formed at the junction between the iron and the AC interface and this tightly chemosorbed layer prevents detachment of the FeNPs on the AC surface. Other aspects including electronic structure/properties, carbon arrangement defects and rate of adsorptive interaction, which are determined using the Climbing-Image NEB method, are also discussed.

  11. Molecular approach to ayurveda.

    PubMed

    Tripathi, Y B

    2000-05-01

    In ayurvedic system of medicine, it is considered that a living system is made of panch-mahabuta, in the form of Vata, pitta and kapha at the physical level and satwa, raja and tama at the mental level. This covers the psychosomatic constitution and commonly known as the Tridosh theory. The imbalance in these body humours is the basic cause of any type of disease manifestation. Till date, several objective parameters have been proposed to monitor the level of these basic humours but none of them is complete. In this exercise, now it is proposed to consider free radical theory of diseases as one of the objective parameters. To be more specific, vata can be monitored in terms of membrane bound signal transduction, pitta as the process of phosphorylation and de-phosphorylation of different proteins (signalling moieties and enzymes) and kapha can be viewed as the degree of gene expression as protein synthesis. This can be correlated with the ojas of the body or total body defence mechanism.

  12. Molecular Mechanism of Water Evaporation.

    PubMed

    Nagata, Yuki; Usui, Kota; Bonn, Mischa

    2015-12-04

    Evaporation is the process by which water changes from a liquid to a gas or vapor, and is a key step in Earth's water cycle. At the molecular level, evaporation requires breaking at least one very strong intermolecular bond between two water molecules at the interface. Despite the importance of this process the molecular mechanism by which an evaporating water molecule gains sufficient energy to escape from the surface has remained elusive. Here, we show, using molecular dynamics simulations at the water-air interface with polarizable classical force field models, that the high kinetic energy of the evaporated water molecule is enabled by a well-timed making and breaking of hydrogen bonds involving at least three water molecules at the interface, the recoil of which allows one of the molecules to escape. The evaporation of water is thus enabled by concerted, ultrafast hydrogen-bond dynamics of interfacial water, and follows one specific molecular pathway.

  13. Molecular Mechanism of Water Evaporation

    NASA Astrophysics Data System (ADS)

    Nagata, Yuki; Usui, Kota; Bonn, Mischa

    2015-12-01

    Evaporation is the process by which water changes from a liquid to a gas or vapor, and is a key step in Earth's water cycle. At the molecular level, evaporation requires breaking at least one very strong intermolecular bond between two water molecules at the interface. Despite the importance of this process the molecular mechanism by which an evaporating water molecule gains sufficient energy to escape from the surface has remained elusive. Here, we show, using molecular dynamics simulations at the water-air interface with polarizable classical force field models, that the high kinetic energy of the evaporated water molecule is enabled by a well-timed making and breaking of hydrogen bonds involving at least three water molecules at the interface, the recoil of which allows one of the molecules to escape. The evaporation of water is thus enabled by concerted, ultrafast hydrogen-bond dynamics of interfacial water, and follows one specific molecular pathway.

  14. [Molecular mechanisms of bone calcification].

    PubMed

    Hoshi, Kazuto; Ozawa, Hidehiro

    2003-04-01

    Bone matrix consists mainly of hydroxyapatite and organics. The latter include various substances which interact with minerals. Osteoblasts secrete these organic substances and control crystal formation and growth of hydroxyapatite. The authors discuss the molecular mechanisms of calcification by focusing on the mineral/organic interaction.

  15. Molecular mechanisms of neurite extension.

    PubMed Central

    Valtorta, F; Leoni, C

    1999-01-01

    The extension of neurites is a major task of developing neurons, requiring a significant metabolic effort to sustain the increase in molecular synthesis necessary for plasma membrane expansion. In addition, neurite extension involves changes in the subsets of expressed proteins and reorganization of the cytomatrix. These phenomena are driven by environmental cues which activate signal transduction processes as well as by the intrinsic genetic program of the cell. The present review summarizes some of the most recent progress made in the elucidation of the molecular mechanisms underlying these processes. PMID:10212488

  16. 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. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Anticancer compound plumbagin and its molecular targets: a structural insight into the inhibitory mechanisms using computational approaches.

    PubMed

    Jamal, Mohammad S; Parveen, Shadma; Beg, Mohd A; Suhail, Mohd; Chaudhary, Adeel G A; Damanhouri, Ghazi A; Abuzenadah, Adel M; Rehan, Mohd

    2014-01-01

    Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a naphthoquinone derivative from the roots of plant Plumbago zeylanica and belongs to one of the largest and diverse groups of plant metabolites. The anticancer and antiproliferative activities of plumbagin have been observed in animal models as well as in cell cultures. Plumbagin exerts inhibitory effects on multiple cancer-signaling proteins, however, the binding mode and the molecular interactions have not yet been elucidated for most of these protein targets. The present study is the first attempt to provide structural insights into the binding mode of plumbagin to five cancer signaling proteins viz. PI3Kγ, AKT1/PKBα, Bcl-2, NF-κB, and Stat3 using molecular docking and (un)binding simulation analysis. We validated plumbagin docking to these targets with previously known important residues. The study also identified and characterized various novel interacting residues of these targets which mediate the binding of plumbagin. Moreover, the exact modes of inhibition when multiple mode of inhibition existed was also shown. Results indicated that the engaging of these important interacting residues in plumbagin binding leads to inhibition of these cancer-signaling proteins which are key players in the pathogenesis of cancer and thereby ceases the progression of the disease.

  18. 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

  19. Molecular mechanisms of dendrite morphogenesis

    PubMed Central

    Arikkath, Jyothi

    2012-01-01

    Dendrites are key integrators of synaptic information in neurons and play vital roles in neuronal plasticity. Hence, it is necessary that dendrite arborization is precisely controlled and coordinated with synaptic activity to ensure appropriate functional neural network integrity. In the past several years, it has become increasingly clear that several cell intrinsic and extrinsic mechanisms contribute to dendritic arborization. In this review, we will discuss some of the molecular mechanisms that regulate dendrite morphogenesis, particularly in cortical and hippocampal pyramidal neurons and some of the implications of aberrant dendritic morphology for human disease. Finally, we will discuss the current challenges and future directions in the field. PMID:23293584

  20. In silico approach to explore the disruption in the molecular mechanism of human hyaluronidase 1 by mutant E268K that directs Natowicz syndrome.

    PubMed

    Meshach Paul, D; Rajasekaran, R

    2017-03-01

    Natowicz syndrome (mucopolysaccharidoses type 9) is a lysosomal storage disorder caused by deficient or defective human hyaluronidase 1. The disorder is not well studied at the molecular level. Therefore, a new in silico approach was proposed to study the molecular basis on which one clinically observed mutation, Glu268Lys, results in a defective enzyme. The native and mutant structures were subjected to comparative analyses using a conformational sampling approach for geometrical variables viz, RMSF, RMSD, and Ramachandran plot. In addition, the strength of a Cys207-Cys221 disulfide bond and electrostatic interaction between Arg265 and Asp206 were studied, as they are known to be involved in the catalytic activity of the enzyme. Native and mutant E268K showed statistically significant variations with p < 0.05 in RMSD, Ramachandran plot, strengths of disulfide bond, and electrostatic interactions. Further, single model analysis showed variations between native and mutant structures in terms of intra-protein interactions, hydrogen bond dilution, secondary structure, and dihedral angles. Docking analysis predicted the mutant to have a less favorable substrate binding energy compared to the native protein. Additionally, steered MD analysis indicated that the substrate should have more affinity to the native than mutant enzymes. The observed changes theoretically explain the less favorable binding energy of substrate towards mutant E268K, thereby providing a structural basis for its reduced catalytic activity. Hence, our study provides a basis for understanding the disruption in the molecular mechanism of human hyaluronidase 1 by mutation E268K, which may prove useful for the development of synthetic chaperones as a treatment option for Natowicz syndrome.

  1. 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

  2. Solvation Dynamics of CO₂(g) by Monoethanolamine at the Gas-Liquid Interface: A Molecular Mechanics Approach.

    PubMed

    Huang, I-Shou; Li, Jia-Jen; Tsai, Ming-Kang

    2016-12-23

    A classical force field approach was used to characterize the solvation dynamics of high-density CO₂(g) by monoethanolamine (MEA) at the air-liquid interface. Intra- and intermolecular CO₂ and MEA potentials were parameterized according to the energetics calculated at the MP2 and BLYP-D2 levels of theory. The thermodynamic properties of CO₂ and MEA, such as heat capacity and melting point, were consistently predicted using this classical potential. An approximate interfacial simulation for CO₂(g)/MEA(l) was performed to monitor the depletion of the CO₂(g) phase, which was influenced by amino and hydroxyl groups of MEA. There are more intramolecular hydrogen bond interactions notably identified in the interfacial simulation than the case of bulk MEA(l) simulation. The hydroxyl group of MEA was found to more actively approach CO₂ and overpower the amino group to interact with CO₂ at the air-liquid interface. With artificially reducing the dipole moment of the hydroxyl group, CO₂-amino group interaction was enhanced and suppressed CO₂(g) depletion. The hydroxyl group of MEA was concluded to play dual but contradictory roles for CO₂ capture.

  3. An integrated approach of bioassay and molecular docking to study the dihydroxylation mechanism of pyrene by naphthalene dioxygenase in Rhodococcus sp. ustb-1.

    PubMed

    Jin, Jing-Nan; Yao, Jun; Zhang, Qing-Ye; Yu, Chan; Chen, Peng; Liu, Wen-Juan; Peng, Dan-Ning; Choi, Martin M F

    2015-06-01

    Naphthalene dioxygenase (NDO) is the initial enzyme catalyzing the biodegradation of aromatic compounds, and it plays a key role in microbial remediation of polluting sites. In this study, Rhodococcus sp. ustb-1 derived from crude oil was selected to investigate the biodegradation characters and dihydroxylation mechanism of pyrene by an integrated approach of bioassay and molecular docking. The biodegradation experiment proved that the strain ustb-1 shows high effective biodegradability to pyrene with a 70.8% degradation on the 28th day and the metabolite pyrene cis-4,5-dihydrodiol was found. The results of molecular docking indicated that the regions surrounding pyrene are defined by hydrophobic amino acids which are favorable for the binding of dioxygen molecule at C4 and C5 positions of pyrene in a side-on mode. The binding positions of dioxygen are in agreement with the mass spectral analysis of the metabolite pyrene cis-4,5-dihydrodiol. In summary, this study provides a promising explanation for the possible binding behavior between pyrene and active site of NDO.

  4. Electronic excitation of Cl- in liquid water and at the surface of a cluster: a sequential Born-Oppenheimer molecular dynamics/quantum mechanics approach.

    PubMed

    Galamba, Nuno; Mata, Ricardo A; Cabral, Benedito J Costa

    2009-12-31

    A sequential molecular dynamics/quantum mechanics approach is applied to investigate the electronic excitation of Cl(-) in liquid water and in a water cluster. Time-dependent density functional theory (TDDFT) and equation-of-motion coupled-cluster with single and double excitations (EOM-CCSD) are used to calculate the excitation energies from Born-Oppenheimer molecular dynamics configurations. The selected configurations include a quantum system with the Cl(-) anion and a number of explicit water molecules (n(w)) as well as an embedding background defined by fractional point charges on the remaining water molecules. Our results indicate that for both the liquid and the cluster environments the excited electron is delocalized on the hydrogen atoms of the first hydration shell and in a nearby cavity. Convergence of the charge-transfer-to-solvent (CTTS) energy with the number of water molecules is observed for a quantum system embedded in the polarizing charge background for n(w) > or = 3. Furthermore, we find that the CTTS energy of Cl(-) in both solution and cluster environments is very similar. The predicted CTTS energy threshold for the ionic solution (approximately 6.6 +/- 0.3 eV) is in good agreement with experiment (6.8 and 7.1 eV).

  5. 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

  6. Molecular mechanisms of antibiotic resistance.

    PubMed

    Wright, Gerard D

    2011-04-14

    Over the past decade, resistance to antibiotics has emerged as a crisis of global proportion. Microbes resistant to many and even all clinically approved antibiotics are increasingly common and easily spread across continents. At the same time there are fewer new antibiotic drugs coming to market. We are reaching a point where we are no longer able to confidently treat a growing number of bacterial infections. The molecular mechanisms of drug resistance provide the essential knowledge on new drug development and clinical use. These mechanisms include enzyme catalyzed antibiotic modifications, bypass of antibiotic targets and active efflux of drugs from the cell. Understanding the chemical rationale and underpinnings of resistance is an essential component of our response to this clinical challenge.

  7. 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

  8. Anticancer Molecular Mechanisms of Resveratrol.

    PubMed

    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.

  9. Identifying Cellular and Molecular Mechanisms for Magnetosensation

    PubMed Central

    Clites, Benjamin L.; Pierce, Jonathan T.

    2017-01-01

    Diverse animals ranging from worms and insects to birds and turtles perf orm impressive journeys using the magnetic field of the earth as a cue. Although major cellular and molecular mechanisms for sensing mechanical and chemical cues have been elucidated over the past three decades, the mechanisms that animals use to sense magnetic fields remain largely mysterious. Here we survey progress on the search for magnetosensory neurons and magnetosensitive molecules important for animal behaviors. Emphasis is placed on magnetosensation in insects and birds, as well as on the magnetosensitive neuron pair AFD in the nematode Caenorhabditis elegans. We also review conventional criteria used to define animal magnetoreceptors and suggest how approaches used to identify receptors for other sensory modalities may be adapted for magnetoreceptors. Finally, we discuss prospects for under-utilized and novel approaches to identify the elusive magnetoreceptors in animals. PMID:28772099

  10. 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

  11. Molecular mechanisms of renal aging.

    PubMed

    Schmitt, Roland; Melk, Anette

    2017-09-01

    Epidemiologic, clinical, and molecular evidence suggest that aging is a major contributor to the increasing incidence of acute kidney injury and chronic kidney disease. The aging kidney undergoes complex changes that predispose to renal pathology. The underlying molecular mechanisms could be the target of therapeutic strategies in the future. Here, we summarize recent insight into cellular and molecular processes that have been shown to contribute to the renal aging phenotype.The main clinical finding of renal aging is the decrease in glomerular filtration rate, and its structural correlate is the loss of functioning nephrons. Mechanistically, this has been linked to different processes, such as podocyte hypertrophy, glomerulosclerosis, tubular atrophy, and gradual microvascular rarefaction. Renal functional recovery after an episode of acute kidney injury is significantly worse in elderly patients. This decreased regenerative potential, which is a hallmark of the aging process, may be caused by cellular senescence. Accumulation of senescent cells could explain insufficient repair and functional loss, a view that has been strengthened by recent studies showing that removal of senescent cells results in attenuation of renal aging. Other potential mechanisms are alterations in autophagy as an important component of a disturbed renal stress response and functional differences in the inflammatory system. Promising therapeutic measures to counteract these age-related problems include mimetics of caloric restriction, pharmacologic renin-angiotensin-aldosterone system inhibition, and novel strategies of senotherapy with the goal of reducing the number of senescent cells to decrease aging-related disease in the kidney. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  12. Molecular approaches to allergen standardization.

    PubMed

    Chapman, Martin D; Briza, Peter

    2012-10-01

    Molecular approaches to allergen standardization include the development of purified natural or recombinant allergen standards whose structural and allergenic properties have been validated, in tandem with certified immunoassays for allergen measurement. Purified allergens can be used individually or incorporated into multiple allergen standards. Multicenter international collaborative studies are required to validate candidate allergen standards and immunoassays, as a prelude to being approved by regulatory agencies. Mass spectrometry is a sophisticated and powerful proteomics tool that is being developed for allergen analysis. Recent results using pollen allergens show that mass spectrometry can identify and measure specific allergens in a complex mixture and can provide precise information of the variability of natural allergen extracts. In future, the combined use of immunoassays and mass spectrometry will provide complete standardization of allergenic products. Molecular standardization will form the basis of new allergy diagnostics and therapeutics, as well as assessment of environmental exposure, and will improve the quality of treatment options for allergic patients.

  13. 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.

  14. Molecular Mechanisms of Anthracycline Activity

    NASA Astrophysics Data System (ADS)

    Beretta, Giovanni Luca; Zunino, Franco

    On the basis of evidence that anthracyclines are DNA intercalating agents and DNA is the primary target, a large number of analogs and related intercalators have been developed. However, doxorubicin and closely related anthracyclines still remain among the most effective antitumor agents. Multiple mechanisms have been proposed to explain their efficacy. They include inhibition of DNA-dependent functions, free radical formation, and membrane interactions. The primary mechanism of action is now ascribed to drug interference with the function of DNA topoisomerase II. The stabilization of the topoisomerase-mediated cleavable complex results in a specific type of DNA damage (i.e., double-strand protein-associated DNA breaks). The drug-stabilized cleavable complex is a potentially reversible molecular event and its persistence, as a consequence of strong DNA binding, may be recognized as an apoptotic stimulus. Indirect evidence supports the notion that the bioreductive processes of the quinone moiety generating the semiquinone radical with concomitant production of reactive oxygen species may contribute to the drug effects. The cellular defense mechanisms and response to genotoxic/cytotoxic stress appear to be critical determinants of the tumor sensitivity to anthracyclines.

  15. Molecular mechanisms of maculopapular exanthema.

    PubMed

    Fernández, Tahia D; Canto, Gabriela; Blanca, Miguel

    2009-06-01

    Maculopapular exanthema is a common cutaneous manifestation of many diseases produced by several agents able to activate the immune system, the most common of which are drugs and viruses. In spite of its high frequency, knowledge of the molecular mechanisms involved remains scarce. The cytokine patterns in maculopapular exanthema have a Th1 or Th0 pattern, according to whether the reaction is induced by a drug or a virus, respectively. Additionally, the involvement of CD4 T-lymphocytes with cytotoxic capabilities has been shown in the former. Different chemokines and their receptors are also involved in skin homing, such as CCL20, CCL27, CXCL9 or CXCL10, and oxidative stress can help exacerbate the symptoms. These findings may be very important for the diagnostic evaluation of these entities and for the development of new tools for diagnosis and treatment.

  16. Molecular mechanisms of microglial activation.

    PubMed

    Zielasek, J; Hartung, H P

    1996-01-01

    Microglial cells are brain macrophages which serve specific functions in the defense of the central nervous system (CNS) against microorganisms, the removal of tissue debris in neurodegenerative diseases or during normal development, and in autoimmune inflammatory disorders of the brain. In cultured microglial cells, several soluble inflammatory mediators such as cytokines and bacterial products like lipopolysaccharide (LPS) were demonstrated to induce a wide range of microglial activities, e.g. increased phagocytosis, chemotaxis, secretion of cytokines, activation of the respiratory burst and induction of nitric oxide synthase. Since heightened microglial activation was shown to play a role in the pathogenesis of experimental inflammatory CNS disorders, understanding the molecular mechanisms of microglial activation may lead to new treatment strategies for neurodegenerative disorders, multiple sclerosis and bacterial or viral infections of the nervous system.

  17. Molecular mechanisms of cryptococcal meningitis.

    PubMed

    Liu, Tong-Bao; Perlin, David S; 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.

  18. Molecular mechanisms of RNA interference.

    PubMed

    Wilson, Ross C; Doudna, Jennifer A

    2013-01-01

    Small RNA molecules regulate eukaryotic gene expression during development and in response to stresses including viral infection. Specialized ribonucleases and RNA-binding proteins govern the production and action of small regulatory RNAs. After initial processing in the nucleus by Drosha, precursor microRNAs (pre-miRNAs) are transported to the cytoplasm, where Dicer cleavage generates mature microRNAs (miRNAs) and short interfering RNAs (siRNAs). These double-stranded products assemble with Argonaute proteins such that one strand is preferentially selected and used to guide sequence-specific silencing of complementary target mRNAs by endonucleolytic cleavage or translational repression. Molecular structures of Dicer and Argonaute proteins, and of RNA-bound complexes, have offered exciting insights into the mechanisms operating at the heart of RNA-silencing pathways.

  19. Cancer chemoprevention - selected molecular mechanisms.

    PubMed

    Walczak, Katarzyna; Marciniak, Sebastian; Rajtar, Grażyna

    2017-03-02

    The effect of diet on cancer formation and prevention of carcinogenesis has attracted considerable attention for years and is the subject of several studies. Some components of the daily diet, such as resveratrol, curcumin, genistein, gingerol, can significantly reduce the risk of cancer or affect the rate of tumor progression. Cancer chemoprevention assumes the use of natural or synthetic biologically active substances in order to prevent, inhibit or reverse the progression of cancer. There are many biologically active compounds in several natural products, i.e. garlic, ginger, soy, curcuma, tomatoes, cruciferous plants or green tea. Their chemopreventive activity is based on the inhibition of processes underlying carcinogenesis (inflammation, transformation and proliferation), but also affects the final phase of carcinogenesis - angiogenesis and metastasis. Despite the relatively low toxicity of chemopreventive agents, their molecular targets often coincide with the objectives of the currently used cancer therapies. The widespread use of chemopreventive agents may contribute to reduction of the rate of cancer incidence, and increase the effectiveness of conventional cancer therapies. In the present study, selected molecular mechanisms of the chemopreventive activity have been discussed, especially their involvement in the regulation of signal transduction, cell cycle regulation, apoptosis, metastasis and angiogenesis. The role of chemopreventive agents in the inflammatory process, the metabolism of xenobiotics and multidrug resistance has been also characterized.

  20. 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.

  1. 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

  2. Identification of disease comorbidity through hidden molecular mechanisms

    PubMed Central

    Ko, Younhee; Cho, Minah; Lee, Jin-Sung; Kim, Jaebum

    2016-01-01

    Despite multiple diseases co-occur, their underlying common molecular mechanisms remain elusive. Identification of comorbid diseases by considering the interactions between molecular components is a key to understand the underlying disease mechanisms. Here, we developed a novel approach utilizing both common disease-causing genes and underlying molecular pathways to identify comorbid diseases. Our approach enables the analysis of common pathologies shared by comorbid diseases through molecular interaction networks. We found that the integration of direct genetic sharing and indirect high-level molecular associations revealed significantly strong consistency with known comorbid diseases. In addition, neoplasm-related diseases showed high comorbidity patterns within themselves as well as with other diseases, indicating severe complications. This study demonstrated that molecular pathway information could be used to discover disease comorbidity and hidden biological mechanism to understand pathogenesis and provide new insight on disease pathology. PMID:27991583

  3. 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.

  4. [Molecular mechanisms of antibody synthesis].

    PubMed

    Bartram, C R; Kleihauer, E

    1984-10-01

    Antibodies or immunoglobulins play a central part in the immune system. The basic unit of an antibody is composed of two identical light and two identical heavy chains; each chain contains two functionally and structurally distinct regions: an amino-terminal variable or antigen-binding site, and a carboxy-terminal constant region responsible for immunological effector functions. Thanks to recombinant DNA technology the paradox of a limited number of genes and a virtually unlimited capacity to generate specific antibodies has now been resolved at least in outline. Immunoglobulin chains are encoded in multiple gene segments of three unlinked gene families scattered along chromosomes 2 (kappa light chain), 14 (heavy chain) and 22 (lambda light chain). During B-cell differentiation these genes are assembled by somatic recombination mechanisms to form active genes. The enormous diversity generated by means of DNA rearrangements is supplemented by mutations somatically introduced into variable region sequences. The medical impact of these discoveries will be substantial. Possible applications include identification of B-cell precursors lacking conventional markes, a molecular classification of lymphomas and a precise distinction between monoclonal and polyclonal lymphoproliferative disorders.

  5. 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

  6. Molecular mechanisms of drug addiction.

    PubMed

    Nestler, Eric J

    2004-01-01

    Regulation of gene expression is one mechanism by which drugs of abuse can induce relatively long-lasting changes in the brain to cause a state of addiction. Here, we focus on two transcription factors, CREB (cAMP response element binding protein) and DeltaFosB, which contribute to drug-induced changes in gene expression. Both are activated in the nucleus accumbens, a major brain reward region, but mediate different aspects of the addicted state. CREB mediates a form of tolerance and dependence, which dampens an individual's sensitivity to subsequent drug exposure and contributes to a negative emotional state during early phases of withdrawal. In contrast, DeltaFosB mediates a state of relatively prolonged sensitization to drug exposure and may contribute to the increased drive and motivation for drug, which is a core symptom of addictive disorders. A major goal of current research is to identify the many target genes through which CREB and DeltaFosB mediate these behavioral states. In addition, future work needs to understand how CREB and DeltaFosB, acting in concert with numerous other drug-induced molecular changes in nucleus accumbens and many other brain regions, interact with one another to produce the complex behavioral phenotype that defines addiction.

  7. Molecular approaches to fish vaccines

    USGS Publications Warehouse

    Winton, J.R.

    1998-01-01

    For more than 50 years, researchers have tested a variety of killed, attenuated, and subunit preparations for control offish diseases. The earliest fish vaccines used killed preparations containing whole bacteria, viruses, or parasites and today, several bacterins have become commercially successful with more expected as improved delivery systems and adjuvants are realized. Live, attenuated vaccines have been developed by serial passage of a pathogen in culture or by using naturally occurring mutants and cross-reacting strains. These generally offer excellent protection and are cost-effective, but concerns about residual virulence or their effects on other aquatic species make them difficult candidates for licensing. In recent years, the tools of molecular biology have been applied to construction of a variety of recombinant, engineered, or subunit vaccines for fish. Among the approaches to be discussed are: attenuated strains of viruses and bacteria created by deletion of specific genes associated with virulence, in vitro synthesis of protective antigens from genes cloned into E. coli or baculovirus expression systems, chemical synthesis of peptides that represent protective epitopes, and direct immunization with DNA coding for protective antigens. Preparations representing each of these approaches have been tested in laboratory or field trials with various results and such vaccines promise to be safe and relatively inexpensive if they are able to provide protection when delivered by immersion. A significant advantage of genetically engineered vaccines is the ability to construct multivalent preparations that can protect fish against several pathogens or different strains of the same pathogen. While many of these novel vaccine strategies have been effective at stimulating specific immunity in the laboratory, more work is needed to develop better delivery systems and to overcome potential regulatory concerns.

  8. Understanding the Molecular Mechanism of Interventions in Treating Rheumatoid Arthritis Patients with Corresponding Traditional Chinese Medicine Patterns Based on Bioinformatics Approach

    PubMed Central

    Jiang, Miao; Lu, Cheng; Chen, Gao; Xiao, Cheng; Zha, Qinglin; Niu, Xuyan; Chen, Shilin; Lu, Aiping

    2012-01-01

    Better effectiveness would be achieved when interventions are used in treating patients with a specific traditional Chinese medicine (TCM) pattern. In this paper, the effectiveness in treating rheumatoid arthritis (RA) patients in a randomized clinical trial as reanalyzed after the patients were classified into different TCM patterns and the underlying mechanism of how the TCM pattern influences the clinical effectiveness of interventions (TCM and biomedicine therapy) was explored. The pharmacological networks of interventions were builtup with protein and protein interaction analyses based on all the related targeted proteins obtained from PubChem. The underlying mechanism was explored by merging the pharmacological networks with the molecular networks of TCM cold and hot patterns in RA. The results show that the TCM therapy is better in treating the RA patients with TCM hot pattern, and the biomedical therapy is better in the RA patients with cold pattern. The pharmacological network of TCM intervention is merged well with the molecular network of TCM hot pattern, and the pharmacological network of biomedical therapy is merged well with the network of cold pattern. The finding indicates that molecular network analysis could give insight into the full understanding of the underlying mechanism of how TCM pattern impacts the efficacy. PMID:23118783

  9. Protein mechanics: how force regulates molecular function.

    PubMed

    Seifert, Christian; Gräter, Frauke

    2013-10-01

    Regulation of proteins is ubiquitous and vital for any organism. Protein activity can be altered chemically, by covalent modifications or non-covalent binding of co-factors. Mechanical forces are emerging as an additional way of regulating proteins, by inducing a conformational change or by partial unfolding. We review some advances in experimental and theoretical techniques to study protein allostery driven by mechanical forces, as opposed to the more conventional ligand driven allostery. In this respect, we discuss recent single molecule pulling experiments as they have substantially augmented our view on the protein allostery by mechanical signals in recent years. Finally, we present a computational analysis technique, Force Distribution Analysis, that we developed to reveal allosteric pathways in proteins. Any kind of external perturbation, being it ligand binding or mechanical stretching, can be viewed as an external force acting on the macromolecule, rendering force-based experimental or computational techniques, a very general approach to the mechanics involved in protein allostery. This unifying view might aid to decipher how complex allosteric protein machineries are regulated on the single molecular level. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Molecular mechanisms of synaptic plasticity and memory.

    PubMed

    Elgersma, Y; Silva, A J

    1999-04-01

    To unravel the molecular and cellular bases of learning and memory is one of the most ambitious goals of modern science. The progress of recent years has not only brought us closer to understanding the molecular mechanisms underlying stable, long-lasting changes in synaptic strength, but it has also provided further evidence that these mechanisms are required for memory formation.

  11. 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.

  12. Multiscale Quantum Mechanics/Molecular Mechanics Simulations with Neural Networks.

    PubMed

    Shen, Lin; Wu, Jingheng; Yang, Weitao

    2016-10-11

    Molecular dynamics simulation with multiscale quantum mechanics/molecular mechanics (QM/MM) methods is a very powerful tool for understanding the mechanism of chemical and biological processes in solution or enzymes. However, its computational cost can be too high for many biochemical systems because of the large number of ab initio QM calculations. Semiempirical QM/MM simulations have much higher efficiency. Its accuracy can be improved with a correction to reach the ab initio QM/MM level. The computational cost on the ab initio calculation for the correction determines the efficiency. In this paper we developed a neural network method for QM/MM calculation as an extension of the neural-network representation reported by Behler and Parrinello. With this approach, the potential energy of any configuration along the reaction path for a given QM/MM system can be predicted at the ab initio QM/MM level based on the semiempirical QM/MM simulations. We further applied this method to three reactions in water to calculate the free energy changes. The free-energy profile obtained from the semiempirical QM/MM simulation is corrected to the ab initio QM/MM level with the potential energies predicted with the constructed neural network. The results are in excellent accordance with the reference data that are obtained from the ab initio QM/MM molecular dynamics simulation or corrected with direct ab initio QM/MM potential energies. Compared with the correction using direct ab initio QM/MM potential energies, our method shows a speed-up of 1 or 2 orders of magnitude. It demonstrates that the neural network method combined with the semiempirical QM/MM calculation can be an efficient and reliable strategy for chemical reaction simulations.

  13. Molecular mechanisms of phase change in locusts.

    PubMed

    Wang, Xianhui; Kang, Le

    2014-01-01

    Phase change in locusts is an ideal model for studying the genetic architectures and regulatory mechanisms associated with phenotypic plasticity. The recent development of genomic and metabolomic tools and resources has furthered our understanding of the molecular basis of phase change in locusts. Thousands of phase-related genes and metabolites have been highlighted using large-scale expressed sequence tags, microarrays, high-throughput transcriptomic sequences, or metabolomic approaches. However, only several key factors, including genes, metabolites, and pathways, have a critical role in phase transition in locusts. For example, CSP (chemosensory protein) and takeout genes, the dopamine pathway, protein kinase A, and carnitines were found to be involved in the regulation of behavioral phase change and gram-negative bacteria-binding proteins in prophylaxical disease resistance of gregarious locusts. Epigenetic mechanisms including small noncoding RNAs and DNA methylation have been implicated. We review these new advances in the molecular basis of phase change in locusts and present some challenges that need to be addressed.

  14. Quantum mechanics/molecular mechanics dual Hamiltonian free energy perturbation.

    PubMed

    Polyak, Iakov; Benighaus, Tobias; Boulanger, Eliot; Thiel, Walter

    2013-08-14

    The dual Hamiltonian free energy perturbation (DH-FEP) method is designed for accurate and efficient evaluation of the free energy profile of chemical reactions in quantum mechanical/molecular mechanical (QM/MM) calculations. In contrast to existing QM/MM FEP variants, the QM region is not kept frozen during sampling, but all degrees of freedom except for the reaction coordinate are sampled. In the DH-FEP scheme, the sampling is done by semiempirical QM/MM molecular dynamics (MD), while the perturbation energy differences are evaluated from high-level QM/MM single-point calculations at regular intervals, skipping a pre-defined number of MD sampling steps. After validating our method using an analytic model potential with an exactly known solution, we report a QM/MM DH-FEP study of the enzymatic reaction catalyzed by chorismate mutase. We suggest guidelines for QM/MM DH-FEP calculations and default values for the required computational parameters. In the case of chorismate mutase, we apply the DH-FEP approach in combination with a single one-dimensional reaction coordinate and with a two-dimensional collective coordinate (two individual distances), with superior results for the latter choice.

  15. Quantum mechanics/molecular mechanics dual Hamiltonian free energy perturbation

    NASA Astrophysics Data System (ADS)

    Polyak, Iakov; Benighaus, Tobias; Boulanger, Eliot; Thiel, Walter

    2013-08-01

    The dual Hamiltonian free energy perturbation (DH-FEP) method is designed for accurate and efficient evaluation of the free energy profile of chemical reactions in quantum mechanical/molecular mechanical (QM/MM) calculations. In contrast to existing QM/MM FEP variants, the QM region is not kept frozen during sampling, but all degrees of freedom except for the reaction coordinate are sampled. In the DH-FEP scheme, the sampling is done by semiempirical QM/MM molecular dynamics (MD), while the perturbation energy differences are evaluated from high-level QM/MM single-point calculations at regular intervals, skipping a pre-defined number of MD sampling steps. After validating our method using an analytic model potential with an exactly known solution, we report a QM/MM DH-FEP study of the enzymatic reaction catalyzed by chorismate mutase. We suggest guidelines for QM/MM DH-FEP calculations and default values for the required computational parameters. In the case of chorismate mutase, we apply the DH-FEP approach in combination with a single one-dimensional reaction coordinate and with a two-dimensional collective coordinate (two individual distances), with superior results for the latter choice.

  16. Molecular mechanics of tropocollagen-hydroxyapatite biomaterials

    NASA Astrophysics Data System (ADS)

    Dubey, Devendra Kumar

    Hard biomaterials such as bone, dentin, and nacre show remarkable mechanical performance and serve as inspiration for development of next generation of composite materials with high strength and toughness. Such materials have primarily an organic phase (e.g. tropocollagen (TC) or chitin) and a mineral phase (e.g. hydroxyapatite (HAP) or aragonite) arranged in a staggered arrangement at nanoscopic length scales. Interfacial interactions between the organic phases and the mineral phases and structural effects arising due to the staggered and hierarchical arrangements are identified to be the two most important determinants for high mechanical performance of such biomaterials. Effects of these determinants in such biomaterials are further intertwined with factors such as loading configuration, chemical environment, mineral crystal shape, and residue sequences in polymer chains. Atomistic modeling is a desired approach to investigate such sub nanoscale issues as experimental techniques for investigations at such small scale are still in nascent stage. For this purpose, explicit three dimensional (3D) molecular dynamics (MD) and ab initio MD simulations of quasi-static mechanical deformations of idealized Tropocollagen-Hydroxyapatite (TC-HAP) biomaterials with distinct interfacial arrangements and different loading configurations are performed. Focus is on developing insights into the molecular level mechanics of TC-HAP biomaterials at fundamental lengthscale with emphasis on interface phenomenon. Idealized TC-HAP atomistic models are analyzed for their mechanical strength and fracture failure behavior from the viewpoint of interfacial interactions between TC and HAP and associated molecular mechanisms. In particular, study focuses on developing an understanding of factors such as role of interfacial structural arrangement, hierarchical structure design, influence of water, effect of changes in HAP crystal shape, and mutations in TC molecule on the mechanical strength

  17. Molecular Mechanisms of Nitroarene Degradation

    DTIC Science & Technology

    2002-09-17

    nitrobenzene with the concomitant formation of catechol . The analogous enzyme system in Pseudomonas JS42 oxidizes 2-nitrotoluene to 3-methylcatechol and...2NTDO) system from Pseudomonas JS42. The enzymes catalyzing the initial oxidations of nitrobenzene and 2-nitrotoluene belong to a family of...color and the native molecular weight (35,000) showed that the active enzyme was a monomer. The N-terminal sequence of the recombinant reductase was

  18. Molecular Mechanisms and Apoptosis in Pdt

    NASA Astrophysics Data System (ADS)

    Krammer, Barbara; Verwanger, Thomas

    2010-04-01

    Photodynamic Therapy (PDT) is a successful new therapy for malignant and non-malignant diseases. It is based on the activation of a photosensitizing dye by visible light in the target tissue, followed by production of cytotoxic substances. The article gives a short overview on the field of PDT with main focus on molecular mechanisms and apoptosis. It includes photodynamic principles, clinical application and procedures, biological effects, molecular mechanisms of damage processing and apoptosis.

  19. Mechanisms of Multiphoton Dissociation of Molecular Ions.

    DTIC Science & Technology

    1981-04-30

    dissociation energy and are thus re- Thus, some small fraction of all ions produced in our moved from the beam by unimolecular decomposition. source probably...AD-A099 121 SRI INTERNATIONAL MENLO PARK CA F/6 7/5 MECHANISMS OF MULTIPHOTON DISSOCIATION OF MOLECULAR IONS, U) APR 81 M J COGGIOLA. J R PETERSON, P...Final Report MECHANISMS OF MULTIPHOTON DISSOCIATION OF MOLECULAR IONS By: Michael J. Coggiola, Project Leader James R. Peterson, Project Supervisor

  20. Molecular mechanisms of antibiotic resistance.

    PubMed

    Blair, Jessica M A; Webber, Mark A; Baylay, Alison J; Ogbolu, David O; Piddock, Laura J V

    2015-01-01

    Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.

  1. 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.

  2. Molecular mechanisms of cancer pain.

    PubMed

    Mantyh, Patrick W; Clohisy, Denis R; Koltzenburg, Martin; Hunt, Steve P

    2002-03-01

    Pain is the most disruptive influence on the quality of life of cancer patients. Although significant advances are being made in cancer treatment and diagnosis, the basic neurobiology of cancer pain is poorly understood. New insights into these mechanisms are now arising from animal models, and have the potential to fundamentally change the way that cancer pain is controlled.

  3. 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.

  4. Cellular and molecular mechanisms in kidney fibrosis

    PubMed Central

    Duffield, Jeremy S.

    2014-01-01

    Fibrosis is a characteristic feature of all forms of chronic kidney disease. Deposition of pathological matrix in the interstitial space and within the walls of glomerular capillaries as well as the cellular processes resulting in this deposition are increasingly recognized as important factors amplifying kidney injury and accelerating nephron demise. Recent insights into the cellular and molecular mechanisms of fibrogenesis herald the promise of new therapies to slow kidney disease progression. This review focuses on new findings that enhance understanding of cellular and molecular mechanisms of fibrosis, the characteristics of myofibroblasts, their progenitors, and molecular pathways regulating both fibrogenesis and its resolution. PMID:24892703

  5. 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.

  6. 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

  7. Molecular mechanisms in neurologic disorders.

    PubMed

    Cunniff, C

    2001-09-01

    Although many pediatric neurologic disorders, such as epilepsy and mental retardation, are the result of a combination of genetic and environmental factors, many others are the result of mutations of single genes. Most of these single gene traits are inherited in autosomal dominant, autosomal recessive, or X-linked fashion. The diversity of mutations that are responsible for these diseases produces variability in phenotypic expression. However, there are other important features of many neurologic disorders that cannot be explained by standard models of mendelian inheritance. This review focuses on recently described mechanisms, such as genomic imprinting, germline mosaicism, mitochondrial inheritance, and triplet repeat expansion. The diagnostic evaluation, prognostic significance, and recurrence risk for specific neurogenetic disorders is correlated with these underlying disease mechanisms.

  8. 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.

  9. Molecular approach to echinoderm regeneration.

    PubMed

    Thorndyke, M C; Chen, W C; Beesley, P W; Patruno, M

    2001-12-15

    Until very recently echinoderm regeneration research and indeed echinoderm research in general has suffered because of the lack of critical mass. In terms of molecular studies of regeneration, echinoderms in particular have lagged behind other groups in this respect. This is in sharp contrast to the major advances achieved with molecular and genetic techniques in the study of embryonic development in echinoderms. The aim of our studies has been to identify genes involved in the process of regeneration and in particular neural regeneration in different echinoderm species. Our survey included the asteroid Asterias rubens and provided evidence for the expression of Hox gene homologues in regenerating radial nerve cords. Present evidence suggests: 1) ArHox1 expression is maintained in intact radial nerve cord and may be upregulated during regeneration. 2) ArHox1 expression may contribute to the dedifferentiation and/or cell proliferation process during epimorphic regeneration. From the crinoid Antedon bifida, we have been successful in cloning a fragment of a BMP2/4 homologue (AnBMP2/4) and analysing its expression during arm regeneration. Here, we discuss the importance of this family of growth factors in several regulatory spheres, including maintaining the identity of pluripotent blastemal cells or as a classic skeletal morphogenic regulator. There is clearly substantial scope for future echinoderm research in the area of molecular biology and certain aspects are discussed in this review.

  10. Molecular Approaches to Taenia asiatica

    PubMed Central

    Jeon, Hyeong-Kyu

    2013-01-01

    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

  11. 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. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Dictyostelium discoideum: Molecular approaches to cell biology

    SciTech Connect

    Spudich, J.A.

    1987-01-01

    The central point of this book is to present Dictyostelium as a valuable eukaryotic organism for those interested in molecular studies that require a combined biochemical, structural, and genetic approach. The book is not meant to be a comprehensive compilation of all methods involving Dictyostelium, but instead is a selective set of chapters that demonstrates the utility of the organism for molecular approaches to interesting cell biological problems.

  13. 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.

  14. Molecular mechanisms of appetite regulation.

    PubMed

    Yu, Ji Hee; Kim, Min-Seon

    2012-12-01

    The prevalence of obesity has been rapidly increasing worldwide over the last several decades and has become a major health problem in developed countries. The brain, especially the hypothalamus, plays a key role in the control of food intake by sensing metabolic signals from peripheral organs and modulating feeding behaviors. To accomplish these important roles, the hypothalamus communicates with other brain areas such as the brainstem and reward-related limbic pathways. The adipocyte-derived hormone leptin and pancreatic β-cell-derived insulin inform adiposity to the hypothalamus. Gut hormones such as cholecystokinin, peptide YY, pancreatic polypeptide, glucagon-like peptide 1, and oxyntomodulin transfer satiety signals to the brain and ghrelin relays hunger signals. The endocannabinoid system and nutrients are also involved in the physiological regulation of food intake. In this article, we briefly review physiological mechanisms of appetite regulation.

  15. Modelling approaches for evaluating multiscale tendon mechanics

    PubMed Central

    Fang, Fei; Lake, Spencer P.

    2016-01-01

    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. PMID:26855747

  16. Molecular mechanisms of Ebola pathogenesis.

    PubMed

    Rivera, Andrea; Messaoudi, Ilhem

    2016-11-01

    Ebola viruses (EBOVs) and Marburg viruses (MARVs) are among the deadliest human viruses, as highlighted by the recent and widespread Ebola virus outbreak in West Africa, which was the largest and longest epidemic of Ebola virus disease (EVD) in history, resulting in significant loss of life and disruptions across multiple continents. Although the number of cases has nearly reached its nadir, a recent cluster of 5 cases in Guinea on March 17, 2016, has extended the enhanced surveillance period to June 15, 2016. New, enhanced 90-d surveillance windows replaced the 42-d surveillance window to ensure the rapid detection of new cases that may arise from a missed transmission chain, reintroduction from an animal reservoir, or more important, reemergence of the virus that has persisted in an EVD survivor. In this review, we summarize our current understanding of EBOV pathogenesis, describe vaccine and therapeutic candidates in clinical trials, and discuss mechanisms of viral persistence and long-term health sequelae for EVD survivors. © Society for Leukocyte Biology.

  17. 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.

  18. Spiers Memorial Lecture. Molecular mechanics and molecular electronics.

    PubMed

    Beckman, Robert; Beverly, Kris; Boukai, Akram; Bunimovich, Yuri; Choi, Jang Wook; DeIonno, Erica; Green, Johnny; Johnston-Halperin, Ezekiel; Luo, Yi; Sheriff, Bonnie; Stoddart, Fraser; Heath, James R

    2006-01-01

    We describe our research into building integrated molecular electronics circuitry for a diverse set of functions, and with a focus on the fundamental scientific issues that surround this project. In particular, we discuss experiments aimed at understanding the function of bistable rotaxane molecular electronic switches by correlating the switching kinetics and ground state thermodynamic properties of those switches in various environments, ranging from the solution phase to a Langmuir monolayer of the switching molecules sandwiched between two electrodes. We discuss various devices, low bit-density memory circuits, and ultra-high density memory circuits that utilize the electrochemical switching characteristics of these molecules in conjunction with novel patterning methods. We also discuss interconnect schemes that are capable of bridging the micrometre to submicrometre length scales of conventional patterning approaches to the near-molecular length scales of the ultra-dense memory circuits. Finally, we discuss some of the challenges associated with fabricated ultra-dense molecular electronic integrated circuits.

  19. Molecular Approach to Hypothalamic Rhythms

    DTIC Science & Technology

    1998-06-24

    expressed predominanyly by cortical and hippocampal interneurons that affects the onset of slow-wave sleep. To learn about the cellular mechanisms of...partially overlap with those expressing somatostatin. A significant percentage of cortistatin-positive neurons is also positive for parvalbumin . In...the rat, mouse preprocortistatin mRNA is present in GABAergic interneurons in the cerebral cortex and hippocampus. The preprocortistatin gene

  20. Multiresolution molecular mechanics: Implementation and efficiency

    NASA Astrophysics Data System (ADS)

    Biyikli, Emre; To, Albert C.

    2017-01-01

    Atomistic/continuum coupling methods combine accurate atomistic methods and efficient continuum methods to simulate the behavior of highly ordered crystalline systems. Coupled methods utilize the advantages of both approaches to simulate systems at a lower computational cost, while retaining the accuracy associated with atomistic methods. Many concurrent atomistic/continuum coupling methods have been proposed in the past; however, their true computational efficiency has not been demonstrated. The present work presents an efficient implementation of a concurrent coupling method called the Multiresolution Molecular Mechanics (MMM) for serial, parallel, and adaptive analysis. First, we present the features of the software implemented along with the associated technologies. The scalability of the software implementation is demonstrated, and the competing effects of multiscale modeling and parallelization are discussed. Then, the algorithms contributing to the efficiency of the software are presented. These include algorithms for eliminating latent ghost atoms from calculations and measurement-based dynamic balancing of parallel workload. The efficiency improvements made by these algorithms are demonstrated by benchmark tests. The efficiency of the software is found to be on par with LAMMPS, a state-of-the-art Molecular Dynamics (MD) simulation code, when performing full atomistic simulations. Speed-up of the MMM method is shown to be directly proportional to the reduction of the number of the atoms visited in force computation. Finally, an adaptive MMM analysis on a nanoindentation problem, containing over a million atoms, is performed, yielding an improvement of 6.3-8.5 times in efficiency, over the full atomistic MD method. For the first time, the efficiency of a concurrent atomistic/continuum coupling method is comprehensively investigated and demonstrated.

  1. Multiresolution molecular mechanics: Implementation and efficiency

    SciTech Connect

    Biyikli, Emre; To, Albert C.

    2017-01-01

    Atomistic/continuum coupling methods combine accurate atomistic methods and efficient continuum methods to simulate the behavior of highly ordered crystalline systems. Coupled methods utilize the advantages of both approaches to simulate systems at a lower computational cost, while retaining the accuracy associated with atomistic methods. Many concurrent atomistic/continuum coupling methods have been proposed in the past; however, their true computational efficiency has not been demonstrated. The present work presents an efficient implementation of a concurrent coupling method called the Multiresolution Molecular Mechanics (MMM) for serial, parallel, and adaptive analysis. First, we present the features of the software implemented along with the associated technologies. The scalability of the software implementation is demonstrated, and the competing effects of multiscale modeling and parallelization are discussed. Then, the algorithms contributing to the efficiency of the software are presented. These include algorithms for eliminating latent ghost atoms from calculations and measurement-based dynamic balancing of parallel workload. The efficiency improvements made by these algorithms are demonstrated by benchmark tests. The efficiency of the software is found to be on par with LAMMPS, a state-of-the-art Molecular Dynamics (MD) simulation code, when performing full atomistic simulations. Speed-up of the MMM method is shown to be directly proportional to the reduction of the number of the atoms visited in force computation. Finally, an adaptive MMM analysis on a nanoindentation problem, containing over a million atoms, is performed, yielding an improvement of 6.3–8.5 times in efficiency, over the full atomistic MD method. For the first time, the efficiency of a concurrent atomistic/continuum coupling method is comprehensively investigated and demonstrated.

  2. Molecular approach of auditory neuropathy.

    PubMed

    Silva, Magali Aparecida Orate Menezes da; Piatto, Vânia Belintani; Maniglia, Jose Victor

    2015-01-01

    Mutations in the otoferlin gene are responsible for auditory neuropathy. To investigate the prevalence of mutations in the mutations in the otoferlin gene in patients with and without auditory neuropathy. This original cross-sectional case study evaluated 16 index cases with auditory neuropathy, 13 patients with sensorineural hearing loss, and 20 normal-hearing subjects. DNA was extracted from peripheral blood leukocytes, and the mutations in the otoferlin gene sites were amplified by polymerase chain reaction/restriction fragment length polymorphism. The 16 index cases included nine (56%) females and seven (44%) males. The 13 deaf patients comprised seven (54%) males and six (46%) females. Among the 20 normal-hearing subjects, 13 (65%) were males and seven were (35%) females. Thirteen (81%) index cases had wild-type genotype (AA) and three (19%) had the heterozygous AG genotype for IVS8-2A-G (intron 8) mutation. The 5473C-G (exon 44) mutation was found in a heterozygous state (CG) in seven (44%) index cases and nine (56%) had the wild-type allele (CC). Of these mutants, two (25%) were compound heterozygotes for the mutations found in intron 8 and exon 44. All patients with sensorineural hearing loss and normal-hearing individuals did not have mutations (100%). There are differences at the molecular level in patients with and without auditory neuropathy. Copyright © 2015 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  3. 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.

  4. Molecular mechanisms and regulation of iron transport.

    PubMed

    Chung, Jayong; Wessling-Resnick, Marianne

    2003-04-01

    Iron homeostasis is primarily maintained through regulation of its transport. This review summarizes recent discoveries in the field of iron transport that have shed light on the molecular mechanisms of dietary iron uptake, pathways for iron efflux to and between peripheral tissues, proteins implicated in organellar transport of iron (particularly the mitochondrion), and novel regulators that have been proposed to control iron assimilation. The transport of both transferrin-bound and nontransferrin-bound iron to peripheral tissues is discussed. Finally, the regulation of iron transport is also considered at the molecular level, with posttranscriptional, transcriptional, and posttranslational control mechanisms being reviewed.

  5. Cellular and molecular mechanisms of intestinal fibrosis

    PubMed Central

    Speca, Silvia; Giusti, Ilaria; Rieder, Florian; Latella, Giovanni

    2012-01-01

    Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelial- and endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic process, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches. PMID:22851857

  6. Modelling the molecular mechanisms of aging

    PubMed Central

    Mc Auley, Mark T.; Guimera, Alvaro Martinez; Hodgson, David; Mcdonald, Neil; Mooney, Kathleen M.; Morgan, Amy E.

    2017-01-01

    The aging process is driven at the cellular level by random molecular damage that slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the aging process. The complexity of the aging process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards and discusses many specific examples of models that have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field. PMID:28096317

  7. Pathogenesis and Molecular Mechanisms of Zika Virus.

    PubMed

    Nayak, Shriddha; Lei, Jun; Pekosz, Andrew; Klein, Sabra; Burd, Irina

    2016-09-01

    Zika virus (ZIKV) is one of the most important emerging viruses of 2016. A developing outbreak in the Americas has demonstrated an association between the virus and serious clinical manifestations, such as Guillain-Barré syndrome in adults and congenital malformations in infants born to infected mothers. Pathogenesis and mechanisms of neurologic or immune disease by ZIKV have not been clearly delineated. However, several pathways have been described to explain viral involvement in brain and immune system as well as other organ systems such as eye, skin, and male and female reproductive tracts. ZIKV activates toll-like receptor 3 and several pathways have been described to explain the mechanisms at a molecular level. The mechanism of microcephaly has been more difficult to demonstrate experimentally, likely due to the multifactorial and complex nature of the phenotype. This article provides an overview of existing literature on ZIKV pathogenicity and possible molecular mechanisms of disease as outlined to date.

  8. Modelling the molecular mechanisms of aging.

    PubMed

    Mc Auley, Mark T; Guimera, Alvaro Martinez; Hodgson, David; Mcdonald, Neil; Mooney, Kathleen M; Morgan, Amy E; Proctor, Carole J

    2017-02-28

    The aging process is driven at the cellular level by random molecular damage that slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the aging process. The complexity of the aging process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards and discusses many specific examples of models that have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field.

  9. 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.

  10. Molecular Proxy Approaches for Paleohydrology

    NASA Astrophysics Data System (ADS)

    Freeman, K. H.; Smith, F. A.; Polissar, P.; Turich, C. H.; Pedentchouk, N.

    2004-12-01

    There is a rich assembly of isotopic and mineral indicators for paleohydrologic properties of ancient environments. Commonly employed examples include mineral abundance ratios and the isotopic signatures of minerals and macromolecular organic phases such as cellulose. Preservation of these materials can be influenced strongly by natural processes in the environment, most notably resulting in the alteration or loss of carbonate mineral isotopic signatures. In order to expand our ability to document paleoclimatic conditions in continental environments, additional tools for both aquatic and terrestrial settings are in development based on the hydrogen isotopic signatures of individual lipids from microbes, algae and vascular plants. Plant leaf waxes (long-chain n-alkanes) preserve well in soils and aquatic sediments. Deuterium signatures in ancient leaf lipids potentially record isotopic properties of ancient plant water, reflecting isotopic signatures of rainfall and soil waters as well as the level of relative humidity. We have studied grasses, trees and other plant types from both greenhouse and field localities in order to understand the relative influences of plant physiology, physiognomy,and growth conditions (humidity) on lipids as recorders of plant water isotopic signatures. Submerged aquatic algae are not directly influenced by humidity, and recent work has shown their biomarkers to be promising paleolimnological proxies. We will discuss the potential for algal compounds as recorders of waters in modern high altitude sites and for ancient paleoaltimetry applications. Recent theoretical considerations in conjunction with analyses of lipids from ancient sediments point to the limitation of the preservation of paleohydrologic signatures set by thermal maturation approaching oil-generating conditions.

  11. 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

  12. Disease resistance: Molecular mechanisms and biotechnological applications

    USDA-ARS?s Scientific Manuscript database

    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 ...

  13. Mechanisms and economy of molecular machines

    NASA Astrophysics Data System (ADS)

    Klumpp, Stefan

    2012-11-01

    Cells contain millions of biomolecules that function as molecular machines. This paper reviews aspects of the mechanisms of these machines (alternative pathways and cooperativity) as well as the economic principles of their use in cells. The focus is on the machines that process the genetic information, in particular RNA polymerases.

  14. Mechanical transduction mechanisms of RecA-like molecular motors.

    PubMed

    Liao, Jung-Chi

    2011-12-01

    A majority of ATP-dependent molecular motors are RecA-like proteins, performing diverse functions in biology. These RecA-like molecular motors consist of a highly conserved core containing the ATP-binding site. Here I examined how ATP binding within this core is coupled to the conformational changes of different RecA-like molecular motors. Conserved hydrogen bond networks and conformational changes revealed two major mechanical transduction mechanisms: (1) intra-domain conformational changes and (2) inter-domain conformational changes. The intra-domain mechanism has a significant hydrogen bond rearrangement within the domain containing the P-loop, causing relative motion between two parts of the protein. The inter-domain mechanism exhibits little conformational change in the P-loop domain. Instead, the major conformational change is observed between the P-loop domain and an adjacent domain or subunit containing the arginine finger. These differences in the mechanical transduction mechanisms may link to the underlying energy surface governing a Brownian ratchet or a power stroke.

  15. Drug-Target Binding Investigated by Quantum Mechanical/Molecular Mechanical (QM/MM) Methods

    NASA Astrophysics Data System (ADS)

    Rothlisberger, U.; Carloni, P.

    Many important drugs, also used in the clinics, exert their function by binding covalently to their targets. Understanding their action requires quantum mechanical simulations. Here, after briefly reviewing few basic concepts of thermodynamics and kinetics of drug-target binding, we summarize principles and applications of Car-Parrinello quantum mechanics/molecular mechanics (QM/MM) simulations. From this discussion, this approach emerges as a computational methodology particularly well suited to investigate covalent binding in systems of pharmacological relevance.

  16. [Cellular and molecular mechanisms of memory].

    PubMed

    Laroche, Serge

    2010-01-01

    A defining characteristic of the brain is its remarkable capacity to undergo activity-dependent functional and morphological remodelling via mechanisms of plasticity that form the basis of our capacity to encode and retain memories. Today, it is generally accepted that one key neurobiological mechanism underlying the formation of memories reside in activity-driven modifications of synaptic strength and structural remodelling of neural networks activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation, a long-lasting activity-dependent form of synaptic strengthening, opened a new chapter in the study of the neurobiological substrate of memory in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular bases of learning and memory. To date, the key events in the cellular and molecular mechanisms underlying synaptic plasticity and memory formation are starting to be identified. They require the activation of specific receptors and of several molecular cascades to convert extracellular signals into persistent functional changes in neuronal connectivity. Accumulating evidence suggests that the rapid activation of neuronal gene programs is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. The recent developments in the search for the cellular and molecular mechanisms of memory storage are reviewed.

  17. [Neonatal hyperbilirubinemia and molecular mechanisms of jaundice].

    PubMed

    Jirsa, M; Sticová, E

    2013-07-01

    The introductory summarises the classical path of heme degradation and classification of jaundice. Subsequently, a description of neonatal types of jaundice is given, known as Crigler Najjar, Gilberts, DubinJohnson and Rotor syndromes, emphasising the explanation of the molecular mechanisms of these metabolic disorders. Special attention is given to a recently discovered molecular mechanism of the Rotor syndrome. The mechanism is based on the inability of the liver to retrospectively uptake the conjugated bilirubin fraction primarily excreted into the blood, not bile. A reduced ability of the liver to uptake the conjugated bilirubin contributes to the development of hyperbilirubinemia in common disorders of the liver and bile ducts and to the toxicity of xenobiotics and drugs using transport proteins for conjugated bilirubin.

  18. 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.

  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. 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.

  1. 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.

  2. 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

  3. Molecular Mechanisms of Inherited Demyelinating Neuropathies

    PubMed Central

    SCHERER, STEVEN S.; WRABETZ, LAWRENCE

    2008-01-01

    The past 15 years have witnessed the identification of more than 25 genes responsible for inherited neuropathies in humans, many associated with primary alterations of the myelin sheath. A remarkable body of work in patients, as well as animal and cellular models, has defined the clinical and molecular genetics of these illnesses and shed light on how mutations in associated genes produce the heterogeneity of dysmyelinating and demyelinating phenotypes. Here, we review selected recent developments from work on the molecular mechanisms of these disorders and their implications for treatment strategies. PMID:18803325

  4. Cellular and molecular mechanisms underlying muscular dystrophy

    PubMed Central

    2013-01-01

    The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes. PMID:23671309

  5. Molecular mechanisms and clinical applications of angiogenesis

    PubMed Central

    Carmeliet, Peter; Jain, Rakesh K.

    2014-01-01

    Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies. PMID:21593862

  6. Molecular mechanisms for proton transport in membranes.

    PubMed Central

    Nagle, J F; Morowitz, H J

    1978-01-01

    Likely mechanisms for proton transport through biomembranes are explored. The fundamental structural element is assumed to be continuous chains of hydrogen bonds formed from the protein side groups, and a molecular example is presented. From studies in ice, such chains are predicted to have low impedance and can function as proton wires. In addition, conformational changes in the protein may be linked to the proton conduction. If this possibility is allowed, a simple proton pump can be described that can be reversed into a molecular motor driven by an electrochemical potential across the membrane. PMID:272644

  7. Molecular Mechanisms of Neuroplasticity: An Expanding Universe.

    PubMed

    Gulyaeva, N V

    2017-03-01

    Biochemical processes in synapses and other neuronal compartments underlie neuroplasticity (functional and structural alterations in the brain enabling adaptation to the environment, learning, memory, as well as rehabilitation after brain injury). This basic molecular level of brain plasticity covers numerous specific proteins (enzymes, receptors, structural proteins, etc.) participating in many coordinated and interacting signal and metabolic processes, their modulation forming a molecular basis for brain plasticity. The articles in this issue are focused on different "hot points" in the research area of biochemical mechanisms supporting neuroplasticity.

  8. Molecular mechanics models for tetracycline analogs.

    PubMed

    Aleksandrov, Alexey; Simonson, Thomas

    2009-01-30

    Tetracyclines (Tcs) are an important family of antibiotics that bind to the ribosome and several proteins. To model Tc interactions with protein and RNA, we have developed a molecular mechanics force field for 12 tetracyclines, consistent with the CHARMM force field. We considered each Tc variant in its zwitterionic tautomer, with and without a bound Mg(2+). We used structures from the Cambridge Crystallographic Data Base to identify the conformations likely to be present in solution and in biomolecular complexes. A conformational search by simulated annealing was undertaken, using the MM3 force field, for tetracycline, anhydrotetracycline, doxycycline, and tigecycline. Resulting, low-energy structures were optimized with an ab initio method. We found that Tc and its analogs all adopt an extended conformation in the zwitterionic tautomer and a twisted one in the neutral tautomer, and the zwitterionic-extended state is the most stable in solution. Intermolecular force field parameters were derived from a standard supermolecule approach: we considered the ab initio energies and geometries of a water molecule interacting with each Tc analog at several different positions. The final, rms deviation between the ab initio and force field energies, averaged over all forms, was 0.35 kcal/mol. Intramolecular parameters were adopted from either the standard CHARMM force field, the ab initio structure, or the earlier, plain Tc force field. The model reproduces the ab initio geometry and flexibility of each Tc. As tests, we describe MD and free energy simulations of a solvated complex between three Tcs and the Tet repressor protein. (c) 2008 Wiley Periodicals, Inc.

  9. The molecular mechanism of plant gravitropism.

    PubMed

    Di, Wu; Linzhou, Huang; Jin, Gao; Yonghong, Wang

    2016-07-20

    Gravity is an important environmental factor that regulates plant growth and morphogenesis. In response to gravity stimulus, plants can set the optimum angle between the organs and the gravity vector. Plant gravitropism is divided into four sequential steps, including gravity perception, signal transduction, asymmetrical distribution of auxin, and organ curvature. In recent years, large numbers of mutants with defective gravitropism have been identified and genes involved in the regulation of gravitropism have been functionally characterized. In particular, progress has been achieved on elucidating the molecular mechanisms of gravity perception and asymmetrical distribution of auxin. As one of the most important strategies for plant to adapt environmental changes, gravitropism is also involved in the regulation of rice plant architecture and grain yield through modulating rice tiller angle. Therefore, the investigation of plant gravitropism not only contributes to decipher the regulatory mechanisms of plant growth and development, but also helps to guide the genetic improvement of crop architecture. However, the molecular mechanisms and regulatory network of gravitropism remain to be elusive. In this review, we focus on recent progress on elucidating molecular mechanisms underlying gravitropism and its involvement in regulating rice tiller angle, which is an important agronomic trait that determines rice plant architecture and thus grain yields.

  10. 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.

  11. Molecular genetic approaches to understanding the comorbidity of psychiatric disorders

    PubMed Central

    Gizer, Ian R.

    2016-01-01

    Epidemiologic studies demonstrating high rates of co-occurrence among psychiatric disorders at the population level have contributed to large literatures focused on identifying the causal mechanisms underlying the patterns of co-occurrence among these disorders. Such efforts have long represented a core focus of developmental psychopathologists and have more recently been supported by the Research Domain Criteria (RDoC) initiative developed by the National Institute of Mental Health (NIMH), which provides a further framework for how the hypothesized mechanisms can be studied at different levels of analysis. The present overview focuses on molecular genetic approaches that are being used currently to study the etiology of psychiatric disorders, and how these approaches have been applied in efforts to understand the biological mechanisms that give rise to comorbid conditions. The present report begins with a review of molecular genetic approaches used to identify individual variants that confer risk for multiple disorders and the intervening biological mechanisms that contribute to their comorbidity. This is followed by a review of molecular genetic approaches that use genetic data in aggregate to examine these questions, and concludes with a discussion of how developmental psychopathologists are uniquely positioned to apply these methods in a way that will further our understanding of the causal factors that contribute to the development of comorbid conditions. PMID:27739393

  12. Molecular approaches for safer and stronger vaccines.

    PubMed

    Del Giudice, G; Rappuoli, R

    1999-11-20

    Progress in molecular biology and biotechnology is making possible the development of new vaccines or the improvement of already existing ones. Recombinant DNA technology, genetic attenuation of bacterial and viral pathogens and their use as vectors for heterologous proteins, expression of microbial antigens in transgenic edible plants, and naked nucleic acid technology represent the most popular approaches hitherto adopted. A successful biotechnological approach to the development of new and improved vaccines has been based on genetic detoxification of bacterial toxins, such as the toxin of Bordetella pertussis, the heat-labile enterotoxin of Escherichia coli, and the toxin of Vibrio cholerae. Genetically detoxified Bordetella pertussis is now included in a commercially available acellular vaccine against pertussis. Genetically detoxified Escherichia coli and Vibrio cholerae have been shown to behave as very strong and safe mucosal adjuvants and are now entering the clinical stage. These results demonstrate that a rational molecular approach to the development of safer and stronger vaccines is feasible.

  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 mechanisms of UV-induced apoptosis.

    PubMed

    Kulms, D; Schwarz, T

    2000-10-01

    Sunburn cells, single standing cells with typical morphologic features occurring in UV-exposed skin, have been recognized as keratinocytes undergoing apoptosis following UV irradiation. Induction of apoptosis following UV exposure appears to be a protective mechanism, getting rid off severely damaged cells that bear the risk of malignant transformation. UV-mediated apoptosis is a highly complex process in which different molecular pathways are involved. These include DNA damage, activation of the tumor suppressor gene p53, triggering of cell death receptors either directly by UV or by autocrine release of death ligands, mitochondrial damage and cytochrome C release. Detailed knowledge about the interplay between these pathways will increase our understanding of photocarcinogenesis. This review briefly discusses recent findings concerning the molecular mechanisms underlying UV-induced apoptosis.

  15. 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

  16. 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

    2010-03-09

    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.

  17. 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.

  18. 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.

  19. 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.

  20. Polymer Fluid Dynamics: Continuum and Molecular Approaches.

    PubMed

    Bird, R B; Giacomin, A J

    2016-06-07

    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.

  1. 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.

  2. Cellular and Molecular Mechanisms of Pain

    PubMed Central

    Basbaum, Allan I.; Bautista, Diana M.; Scherrer, Grégory; Julius, David

    2009-01-01

    The nervous system detects and interprets a wide range of thermal and mechanical stimuli as well as environmental and endogenous chemical irritants. When intense, these stimuli generate acute pain, and in the setting of persistent injury, both peripheral and central nervous system components of the pain transmission pathway exhibit tremendous plasticity, enhancing pain signals and producing hypersensitivity. When plasticity facilitates protective reflexes, it can be beneficial, but when the changes persist, a chronic pain condition may result. Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain. PMID:19837031

  3. 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

  4. Molecular Mechanisms of Right Ventricular Failure

    PubMed Central

    Reddy, Sushma; Bernstein, Daniel

    2015-01-01

    An abundance of data has provided insight into the mechanisms underlying the development of left ventricular (LV) hypertrophy and its progression to LV failure. In contrast, there is minimal data on the adaptation of the right ventricle (RV) to pressure and volume overload and the transition to RV failure. This is a critical clinical question, as the RV is uniquely at risk in many patients with repaired or palliated congenital heart disease and in those with pulmonary hypertension. Standard heart failure therapies have failed to improve function or survival in these patients, suggesting a divergence in the molecular mechanisms of RV vs. LV failure. Although, on the cellular level, the remodeling responses of the RV and LV to pressure overload are largely similar, there are several key differences: the stressed RV is more susceptible to oxidative stress, has a reduced angiogenic response, and is more likely to activate cell death pathways than the stressed LV. Together, these differences could explain the more rapid progression of the RV to failure vs. the LV. This review will highlight known molecular differences between the RV and LV responses to hemodynamic stress, the unique stressors on the RV associated with congenital heart disease, and the need to better understand these molecular mechanisms if we are to develop RV-specific heart failure therapeutics. PMID:26527692

  5. [Cellular and molecular mechanisms of memory].

    PubMed

    Laroche, S

    2001-01-01

    There has been nearly a century of interest in the idea that information is encoded in the brain as specific spatio-temporal patterns of activity in distributed networks and stored as changes in the efficacy of synaptic connections on neurons that are activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation opened a new chapter in the study of synaptic plasticity in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular bases of learning and memory. To date, the key events in the cellular and molecular mechanisms underlying synaptic plasticity are starting to be identified. They require the activation of specific receptors and of several molecular cascades to convert extracellular signals into persistent functional changes in neuronal connectivity. Accumulating evidence suggests that the rapid activation of the genetic machinery is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. The recent developments in the search for the cellular and molecular mechanisms of memory storage are reviewed.

  6. 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.

  7. Molecular mechanics methods for individual carbon nanotubes and nanotube assemblies

    NASA Astrophysics Data System (ADS)

    Eberhardt, Oliver; Wallmersperger, Thomas

    2015-04-01

    Since many years, carbon nanotubes (CNTs) have been considered for a wide range of applications due to their outstanding mechanical properties. CNTs are tubular structures, showing a graphene like hexagonal lattice. Our interest in the calculation of the mechanical properties is motivated by several applications which demand the knowledge of the material behavior. One application in which the knowledge of the material behavior is vital is the CNT based fiber. Due to the excellent stiffness and strength of the individual CNTs, these fibers are expected to be a promising successor for state of the art carbon fibers. However, the mechanical properties of the fibers fall back behind the properties of individual CNTs. It is assumed that this gap in the properties is a result of the van-der-Waals interactions of the individual CNTs within the fiber. In order to understand the mechanical behavior of the fibers we apply a molecular mechanics approach. The mechanical properties of the individual CNTs are investigated by using a modified structural molecular mechanics approach. This is done by calculating the properties of a truss-beam element framework representing the CNT with the help of a chemical force field. Furthermore, we also investigate the interactions of CNTs arranged in basic CNT assemblies, mimicking the ones in a simple CNT fiber. We consider the van-der-Waals interactions in the structure and calculate the potential surface of the CNT assemblies.

  8. Molecular and structural determinants of adamantyl susceptibility to HLA-DRs allelic variants: an in silico approach to understand the mechanism of MLEs

    NASA Astrophysics Data System (ADS)

    Zaheer-ul-Haq; Khan, Waqasuddin

    2011-01-01

    Class II major histocompatibility complex (MHC II) molecules as expressed by antigen-presenting cells are heterodimeric cell-surface glycoprotein receptors that are fundamental in initiating and propagating an immune response by presenting tumor-associated antigenic peptides to CD4+/TH cells. The loading efficiency of such peptides can be improved by small organic compounds (MHC Loading Enhancers—MLEs), that convert the non-receptive peptide conformation of MHC II to a peptide-receptive conformation. In a reversible reaction, these compounds open up the binding site of MHC II molecules by specific interactions with a yet undefined pocket. Here, we performed molecular docking and molecular dynamics simulation studies of adamantyl compounds on the predicted cavity around the P1 pocket of 2 allelic variants of HLA-DRs. The purpose was to investigate the suitability of adamantyl compounds as MLEs at the dimorphic β86 position. Docking studies revealed that besides numerous molecular interactions formed by the adamantyl compounds, Asnβ82, Tyrβ83, and Thrβ90 are the crucial amino acid residues that are characterized as the "sensors" of peptide loading. Molecular dynamics simulation studies exposed the dynamical structural changes that HLA-DRs adopted as a response to binding of 3-(1-adamantyl)-5-hydrazidocarbonyl-1H-pyrazole (AdCaPy). The conformations of AdCaPy complexed with the Glyβ86 HLA-DR allelic variant are well correlated with the stabilized form of peptide-loaded HLA-DRs, further confirming the role of AdCaPy as a MLE. Hydrogen bonding interaction analysis clearly demonstrated that after making suitable contacts with AdCaPy, HLA-DR changes its local conformation. However, AdCaPy complexed with HLA-DR having Valβ86 at the dimorphic position did not accommodate AdCaPy as MLE due to steric hindrance caused by the valine.

  9. 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.

  10. 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.

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

    NASA Astrophysics Data System (ADS)

    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.

  12. Molecular mechanisms for protein-encoded inheritance.

    PubMed

    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

    2009-09-01

    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.

  13. 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

  14. 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.

  15. Molecular model with quantum mechanical bonding information.

    PubMed

    Bohórquez, Hugo J; Boyd, Russell J; Matta, Chérif F

    2011-11-17

    The molecular structure can be defined quantum mechanically thanks to the theory of atoms in molecules. Here, we report a new molecular model that reflects quantum mechanical properties of the chemical bonds. This graphical representation of molecules is based on the topology of the electron density at the critical points. The eigenvalues of the Hessian are used for depicting the critical points three-dimensionally. The bond path linking two atoms has a thickness that is proportional to the electron density at the bond critical point. The nuclei are represented according to the experimentally determined atomic radii. The resulting molecular structures are similar to the traditional ball and stick ones, with the difference that in this model each object included in the plot provides topological information about the atoms and bonding interactions. As a result, the character and intensity of any given interatomic interaction can be identified by visual inspection, including the noncovalent ones. Because similar bonding interactions have similar plots, this tool permits the visualization of chemical bond transferability, revealing the presence of functional groups in large molecules.

  16. Molecular Mechanisms of Prolactin and Its Receptor

    PubMed Central

    2012-01-01

    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. PMID:22577091

  17. 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.

  18. Molecular mechanics conformational analysis of tylosin

    NASA Astrophysics Data System (ADS)

    Ivanov, Petko M.

    1998-01-01

    The conformations of the 16-membered macrolide antibiotic tylosin were studied with molecular mechanics (AMBER∗ force field) including modelling of the effect of the solvent on the conformational preferences (GB/SA). A Monte Carlo conformational search procedure was used for finding the most probable low-energy conformations. The present study provides complementary data to recently reported analysis of the conformations of tylosin based on NMR techniques. A search for the low-energy conformations of protynolide, a 16-membered lactone containing the same aglycone as tylosin, was also carried out, and the results were compared with the observed conformation in the crystal as well as with the most probable conformations of the macrocyclic ring of tylosin. The dependence of the results on force field was also studied by utilizing the MM3 force field. Some particular conformations were computed with the semiempirical molecular orbital methods AM1 and PM3.

  19. 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.

  20. Measuring the mechanical properties of molecular conformers.

    PubMed

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

    2015-09-21

    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.

  1. Molecular Mechanisms Involved in Schwann Cell Plasticity

    PubMed Central

    Boerboom, Angélique; Dion, Valérie; Chariot, Alain; Franzen, Rachelle

    2017-01-01

    Schwann cell incredible plasticity is a hallmark of the utmost importance following nerve damage or in demyelinating neuropathies. After injury, Schwann cells undergo dedifferentiation before redifferentiating to promote nerve regeneration and complete functional recovery. This review updates and discusses the molecular mechanisms involved in the negative regulation of myelination as well as in the reprogramming of Schwann cells taking place early following nerve lesion to support repair. Significant advance has been made on signaling pathways and molecular components that regulate SC regenerative properties. These include for instance transcriptional regulators such as c-Jun or Notch, the MAPK and the Nrg1/ErbB2/3 pathways. This comprehensive overview ends with some therapeutical applications targeting factors that control Schwann cell plasticity and highlights the need to carefully modulate and balance this capacity to drive nerve repair. PMID:28261057

  2. [Molecular mechanism of idiopathic basal ganglia calcification].

    PubMed

    Wang, Cheng; Xu, Xuan; Li, Lulu; Wang, Tao; Zhang, Min; Shen, Lu; Tang, Beisha; Liu, Jingyu

    2015-08-01

    Idiopathic basal ganglia calcification (IBGC), also known as Fahr’s disease, is an inheritable neurodegenerative syndrome characterized by mineral deposits in the basal ganglia and other brain regions. Patients with IBGC are often accompanied with movement disorders, cognitive impairment as well as psychiatric abnormalities. So far, no therapeutic drug has been developed for the treatment of IBGC. Recently, genetic studies have identified several genes associated with IBGC, including SLC20A2, PDGFRB, PDGFB, ISG15 and XPR1. Loss-of-function mutations in these genes have been associated with disturbance in phosphate homeostasis in brain regions, the dysfunction of blood-brain barrier as well as enhanced IFN-α/β immunity. In this review, we summarize the latest research progress in the studies on molecular genetics of IBGC, and discuss the molecular mechanisms underlying the pathophysiology of mutations of different genes.

  3. Molecular mechanism of Endosulfan action in mammals.

    PubMed

    Sebastian, Robin; Raghavan, Sathees C

    2017-03-01

    Endosulfan is a broad-spectrum organochlorine pesticide, speculated to be detrimental to human health in areas of active exposure. However, the molecular insights to its mechanism of action remain poorly understood. In two recent studies, our group investigated the physiological and molecular aspects of endosulfan action using in vitro, ex vivo and in vivo analyses. The results showed that apart from reducing fertility levels in male animals, Endosulfan induced DNA damage that triggers compromised DNA damage response leading to undesirable processing of broken DNA ends. In this review, pesticide use especially of Endosulfan in the Indian scenario is summarized and the importance of our findings, especially the rationalized use of pesticides in the future, is emphasized.

  4. Modeling molecular mechanisms in the axon

    NASA Astrophysics Data System (ADS)

    de Rooij, R.; Miller, K. E.; Kuhl, E.

    2017-03-01

    Axons are living systems that display highly dynamic changes in stiffness, viscosity, and internal stress. However, the mechanistic origin of these phenomenological properties remains elusive. Here we establish a computational mechanics model that interprets cellular-level characteristics as emergent properties from molecular-level events. We create an axon model of discrete microtubules, which are connected to neighboring microtubules via discrete crosslinking mechanisms that obey a set of simple rules. We explore two types of mechanisms: passive and active crosslinking. Our passive and active simulations suggest that the stiffness and viscosity of the axon increase linearly with the crosslink density, and that both are highly sensitive to the crosslink detachment and reattachment times. Our model explains how active crosslinking with dynein motors generates internal stresses and actively drives axon elongation. We anticipate that our model will allow us to probe a wide variety of molecular phenomena—both in isolation and in interaction—to explore emergent cellular-level features under physiological and pathological conditions.

  5. Modeling molecular mechanisms in the axon

    NASA Astrophysics Data System (ADS)

    de Rooij, R.; Miller, K. E.; Kuhl, E.

    2016-12-01

    Axons are living systems that display highly dynamic changes in stiffness, viscosity, and internal stress. However, the mechanistic origin of these phenomenological properties remains elusive. Here we establish a computational mechanics model that interprets cellular-level characteristics as emergent properties from molecular-level events. We create an axon model of discrete microtubules, which are connected to neighboring microtubules via discrete crosslinking mechanisms that obey a set of simple rules. We explore two types of mechanisms: passive and active crosslinking. Our passive and active simulations suggest that the stiffness and viscosity of the axon increase linearly with the crosslink density, and that both are highly sensitive to the crosslink detachment and reattachment times. Our model explains how active crosslinking with dynein motors generates internal stresses and actively drives axon elongation. We anticipate that our model will allow us to probe a wide variety of molecular phenomena—both in isolation and in interaction—to explore emergent cellular-level features under physiological and pathological conditions.

  6. 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

  7. Pitfall in quantum mechanical/molecular mechanical molecular dynamics simulation of small solutes in solution.

    PubMed

    Hu, Hao; Liu, Haiyan

    2013-05-30

    Developments in computing hardware and algorithms have made direct molecular dynamics simulation with the combined quantum mechanical/molecular mechanical methods affordable for small solute molecules in solution, in which much improved accuracy can be obtained via the quantum mechanical treatment of the solute molecule and even sometimes water molecules in the first solvation shell. However, unlike the conventional molecular mechanical simulations of large molecules, e.g., proteins, in solutions, special care must be taken in the technical details of the simulation, including the thermostat of the solute/solvent system, so that the conformational space of the solute molecules can be properly sampled. We show here that the common setup for classical molecular mechanical molecular dynamics simulations, such as the Berendsen or single Nose-Hoover thermostat, and/or rigid water models could lead to pathological sampling of the solutes' conformation. In the extreme example of a methanol molecule in aqueous solution, improper and sluggish setups could generate two peaks in the distribution of the O-H bond length. We discuss the factors responsible for this somewhat unexpected result and evoke a simple and ancient technical fix-up to resolve this problem.

  8. Molecular mechanisms of metal hyperaccumulation in plants.

    PubMed

    Verbruggen, Nathalie; Hermans, Christian; Schat, Henk

    2009-03-01

    Metal hyperaccumulator plants accumulate and detoxify extraordinarily high concentrations of metal ions in their shoots. Metal hyperaccumulation is a fascinating phenomenon, which has interested scientists for over a century. Hyperaccumulators constitute an exceptional biological material for understanding mechanisms regulating plant metal homeostasis as well as plant adaptation to extreme metallic environments.Our understanding of metal hyperaccumulation physiology has recently increased as a result of the development of molecular tools. This review presents key aspects of our current understanding of plant metal – in particular cadmium (Cd),nickel (Ni) and zinc (Zn) – hyperaccumulation.

  9. Quantum Mechanical Studies of Molecular Hyperpolarizabilities.

    DTIC Science & Technology

    1980-04-30

    exponent , reflects the screening of an electron in a given orbital by the interior electrons in the atom or molecule. In practice, when studying...Basis sets have evolved over the years in molecular quantum mechanics until sets of orbital exponents for the different atoms composing the molecule have...and R. P. Hurst , J. Chem. Phys. 46, 2356 (1967); S. P. LickmannI and J. W. Moskowitz, J. Chem. Phys. 54, 3622 7T971). 26. T. H. Dunning, J. Chem. Phys

  10. 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

  11. Molecular mechanisms of head and neck cancer.

    PubMed

    Deshpande, Amit M; Wong, David T

    2008-05-01

    Despite advances in understanding the underlying genetics, squamous cell carcinoma of the head and neck (SCCHN) remains a major health risk and one of the leading causes of mortality in the world. Current standards of treatment have significantly improved long-term survival rates of patients, but second tumors and metastases still remain the most frequent cause of high mortality in SCCHN patients. A better understanding of the underlying genetic mechanisms of SCCHN tumorigenesis will help in developing better diagnostics and, hence, better cures. In this article we will briefly outline the current state of diagnostics and treatment and our understanding of the molecular causes of SCCHN.

  12. Molecular mechanisms of astrocyte-induced synaptogenesis.

    PubMed

    Baldwin, Katherine T; Eroglu, Cagla

    2017-08-01

    Astrocytes are morphologically complex cells that perform a wide variety of critical functions in the brain. As a structurally and functionally integrated component of the synapse, astrocytes secrete proteins, lipids, and small molecules that bind neuronal receptors to promote synaptogenesis and regulate synaptic connectivity. Additionally, astrocytes are key players in circuit formation, instructing the formation of synapses between distinct classes of neurons. This review highlights recent publications on the topic of astrocyte-mediated synaptogenesis, with a focus on the molecular mechanisms through which astrocytes orchestrate the formation of synaptic circuits. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Simulation with quantum mechanics/molecular mechanics for drug discovery.

    PubMed

    Barbault, Florent; Maurel, François

    2015-10-01

    Biological macromolecules, such as proteins or nucleic acids, are (still) molecules and thus they follow the same chemical rules that any simple molecule follows, even if their size generally renders accurate studies unhelpful. However, in the context of drug discovery, a detailed analysis of ligand association is required for understanding or predicting their interactions and hybrid quantum mechanics/molecular mechanics (QM/MM) computations are relevant tools to help elucidate this process. In this review, the authors explore the use of QM/MM for drug discovery. After a brief description of the molecular mechanics (MM) technique, the authors describe the subtractive and additive techniques for QM/MM computations. The authors then present several application cases in topics involved in drug discovery. QM/MM have been widely employed during the last decades to study chemical processes such as enzyme-inhibitor interactions. However, despite the enthusiasm around this area, plain MM simulations may be more meaningful than QM/MM. To obtain reliable results, the authors suggest fixing several keystone parameters according to the underlying chemistry of each studied system.

  14. Simulation with quantum mechanics/molecular mechanics for drug discovery.

    PubMed

    Barbault, Florent; Maurel, François

    2015-08-08

    Biological macromolecules, such as proteins or nucleic acids, are (still) molecules and thus they follow the same chemical rules that any simple molecule follows, even if their size generally renders accurate studies unhelpful. However, in the context of drug discovery, a detailed analysis of ligand association is required for understanding or predicting their interactions and hybrid quantum mechanics/molecular mechanics (QM/MM) computations are relevant tools to help elucidate this process. Areas covered: In this review, the authors explore the use of QM/MM for drug discovery. After a brief description of the molecular mechanics (MM) technique, the authors describe the subtractive and additive techniques for QM/MM computations. The authors then present several application cases in topics involved in drug discovery. Expert opinion: QM/MM have been widely employed during the last decades to study chemical processes such as enzyme-inhibitor interactions. However, despite the enthusiasm around this area, plain MM simulations may be more meaningful than QM/MM. To obtain reliable results, the authors suggest fixing several keystone parameters according to the underlying chemistry of each studied system.

  15. 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.

  16. Molecular mechanisms of glucocorticoid receptor signaling.

    PubMed

    Labeur, Marta; Holsboer, Florian

    2010-01-01

    This review highlights the most recent findings on the molecular mechanisms of the glucocorticoid receptor (GR). Most effects of glucocorticoids are mediated by the intracellular GR which is present in almost every tissue and controls transcriptional activation via direct and indirect mechanisms. Nevertheless the glu-cocorticoid responses are tissue -and gene- specific. GR associates selectively with corticosteroid ligands produced in the adrenal gland in response to changes of humoral homeostasis. Ligand interaction with GR promotes either GR binding to genomic glucocorticoid response elements, in turn modulating gene transcription, or interaction of GR monomers with other transcription factors activated by other signalling pathways leading to transrepression. The GR regulates a broad spectrum of physiological functions, including cell differentiation, metabolism and inflammatory responses. Thus, disruption or dysregulation of GR function will result in severe impairments in the maintenance of homeostasis and the control of adaptation to stress.

  17. [Molecular genetic mechanism of the kidney cancer].

    PubMed

    Nakaigawa, N; Yao, M; Kishida, T; Kubota, Y

    2001-01-01

    The oncogenic mechanisms of renal cell carcinoma(RCC) are becoming elucidated with recent advances in molecular biology. von Hipple-Lindau disease(VHL) tumor suppressor gene is mutated and inactivated frequently in clear cell type RCCs. The VHL protein forms a complex which shows a ubiquitin ligase activity. The lost of the ubiquitin ligase activity of VHL protein may be a key step for clear cell tumorigenesis. Papillary renal cell carcinomas are caused by activating mutation in the tyrosine kinase domain of the MET gene. This tumorigenic pathway is regulated by c-Src. Immunogene therapies have been started for the patients with advanced RCC. The information based on microarray and Serial Analysis of Gene Expression(SAGE) will provide novel diagnosis and therapy which focus on the tumorigenic mechanism of RCC in the near future.

  18. Quantum molecular dynamics approach to heavy ion collisions: Description of the model, comparison with fragmentation data, and the mechanism of fragment formation

    NASA Astrophysics Data System (ADS)

    Aichelin, J.; Peilert, G.; Bohnet, A.; Rosenhauer, A.; Stöcker, H.; Greiner, W.

    1988-06-01

    We present a detailed microscopic quantum molecular dynamic analysis of fragment formation in the reaction Ne(1.05 GeV/nucleon) + Au. The theoretical predictions of the total mass yield, the multiplicity distribution of clusters, their average momentum, and their angular distribution agree well with the available data. We find a rather localized hot participant zone, which predominantly emits protons and neutrons. The multiplicity of light clusters depends strongly on the impact parameter whereas the heavier fragments A>=40 result from the decay of spectator residues. Their yield can provide a good measure for the impact parameter. The hypothesis of a compound system of AP and AT nucleons which is globally heated and equilibrated is not supported by our results. Light and massive fragments occupy different regions in phase space. Semiperipheral reactions do not lead to a stopping of the projectile. We observe a power law behavior of the inclusive mass yield distribution. Its form, however, is caused by averaging over different impact parameters. This rules out inclusive mass yield distributions as candidates for revealing a possible liquid gas phase transition. Light and intermediate mass fragments are formed during the early compressional stage of the reaction. We find that the projectile causes a high density wave to travel through the target. It causes the target to fragment and transfers transverse momentum to the intermediate mass fragments. Lighter fragments receive additional momentum transfer due to n-n collisions.

  19. Molecular inhibitory mechanism of tricin on tyrosinase

    NASA Astrophysics Data System (ADS)

    Mu, Yan; Li, Lin; Hu, Song-Qing

    2013-04-01

    Tricin was evaluated as a type of tyrosinase inhibitor with good efficacy compared to arbutin. Tricin functioned as a non-competitive inhibitor of tyrosinase, with an equilibrium constant of 2.30 mmol/L. The molecular mechanisms underlying the inhibition of tyrosinase by tricin were investigated by means of circular dichroism spectra, fluorescence quenching and molecular docking. These assays demonstrated that the interactions between tricin and tyrosinase did not change the secondary structure. The interaction of tricin with residues in the hydrophobic pocket of tyrosinase was revealed by fluorescence quenching; the complex was stabilized by hydrophobic associations and hydrogen bonding (with residues Asn80 and Arg267). Docking results implied that the possible inhibitory mechanisms may be attributed to the stereospecific blockade effects of tricin on substrates or products and flexible conformation alterations in the tyrosinase active center caused by weak interactions between tyrosinase and tricin. The application of this type of flavonoid as a tyrosinase inhibitor will lead to significant advances in the field of depigmentation.

  20. Understanding the molecular mechanisms of reprogramming

    SciTech Connect

    Krause, Marie N.; Sancho-Martinez, Ignacio; Izpisua Belmonte, Juan Carlos

    2016-05-06

    Despite the profound and rapid advancements in reprogramming technologies since the generation of the first induced pluripotent stem cells (iPSCs) in 2006[1], the molecular basics of the process and its implications are still not fully understood. Recent work has suggested that a subset of TFs, so called “Pioneer TFs”, play an important role during the stochastic phase of iPSC reprogramming [2–6]. Pioneer TFs activities differ from conventional transcription factors in their mechanism of action. They bind directly to condensed chromatin and elicit a series of chromatin remodeling events that lead to opening of the chromatin. Chromatin decondensation by pioneer factors progressively occurs during cell division and in turn exposes specific gene promoters in the DNA to which TFs can now directly bind to promoters that are readily accessible[2, 6]. Here, we will summarize recent advancements on our understanding of the molecular mechanisms underlying reprogramming to iPSC as well as the implications that pioneer Transcription Factor activities might play during different lineage conversion processes. - Highlights: • Pioneer transcription factor activity underlies the initial steps of iPSC generation. • Reprogramming can occur by cis- and/or trans- reprogramming events. • Cis-reprogramming implies remodeling of the chromatin for enabling TF accessibility. • Trans-reprogramming encompasses direct binding of Tfs to their target gene promoters.

  1. 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

  2. Cellular and molecular mechanisms of dental nociception.

    PubMed

    Chung, G; Jung, S J; Oh, S B

    2013-11-01

    Due, in part, to the unique structure of the tooth, dental pain is initiated via distinct mechanisms. Here we review recent advances in our understanding of inflammatory tooth pain and discuss 3 hypotheses proposed to explain dentinal hypersensitivity: The first hypothesis, supported by functional expression of temperature-sensitive transient receptor potential channels, emphasizes the direct transduction of noxious temperatures by dental primary afferent neurons. The second hypothesis, known as hydrodynamic theory, attributes dental pain to fluid movement within dentinal tubules, and we discuss several candidate cellular mechanical transducers for the detection of fluid movement. The third hypothesis focuses on the potential sensory function of odontoblasts in the detection of thermal or mechanical stimuli, and we discuss the accumulating evidence that supports their excitability. We also briefly update on a novel strategy for local nociceptive anesthesia via nociceptive transducer molecules in dental primary afferents with the potential to specifically silence pain fibers during dental treatment. Further understanding of the molecular mechanisms of dental pain would greatly enhance the development of therapeutics that target dental pain.

  3. Molecular Mechanisms Regulating Macrophage Response to Hypoxia

    PubMed Central

    Rahat, Michal A.; Bitterman, Haim; Lahat, Nitza

    2011-01-01

    Monocytes and Macrophages (Mo/Mɸ) exhibit great plasticity, as they can shift between different modes of activation and, driven by their immediate microenvironment, perform divergent functions. These include, among others, patrolling their surroundings and maintaining homeostasis (resident Mo/Mɸ), combating invading pathogens and tumor cells (classically activated or M1 Mo/Mɸ), orchestrating wound healing (alternatively activated or M2 Mo/Mɸ), and restoring homeostasis after an inflammatory response (resolution Mɸ). Hypoxia is an important factor in the Mɸ microenvironment, is prevalent in many physiological and pathological conditions, and is interdependent with the inflammatory response. Although Mo/Mɸ have been studied in hypoxia, the mechanisms by which hypoxia influences the different modes of their activation, and how it regulates the shift between them, remain unclear. Here we review the current knowledge about the molecular mechanisms that mediate this hypoxic regulation of Mɸ activation. Much is known about the hypoxic transcriptional regulatory network, which includes the master regulators hypoxia-induced factor-1 and NF-κB, as well as other transcription factors (e.g., AP-1, Erg-1), but we also highlight the role of post-transcriptional and post-translational mechanisms. These mechanisms mediate hypoxic induction of Mɸ pro-angiogenic mediators, suppress M1 Mɸ by post-transcriptionally inhibiting pro-inflammatory mediators, and help shift the classically activated Mɸ into an activation state which approximate the alternatively activated or resolution Mɸ. PMID:22566835

  4. Molecular Mechanisms of Chromium in Alleviating Insulin Resistance

    PubMed Central

    Hua, Yinan; Clark, Suzanne; Ren, Jun; Sreejayan, Nair

    2011-01-01

    Type 2 diabetes is often associated with obesity, dyslipidemia, and cardiovascular anomalies and is a major health problem approaching global epidemic proportions. Insulin resistance, a prediabetic condition, precedes the onset of frank type 2 diabetes and offers potential avenues for early intervention to treat the disease. Although lifestyle modifications and exercise can reduce the incidence of diabetes, compliance has proved to be difficult, warranting pharmacological interventions. However, most of the currently available drugs that improve insulin sensitivity have adverse effects. Therefore, attractive strategies to alleviate insulin resistance include dietary supplements. One such supplement is chromium, which has been shown reduce insulin resistance in some, but not all, studies. Furthermore, the molecular mechanisms of chromium in alleviating insulin resistance remain elusive. This review examines emerging reports on the effect of chromium, as well as molecular and cellular mechanisms by which chromium may provide beneficial effects in alleviating insulin resistance. PMID:22423897

  5. Mechanical approach to chemical transport

    PubMed Central

    Kocherginsky, Nikolai; Gruebele, Martin

    2016-01-01

    Nonequilibrium thermodynamics describes the rates of transport phenomena with the aid of various thermodynamic forces, but often the phenomenological transport coefficients are not known, and the description is not easily connected with equilibrium relations. We present a simple and intuitive model to address these issues. Our model is based on Lagrangian dynamics for chemical systems with dissipation, so one may think of the model as physicochemical mechanics. Using one main equation, the model allows a systematic derivation of all transport and equilibrium equations, subject to the limitation that heat generated or absorbed in the system must be small for the model to be valid. A table with all major examples of transport and equilibrium processes described using physicochemical mechanics is given. In equilibrium, physicochemical mechanics reduces to standard thermodynamics and the Gibbs–Duhem relation, and we show that the First and Second Laws of thermodynamics are satisfied for our system plus bath model. Out of equilibrium, our model provides relationships between transport coefficients and describes system evolution in the presence of several simultaneous external fields. The model also leads to an extension of the Onsager–Casimir reciprocal relations for properties simultaneously transported by many components. PMID:27647899

  6. Cellular and molecular mechanisms of fibrosis.

    PubMed

    Wynn, T A

    2008-01-01

    Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being

  7. 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

  8. Molecular Mechanisms of Placebo Responses In Humans

    PubMed Central

    Peciña, Marta; Zubieta, Jon-Kar

    2014-01-01

    Endogenous opioid and non-opioid mechanisms [e.g. dopamine (DA), endocannabinoids (eCB)] have been implicated in the formation of placebo analgesic effects, with initial reports dating back three-decades. Besides the perspective that placebo effects confound randomized clinical trials (RCTs), the information so far acquired points to neurobiological systems that when activated by positive expectations and maintained through conditioning and reward learning are capable of inducing physiological changes that lead to the experience of analgesia and improvements in emotional state. Molecular neuroimaging techniques with positron emission tomography (PET) and the selective μ-opioid and D2/3 radiotracers [11C]carfentanil and [11C]raclopride have significantly contributed to our understanding of the neurobiological systems involved in the formation of placebo effects. This line of research has described neural and neurotransmitter networks implicated in placebo responses and provided the technical tools to examine inter-individual differences in the function of placebo responsive mechanisms, and potential surrogates (biomarkers). As a consequence, the formation of biological placebo effects is now being linked to the concept of resiliency mechanisms, partially determined by genetic factors, and uncovered by the cognitive emotional integration of the expectations created by the therapeutic environment and its maintenance through learning mechanisms. Further work needs to extend this research into clinical conditions where the rates of placebo responses are high and its neurobiological mechanisms have been largely unexplored (e.g. mood and anxiety disorders, persistent pain syndromes, or even Parkinson Disease and multiple sclerosis). The delineation of these processes within and across diseases would point to biological targets that have not been contemplated in traditional drug development. PMID:25510510

  9. A systems biology-based approach to uncovering the molecular mechanisms underlying the effects of dragon's blood tablet in colitis, involving the integration of chemical analysis, ADME prediction, and network pharmacology.

    PubMed

    Xu, Haiyu; Zhang, Yanqiong; Lei, Yun; Gao, Xiumei; Zhai, Huaqiang; Lin, Na; Tang, Shihuan; Liang, Rixin; Ma, Yan; Li, Defeng; Zhang, Yi; Zhu, Guangrong; Yang, Hongjun; Huang, Luqi

    2014-01-01

    Traditional Chinese medicine (TCM) is one of the oldest East Asian medical systems. The present study adopted a systems biology-based approach to provide new insights relating to the active constituents and molecular mechanisms underlying the effects of dragon's blood (DB) tablets for the treatment of colitis. This study integrated chemical analysis, prediction of absorption, distribution, metabolism, and excretion (ADME), and network pharmacology. Firstly, a rapid, reliable, and accurate ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry method was employed to identify 48 components of DB tablets. In silico prediction of the passive absorption of these compounds, based on Caco-2 cell permeability, and their P450 metabolism enabled the identification of 22 potentially absorbed components and 8 metabolites. Finally, networks were constructed to analyze interactions between these DB components/metabolites absorbed and their putative targets, and between the putative DB targets and known therapeutic targets for colitis. This study provided a great opportunity to deepen the understanding of the complex pharmacological mechanisms underlying the effects of DB in colitis treatment.

  10. A Systems Biology-Based Approach to Uncovering the Molecular Mechanisms Underlying the Effects of Dragon's Blood Tablet in Colitis, Involving the Integration of Chemical Analysis, ADME Prediction, and Network Pharmacology

    PubMed Central

    Gao, Xiumei; Zhai, Huaqiang; Lin, Na; Tang, Shihuan; Liang, Rixin; Ma, Yan; Li, Defeng; Zhang, Yi; Zhu, Guangrong; Yang, Hongjun; Huang, Luqi

    2014-01-01

    Traditional Chinese medicine (TCM) is one of the oldest East Asian medical systems. The present study adopted a systems biology-based approach to provide new insights relating to the active constituents and molecular mechanisms underlying the effects of dragon's blood (DB) tablets for the treatment of colitis. This study integrated chemical analysis, prediction of absorption, distribution, metabolism, and excretion (ADME), and network pharmacology. Firstly, a rapid, reliable, and accurate ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry method was employed to identify 48 components of DB tablets. In silico prediction of the passive absorption of these compounds, based on Caco-2 cell permeability, and their P450 metabolism enabled the identification of 22 potentially absorbed components and 8 metabolites. Finally, networks were constructed to analyze interactions between these DB components/metabolites absorbed and their putative targets, and between the putative DB targets and known therapeutic targets for colitis. This study provided a great opportunity to deepen the understanding of the complex pharmacological mechanisms underlying the effects of DB in colitis treatment. PMID:25068885

  11. 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.

  12. Molecular Mechanisms of DNA Replication Checkpoint Activation

    PubMed Central

    Recolin, Bénédicte; van der Laan, Siem; Tsanov, Nikolay; Maiorano, Domenico

    2014-01-01

    The major challenge of the cell cycle is to deliver an intact, and fully duplicated, genetic material to the daughter cells. To this end, progression of DNA synthesis is monitored by a feedback mechanism known as replication checkpoint that is untimely linked to DNA replication. This signaling pathway ensures coordination of DNA synthesis with cell cycle progression. Failure to activate this checkpoint in response to perturbation of DNA synthesis (replication stress) results in forced cell division leading to chromosome fragmentation, aneuploidy, and genomic instability. In this review, we will describe current knowledge of the molecular determinants of the DNA replication checkpoint in eukaryotic cells and discuss a model of activation of this signaling pathway crucial for maintenance of genomic stability. PMID:24705291

  13. Molecular mechanisms for enhanced DNA vaccine immunogenicity

    PubMed Central

    Li, Lei; Petrovsky, Nikolai

    2016-01-01

    Summary In the two decades since their initial discovery, DNA vaccines technologies have come a long way. Unfortunately, when applied to human subjects inadequate immunogenicity is still the biggest challenge for practical DNA vaccine use. Many different strategies have been tested in preclinical models to address this problem, including novel plasmid vectors and codon optimization to enhance antigen expression, new gene transfection systems or electroporation to increase delivery efficiency, protein or live virus vector boosting regimens to maximise immune stimulation, and formulation of DNA vaccines with traditional or molecular adjuvants. Better understanding of the mechanisms of action of DNA vaccines has also enabled better use of the intrinsic host response to DNA to improve vaccine immunogenicity. This review summarizes recent advances in DNA vaccine technologies and related intracellular events and how these might impact on future directions of DNA vaccine development. PMID:26707950

  14. Molecular Mechanisms of Midfacial Developmental Defects

    PubMed Central

    Suzuki, Akiko; Sangani, Dhruvee R.; Ansari, Afreen; Iwata, Junichi

    2015-01-01

    The morphogenesis of midfacial processes requires the coordination of a variety of cellular functions of both mesenchymal and epithelial cells to develop complex structures. Any failure or delay in midfacial development as well as any abnormal fusion of the medial and lateral nasal and maxillary prominences will result in developmental defects in the midface with a varying degree of severity, including cleft, hypoplasia, and midline expansion. In spite of the advances in human genome sequencing technology, the causes of nearly 70 percent of all birth defects, which include midfacial development defects, remain unknown. Recent studies in animal models have highlighted the importance of specific signaling cascades and genetic-environmental interactions in the development of the midfacial region. This review will summarize the current understanding of the morphogenetic processes and molecular mechanisms underlying midfacial birth defects based on mouse models with midfacial developmental abnormalities. PMID:26562615

  15. Molecular mechanics calculations on muscarinic agonists

    NASA Astrophysics Data System (ADS)

    Kooijman, Huub; Kanters, Jan A.; Kroon, Jan

    1990-10-01

    Molecular mechanics calculations have been performed on the conformation freedom with respect to the torsion angles OCCN and COCC of acetylcholine, α( R-methylacetylcholine,β( S)-methylacetylcholine, α( R),β( S)-diemthylacetylcholine and muscarine, in order to obtain information about the active conformation and its interaction with the muscarinic cholinergic receptor. Muscarine has a rather flexible ring system, which makes modelling of the receptor site on the active conformation of this particular ligand a difficult problem. A common minimum for these compounds was found at {+ gauche,anti}), which is identified with the active conformation. However, OCCN angles of up to 120° can be accommodated in the receptor site. The reduced cholinergic activity of the α-methyl derivatives is probably caused by unfavourable interactions between the α-methyl group and the receptor site. The apparent contradictory high activity of the 2-acetyloxycyclopropylammonium ion can be explained by the distorted geometry of α substitution.

  16. Molecular and cellular mechanisms of heterotopic ossification.

    PubMed

    Ramirez, Diana M; Ramirez, Melissa R; Reginato, Anthony M; Medici, Damian

    2014-10-01

    Heterotopic ossification (HO) is a debilitating condition in which cartilage and bone forms in soft tissues such as muscle, tendon, and ligament causing immobility. This process is induced by inflammation associated with traumatic injury. In an extremely rare genetic disorder called fibrodysplasia ossificans progessiva (FOP), a combination of inflammation associated with minor soft tissue injuries and a hereditary genetic mutation causes massive HO that progressively worsens throughout the patients' lifetime leading to the formation of an ectopic skeleton. An activating mutation in the BMP type I receptor ALK2 has been shown to contribute to the heterotopic lesions in FOP patients, yet recent studies have shown that other events are required to stimulate HO including activation of sensory neurons, mast cell degranulation, lymphocyte infiltration, skeletal myocyte cell death, and endothelial-mesenchymal transition (EndMT). In this review, we discuss the recent evidence and mechanistic data that describe the cellular and molecular mechanisms that give rise to heterotopic bone.

  17. Molecular and cellular mechanisms of heterotopic ossification

    PubMed Central

    Ramirez, Diana M.; Ramirez, Melissa R.; Reginato, Anthony M.; Medici, Damian

    2015-01-01

    Summary Heterotopic ossification (HO) is a debilitating condition in which cartilage and bone forms in soft tissues such as muscle, tendon, and ligament causing immobility. This process is induced by inflammation associated with traumatic injury. In an extremely rare genetic disorder called fibrodysplasia ossificans progessiva (FOP), a combination of inflammation associated with minor soft tissue injuries and a hereditary genetic mutation causes massive HO that progressively worsens throughout the patients’ lifetime leading to the formation of an ectopic skeleton. An activating mutation in the BMP type I receptor ALK2 has been shown to contribute to the heterotopic lesions in FOP patients, yet recent studies have shown that other events are required to stimulate HO including activation of sensory neurons, mast cell degranulation, lymphocyte infiltration, skeletal myocyte cell death, and endothelial-mesenchymal transition (EndMT). In this review, we discuss the recent evidence and mechanistic data that describe the cellular and molecular mechanisms that give rise to heterotopic bone. PMID:24796520

  18. Sarcopenia: monitoring, molecular mechanisms, and physical intervention.

    PubMed

    Zembroń-Łacny, A; Dziubek, W; Rogowski, Ł; Skorupka, E; Dąbrowska, G

    2014-01-01

    According to European Working Group on Sarcopenia in Older People (EWGSOP) sarcopenia includes both a loss of muscle strength and a decline in functional quality in addition to the loss of muscle protein mass. In order to develop strategies to prevent and treat sarcopenia, the risk factors and causes of sarcopenia must be identified. Age-related muscle loss is characterized by the contribution of multiple factors, and there is growing evidence for a prominent role of low-grade chronic inflammation in sarcopenia. The elderly who are less physically active are more likely to have lower skeletal muscle mass and strength and are at increased risk of developing sarcopenia. Resistance training added to aerobic exercise or high-intensity interval training promote numerous changes in skeletal muscle, many of which may help to prevent or reverse sarcopenia. In this review, we provided current information on definition and monitoring, molecular mechanisms, and physical intervention to counteract sarcopenia.

  19. Molecular mechanisms of insulin resistance in diabetes.

    PubMed

    Soumaya, Kouidhi

    2012-01-01

    Molecular components of impaired insulin signaling pathway have emerged with growing interest to understand how the environment and genetic susceptibility combine to cause defects in this fundamental pathway that lead to insulin resistance. When insulin resistance is combined with beta-cell defects in glucose-stimulated insulin secretion, impaired glucose tolerance, hyperglycemia, or Type 2 diabetes can result. The most common underlying cause is obesity, although primary insulin resistance in normal-weight individuals is also possible. The adipose tissue releases free fatty acids that contribute to insulin resistance and also acts as a relevant endocrine organ producing mediators (adipokines) that can modulate insulin signalling. This chapter deals with the core elements promoting, insulin resistance, associated with impaired insulin signalling pathway and adipocyte dysfunction. A detailed understanding of these basic pathophysiological mechanisms is critical for the development of novel therapeutic strategies to treat diabetes.

  20. Molecular mechanisms for enhanced DNA vaccine immunogenicity.

    PubMed

    Li, Lei; Petrovsky, Nikolai

    2016-01-01

    In the two decades since their initial discovery, DNA vaccines technologies have come a long way. Unfortunately, when applied to human subjects inadequate immunogenicity is still the biggest challenge for practical DNA vaccine use. Many different strategies have been tested in preclinical models to address this problem, including novel plasmid vectors and codon optimization to enhance antigen expression, new gene transfection systems or electroporation to increase delivery efficiency, protein or live virus vector boosting regimens to maximise immune stimulation, and formulation of DNA vaccines with traditional or molecular adjuvants. Better understanding of the mechanisms of action of DNA vaccines has also enabled better use of the intrinsic host response to DNA to improve vaccine immunogenicity. This review summarizes recent advances in DNA vaccine technologies and related intracellular events and how these might impact on future directions of DNA vaccine development.

  1. 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

  2. Molecular mechanisms of pancreatitis: current opinion.

    PubMed

    Vonlaufen, Alain; Wilson, Jeremy S; Apte, Minoti V

    2008-09-01

    Pancreatitis (necroinflammation of the pancreas) has both acute and chronic manifestations. Gallstones are the major cause of acute pancreatitis, whereas alcohol is associated with acute as well as chronic forms of the disease. Cases of true idiopathic pancreatitis are steadily diminishing as more genetic causes of the disease are discovered. The pathogenesis of acute pancreatitis has been extensively investigated over the past four decades; the general current consensus is that the injury is initiated within pancreatic acinar cells subsequent to premature intracellular activation of digestive enzymes. Repeated attacks of acute pancreatitis have the potential to evolve into chronic disease characterized by fibrosis and loss of pancreatic function. Our knowledge of the process of scarring has advanced considerably with the isolation and study of pancreatic stellate cells, now established as the key cells in pancreatic fibrogenesis. The present review summarizes recent developments in the field particularly with respect to the progress made in unraveling the molecular mechanisms of acute and chronic pancreatic injury secondary to gallstones, alcohol and genetic factors. It is anticipated that continued research in the area will lead to the identification and characterization of molecular pathways that may be therapeutically targeted to prevent/inhibit the initiation and progression of the disease.

  3. Molecular Mechanisms Governing IL-24 Gene Expression

    PubMed Central

    Sahoo, Anupama

    2012-01-01

    Interleukin-24 (IL-24) belongs to the IL-10 family of cytokines and is well known for its tumor suppressor activity. This cytokine is released by both immune and nonimmune cells and acts on non-hematopoietic tissues such as skin, lung and reproductive tissues. Apart from its ubiquitous tumor suppressor function, IL-24 is also known to be involved in the immunopathology of autoimmune diseases like psoriasis and rheumatoid arthritis. Although the cellular sources and functions of IL-24 are being increasingly investigated, the molecular mechanisms of IL-24 gene expression at the levels of signal transduction, epigenetics and transcription factor binding are still unclear. Understanding the specific molecular events that regulate the production of IL-24 will help to answer the remaining questions that are important for the design of new strategies of immune intervention involving IL-24. Herein, we briefly review the signaling pathways and transcription factors that facilitate, induce, or repress production of this cytokine along with the cellular sources and functions of IL-24. PMID:22536164

  4. Molecular approaches to epidemiology and clinical aspects of malaria.

    PubMed

    Brown, G V; Beck, H P; Molyneux, M; Marsh, K

    2000-10-01

    Malaria is a problem of global importance, responsible for 1-2 million deaths per year, mainly in African children, as well as considerable morbidity manifested as severe anaemia and encephalopathy in young children. Fundamental to the development of new tools for malaria control in humans is an increased understanding of key features of malaria infection, such as the diversity of outcome in different individuals, the understanding of different manifestations of the disease and of the mechanisms of immunity that allow clinical protection in the face of ongoing low-grade infection (concomitant immunity or premunition). Here, Graham Brown and colleagues review some of the ways in which molecular approaches might be used to increase our understanding of the epidemiology and clinical manifestations of malaria, as discussed at the Molecular Approaches to Malaria conference (MAM2000), Lorne, Australia, 2-5 February 2000.

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

    PubMed

    Sun, Qiming; Chan, Garnet Kin-Lic

    2014-09-09

    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.

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

    PubMed Central

    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. PMID:25882670

  7. The molecular mechanisms of oesophageal cancer.

    PubMed

    McCabe, M L; Dlamini, Z

    2005-07-01

    Apoptosis is a process of programmed cell death, which is as essential as cell growth, for the maintenance of homeostasis. When these processes loose integration such as cancer, then uncontrolled cell growth occurs. Cancer of the oesophagus ranks as the ninth most common malignancy in the world, and recent evidence shows that its incidence is increasing. Prognosis of this disease is poor, with an overall 5-year survival rate of less than 10%. Unraveling the mechanisms or developing animal models for oesophageal carcinoma have thus far not been successful. It is believed that oesophageal cancer has an intricate molecular mechanism of evading apoptosis by the down-regulation of Bax, up-regulation of Bcl-2, Bcl-xl and Survivin, mutation of p53 and alteration in Fas expression. A great deal of research has been performed in order to determine the key genes that initiate and promote the growth of oesophageal cancer. This review focuses on apoptosis and candidate genes linked to the development of oesophageal cancer, which it is hoped may provide diagnostic and therapeutic tools, and potential therapeutic strategies for the management of this carcinoma.

  8. Cellular and molecular approaches to memory storage.

    PubMed

    Laroche, S

    2000-01-01

    There has been nearly a century of interest in the idea that information is stored in the brain as changes in the efficacy of synaptic connections on neurons that are activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation opened a new chapter in the study of synaptic plasticity in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular bases of learning and memory. To date, considerable progress has been made in understanding the cellular and molecular mechanisms underlying synaptic plasticity and in identifying the neural systems which express it. In parallel, the hypothesis that the mechanisms underlying synaptic plasticity are activated during learning and serve learning and memory has gained much empirical support. Accumulating evidence suggests that the rapid activation of the genetic machinery is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. These advances are reviewed below.

  9. Kinetics and Mechanism--A Games Approach.

    ERIC Educational Resources Information Center

    Harsch, Gunther

    1984-01-01

    Proposes an approach to chemical kinetics and mechanism using statistical games, illustrating its use in monomolecular, catalytic, autocatalytic, consecutive, and equilibrium reactions. Major features of the games are also outlined and discussed. (JN)

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

    PubMed

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

    2013-12-05

    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.

  11. Molecular Mechanism of Overhauser Dynamic Nuclear Polarization in Insulating Solids.

    PubMed

    Pylaeva, Svetlana; Ivanov, Konstantin L; Baldus, Marc; Sebastiani, Daniel; Elgabarty, Hossam

    2017-05-18

    Dynamic nuclear polarization (DNP), a technique that significantly enhances NMR signals, is experiencing a renaissance owing to enormous methodological developments. In the heart of DNP is a polarization transfer mechanism that endows nuclei with much larger electronic spin polarization. Polarization transfer via the Overhauser effect (OE) is traditionally known to be operative only in liquids and conducting solids. Very recently, surprisingly strong OE-DNP in insulating solids has been reported, with a DNP efficiency that increases with the magnetic field strength. Here we offer an explanation for these perplexing observations using a combination of molecular dynamics and spin dynamics simulations. Our approach elucidates the underlying molecular stochastic motion, provides cross-relaxation rates, explains the observed sign of the NMR enhancement, and estimates the role of nuclear spin diffusion. The presented theoretical description opens the door for rational design of novel polarizing agents for OE-DNP in insulating solids.

  12. 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.

  13. 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.

  14. 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)

  15. Semiclassical approach to atomic and molecular interactions

    NASA Technical Reports Server (NTRS)

    Kunc, Joseph A.

    1989-01-01

    A general approach, combining quantum and classical mechanics, is used to determine the electron position and velocity distributions in atoms and atomic ions (positive and negative). The Hartree-Fock electronic wave functions and the classical central field approximation are used for evaluation of the dynamic properties of the localized electrons. The distributions, which are of fundamental importance in applications of the binary encounter approximation to description of atomic and ionic collissions, are obtained in the form of simple analytical expressions. The quantum-classical distributions of this work are compared with several other distributions in Ne, Ar, and Al atoms in the ground state.

  16. 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

  17. [Ontogenetic clock: molecular-genetic mechanism].

    PubMed

    Pisaruk, A V

    2010-01-01

    Proposed is a hypothesis of the mechanism providing for the cell to count out the time of life and to change (according to the set program) the expression of chromosomal genes in order to control ontogenesis ("ontogenetic clock"). This mechanism represents an autonomous molecular-genetic oscillator, which memorizes the number of cycles of own oscillations through cutting the terminal tau-segment of chrono-DNA using special restrictase. The latter is formed at this segment out of two sub-units (proteins) in each cycle of oscillator operation. These proteins are alternately synthesized on ribosomes, since each inhibits the synthesis of the other, thus ensuring successive binding of restrictase sub-units at the terminal segment of chrono-DNA and its single section in one cycle. In addition, each of these proteins is a repressor of own gene and activator of the gene of the other protein, thus ensuring efficiency and reliability of oscillator operation. The design of oscillator of ontogenetic clock is similar to that of circadian oscillator, but its frequency is not synchronized with the nature's physical rhythms and depends on body temperature. Therefore, it is physical rather than biological time that is measured. The chrono-DNA consists of short repetitive sequences of nucleotides (tau-segments) and temporal (regulatory) genes inserted over specified number of these segments. The shortening of chrono-DNA leads to uncovering the next gene and to its destruction by exonuclease. As a result, the synthesis of activator (repressor) stops and the expression of some chromosomal genes changes, initiating the next stage of ontogenesis.

  18. Molecular mechanisms of muscle plasticity with exercise.

    PubMed

    Hoppeler, Hans; Baum, Oliver; Lurman, Glenn; Mueller, Matthias

    2011-07-01

    The skeletal muscle phenotype is subject to considerable malleability depending on use. Low-intensity endurance type exercise leads to qualitative changes of muscle tissue characterized mainly by an increase in structures supporting oxygen delivery and consumption. High-load strength-type exercise leads to growth of muscle fibers dominated by an increase in contractile proteins. In low-intensity exercise, stress-induced signaling leads to transcriptional upregulation of a multitude of genes with Ca(2+) signaling and the energy status of the muscle cells sensed through AMPK being major input determinants. Several parallel signaling pathways converge on the transcriptional co-activator PGC-1α, perceived as being the coordinator of much of the transcriptional and posttranscriptional processes. High-load training is dominated by a translational upregulation controlled by mTOR mainly influenced by an insulin/growth factor-dependent signaling cascade as well as mechanical and nutritional cues. Exercise-induced muscle growth is further supported by DNA recruitment through activation and incorporation of satellite cells. Crucial nodes of strength and endurance exercise signaling networks are shared making these training modes interdependent. Robustness of exercise-related signaling is the consequence of signaling being multiple parallel with feed-back and feed-forward control over single and multiple signaling levels. We currently have a good descriptive understanding of the molecular mechanisms controlling muscle phenotypic plasticity. We lack understanding of the precise interactions among partners of signaling networks and accordingly models to predict signaling outcome of entire networks. A major current challenge is to verify and apply available knowledge gained in model systems to predict human phenotypic plasticity.

  19. 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

  20. 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.

  1. Decomposition of amino diazeniumdiolates (NONOates): molecular mechanisms.

    PubMed

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

    2014-12-01

    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; and 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 NN heterolytic bond cleavage (kd~10(7) 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 three NONOates that have been investigated are subject to additional acid catalysis that occurs through di-protonation of the [NN(O)NO](-) group. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. 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.

  3. Anemia: progress in molecular mechanisms and therapies.

    PubMed

    Sankaran, Vijay G; Weiss, Mitchell J

    2015-03-01

    Anemia is a major source of morbidity and mortality worldwide. Here we review recent insights into how red blood cells (RBCs) are produced, the pathogenic mechanisms underlying various forms of anemia, and novel therapies derived from these findings. It is likely that these new insights, mainly arising from basic scientific studies, will contribute immensely to both the understanding of frequently debilitating forms of anemia and the ability to treat affected patients. Major worldwide diseases that are likely to benefit from new advances include the hemoglobinopathies (β-thalassemia and sickle cell disease); rare genetic disorders of RBC production; and anemias associated with chronic kidney disease, inflammation, and cancer. Promising new approaches to treatment include drugs that target recently defined pathways in RBC production, iron metabolism, and fetal globin-family gene expression, as well as gene therapies that use improved viral vectors and newly developed genome editing technologies.

  4. Molecular mechanisms controlling legume autoregulation of nodulation

    PubMed Central

    Reid, Dugald E.; Ferguson, Brett J.; Hayashi, Satomi; Lin, Yu-Hsiang; Gresshoff, Peter M.

    2011-01-01

    Background High input costs and environmental pressures to reduce nitrogen use in agriculture have increased the competitive advantage of legume crops. The symbiotic relationship that legumes form with nitrogen-fixing soil bacteria in root nodules is central to this advantage. Scope Understanding how legume plants maintain control of nodulation to balance the nitrogen gains with their energy needs and developmental costs will assist in increasing their productivity and relative advantage. For this reason, the regulation of nodulation has been extensively studied since the first mutants exhibiting increased nodulation were isolated almost three decades ago. Conclusions Nodulation is regulated primarily via a systemic mechanism known as the autoregulation of nodulation (AON), which is controlled by a CLAVATA1-like receptor kinase. Multiple components sharing homology with the CLAVATA signalling pathway that maintains control of the shoot apical meristem in arabidopsis have now been identified in AON. This includes the recent identification of several CLE peptides capable of activating nodule inhibition responses, a low molecular weight shoot signal and a role for CLAVATA2 in AON. Efforts are now being focused on directly identifying the interactions of these components and to identify the form that long-distance transport molecules take. PMID:21856632

  5. Molecular mechanisms controlling legume autoregulation of nodulation.

    PubMed

    Reid, Dugald E; Ferguson, Brett J; Hayashi, Satomi; Lin, Yu-Hsiang; Gresshoff, Peter M

    2011-10-01

    High input costs and environmental pressures to reduce nitrogen use in agriculture have increased the competitive advantage of legume crops. The symbiotic relationship that legumes form with nitrogen-fixing soil bacteria in root nodules is central to this advantage. Understanding how legume plants maintain control of nodulation to balance the nitrogen gains with their energy needs and developmental costs will assist in increasing their productivity and relative advantage. For this reason, the regulation of nodulation has been extensively studied since the first mutants exhibiting increased nodulation were isolated almost three decades ago. Nodulation is regulated primarily via a systemic mechanism known as the autoregulation of nodulation (AON), which is controlled by a CLAVATA1-like receptor kinase. Multiple components sharing homology with the CLAVATA signalling pathway that maintains control of the shoot apical meristem in arabidopsis have now been identified in AON. This includes the recent identification of several CLE peptides capable of activating nodule inhibition responses, a low molecular weight shoot signal and a role for CLAVATA2 in AON. Efforts are now being focused on directly identifying the interactions of these components and to identify the form that long-distance transport molecules take.

  6. Molecular mechanisms of cadmium induced mutagenicity.

    PubMed

    Filipic, M; Fatur, T; Vudrag, M

    2006-02-01

    Cadmium is a human carcinogen of worldwide concern because it accumulates in the environment due to its extremely long half-life. Its compounds are classified as human carcinogens by several regulatory agencies. Cadmium affects cell proliferation, differentiation, apoptosis and other cellular activities and can cause numerous molecular lesions that would be relevant to carcinogenesis. For a long time cadmium has been considered as a non-genotoxic carcinogen, as it is only weakly mutagenic in bacterial and mammalian cell test systems. Recently, we presented evidence that when assayed in a test system, in which both intragenic and multilocus mutations can be detected, cadmium acts as a strong mutagen which induces predominantly multilocus deletions. In this review, we discuss two mechanisms that play an important role in cadmium mutagenicity: (i) induction of reactive oxygen species (ROS); and (ii) inhibition of DNA repair. Experimental evidence suggests that cadmium at low, for environmental exposure relevant concentrations, induces mutations by inducing oxidative DNA damage and that it decreases genetic stability by inhibiting the repair of endogenous and exogenous DNA lesions, which in turn increase the probability of mutations and consequently cancer initiation by this metal.

  7. 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.

  8. 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

  9. Molecular mechanisms of asymmetric division in oocytes.

    PubMed

    Sun, Shao-Chen; Kim, Nam-Hyung

    2013-08-01

    In contrast to symmetric division in mitosis, mammalian oocyte maturation is characterized by asymmetric cell division that produces a large egg and a small polar body. The asymmetry results from oocyte polarization, which includes spindle positioning, migration, and cortical reorganization, and this process is critical for fertilization and the retention of maternal components for early embryo development. Although actin dynamics are involved in this process, the molecular mechanism underlying this remained unclear until the use of confocal microscopy and live cell imaging became widespread in recent years. Information obtained through a PubMed database search of all articles published in English between 2000 and 2012 that included the phrases "oocyte, actin, spindle migration," "oocyte, actin, polar body," or "oocyte, actin, asymmetric division" was reviewed. The actin nucleation factor actin-related protein 2/3 complex and its nucleation-promoting factors, formins and Spire, and regulators such as small GTPases, partitioning-defective/protein kinase C, Fyn, microRNAs, cis-Golgi apparatus components, myosin/myosin light-chain kinase, spindle stability regulators, and spindle assembly checkpoint regulators, play critical roles in asymmetric cell division in oocytes. This review summarizes recent findings on these actin-related regulators in mammalian oocyte asymmetric division and outlines a complete signaling pathway.

  10. 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

  11. Dissecting the Molecular Mechanisms of Neurodegenerative Diseases through Network Biology.

    PubMed

    Santiago, Jose A; Bottero, Virginie; Potashkin, Judith A

    2017-01-01

    Neurodegenerative diseases are rarely caused by a mutation in a single gene but rather influenced by a combination of genetic, epigenetic and environmental factors. Emerging high-throughput technologies such as RNA sequencing have been instrumental in deciphering the molecular landscape of neurodegenerative diseases, however, the interpretation of such large amounts of data remains a challenge. Network biology has become a powerful platform to integrate multiple omics data to comprehensively explore the molecular networks in the context of health and disease. In this review article, we highlight recent advances in network biology approaches with an emphasis in brain-networks that have provided insights into the molecular mechanisms leading to the most prevalent neurodegenerative diseases including Alzheimer's (AD), Parkinson's (PD) and Huntington's diseases (HD). We discuss how integrative approaches using multi-omics data from different tissues have been valuable for identifying biomarkers and therapeutic targets. In addition, we discuss the challenges the field of network medicine faces toward the translation of network-based findings into clinically actionable tools for personalized medicine applications.

  12. Discovering novel ligands for understanding molecular mechanism of bacteria chemotaxis

    NASA Astrophysics Data System (ADS)

    Lai, Luhua

    2015-03-01

    In order to understand the molecular mechanism of bacteria chemotaxis, we used a combined experimental and computational approach to discover novel chemoeffector molecules and compare their binding features, as well as the conformational changes they produce. We first used molecular docking to computationally screen a large chemical library and tested binding strengths of the top-ranking molecules for the E. coli chemoreceptor Tar. Chemotactic properties of the binding molecules were then studied using a specially designed microfluidic device. Novel attractant and antagonist molecules were identified that bind directly with the E. coli chemoreceptor Tar. Molecular dynamics simulations showed that attractant and antagonist binding result in distinct conformational changes in Tar. Differences of antagonist and attractant binding suggest that molecules lacking triggering interaction with the receptor behave as antagonist. For Tar, the triggering interaction is mediated by the hydrogen bonds formed between a donor group in the attractant and the main-chain carbonyls in the fourth helix of Tar. This ?bind-and-trigger? mechanism of receptor signaling is verified experimentally by converting an antagonist into an attractant when introducing an NH group into the antagonist compound. Similar conformational changes were also observed in the E. coli Tsr system.

  13. Advances in molecular mechanism of cardioprotection induced by helium

    PubMed Central

    Ding, Yi-ping; Zhang, Ju-yi; Feng, Dong-xia; Kong, Yan; Xu, Zhuan; Chen, Gang

    2017-01-01

    Helium has been classified as a kind of inert gas that is not effortless to spark chemical reactions with other substances in the past decades. Nevertheless, the cognition of scientists has gradually changed accompanied with a variety of studies revealing the potential molecular mechanism underlying organ-protection induced by helium. Especially, as a non-anesthetic gas which is deficient of relevant cardiopulmonary side effects, helium conditioning is recognized as an emerging and promising approach to exert favorable effects by mimicking the cardioprotection of anesthetic gases or xenon. In this review we will summarize advances in the underlying biological mechanisms and clinical applicability with regards to the cardioprotective effects of helium. PMID:28744366

  14. 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…

  15. 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…

  16. Molecular Mechanisms of Iron Oxyhydroxide Biomineralization

    NASA Astrophysics Data System (ADS)

    Chan, C. S.; Fakra, S.; de Stasio, G.; Banfield, J. F.

    2003-12-01

    Neutrophilic iron-oxidizing microbes such as Gallionella and PV-1 (Emerson and Moyer, 1997) extrude polymers that become encrusted with iron oxides. Little is known about the identity of these polymers, their biological function and the roles they play in mineralization. To this end, we are investigating iron oxidizers in natural terrestrial iron-rich microbial mat communities, culturing and characterizing them in the laboratory and performing abiotic synthesis experiments based on the natural mineralization processes. Our sampling site is in a flooded former lead-zinc mine in Tennyson, WI, which is host to thick reddish-orange microbial mats. Scanning and transmission electron microscopy studies show that the mat is composed of iron oxide-covered stalks and sheaths (like those formed by Gallionella and Leptothrix spp.), as well as tangled masses of mineralized filaments. There is evidence of polymer influence on mineral phase and morphology in the form of extremely thin (few-unit cell wide), microns-long akaganeite (β -FeOOH) crystals at the center of these mineralized filaments. We are using synchrotron-based X-ray spectromicroscopy (PEEM-photoelectron emisson microscopy and STXM-scanning transmission X-ray microscopy), which has the ability to give chemical information on heterogenous samples at high spatial resolutions. Both PEEM and STXM show that these filaments contain polysaccharides, which are likely templating the akaganeite formation. Initial iron oxide synthesis experiments using model microbial polysaccharides support this hypothesis. Further synthesis and characterization by X-ray absorption and infrared spectroscopy methods is being performed in order to elucidate the molecular mechanisms of mineral nucleation and growth.

  17. [Molecular mechanisms underlying thermosensation in mammals].

    PubMed

    Sokabe, Takaaki; Tominaga, Makoto

    2009-07-01

    Sensing environmental temperature is one of the most important fundamental functions of the living things on the earth. Recently, it has been revealed that several members of the TRP ion channel super family are activated by temperature changes. A number of reports clearly demonstrate that thermal activation of these thermosensitive TRP channels contributes to various temperature-dependent responses in vivo, such as thermosensation, thermotaxis, and the regulation of cellular/tissue functions at physiological body temperature. Nine TRP channels have been reported to respond to a physiological range of temperatures in mammals. TRPV1 and TRPV2 expressed in nociceptive neurons are activated by heat (> 43 degrees C and > 52 degrees C, respectively), and TRPV1-null mice show defects in sensing noxious heat. TRPV3 and TRPV4 are predominantly expressed in skin keratinocytes rather than in sensory neurons, and the gene knock-out of each channel causes abnormal thermotaxis in vivo. TRPM8, which senses cold temperatures (< 27 degrees C), is expressed in nociceptive and non-nociceptive neurons and its loss impairs cold sensitivity. TRPA1 is expressed in nociceptive neurons and acts as a sensor for various harmful stimuli, whereas its responsiveness to noxious cold stimuli is controversial even after the analysis of mice lacking the channel. Other thermoTRPs, TRPM2, TRPM4, and TRPM5 are not expressed in sensory neurons, and are reportedly involved in several functions at physiological body temperatures including insulin secretion, taste sensation, and immune response. In this review, I summarize the molecular mechanisms of thermosensation in mammals by focusing on thermosensitive TRP channels.

  18. 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.

  19. 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 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; and 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.

  20. 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.

  1. 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. © The Author 2015. Published by

  2. 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.

  3. 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.

  4. Gauge-origin independent magnetizabilities from hybrid quantum mechanics/molecular mechanics models: Theory and applications to liquid water

    NASA Astrophysics Data System (ADS)

    Aidas, Kestutis; Kongsted, Jacob; Nielsen, Christian B.; Mikkelsen, Kurt V.; Christiansen, Ove; Ruud, Kenneth

    2007-07-01

    The theory of a hybrid quantum mechanics/molecular mechanics (QM/MM) approach for gauge-origin independent calculations of the molecular magnetizability using Hartree-Fock or Density Functional Theory is presented. The method is applied to liquid water using configurations generated from classical Molecular Dynamics simulation to calculate the statistical averaged magnetizability. Based on a comparison with experimental data, treating only one water molecule quantum mechanically appears to be insufficient, while a quantum mechanical treatment of also the first solvation shell leads to good agreement between theory and experiment. This indicates that the gas-to-liquid phase shift for the molecular magnetizability is to a large extent of non-electrostatic nature.

  5. 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…

  6. Molecular basis of glyphosate resistance: Different approaches through protein engineering

    PubMed Central

    Pollegioni, Loredano; Schonbrunn, Ernst; Siehl, Daniel

    2011-01-01

    Glyphosate (N-phosphonomethyl-glycine) is the most-used herbicide in the world: glyphosate-based formulations exhibit broad-spectrum herbicidal activity with minimal human and environmental toxicity. The extraordinary success of this simple small molecule is mainly due to the high specificity of glyphosate towards the plant enzyme enolpyruvylshikimate-3-phosphate synthase in the shikimate pathway leading to biosynthesis of aromatic amino acids. Starting in 1996, transgenic glyphosate-resistant plants were introduced thus allowing the application of the herbicide to the crop (post-emergence) to remove emerged weeds without crop damage. This review focuses on the evolution of mechanisms of resistance to glyphosate as obtained through natural diversity, the gene shuffling approach to molecular evolution, and a rational, structure-based approach to protein engineering. In addition, we offer rationale for the means by which the modifications made have had their intended effect. PMID:21668647

  7. 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.

  8. 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

    2015-03-07

    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 A1 symmetry on the 9a1 momentum profile, which can be unravelled from considerations on the symmetry characteristics of orbitals and their energy spacing.

  9. Application of high level wavefunction methods in quantum mechanics/molecular mechanics hybrid schemes.

    PubMed

    Mata, Ricardo A

    2010-05-21

    In this Perspective, several developments in the field of quantum mechanics/molecular mechanics (QM/MM) approaches are reviewed. Emphasis is placed on the use of correlated wavefunction theory and new state of the art methods for the treatment of large quantum systems. Until recently, computational chemistry approaches to large/complex chemical problems have seldom been considered as tools for quantitative predictions. However, due to the tremendous development of computational resources and new quantum chemical methods, it is nowadays possible to describe the electronic structure of biomolecules at levels of theory which a decade ago were only possible for system sizes of up to 20 atoms. These advances are here outlined in the context of QM/MM. The article concludes with a short outlook on upcoming developments and possible bottlenecks for future applications.

  10. Molecular Mechanisms of Par-4-Induced Apoptosis in Prostate Cancer

    DTIC Science & Technology

    2007-05-01

    Sambrook J, Fritsch EF, Maniatis T. (1989). Molecular Cloning : A Laboratory Manual (Cold Spring Harbor, New York: Cold Spring Harbor Laboratory...AD_________________ Award Number: W81XWH-05-1-0622 TITLE: Molecular Mechanisms of Par-4-Induced...SUBTITLE 5a. CONTRACT NUMBER Molecular Mechanisms of Par-4-Induced Apoptosis in Prostate Cancer 5b. GRANT NUMBER W81XWH-05-1-0622 5c. PROGRAM

  11. Effects of Maternal Obesity on Fetal Programming: Molecular Approaches.

    PubMed

    Neri, Caterina; Edlow, Andrea G

    2015-09-03

    Maternal obesity has become a worldwide epidemic. Obesity and a high-fat diet have been shown to have deleterious effects on fetal programming, predisposing offspring to adverse cardiometabolic and neurodevelopmental outcomes. Although large epidemiological studies have shown an association between maternal obesity and adverse outcomes for offspring, the underlying mechanisms remain unclear. Molecular approaches have played a key role in elucidating the mechanistic underpinnings of fetal malprogramming in the setting of maternal obesity. These approaches include, among others, characterization of epigenetic modifications, microRNA expression, the gut microbiome, the transcriptome, and evaluation of specific mRNA expression via quantitative reverse transcription polmerase chain reaction (RT-qPCR) in fetuses and offspring of obese females. This work will review the data from animal models and human fluids/cells regarding the effects of maternal obesity on fetal and offspring neurodevelopment and cardiometabolic outcomes, with a particular focus on molecular approaches. Copyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.

  12. Molecular mechanisms driving homeostatic plasticity of neurotransmitter release

    PubMed Central

    Lazarevic, Vesna; Pothula, Santosh; Andres-Alonso, Maria; Fejtova, Anna

    2013-01-01

    Homeostatic plasticity is a process by which neurons adapt to the overall network activity to keep their firing rates in a reasonable range. At the cellular level this kind of plasticity comprises modulation of cellular excitability and tuning of synaptic strength. In this review we concentrate on presynaptic homeostatic plasticity controlling the efficacy of neurotransmitter release from presynaptic boutons. While morphological and electrophysiological approaches were successful to describe homeostatic plasticity-induced changes in the presynaptic architecture and function, cellular and molecular mechanisms underlying those modifications remained largely unknown for a long time. We summarize the latest progress made in the understanding of homeostasis-induced regulation of different steps of the synaptic vesicle cycle and the molecular machineries involved in this process. We particularly focus on the role of presynaptic scaffolding proteins, which functionally and spatially organize synaptic vesicle clusters, neurotransmitter release sites and the associated endocytic machinery. These proteins turned out to be major presynaptic substrates for remodeling during homeostatic plasticity. Finally, we discuss cellular processes and signaling pathways acting during homeostatic molecular remodeling and their potential involvement in the maladaptive plasticity occurring in multiple neuropathologic conditions such as neurodegeneration, epilepsy and neuropsychiatric disorders. PMID:24348337

  13. 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…

  14. 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…

  15. 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.

  16. Graphene Young's modulus: Molecular mechanics and DFT treatments

    NASA Astrophysics Data System (ADS)

    Memarian, F.; Fereidoon, A.; Darvish Ganji, M.

    2015-09-01

    Despite of the numerous theoretical and experimental investigations on the mechanical properties of graphene as a unique nano-structured material, a precious value for this important property has not yet been presented. In the present work, the Young's modulus of single layer graphene sheet has been investigated by using comprehensive classic as well as quantum mechanics (QM) calculations. Molecular mechanics (MM) approach with various well-defined force-fields such as AIREBO, Tresoff and EDIP potentials have been considered. In QM category, several conventional methods (DFTB and DFT-LDA/GGA) have been employed. The results show that EDIP potential method predicts more accurately the graphene Young's modulus value compared to experimental results. Furthermore, despite the various theoretical results reported elsewhere, the EDIP potential calculations result reveals that Young's modulus has the same value at both zigzag and armchair directions. From the results obtained here, we found that among the various MM and QM methods considered here the EDIP method seems to be the most convenient method for evaluation of both structural geometries and mechanical properties of carbon based graphene-like materials. This is because of its less computational costs accompanied with reliable results comparable with the experiments.

  17. Traditional Approaches to Molecular Genetic Analysis.

    PubMed

    Walker, Christopher J; Goodfellow, Paul J

    2017-01-01

    Molecular studies of endometrial cancer have evolved with the tools available to researchers: the methods for measuring nucleic acids, protein expression, and combinations thereof. Today "molecular genetic analysis" implies a broad range of indirect and direct tests that yield molecular phenotypes or genotypes, immunotypes, or signatures that were not conceived of when the histologic and biologic heterogeneity was first fully acknowledged.We will provide a historical perspective on molecular genetic studies of endometrial cancers focusing on candidate genes and how early foundational research shaped both our understanding of the disease and current research directions. Examples of direct tests (mutation, DNA methylation, and/or protein expression) will be provided along with examples of indirect tests that have been and continue to be central to endometrial cancer molecular biology, such as DNA content or microsatellite instability analysis. We will highlight clinically relevant examples of molecular phenotyping and direct evaluation of candidate genes that integrate direct and indirect testing as part of routine patient care. This is not intended to be an exhaustive review but rather an overview of the progress that has been made and how early work is shaping current molecular, clinical, and biologic studies of endometrial cancer.

  18. 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.

  19. Quantum Mechanics/Molecular Mechanics Study of the Sialyltransferase Reaction Mechanism.

    PubMed

    Hamada, Yojiro; Kanematsu, Yusuke; Tachikawa, Masanori

    2016-10-11

    The sialyltransferase is an enzyme that transfers the sialic acid moiety from cytidine 5'-monophospho-N-acetyl-neuraminic acid (CMP-NeuAc) to the terminal position of glycans. To elucidate the catalytic mechanism of sialyltransferase, we explored the potential energy surface along the sialic acid transfer reaction coordinates by the hybrid quantum mechanics/molecular mechanics method on the basis of the crystal structure of sialyltransferase CstII. Our calculation demonstrated that CstII employed an SN1-like reaction mechanism via the formation of a short-lived oxocarbenium ion intermediate. The computational barrier height was 19.5 kcal/mol, which reasonably corresponded with the experimental reaction rate. We also found that two tyrosine residues (Tyr156 and Tyr162) played a vital role in stabilizing the intermediate and the transition states by quantum mechanical interaction with CMP.

  20. Molecular Mechanisms Underlying Solute Retention at Heterogeneous Interfaces.

    PubMed

    El Hage, Krystel; Gupta, Prashant Kumar; Bemish, Raymond; Meuwly, Markus

    2017-09-21

    Despite considerable effort, a molecular-level understanding of the mechanisms governing adsorption/desorption in reversed-phase liquid chromatography is still lacking. This impedes rational design of columns and the development of reliable, computationally more efficient approaches to predict the selectivity of a particular column design. Using state-of-the art, validated force fields and free-energy simulations, the adsorption thermodynamics of benzene derivatives is investigated in atomistic detail and provides a quantitative microscopic understanding of retention when compared with experimental data. It is found that pure partitioning or pure adsorption is rather the exception than the rule. Typically, a pronounced ∼1 kcal/mol stabilization on the surface is accompanied by a broad trough indicative of partitioning before the probe molecule incorporates into the mobile phase. The present findings provide a quantitative and rational basis to develop improved effective, coarse-grained computational models and to design columns for specific applications.

  1. 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

  2. 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.

  3. Molecular mechanisms of phytochrome signal transduction in higher plants.

    PubMed

    Chu, Li-Ye; Shao, Hong-Bo; Li, Mao-Yau

    2005-11-10

    Phytochromes in higher plants play a great role in development, responses to environmental stresses and signal transduction, which are the fundamental principles for higher plants to be adapted to changing environment. Deep and systematic understanding of the phytochrome in higher plants is of crucial importance to molecular biology, purposeful improvement of environment in practice, especially molecular mechanism by which higher plants perceive UV-B stress. The last more than 10 years have seen rapid progress in this field with the aid of a combination of molecular, genetic and cell biological approaches. No doubt, what is the most important, is the application of Arabidopsis experimental system and the generation of various mutants regarding phytochromes (phy A-E). Increasing evidence demonstrates that phytochrome signaling transduction constitutes a highly ordered multidimensional network of events. Some phytochromes and signaling intermediates show light-dependent nuclear-cytoplasmic partitioning, which implies that early signaling events take place in the nucleus and that subcellular localization patterns most probably represent an important signaling control point. The main subcellular localization includes nucleus, cytosol and chloroplasts, respectively. Additionally, proteasome-mediated degradation of signaling intermediates most possibly function in concert with subcellular partitioning events as an integrated checkpoint. What higher plants do in this way is to execute accurate responses to the changes in the light environment on the basis of interconnected subcellular organelles. By integrating the available data, at the molecular level and from the angle of eco-environment, we should be able to construct a solid foundation for further dissection of phytochrome signaling transduction in higher plants.

  4. Molecular approaches to measuring microbial marine pollution.

    PubMed

    Pommepuy, M; Le Guyader, F

    1998-06-01

    Developments in the rapid detection of pathogens (PCR and its variations) and molecular typing of strains isolated from the ecosystem illustrate the stimulation of research due to the recent foodborne and waterborne disease outbreaks.

  5. Cell and molecular mechanics of biological materials

    NASA Astrophysics Data System (ADS)

    Bao, G.; Suresh, S.

    2003-11-01

    Living cells can sense mechanical forces and convert them into biological responses. Similarly, biological and biochemical signals are known to influence the abilities of cells to sense, generate and bear mechanical forces. Studies into the mechanics of single cells, subcellular components and biological molecules have rapidly evolved during the past decade with significant implications for biotechnology and human health. This progress has been facilitated by new capabilities for measuring forces and displacements with piconewton and nanometre resolutions, respectively, and by improvements in bio-imaging. Details of mechanical, chemical and biological interactions in cells remain elusive. However, the mechanical deformation of proteins and nucleic acids may provide key insights for understanding the changes in cellular structure, response and function under force, and offer new opportunities for the diagnosis and treatment of disease. This review discusses some basic features of the deformation of single cells and biomolecules, and examines opportunities for further research.

  6. Molecular and cellular mechanisms of dendritic morphogenesis

    PubMed Central

    Gao, Fen-Biao

    2008-01-01

    Summary Dendrites exhibit unique cell-type specific branching patterns and targeting specificity that are critically important for neuronal function and connectivity. Recent evidence indicates that highly complex transcriptional regulatory networks dictate various aspects of dendritic outgrowth, branching, and routing. In addition to other intrinsic molecular pathways such as membrane protein trafficking, interactions between neighboring dendritic branches also contribute to the final specification of dendritic morphology. Nonredundant coverage by dendrites of same type of neurons, known as tiling, requires the actions of the Tricornered/Furry (Sax-1/Sax-2) signaling pathway. However, the dendrites of a neuron do not cross over each other, a process called self-avoidance that is mediated by Down’s syndrome cell adhesion molecule (Dscam). Those exciting findings have enhanced significantly our understanding of dendritic morphogenesis and revealed the magnitude of complexity in the underlying molecular regulatory networks. PMID:17933513

  7. Molecular Mechanism of Cyclodextrin Mediated Cholesterol Extraction

    PubMed Central

    López, Cesar A.; de Vries, Alex H.; Marrink, Siewert J.

    2011-01-01

    The depletion of cholesterol from membranes, mediated by β-cyclodextrin (β-CD) is well known and documented, but the molecular details of this process are largely unknown. Using molecular dynamics simulations, we have been able to study the CD mediated extraction of cholesterol from model membranes, in particular from a pure cholesterol monolayer, at atomic resolution. Our results show that efficient cholesterol extraction depends on the structural distribution of the CDs on the surface of the monolayer. With a suitably oriented dimer, cholesterol is extracted spontaneously on a nanosecond time scale. Additional free energy calculations reveal that the CDs have a strong affinity to bind to the membrane surface, and, by doing so, destabilize the local packing of cholesterol molecules making their extraction favorable. Our results have implications for the interpretation of experimental measurements, and may help in the rational design of efficient CD based nano-carriers. PMID:21455285

  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. Glioblastoma: pathology, molecular mechanisms and markers.

    PubMed

    Aldape, Kenneth; Zadeh, Gelareh; Mansouri, Sheila; Reifenberger, Guido; von Deimling, Andreas

    2015-06-01

    Recent advances in genomic technology have led to a better understanding of key molecular alterations that underlie glioblastoma (GBM). The current WHO-based classification of GBM is mainly based on histologic features of the tumor, which frequently do not reflect the molecular differences that describe the diversity in the biology of these lesions. The current WHO definition of GBM relies on the presence of high-grade astrocytic neoplasm with the presence of either microvascular proliferation and/or tumor necrosis. High-throughput analyses have identified molecular subtypes and have led to progress in more accurate classification of GBM. These findings, in turn, would result in development of more effective patient stratification, targeted therapeutics, and prediction of patient outcome. While consensus has not been reached on the precise nature and means to sub-classify GBM, it is clear that IDH-mutant GBMs are clearly distinct from GBMs without IDH1/2 mutation with respect to molecular and clinical features, including prognosis. In addition, recent findings in pediatric GBMs regarding mutations in the histone H3F3A gene suggest that these tumors may represent a 3rd major category of GBM, separate from adult primary (IDH1/2 wt), and secondary (IDH1/2 mut) GBMs. In this review, we describe major clinically relevant genetic and epigenetic abnormalities in GBM-such as mutations in IDH1/2, EGFR, PDGFRA, and NF1 genes-altered methylation of MGMT gene promoter, and mutations in hTERT promoter. These markers may be incorporated into a more refined classification system and applied in more accurate clinical decision-making process. In addition, we focus on current understanding of the biologic heterogeneity and classification of GBM and highlight some of the molecular signatures and alterations that characterize GBMs as histologically defined. We raise the question whether IDH-wild type high grade astrocytomas without microvascular proliferation or necrosis might best be

  10. 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

    2015-11-06

    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.

  11. An Approach with Hybrid Segmental Mechanics

    PubMed Central

    Mishra, Harsh Ashok

    2016-01-01

    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

  12. Neural mechanisms of cue-approach training.

    PubMed

    Bakkour, Akram; Lewis-Peacock, Jarrod A; Poldrack, Russell A; Schonberg, Tom

    2017-05-01

    Biasing choices may prove a useful way to implement behavior change. Previous work has shown that a simple training task (the cue-approach task), which does not rely on external reinforcement, can robustly influence choice behavior by biasing choice toward items that were targeted during training. In the current study, we replicate previous behavioral findings and explore the neural mechanisms underlying the shift in preferences following cue-approach training. Given recent successes in the development and application of machine learning techniques to task-based fMRI data, which have advanced understanding of the neural substrates of cognition, we sought to leverage the power of these techniques to better understand neural changes during cue-approach training that subsequently led to a shift in choice behavior. Contrary to our expectations, we found that machine learning techniques applied to fMRI data during non-reinforced training were unsuccessful in elucidating the neural mechanism underlying the behavioral effect. However, univariate analyses during training revealed that the relationship between BOLD and choices for Go items increases as training progresses compared to choices of NoGo items primarily in lateral prefrontal cortical areas. This new imaging finding suggests that preferences are shifted via differential engagement of task control networks that interact with value networks during cue-approach training. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Genomic approaches for investigating mechanisms of genotoxicity.

    PubMed

    Caba, Ebru; Aubrecht, Jiri

    2006-01-01

    The current genetic toxicity testing battery enables an accurate and effective detection of genotoxicity associated with exposure to chemicals. However, the interpretation of the data in light of the relevant risk to humans is often difficult due to limited insight into underlying genotoxic mechanisms. Thus, the development of experimental approaches capable of differentiating genotoxic mechanisms is expected to facilitate risk assessment. Recent progress in science and technology has enabled the investigation of the stress response associated with chemical exposure at the genomic level. For instance, gene expression profile analysis, transcriptomics, was proposed as a tool for evaluating toxic mechanisms. In addition, the advancement in genetic tools has allowed the study of stress response on a functional level, functional genomics. This review will outline a number of recent developments in genomic analyses of genotoxic stress response and provide a perspective on their application in genetic toxicology.

  14. Emerging molecular approaches in stem cell biology.

    PubMed

    Jaishankar, Amritha; Vrana, Kent

    2009-04-01

    Stem cells are characterized by their ability to self-renew and differentiate into multiple adult cell types. Although substantial progress has been made over the last decade in understanding stem cell biology, recent technological advances in molecular and systems biology may hold the key to unraveling the mystery behind stem cell self-renewal and plasticity. The most notable of these advances is the ability to generate induced pluripotent cells from somatic cells. In this review, we discuss our current understanding of molecular similarities and differences among various stem cell types. Moreover, we survey the current state of systems biology and forecast future needs and direction in the stem cell field.

  15. Mechanism of Spontaneous Oscillation Emerging from Collective Molecular Motors

    NASA Astrophysics Data System (ADS)

    Shimamoto, Yuta; Ishiwata, Shin'ichi

    2008-04-01

    Biological systems include a large number and various kinds of molecular machines. Individual molecular machines work stochastically, while the systems constructed of the ensembles of these machines exhibit dynamically-ordered phenomena, rather than a simple sum of individual parts. Here we focus on the spontaneous oscillatory contraction (SPOC) observed in the contractile system of muscle. From the mechanical measurements in the precursor state of SPOC, we discuss how the functions of individual molecular motors are autonomously regulated in the contractile system.

  16. 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)

  17. GPU-accelerated molecular mechanics computations.

    PubMed

    Anthopoulos, Athanasios; Grimstead, Ian; Brancale, Andrea

    2013-10-05

    In this article, we describe an improved cell-list approach designed to match the Kepler architecture of General-purpose graphics processing units (GPGPU). We explain how our approach improves load balancing for the above algorithm and how warp intrinsics are used to implement Newton's third law for the nonbonded force calculations. We also talk through our approach to exclusions handling together with a method to calculate bonded forces and 1-4 electrostatic scaling using a single Cuda kernel. Performance benchmarks are included in the last sections to show the linear scaling of our implementation using a step minimization method. In addition, multiple performance benchmarks demonstrate the contribution of various optimizations we used for our implementations. © 2013 Wiley Periodicals, Inc.

  18. Insect pathogens: molecular approaches and techniques

    USDA-ARS?s Scientific Manuscript database

    This book serves as a primer for molecular techniques in insect pathology and is tailored for a wide scientific audience. Contributing authors are internationally recognized experts. The book comprises four sections: 1) pathogen identification and diagnostics, 2) pathogen population genetics and p...

  19. Molecular Mechanisms and Treatment of Radiation-Induced Lung Fibrosis

    PubMed Central

    Ding, Nian-Hua; Li, Jian Jian; Sun, Lun-Quan

    2014-01-01

    Radiation-induced lung fibrosis (RILF) is a severe side effect of radiotherapy in lung cancer patients that presents as a progressive pulmonary injury combined with chronic inflammation and exaggerated organ repair. RILF is a major barrier to improving the cure rate and well-being of lung cancer patients because it limits the radiation dose that is required to effectively kill tumor cells and diminishes normal lung function. Although the exact mechanism is unclear, accumulating evidence suggests that various cells, cytokines and regulatory molecules are involved in the tissue reorganization and immune response modulation that occur in RILF. In this review, we will summarize the general symptoms, diagnostics, and current understanding of the cells and molecular factors that are linked to the signaling networks implicated in RILF. Potential approaches for the treatment of RILF will also be discussed. Elucidating the key molecular mediators that initiate and control the extent of RILF in response to therapeutic radiation may reveal additional targets for RILF treatment to significantly improve the efficacy of radiotherapy for lung cancer patients. PMID:23909719

  20. 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

  1. Molecular and cellular mechanisms of pulmonary fibrosis

    PubMed Central

    2012-01-01

    Pulmonary fibrosis is a chronic lung disease characterized by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture. Idiopathic pulmonary fibrosis is considered the most common and severe form of the disease, with a median survival of approximately three years and no proven effective therapy. Despite the fact that effective treatments are absent and the precise mechanisms that drive fibrosis in most patients remain incompletely understood, an extensive body of scientific literature regarding pulmonary fibrosis has accumulated over the past 35 years. In this review, we discuss three broad areas which have been explored that may be responsible for the combination of altered lung fibroblasts, loss of alveolar epithelial cells, and excessive accumulation of ECM: inflammation and immune mechanisms, oxidative stress and oxidative signaling, and procoagulant mechanisms. We discuss each of these processes separately to facilitate clarity, but certainly significant interplay will occur amongst these pathways in patients with this disease. PMID:22824096

  2. 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

  3. 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

  4. Etiologies and molecular mechanisms of communication disorders.

    PubMed

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

    2010-09-01

    Quantitative behavioral genetic studies have made it clear that communication disorders such as reading disability, language impairment, and autism spectrum disorders follow some basic principles: (1) complex disorders have complex causes, in which 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. However, these goals are still in the future. 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 are 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.

  5. [Molecular biology and immunopathogenetic mechanisms of sepsis].

    PubMed

    Průcha, M

    2009-01-01

    Sepsis, the systemic inflammatory response to infection, causes high mortality in patients in non-coronary units of intensive care. The most important characteristic of sepsis is the interaction between two subjects, the macro and the microorganism, associated with the dysfunction of innate and adaptive immunity. Sepsis is understood more as a dynamic syndrome characterized by many phenomenona which are often antagonistic. The inflammation, characterizing sepsis, does not act as a primary physiological compensatory mechanism and rather oscillates between the phase of hyperinflammatory response and anergy or immunoparalysis. The elucidation of the pathogenesis of sepsis is linked to the understanding of immunopathogenetic mechanisms, which characterize the interaction between the macro and microorganisms.

  6. 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

  7. 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

  8. 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.

  9. 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)

  10. 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.

  11. 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)

  12. Emerging mechanisms of molecular pathology in ALS

    PubMed Central

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

    2015-01-01

    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

  13. 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.

  14. 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

  15. Molecular mechanisms of synaptic remodeling in alcoholism.

    PubMed

    Kyzar, Evan J; Pandey, Subhash C

    2015-08-05

    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. Published by Elsevier Ireland Ltd.

  16. Molecular mechanics modeling of azobenzene-based photoswitches.

    PubMed

    Duchstein, Patrick; Neiss, Christian; Görling, Andreas; Zahn, Dirk

    2012-06-01

    We present an extension of the generalized amber force field to allow the modeling of azobenzenes by means of classical molecular mechanics. TD-DFT calculations were employed to derive different interaction models for 4-hydroxy-4'-methyl-azobenzene, including the ground (S(0)) and S(1) excited state. For both states, partial charges and the -N = N- torsion potentials were characterized. On this basis, we pave the way to large-scale model simulations involving azobenzene molecular switches. Using the example of an isolated molecule, the mechanics of cyclic switching processes are demonstrated by classical molecular dynamics simulations.

  17. 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.

  18. Molecular and biochemical mechanisms of preterm labour.

    PubMed

    Mohan, Aarthi R; Loudon, Jenifer A; Bennett, Phillip R

    2004-12-01

    Parturition involves the synchronization of myometrial activity and structural changes of the cervix, leading to regular co-ordinated uterine contractions and cervical dilatation and effacement. The biochemical events involved in parturition resemble an inflammatory reaction, with growing evidence pointing to a crucial role for pro-inflammatory cytokines and prostaglandins in labour. There is accumulating evidence that there are common mediators involved in the regulation of 'labour-associated proteins', and that, in each case, an increase or decrease in gene expression mediates changes in their concentration. It is possible, therefore, that targeting these common mediators may represent newer strategies for the prevention of preterm labour. Our aim is to review the mechanical and biochemical mechanisms that may be involved in the processes of term and preterm labour. Specifically, we will consider the regulation of some of the 'labour-associated proteins', chemotactic cytokines, prostaglandins and enzymes of the prostaglandin biosynthetic pathway and the oxytocin receptor.

  19. 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

  20. 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.

  1. Cellular and molecular mechanisms of muscle atrophy

    PubMed Central

    Bonaldo, Paolo; Sandri, Marco

    2013-01-01

    Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases. PMID:23268536

  2. 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.

  3. 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

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

    PubMed

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

    2015-01-01

    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.

  5. 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)

  6. 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

  7. Advanced Lung Cancer Screening: An Individualized Molecular Nanotechnology Approach

    DTIC Science & Technology

    2016-03-01

    Award Number: W81XWH-12-1-0323 TITLE: Advanced Lung Cancer Screening: An Individualized Molecular Nanotechnology Approach PRINCIPAL... control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE March 2016 2. REPORT TYPE Final 3. DATES COVERED 4. TITLE AND...SUBTITLE Advanced Lung Cancer Screening: An Individualized Molecular Nanotechnology Approach 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT

  8. 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

  9. HIV-1 evolution: frustrating therapies, but disclosing molecular mechanisms

    PubMed Central

    Das, Atze T.; Berkhout, Ben

    2010-01-01

    Replication of HIV-1 under selective pressure frequently results in the evolution of virus variants that replicate more efficiently under the applied conditions. For example, in patients on antiretroviral therapy, such evolution can result in variants that are resistant to the HIV-1 inhibitors, thus frustrating the therapy. On the other hand, virus evolution can help us to understand the molecular mechanisms that underlie HIV-1 replication. For example, evolution of a defective virus mutant can result in variants that overcome the introduced defect by restoration of the original sequence or by the introduction of additional mutations in the viral genome. Analysis of the evolution pathway can reveal the requirements of the element under study and help to understand its function. Analysis of the escape routes may generate new insight in the viral life cycle and result in the identification of unexpected biological mechanisms. We have developed in vitro HIV-1 evolution into a systematic research tool that allows the study of different aspects of the viral replication cycle. We will briefly review this method of forced virus evolution and provide several examples that illustrate the power of this approach. PMID:20478891

  10. HIV-1 evolution: frustrating therapies, but disclosing molecular mechanisms.

    PubMed

    Das, Atze T; Berkhout, Ben

    2010-06-27

    Replication of HIV-1 under selective pressure frequently results in the evolution of virus variants that replicate more efficiently under the applied conditions. For example, in patients on antiretroviral therapy, such evolution can result in variants that are resistant to the HIV-1 inhibitors, thus frustrating the therapy. On the other hand, virus evolution can help us to understand the molecular mechanisms that underlie HIV-1 replication. For example, evolution of a defective virus mutant can result in variants that overcome the introduced defect by restoration of the original sequence or by the introduction of additional mutations in the viral genome. Analysis of the evolution pathway can reveal the requirements of the element under study and help to understand its function. Analysis of the escape routes may generate new insight in the viral life cycle and result in the identification of unexpected biological mechanisms. We have developed in vitro HIV-1 evolution into a systematic research tool that allows the study of different aspects of the viral replication cycle. We will briefly review this method of forced virus evolution and provide several examples that illustrate the power of this approach.

  11. 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

  12. Structure-based molecular modeling approaches to GPCR oligomerization.

    PubMed

    Kaczor, Agnieszka A; Selent, Jana; Poso, Antti

    2013-01-01

    Classical structure-based drug design techniques using G-protein-coupled receptors (GPCRs) as targets focus nearly exclusively on binding at the orthosteric site of a single receptor. Dimerization and oligomerization of GPCRs, proposed almost 30 years ago, have, however, crucial relevance for drug design. Targeting these complexes selectively or designing small molecules that affect receptor-receptor interactions might provide new opportunities for novel drug discovery. In order to study the mechanisms and dynamics that rule GPCRs oligomerization, it is essential to understand the dynamic process of receptor-receptor association and to identify regions that are suitable for selective drug binding, which may be determined with experimental methods such as Förster resonance energy transfer (FRET) or Bioluminescence resonance energy transfer (BRET) and computational sequence- and structure-based approaches. The aim of this chapter is to provide a comprehensive description of the structure-based molecular modeling methods for studying GPCR dimerization, that is, protein-protein docking, molecular dynamics, normal mode analysis, and electrostatics studies.

  13. 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.

  14. 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

  15. Molecular mechanisms of male germ cell differentiation.

    PubMed

    Hecht, N B

    1998-07-01

    During spermatogenesis, diploid stem cells differentiate, undergo meiosis, and transform into haploid spermatozoa. As this precisely timed series of events proceeds, chromosomal ploidy is reduced and the nucleosomes of the chromatin are replaced by a transcriptionally quiescent protamine-containing nucleus. The premature termination of transcription during the haploid phase of spermatogenesis necessitates an especially prominent role for posttranscriptional regulation in the temporal and spatial expression of many testis-specific proteins and isozymes. In this review article, discussion will focus on novel mechanisms regulating gene expression in mammalian male germ cells from genome to protein.

  16. 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.

  17. Drug discovery in tuberculosis: a molecular approach.

    PubMed

    Mitra, Partha P

    2012-10-01

    Despite unquestionable success of the combination drug therapy, tuberculosis (TB) very recently has drawn major attention because of the global upsurge of MDR-TB, XDR -TB and HIV-TB co-infection cases. In the last four decades, only one compound is added to the treatment regimen leaving ample opportunities to find out a new generation of TB drugs. The modern concept of drug discovery utilizes the integrated knowledge of genomics, proteomics, molecular biology and systems biology to identify more specific targets. The purpose of this review is to revisit the field of tuberculosis drug discovery based on those new concepts to identify novel targets.

  18. 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

  19. Molecular mechanisms of chromosomal rearrangement in fungi.

    PubMed

    Fierro, F; Martín, J F

    1999-01-01

    Both sexual and asexual fungi undergo chromosomal rearrangements, which are the main cause of karyotype variability among the populations. Different recombination processes can produce chromosomal reorganizations, both during mitosis and meiosis, but other mechanisms operate to limit the extent of the rearrangements; some of these mechanisms, such as the RIP (repeat-induced point mutations) of Neurospora crassa, have been well established for sexual fungi. In laboratory strains, treatments such as mutation and transformation enhance the appearance of chromosomal rearrangements. Different DNA sequences present in fungal genomes are able to promote these reorganizations; some of these sequences are involved in well-regulated processes (e.g., site-specific recombination) but most of them act simply as substrates for recombination events leading to DNA rearrangements. In Penicillium chrysogenum we have found that short specific DNA sequences are involved in tandem reiterations leading to amplification of the cluster of the penicillin biosynthesis genes. In some cases, specific chromosomal rearrangements have been associated with particular phenotypes (as occurs in adaptive-like mutants of Candida albicans and Candida stellatoidea), and they may play a role in genetic variability for environmental adaptation.

  20. Raman scattering from molecular conduction junctions: Charge transfer mechanism

    NASA Astrophysics Data System (ADS)

    Oren, Michal; Galperin, Michael; Nitzan, Abraham

    2012-03-01

    We present a model for the charge transfer contribution to surface-enhanced Raman spectroscopy (SERS) in a molecular junction. The model is a generalization of the equilibrium scheme for SERS of a molecule adsorbed on a metal surface [B. N. J. Persson. Chem. Phys. Lett.CHPLBC0009-261410.1016/0009-2614(81)85441-3 82, 561 (1981)]. We extend the same physical consideration to a nonequilibrium situation in a biased molecular junction and to nonzero temperatures. Two approaches are considered and compared: a semiclassical approach appropriate for nonresonance Raman scattering, and a quantum approach based on the nonequilibrium Green's function method. Nonequilibrium effects on this contribution to SERS are demonstrated with numerical examples. It is shown that the semiclassical approach provides an excellent approximation to the full quantum calculation as long as the molecular electronic state is outside the Fermi window, that is, as long as the field-induced charge transfer is small.

  1. 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

  2. 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

  3. Molecular mechanisms of intercellular communication: transmembrane signaling

    SciTech Connect

    Bitensky, M.W.; George, J.S.; Siegel, H.N.; McGregor, D.M.

    1982-01-01

    This short discussion of transmembrane signaling depicts a particular class of signaling devices whose functional characteristics may well be representative of broader classes of membrane switches. These multicomponent aggregates are characterized by tight organization of interacting components which function by conformational interactions to provide sensitive, amplified, rapid, and modulated responses. It is clear that the essential role of such switches in cell-cell interactions necessitated their appearance early in the history of the development of multicellular organisms. It also seems clear that once such devices made their appearance, the conformationally interactive moieties were firmly locked into a regulatory relationship. Since modification of interacting components could perturb or interfere with the functional integrity of the whole switch, genetic drift was only permitted at the input and outflow extremes. However, the GTP binding moiety and its interacting protein domains on contiguous portions of the receptor and readout components were highly conserved. The observed stringent evolutionary conservation of the molecular features of these membrane switches thus applies primarily to the central (GTP binding) elements. An extraordinary degree of variation was permitted within the domains of signal recognition and enzymatic output. Thus, time and evolution have adapted the central logic of the regulatory algorithm to serve a great variety of cellular purposes and to recognize a great variety of chemical and physical signals. This is exemplified by the richness of the hormonal and cellular dialogues found in primates such as man. Here the wealth of intercellular communiation can support the composition and performance of symphonies and the study of cellular immunology.

  4. A rapid molecular approach for chromosomal phasing.

    PubMed

    Regan, John F; Kamitaki, Nolan; Legler, Tina; Cooper, Samantha; Klitgord, Niels; Karlin-Neumann, George; Wong, Catherine; Hodges, Shawn; Koehler, Ryan; Tzonev, Svilen; McCarroll, Steven A

    2015-01-01

    Determining the chromosomal phase of pairs of sequence variants - the arrangement of specific alleles as haplotypes - is a routine challenge in molecular genetics. Here we describe Drop-Phase, a molecular method for quickly ascertaining the phase of pairs of DNA sequence variants (separated by 1-200 kb) without cloning or manual single-molecule dilution. In each Drop-Phase reaction, genomic DNA segments are isolated in tens of thousands of nanoliter-sized droplets together with allele-specific fluorescence probes, in a single reaction well. Physically linked alleles partition into the same droplets, revealing their chromosomal phase in the co-distribution of fluorophores across droplets. We demonstrated the accuracy of this method by phasing members of trios (revealing 100% concordance with inheritance information), and demonstrate a common clinical application by phasing CFTR alleles at genomic distances of 11-116 kb in the genomes of cystic fibrosis patients. Drop-Phase is rapid (requiring less than 4 hours), scalable (to hundreds of samples), and effective at long genomic distances (200 kb).

  5. 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.

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

    PubMed Central

    Daste, Frederic

    2016-01-01

    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

  7. [Molecular mechanisms of skeletal muscle hypertrophy].

    PubMed

    Astratenkova, I V; Rogozkin, V A

    2014-06-01

    Enzymes Akt, AMPK, mTOR, S6K and PGC-1a coactivator take part in skeletal muscles in the regulation of synthesis of proteins. The expression of these proteins is regulated by growth factors, hormones, nutrients, mechanical loading and leads to an increase in muscle mass and skeletal muscle hypertrophy. The review presents the results of studies published in the past four years, which expand knowledge on the effects of various factors on protein synthesis in skeletal muscle. The attention is focused on the achievements that reveal and clarify the signaling pathways involved in the regulation of protein synthesis in skeletal muscle. The central place is taken by mTOR enzyme which controls and regulates the main stages of the cascade of reactions of muscle proteins providing synthesis in the conditions of human life. coactivator PGC-1a.

  8. Cellular and molecular mechanisms coordinating pancreas development.

    PubMed

    Bastidas-Ponce, Aimée; Scheibner, Katharina; Lickert, Heiko; Bakhti, Mostafa

    2017-08-15

    The pancreas is an endoderm-derived glandular organ that participates in the regulation of systemic glucose metabolism and food digestion through the function of its endocrine and exocrine compartments, respectively. While intensive research has explored the signaling pathways and transcriptional programs that govern pancreas development, much remains to be discovered regarding the cellular processes that orchestrate pancreas morphogenesis. Here, we discuss the developmental mechanisms and principles that are known to underlie pancreas development, from induction and lineage formation to morphogenesis and organogenesis. Elucidating such principles will help to identify novel candidate disease genes and unravel the pathogenesis of pancreas-related diseases, such as diabetes, pancreatitis and cancer. © 2017. Published by The Company of Biologists Ltd.

  9. Molecular Mechanisms of Renal Ammonia Transport

    PubMed Central

    Weiner, I. David; Hamm, L. Lee

    2015-01-01

    Acid-base homeostasis to a great extent relies on renal ammonia metabolism. In the past several years, seminal studies have generated important new insights into the mechanisms of renal ammonia transport. In particular, the theory that ammonia transport occurs almost exclusively through nonionic NH3 diffusion and NH4+ trapping has given way to a model postulating that a variety of proteins specifically transport NH3 and NH4+ and that this transport is critical for normal ammonia metabolism. Many of these proteins transport primarily H+ or K+ but also transport NH4+. Nonerythroid Rh glycoproteins transport ammonia and may represent critical facilitators of ammonia transport in the kidney. This review discusses the underlying aspects of renal ammonia transport as well as specific proteins with important roles in renal ammonia transport. PMID:17002591

  10. Flavonoids health benefits and their molecular mechanism.

    PubMed

    Xiao, Z-P; Peng, Z-Y; Peng, M-J; Yan, W-B; Ouyang, Y-Z; Zhu, H-L

    2011-02-01

    Flavonoids are a group of polyphenolic compounds, diverse in chemical structure and characteristics, found ubiquitously in plants. Until now, more than 9000 different flavonoid compounds were described in plants, where they play important biological roles by affecting several developmental processes. There has been increasing interest in the research of flavonoids from dietary sources, due to growing evidence of the versatile health benefits of flavonoids including anti-inflammatory, antioxidant, antiproliferative and anticancer activity, freeradical scavenging capacity, antihypertensive effects, coronary heart disease prevention and anti-human immunodeficiency virus functions. This paper reviews the current advances in flavonoids in food with emphasis on mechanism aspects on the basis of the published literature, which may provide some guidance for researchers in further investigations and for industries in developing practical health agents.

  11. [Molecular mechanism for feeding and food preference regulation].

    PubMed

    Minokoshi, Yasuhiko

    2016-03-01

    Feeding behavior is regulated by homeostatic and hedonic mechanisms. NPY/AgRP neurons in the arcuate hypothalamus are involved in the homeostatic regulation, and dopaminergic neurons in the ventral tegmental area regulating the nucleus of accumbens are involved in the hedonic regulation, respectively. Food preference also appears to be regulated by both homeostatic and hedonic mechanisms. However, molecular mechanism for food preference regulation remains elusive and further studies are necessary.

  12. 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

  13. A mixed molecular modeling-robotics approach to investigate lipase large molecular motions.

    PubMed

    Barbe, Sophie; Cortés, Juan; Siméon, Thierry; Monsan, Pierre; Remaud-Siméon, Magali; André, Isabelle

    2011-08-01

    Large-scale conformational rearrangement of a lid subdomain is a key event in the interfacial activation of many lipases. We present herein a study in which the large-scale "open-to-closed" movement of Burkholderia cepacia lipase lid has been simulated at the atomic level using a hybrid computational method. The two-stage approach combines path-planning algorithms originating from robotics and molecular mechanics methods. In the first stage, a path-planning approach is used to compute continuous and geometrically feasible pathways between two protein conformational states. Then, an energy minimization procedure using classical molecular mechanics is applied to intermediate conformations in the path. The main advantage of such a combination of methods is that only geometrically feasible solutions are prompted for energy calculation in explicit solvent, which allows the atomic-scale description of the transition pathway between two extreme conformations of B. cepacia lipase (BCL; open and closed states) within very short computing times (a few hours on a desktop computer). Of interest, computed pathways enable the description of intermediate conformations along the "open-to-closed" conformational transition of BCL lid and the identification of bottlenecks during the lid closing. Furthermore, consideration of the solvent effect when computing the transition energy profiles provides valuable information regarding the feasibility and the spontaneity of the movement under the influence of the solvent environment. This new hybrid computational method turned out to be well-suited for investigating at an atomistic level large-scale conformational motion and at a qualitative level, the solvent effect on the energy profiles associated with the global motion. Copyright © 2011 Wiley-Liss, Inc.

  14. Molecular mechanisms of retroviral integration site selection

    PubMed Central

    Kvaratskhelia, Mamuka; Sharma, Amit; Larue, Ross C.; Serrao, Erik; Engelman, Alan

    2014-01-01

    Retroviral replication proceeds through an obligate integrated DNA provirus, making retroviral vectors attractive vehicles for human gene-therapy. Though most of the host cell genome is available for integration, the process of integration site selection is not random. Retroviruses differ in their choice of chromatin-associated features and also prefer particular nucleotide sequences at the point of insertion. Lentiviruses including HIV-1 preferentially integrate within the bodies of active genes, whereas the prototypical gammaretrovirus Moloney murine leukemia virus (MoMLV) favors strong enhancers and active gene promoter regions. Integration is catalyzed by the viral integrase protein, and recent research has demonstrated that HIV-1 and MoMLV targeting preferences are in large part guided by integrase-interacting host factors (LEDGF/p75 for HIV-1 and BET proteins for MoMLV) that tether viral intasomes to chromatin. In each case, the selectivity of epigenetic marks on histones recognized by the protein tether helps to determine the integration distribution. In contrast, nucleotide preferences at integration sites seem to be governed by the ability for the integrase protein to locally bend the DNA duplex for pairwise insertion of the viral DNA ends. We discuss approaches to alter integration site selection that could potentially improve the safety of retroviral vectors in the clinic. PMID:25147212

  15. 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.

  16. Towards a mechanism-based approach to pain diagnosis

    PubMed Central

    Vardeh, Daniel

    2016-01-01

    three steps: pain state, pain mechanism and molecular target. Such an approach could serve as the foundation for a new era of individualized/precision pain medicine. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) and American Pain Society (APS) Pain Taxonomy (AAPT) includes pain mechanisms as one of the 5 dimensions that need to be considered when making a diagnostic classification. The diagnostic ladder proposed in this article is both consistent with and an extension of the AAPT. PMID:27586831

  17. 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.

  18. Genomics, Physiology, and Molecular Breeding Approaches for Improving Salt Tolerance.

    PubMed

    Ismail, Abdelbagi M; Horie, Tomoaki

    2017-02-22

    Salt stress reduces land and water productivity and contributes to poverty and food insecurity. Increased salinization caused by human practices and climate change is progressively reducing agriculture productivity despite escalating calls for more food. Plant responses to salt stress are fairly well understood, involving numerous critical processes that are each controlled by multiple genes. Knowledge of the critical mechanisms controlling salt uptake and exclusion from functioning tissues, signaling of salt stress, and the arsenal of protective metabolites is advancing. However, little progress has been made in developing salt-tolerant varieties of crop species using standard (but slow) breeding approaches. The genetic diversity available within cultivated crops and their wild relatives provides rich sources for trait and gene discovery that has yet to be sufficiently utilized. Transforming this knowledge into modern approaches using genomics and molecular tools for precision breeding will accelerate the development of tolerant cultivars and help sustain food production. Expected final online publication date for the Annual Review of Plant Biology Volume 68 is April 29, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  19. 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.

  20. [Molecular genetic and epigenetic mechanisms of hepatocarcinogenesis].

    PubMed

    Xue, Kai-Xian

    2005-06-01

    Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and one of the most frequent human malignant neoplasms. Common risk factors of human HCC include chronic hepatitis virus (HBV and HCV) infection, dietary aflatoxin B1 (AFB1) ingestion, chronic alcohol abuse, and cirrhosis associated with genetic liver diseases. Hepatocarcinogenesis is the result of interaction between hereditary and environmental factors. Inheritance determines individual susceptibility to cancer; environment determines which susceptible individuals express cancer. Studies of genetic and epigenetic mechanisms of hepatocarcinogenesis showed that HCC development is a complex polygene and multipathway process; the activation of proto-oncogenes and the inactivation of tumor suppressor genes induced by genetic and epigenetic alterations are core biological processes of hepatocarcinogenesis; RB1, p53, and Wnt pathways are commonly affected in HCCs of different etiologies, which may reflect common pathologic sequence of HCC: chronic liver injury, cirrhosis, atypical hyperplastic nodules, and HCC of early stages. Hepatitis virus infection-associated HCCs have frequent alterations in RB1 pathway, including methylation of p16INK4a and RB1 genes and amplification of Cyclin D1. AFB1 exposure-associated HCCs have frequent alterations in p53 pathway; the G-->T mutation of p53 gene at codon 249 has been identified as a genetic hallmark of HCC caused by AFB1. Alcoholism-associated HCCs have frequent alterations in both RB1 and p53 pathways. The roles of some important genes related to cell apoptosis, DNA repair, drug metabolism, and tumor metastasis in hepatocarcinogenesis had been discussed.

  1. 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.

  2. Molecular mechanisms of ultraviolet radiation carcinogenesis.

    PubMed

    Ananthaswamy, H N; Pierceall, W E

    1990-12-01

    UV radiation is a potent DNA damaging agent and a known inducer of skin cancer in experimental animals. There is excellent scientific evidence to indicate that most non-melanoma human skin cancers are induced by repeated exposure to sunlight. UV radiation is unique in that it induces DNA damage that differs from the lesions induced by any other carcinogen. The prevalence of skin cancer on sun-exposed body sites in individuals with the inherited disorder XP suggests that defective repair of UV-induced DNA damage can lead to cancer induction. Carcinogenesis in the skin, as elsewhere, is a multistep process in which a series of genetic and epigenetic events leads to the emergence of a clone of cells that have escaped normal growth control mechanisms. The principal candidates that are involved in these events are oncogenes and tumor suppressor genes. Oncogenes display a positive effect on transformation, whereas tumor suppressor genes have an essentially negative effect, blocking transformation. Activated ras oncogenes have been identified in human skin cancers. In most cases, the mutations in the ras oncogenes have been localized to pyrimidine-rich sequences, which indicates that these sites are probably the targets for UV-induced DNA damage and subsequent mutation and transformation. The finding that activation of ras oncogenes in benign and self-regressing keratoacanthomas in both humans and in animals indicates that they play a role in the early stages of carcinogenesis (Corominas et al., 1989; Kumar et al., 1990). Since cancers do not arise immediately after exposure to physical or chemical carcinogens, ras oncogenes must remain latent for long periods of time. Tumor growth and progression into the more malignant stages may require additional events involving activation of other oncogenes or deletion of growth suppressor genes. In addition, amplification of proto-oncogenes or other genes may also be involved in tumor induction or progression. In contrast to the

  3. A molecular dynamics approach to barrodiffusion

    NASA Astrophysics Data System (ADS)

    Cooley, James; Marciante, Mathieu; Murillo, Michael

    2016-10-01

    Unexpected phenomena in the reaction rates for Inertial Confinement Fusion (ICF) capsules have led to a renewed interest in the thermo-dynamically driven diffusion process for the past 10 years, often described collectively as barodiffusion. In the current context, barodiffusion would manifest as a process that separates ions of differing mass and charge ratios due to pressure and temperature gradients set-up through shock structures in the capsule core. Barrodiffusion includes additional mass transfer terms that account for the irreversible transport of species due to gradients in the system, both thermodynamic and electric e.g, i = - ρD [ ∇c +kp ∇ln(pi) +kT(i) ∇ln(Ti) +kt(e) ∇ln(Te) +eke/Ti ∇ϕ ] . Several groups have attacked this phenomena using continuum scale models and supplemented with kinetic theory to derive coefficients for the different diffusion terms based on assumptions about the collisional processes. In contrast, we have applied a molecular dynamics (MD) simulation to this system to gain a first-principle understanding of the rate kinetics and to assess the accuracy of the differin

  4. 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.

  5. 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.

  6. Recent Advances in Molecular Mechanisms of Abdominal Aortic Aneurysm Formation

    PubMed Central

    Annambhotla, Suman; Bourgeois, Sebastian; Wang, Xinwen; Lin, Peter H.; Yao, Qizhi; Chen, Changyi

    2010-01-01

    Abdominal Aortic Aneurysm (AAA) is an increasingly common clinical condition with fatal implications. It is associated with advanced age, male gender, cigarette smoking, atherosclerosis, hypertension, and genetic predisposition. Although significant evidence has emerged in the last decade, the molecular mechanisms of AAA formation remains poorly understood. Currently, the treatment for AAA remains primarily surgical with the lone innovation of endovascular therapy. With advance in the human genome, understanding precisely which molecules and genes mediate AAA development and blocking their activity at the molecular level could lead to important new discoveries and therapies. This review summarizes recent updates in molecular mechanisms of AAA formation including animal models, autoimmune components, infection, key molecules and cytokines, mechanical forces, genetics and pharmacotherapy. This review will be helpful to those who want to recognize the newest endeavors within the field and identify possible lines of investigation in AAA. PMID:18259804

  7. 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.

  8. Quantum approach to classical statistical mechanics.

    PubMed

    Somma, R D; Batista, C D; Ortiz, G

    2007-07-20

    We present a new approach to study the thermodynamic properties of d-dimensional classical systems by reducing the problem to the computation of ground state properties of a d-dimensional quantum model. This classical-to-quantum mapping allows us to extend the scope of standard optimization methods by unifying them under a general framework. The quantum annealing method is naturally extended to simulate classical systems at finite temperatures. We derive the rates to assure convergence to the optimal thermodynamic state using the adiabatic theorem of quantum mechanics. For simulated and quantum annealing, we obtain the asymptotic rates of T(t) approximately (pN)/(k(B)logt) and gamma(t) approximately (Nt)(-c/N), for the temperature and magnetic field, respectively. Other annealing strategies are also discussed.

  9. Graph-drawing algorithms geometries versus molecular mechanics in fullereness

    NASA Astrophysics Data System (ADS)

    Kaufman, M.; Pisanski, T.; Lukman, D.; Borštnik, B.; Graovac, A.

    1996-09-01

    The algorithms of Kamada-Kawai (KK) and Fruchterman-Reingold (FR) have been recently generalized (Pisanski et al., Croat. Chem. Acta 68 (1995) 283) in order to draw molecular graphs in three-dimensional space. The quality of KK and FR geometries is studied here by comparing them with the molecular mechanics (MM) and the adjacency matrix eigenvectors (AME) algorithm geometries. In order to compare different layouts of the same molecule, an appropriate method has been developed. Its application to a series of experimentally detected fullerenes indicates that the KK, FR and AME algorithms are able to reproduce plausible molecular geometries.

  10. Principles of cellular-molecular mechanisms underlying neuron functions.

    PubMed

    Ratushnyak, Alexander S; Zapara, Tatiana A

    2009-12-01

    In the present work, it was experimentally shown that a neuron in vitro was capable of responding in a manner similar to habituation, Pavlov's reflex and avoidance of the reinforcements. The locality of plastic property modifications and molecular morphology, as well as the connection between functional activity and cytoskeleton have been revealed. A hypothesis is formulated that the neuron is a molecular system which may exercise the control, forecast, recognition, and classification. The basic principles of the molecular mechanisms of the responses underlying integrative activity, learning and memory at the neuronal level are discussed.

  11. 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.

  12. 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.

  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 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

  15. 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

  16. Common molecular mechanisms in explicit and implicit memory.

    PubMed

    Barco, Angel; Bailey, Craig H; Kandel, Eric R

    2006-06-01

    Cellular and molecular studies of both implicit and explicit memory suggest that experience-dependent modulation of synaptic strength and structure is a fundamental mechanism by which these memories are encoded and stored within the brain. In this review, we focus on recent advances in our understanding of two types of memory storage: (i) sensitization in Aplysia, a simple form of implicit memory, and (ii) formation of explicit spatial memories in the mouse hippocampus. These two processes share common molecular mechanisms that have been highly conserved through evolution.

  17. [Progress in researches of molecular mechanism of schistosome cercariae infection].

    PubMed

    Du, Xiaofeng; Ju, Chuan; Hu, Wei

    2013-12-01

    Schistosome cercariae must penetrate skin as an initial step to successfully infect the final host. Proteolytic enzymes secreted from the acetabular glands of cercariae contribute significantly to the invasion process. Nowadays, the researches of molecular mechanism of schistosome infection mainly focus on the cercarial secretions including serine protease and cysteine protease. Previous researches already showed that Schistosoma mansoni penetrates the skin mainly depend on cercarial elastease secreted by cercariae while Schistosoma japonicum penetrates the skin chiefly by cathepsin B2. The illustration of molecular mechanism of schistosome cecariae infection will accelerate the identification of novel vaccines and drug targets.

  18. Quantum mechanical/molecular mechanical study on the mechanism of the enzymatic Baeyer-Villiger reaction.

    PubMed

    Polyak, Iakov; Reetz, Manfred T; Thiel, Walter

    2012-02-08

    We report a combined quantum mechanical/molecular mechanical (QM/MM) study on the mechanism of the enzymatic Baeyer-Villiger reaction catalyzed by cyclohexanone monooxygenase (CHMO). In QM/MM geometry optimizations and reaction path calculations, density functional theory (B3LYP/TZVP) is used to describe the QM region consisting of the substrate (cyclohexanone), the isoalloxazine ring of C4a-peroxyflavin, the side chain of Arg-329, and the nicotinamide ring and the adjacent ribose of NADP(+), while the remainder of the enzyme is represented by the CHARMM force field. QM/MM molecular dynamics simulations and free energy calculations at the semiempirical OM3/CHARMM level employ the same QM/MM partitioning. According to the QM/MM calculations, the enzyme-reactant complex contains an anionic deprotonated C4a-peroxyflavin that is stabilized by strong hydrogen bonds with the Arg-329 residue and the NADP(+) cofactor. The CHMO-catalyzed reaction proceeds via a Criegee intermediate having pronounced anionic character. The initial addition reaction has to overcome an energy barrier of about 9 kcal/mol. The formed Criegee intermediate occupies a shallow minimum on the QM/MM potential energy surface and can undergo fragmentation to the lactone product by surmounting a second energy barrier of about 7 kcal/mol. The transition state for the latter migration step is the highest point on the QM/MM energy profile. Gas-phase reoptimizations of the QM region lead to higher barriers and confirm the crucial role of the Arg-329 residue and the NADP(+) cofactor for the catalytic efficiency of CHMO. QM/MM calculations for the CHMO-catalyzed oxidation of 4-methylcyclohexanone reproduce and rationalize the experimentally observed (S)-enantioselectivity for this substrate, which is governed by the conformational preferences of the corresponding Criegee intermediate and the subsequent transition state for the migration step.

  19. 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.

  20. The molecular mechanisms between metabolic syndrome and breast cancer.

    PubMed

    Chen, Yi; Wen, Ya-yuan; Li, Zhi-rong; Luo, Dong-lin; Zhang, Xiao-hua

    2016-03-18

    Metabolic syndrome, which is extremely common in developed and some developing countries, is a clustering of at least three of five of the following medical conditions: abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, and low high-density lipoprotein levels. It has been proved that there is a strong association between metabolic syndrome and breast cancer. Metabolic syndrome could increase the risk of breast cancer and influence the prognosis of the breast cancer patients. Some characteristic of metabolic syndrome such as obesity and lack of physical exercise are all risk factors for developing breast cancer. The metabolic syndrome mainly include obesity, type 2 diabetes, hypercholesterolemia and nonalcoholic fatty liver disease, and each of them impacts the risk of breast cancer and the prognosis of the breast cancer patients in different ways. In this Review, we focus on recently uncovered aspects of the immunological and molecular mechanisms that are responsible for the development of this highly prevalent and serious disease. These studies bring new insight into the complex associations between metabolic syndrome and breast cancer and have led to the development of novel therapeutic strategies that might enable a personalized approach in the management of this disease.

  1. Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab.

    PubMed

    Brand, Toni M; Iida, Mari; Wheeler, Deric L

    2011-05-01

    The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase belonging to the HER family of receptor tyrosine kinases. Receptor activation upon ligand binding leads to down stream activation of the PI3K/AKT, RAS/RAF/MEK/ERK and PLCγ/PKC pathways that influence cell proliferation, survival and the metastatic potential of tumor cells. Increased activation by gene amplification, protein overexpression or mutations of the EGFR has been identified as an etiological factor in a number of human epithelial cancers (e.g., NSCLC, CRC, glioblastoma and breast cancer). Therefore, targeting the EGFR has been intensely pursued as a cancer treatment strategy over the last two decades. To date, five EGFR inhibitors, including three small molecule tyrosine kinase inhibitors (TKIs) and two monoclonal antibodies have gained FDA approval for use in oncology. Both approaches to targeting the EGFR have shown clinical promise and the anti-EGFR antibody cetuximab is used to treat HNSCC and CRC. Despite clinical gains arising from use of cetuximab, both intrinsic resistance and the development of acquired resistance are now well recognized. In this review we focus on the biology of the EGFR, the role of EGFR in human cancer, the development of antibody-based anti-EGFR therapies and a summary of their clinical successes. Further, we provide an in depth discussion of described molecular mechanisms of resistance to cetuximab and potential strategies to circumvent this resistance.

  2. Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab

    PubMed Central

    Brand, Toni M; Iida, Mari

    2011-01-01

    The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase belonging to the HER family of receptor tyrosine kinases. Receptor activation upon ligand binding leads to down stream activation of the PI3K/AKT, RAS/RAF/MEK/ERK and PLCγ/PKC pathways that influence cell proliferation, survival and the metastatic potential of tumor cells. Increased activation by gene amplification, protein overexpression or mutations of the EGFR has been identified as an etiological factor in a number of human epithelial cancers (e.g., NSCLC, CRC, glioblastoma and breast cancer). Therefore, targeting the EGFR has been intensely pursued as a cancer treatment strategy over the last two decades. To date, five EGFR inhibitors, including three small molecule tyrosine kinase inhibitors (TKIs) and two monoclonal antibodies have gained FDA approval for use in oncology. Both approaches to targeting the EGFR have shown clinical promise and the anti-EGFR antibody cetuximab is used to treat HNSCC and CRC. Despite clinical gains arising from use of cetuximab, both intrinsic resistance and the development of acquired resistance are now well recognized. In this review we focus on the biology of the EGFR, the role of EGFR in human cancer, the development of antibody-based anti-EGFR therapies and a summary of their clinical successes. Further, we provide an in depth discussion of described molecular mechanisms of resistance to cetuximab and potential strategies to circumvent this resistance. PMID:21293176

  3. Cell and molecular mechanisms of insulin-induced angiogenesis

    PubMed Central

    Liu, Yan; Petreaca, Melissa; Martins-Green, Manuela

    2009-01-01

    Angiogenesis, the development of new blood vessel from pre-existing vessels, is a key process in the formation of the granulation tissue during wound healing. The appropriate development of new blood vessels, along with their subsequent maturation and differentiation, establishes the foundation for functional wound neovasculature. We performed studies in vivo and used a variety of cellular and molecular approaches in vitro to show that insulin stimulates angiogenesis and to elucidate the signalling mechanisms by which this protein stimulates microvessel development. Mice skin injected with insulin shows longer vessels with more branches, along with increased numbers of associated α-smooth muscle actin-expressing cells, suggesting the appropriate differentiation and maturation of the new vessels. We also found that insulin stimulates human microvascular endothelial cell migration and tube formation, and that these effects occur independently of VEGF/VEGFR signalling, but are dependent upon the insulin receptor itself. Downstream signalling pathways involve PI3K, Akt, sterol regulatory element-binding protein 1 (SREBP-1) and Rac1; inhibition of these pathways results in elimination of endothelial cell migration and tube formation and significantly decreases the development of microvessels. Our findings strongly suggest that insulin is a good candidate for the treatment of ischaemic wounds and other conditions in which blood vessel development is impaired. PMID:19602055

  4. Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

    PubMed Central

    Charlier, Edith; Relic, Biserka; Deroyer, Céline; Malaise, Olivier; Neuville, Sophie; Collée, Julie; Malaise, Michel G.; De Seny, Dominique

    2016-01-01

    Osteoarthritis (OA) is a joint pathology characterized by progressive cartilage degradation. Medical care is mainly based on alleviating pain symptoms. Compelling studies report the presence of empty lacunae and hypocellularity in cartilage with aging and OA progression, suggesting that chondrocyte cell death occurs and participates to OA development. However, the relative contribution of apoptosis per se in OA pathogenesis appears complex to evaluate. Indeed, depending on technical approaches, OA stages, cartilage layers, animal models, as well as in vivo or in vitro experiments, the percentage of apoptosis and cell death types can vary. Apoptosis, chondroptosis, necrosis, and autophagic cell death are described in this review. The question of cell death causality in OA progression is also addressed, as well as the molecular pathways leading to cell death in response to the following inducers: Fas, Interleukin-1β (IL-1β), Tumor Necrosis factor-α (TNF-α), leptin, nitric oxide (NO) donors, and mechanical stresses. Furthermore, the protective role of autophagy in chondrocytes is highlighted, as well as its decline during OA progression, enhancing chondrocyte cell death; the transition being mainly controlled by HIF-1α/HIF-2α imbalance. Finally, we have considered whether interfering in chondrocyte apoptosis or promoting autophagy could constitute therapeutic strategies to impede OA progression. PMID:27999417

  5. Molecular simulations of protein dynamics: new windows on mechanisms in biology.

    PubMed

    Dodson, Guy G; Lane, David P; Verma, Chandra S

    2008-02-01

    Recent advances in computer hardware and software have led to the development of increasingly successful molecular simulations of protein structural dynamics that are intrinsic to biological processes. These simulations have resulted in models that increasingly agree with experimental observations, suggest new experiments and provide insights into biological mechanisms. Used in combination with data obtained with sophisticated experimental techniques, simulations are helping us to understand biological complexity at the atomic and molecular levels and are giving promising insights into the genetic, thermodynamic and functional/mechanistic behaviour of biological processes. Here, we highlight some examples of such approaches that illustrate the current state and potential of the field of molecular simulation.

  6. A coordinated molecular 'fishing' mechanism in heterodimeric kinesin

    NASA Astrophysics Data System (ADS)

    Hou, Ruizheng; Wang, Zhisong

    2010-09-01

    Kar3 is a kinesin motor that facilitates chromosome segregation during cell division. Unlike many members of the kinesin superfamily, Kar3 forms a heterodimer with non-motor protein Vik1 or Cik1 in vivo. The heterodimers show ATP-driven minus-end directed motility along a microtubule (MT) lattice, and also serve as depolymerase at the MT ends. The molecular mechanisms behind this dual functionality remain mysterious. Here, a molecular mechanical model for the Kar3/Vik1 heterodimer based on structural, kinetic and motility data reveals a long-range chemomechanical transmission mechanism that resembles a familiar fishing tactic. By this molecular 'fishing', ATP-binding to Kar3 dissociates catalytically inactive Vik1 off MT to facilitate minus-end sliding of the dimer on the MT lattice. When the dimer binds the frayed ends of MT, the fishing channels ATP hydrolysis energy into MT deploymerization by a mechanochemical effect. The molecular fishing thus provides a unified mechanistic ground for Kar3's dual functionality. The fishing-promoted depolymerization differs from the depolymerase mechanisms found in homodimeric kinesins. The fishing also enables intermolecular coordination with a chemomechanical coupling feature different from the paradigmatic pattern of homodimeric motors. This study rationalizes some puzzling experimental observation, and suggests new experiments for further elucidation of the fishing mechanism.

  7. Multiresolution molecular mechanics: Surface effects in nanoscale materials

    NASA Astrophysics Data System (ADS)

    Yang, Qingcheng; To, Albert C.

    2017-05-01

    Surface effects have been observed to contribute significantly to the mechanical response of nanoscale structures. The newly proposed energy-based coarse-grained atomistic method Multiresolution Molecular Mechanics (MMM) (Yang, To (2015), [57]) is applied to capture surface effect for nanosized structures by designing a surface summation rule SRS within the framework of MMM. Combined with previously proposed bulk summation rule SRB, the MMM summation rule SRMMM is completed. SRS and SRB are consistently formed within SRMMM for general finite element shape functions. Analogous to quadrature rules in finite element method (FEM), the key idea to the good performance of SRMMM lies in that the order or distribution of energy for coarse-grained atomistic model is mathematically derived such that the number, position and weight of quadrature-type (sampling) atoms can be determined. Mathematically, the derived energy distribution of surface area is different from that of bulk region. Physically, the difference is due to the fact that surface atoms lack neighboring bonding. As such, SRS and SRB are employed for surface and bulk domains, respectively. Two- and three-dimensional numerical examples using the respective 4-node bilinear quadrilateral, 8-node quadratic quadrilateral and 8-node hexahedral meshes are employed to verify and validate the proposed approach. It is shown that MMM with SRMMM accurately captures corner, edge and surface effects with less 0.3% degrees of freedom of the original atomistic system, compared against full atomistic simulation. The effectiveness of SRMMM with respect to high order element is also demonstrated by employing the 8-node quadratic quadrilateral to solve a beam bending problem considering surface effect. In addition, the introduced sampling error with SRMMM that is analogous to numerical integration error with quadrature rule in FEM is very small.

  8. 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

  9. Molecular mechanisms controlling the cell cycle in embryonic stem cells.

    PubMed

    Abdelalim, Essam M

    2013-12-01

    Embryonic stem (ES) cells are originated from the inner cell mass of a blastocyst stage embryo. They can proliferate indefinitely, maintain an undifferentiated state (self-renewal), and differentiate into any cell type (pluripotency). ES cells have an unusual cell cycle structure, consists mainly of S phase cells, a short G1 phase and absence of G1/S checkpoint. Cell division and cell cycle progression are controlled by mechanisms ensuring the accurate transmission of genetic information from generation to generation. Therefore, control of cell cycle is a complicated process, involving several signaling pathways. Although great progress has been made on the molecular mechanisms involved in the regulation of ES cell cycle, many regulatory mechanisms remain unknown. This review summarizes the current knowledge about the molecular mechanisms regulating the cell cycle of ES cells and describes the relationship existing between cell cycle progression and the self-renewal.

  10. Systems diagnostics: the systems approach to molecular imaging.

    PubMed

    Lee, Daniel Y; Li, King C P

    2009-08-01

    Molecular imaging has emerged as a powerful technology that has already changed the practice of modern medicine. During this same period, the monumental genome project has sequenced man's entire genetic content. Now the postgenomic aim is to understand the dynamic interactions of the encoded components and their regulatory mechanisms. Molecular imaging is well positioned to play a major role in this massive effort as we move toward a comprehensive paradigm for assessing health and disease.

  11. 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.

  12. Combination of metformin with chemotherapeutic drugs via different molecular mechanisms.

    PubMed

    Peng, Mei; Darko, Kwame Oteng; Tao, Ting; Huang, Yanjun; Su, Qiongli; He, Caimei; Yin, Tao; Liu, Zhaoqian; Yang, Xiaoping

    2017-03-01

    Metformin, a widely prescribed drug for treating type II diabetes, is one of the most extensively recognized metabolic modulators which has shown an important anti-cancer property. However, fairly amount of clinical trials on its single administration have not demonstrated a convincing efficiency yet. Thus, recent studies tend to combine metformin with clinical commonly used chemotherapeutic drugs to decrease their toxicity and attenuate their tumor resistance. These strategies have displayed promising clinical benefits. Interestingly, metformin experiences a diversity of molecular mechanisms when it combines different chemotherapeutic drugs. For example, AMPK/mTOR signaling pathway activation plays a major role when it combines with hormone modulating drugs. In contrast, suppression of HIF-1, p-gp and MRP1 protein expression is its main mechanism when metformin combines with anti-metabolites. Furthermore, when combining of metformin with antibiotics, inhibition of oxidative stress and inflammatory signaling pathway becomes a novel pharmaceutical mechanism for its cardio-protective effect. Induction of apoptotic mitochondria and nucleus could be the major player for the synergistic effect of its combination with cisplatin. In contrast, down-regulation of lipoprotein or cholesterol synthesis might be the undefined molecular base when metformin combines with taxane. Thus, deep exploration of molecular mechanisms of metformin with these different drugs is critical to understand its synergistic effect and help for personalized administration. In this mini-review, detailed molecular mechanisms of these combinations are discussed and summarized. This work will promote better understanding of molecular mechanisms of metformin and provide precise targets to identify specific patient groups to achieve satisfactory treatment efficacy. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    PubMed

    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

    2016-03-24

    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.

  14. 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.

  15. Mechanism of Salinity Tolerance in Plants: Physiological, Biochemical, and Molecular Characterization

    PubMed Central

    Huang, Bingru

    2014-01-01

    Salinity is a major abiotic stress limiting growth and productivity of plants in many areas of the world due to increasing use of poor quality of water for irrigation and soil salinization. Plant adaptation or tolerance to salinity stress involves complex physiological traits, metabolic pathways, and molecular or gene networks. A comprehensive understanding on how plants respond to salinity stress at different levels and an integrated approach of combining molecular tools with physiological and biochemical techniques are imperative for the development of salt-tolerant varieties of plants in salt-affected areas. Recent research has identified various adaptive responses to salinity stress at molecular, cellular, metabolic, and physiological levels, although mechanisms underlying salinity tolerance are far from being completely understood. This paper provides a comprehensive review of major research advances on biochemical, physiological, and molecular mechanisms regulating plant adaptation and tolerance to salinity stress. PMID:24804192

  16. 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

  17. Combined quantum mechanical/molecular mechanics modeling for large organometallic and metallobiochemical systems

    NASA Astrophysics Data System (ADS)

    Leong, Max Kangchien

    A method of combined quantum mechanics/molecular mechanics has been developed to model larger organometallic and metallobiochemical systems where neither quantum mechanics nor molecular mechanics, applied separately, can solve the problem. An electronically transparent interface, which allows charge transfers between the quantum and classical fragments, is devised and realized by employing a special iterative procedure of double (intrafragment and interfragment) self-consistent calculations. The combined QM/MM scheme was successfully applied to model iron picket-fence porphyrin, vitamin B12, aquocobalamin, and vitamin B12 coenzyme molecules.

  18. 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

  19. The molecular mechanisms of hemodialysis vascular access failure

    PubMed Central

    Franzoni, Marco; Misra, Sanjay

    2016-01-01

    The arteriovenous fistula has been used for more than 50 years to provide vascular access for patients undergoing hemodialysis. More than 1.5 million patients worldwide have end stage renal disease and this population will continue to grow. The arteriovenous fistula is the preferred vascular access for patients, but its patency rate at 1 year is only 60%. The majority of arteriovenous fistulas fail because of intimal hyperplasia. In recent years, there have been many studies investigating the molecular mechanisms responsible for intimal hyperplasia and subsequent thrombosis. These studies have identified common pathways including inflammation, uremia, hypoxia, sheer stress, and increased thrombogenicity. These cellular mechanisms lead to increased proliferation, migration, and eventually stenosis. These pathways work synergistically through shared molecular messengers. In this review, we will examine the literature concerning the molecular basis of hemodialysis vascular access malfunction. PMID:26806833

  20. A resonance approach to cochlear mechanics.

    PubMed

    Bell, Andrew

    2012-01-01

    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. 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. 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.

  1. Computational molecular biology approaches to ligand-target interactions

    PubMed Central

    Lupieri, Paola; Nguyen, Chuong Ha Hung; Bafghi, Zhaleh Ghaemi; Giorgetti, Alejandro; Carloni, Paolo

    2009-01-01

    Binding of small molecules to their targets triggers complex pathways. Computational approaches are keys for predictions of the molecular events involved in such cascades. Here we review current efforts at characterizing the molecular determinants in the largest membrane-bound receptor family, the G-protein-coupled receptors (GPCRs). We focus on odorant receptors, which constitute more than half GPCRs. The work presented in this review uncovers structural and energetic aspects of components of the cellular cascade. Finally, a computational approach in the context of radioactive boron-based antitumoral therapies is briefly described. PMID:20119480

  2. Mechanical tuning of conductance and thermopower in helicene molecular junctions

    NASA Astrophysics Data System (ADS)

    Vacek, Jaroslav; Chocholoušová, Jana Vacek; Stará, Irena G.; Starý, Ivo; Dubi, Yonatan

    2015-05-01

    Helicenes are inherently chiral polyaromatic molecules composed of all-ortho fused benzene rings possessing a spring-like structure. Here, using a combination of density functional theory and tight-binding calculations, it is demonstrated that controlling the length of the helicene molecule by mechanically stretching or compressing the molecular junction can dramatically change the electronic properties of the helicene, leading to a tunable switching behavior of the conductance and thermopower of the junction with on/off ratios of several orders of magnitude. Furthermore, control over the helicene length and number of rings is shown to lead to more than an order of magnitude increase in the thermopower and thermoelectric figure-of-merit over typical molecular junctions, presenting new possibilities of making efficient thermoelectric molecular devices. The physical origin of the strong dependence of the transport properties of the junction is investigated, and found to be related to a shift in the position of the molecular orbitals.

  3. A Molecular Mechanics Study of Monensin B Ion Selectivity.

    DTIC Science & Technology

    well known knot theorist working with Jon Simon under the math part of the ONR stereochemical topology project. 2) The 5-rung THYME diol-ditosylate has...trefoil knot, which will posses 100 atoms in the ring. 3) The first molecular mechanics studies on the THYME system have been accomplished. 4) Preliminary

  4. 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

  5. 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.

  6. Molecular Approaches to Understand Nutritional Potential of Coarse Cereals

    PubMed Central

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

    2016-01-01

    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

  7. 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

    2014-08-05

    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.

  8. 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.

  9. Molecular mechanisms underlying the fetal programming of adult disease.

    PubMed

    Vo, Thin; Hardy, Daniel B

    2012-08-01

    Adverse events in utero can be critical in determining quality of life and overall health. It is estimated that up to 50 % of metabolic syndrome diseases can be linked to an adverse fetal environment. However, the mechanisms linking impaired fetal development to these adult diseases remain elusive. This review uncovers some of the molecular mechanisms underlying how normal physiology may be impaired in fetal and postnatal life due to maternal insults in pregnancy. By understanding the mechanisms, which include epigenetic, transcriptional, endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS), we also highlight how intervention in fetal and neonatal life may be able to prevent these diseases long-term.

  10. Novel molecular mechanisms and regeneration therapy for heart failure.

    PubMed

    Oka, Toru; Morita, Hiroyuki; Komuro, Issei

    2016-03-01

    Heart failure (HF) is one of the leading causes of mortality in the world. Various molecular mechanisms have been proposed for HF, but its precise mechanisms are still largely unknown. In this review, summarizing the "President's Distinguished Lecture Award" of XX World Congress of International Society for Heart Research 2010 in Kyoto, Japan, we introduce recent our studies on HF, including 1) p53-induced suppression of Hif-1-induced angiogenesis as a novel mechanism of HF, 2) angiogenesis as a potential therapeutic strategy for HF, and 3) IGFBP-4 as a novel factor for cardiomyogenesis by inhibiting canonical Wnt signaling.

  11. A Molecular Mechanics Analysis of Molecular Recognition by Cyclodextrin Mimics of Alpha-Chymotrypsin

    DTIC Science & Technology

    1989-05-26

    Recognition By Cyclodextrin Mimics of Alpha-Chymotrypsin i by C.A. Venanzi. P.M. Canzius, Z. Zhang, and J.D. Bunce LT IC To Be Published in CLECTE JUN 0 51...Clasification) A Molecular Mechanics Analysis of Molecular Recognition By Cyclodextrin Mimics of Alpha-Chymotrypsin. 12. PERSONAL AUTHOR(S) C.A. Venanzil... CYCLODEXTRIN MIMICS OF 0( -CHYMOTRYPSIN Carol A. Venanzi1 , Preston M. Canzius, Zhifeng Zhang, and Jeffrey D. Bunce Department of Chemical Engineering

  12. Molecular Mechanisms in Mood Regulation Involving the Circadian Clock

    PubMed Central

    Albrecht, Urs

    2017-01-01

    The circadian system coordinates activities and functions in cells and tissues in order to optimize body functions in anticipation to daily changes in the environment. Disruption of the circadian system, due to irregular lifestyle such as rotating shift work, frequent travel across time-zones, or chronic stress, is correlated with several diseases such as obesity, cancer, and neurological disorders. Molecular mechanisms linking the circadian clock with neurological functions have been uncovered suggesting that disruption of the clock may be critically involved in the development of mood disorders. In this mini-review, I will summarize molecular mechanisms in which clock components play a central role for mood regulation. Such mechanisms have been identified in the monoaminergic system, the HPA axis, and neurogenesis. PMID:28223962

  13. Molecular mechanics of mineralized collagen fibrils in bone

    NASA Astrophysics Data System (ADS)

    Nair, Arun K.; Gautieri, Alfonso; Chang, Shu-Wei; Buehler, Markus J.

    2013-04-01

    Bone is a natural composite of collagen protein and the mineral hydroxyapatite. The structure of bone is known to be important to its load-bearing characteristics, but relatively little is known about this structure or the mechanism that govern deformation at the molecular scale. Here we perform full-atomistic calculations of the three-dimensional molecular structure of a mineralized collagen protein matrix to try to better understand its mechanical characteristics under tensile loading at various mineral densities. We find that as the mineral density increases, the tensile modulus of the network increases monotonically and well beyond that of pure collagen fibrils. Our results suggest that the mineral crystals within this network bears up to four times the stress of the collagen fibrils, whereas the collagen is predominantly responsible for the material’s deformation response. These findings reveal the mechanism by which bone is able to achieve superior energy dissipation and fracture resistance characteristics beyond its individual constituents.

  14. Molecular Mechanisms in Mood Regulation Involving the Circadian Clock.

    PubMed

    Albrecht, Urs

    2017-01-01

    The circadian system coordinates activities and functions in cells and tissues in order to optimize body functions in anticipation to daily changes in the environment. Disruption of the circadian system, due to irregular lifestyle such as rotating shift work, frequent travel across time-zones, or chronic stress, is correlated with several diseases such as obesity, cancer, and neurological disorders. Molecular mechanisms linking the circadian clock with neurological functions have been uncovered suggesting that disruption of the clock may be critically involved in the development of mood disorders. In this mini-review, I will summarize molecular mechanisms in which clock components play a central role for mood regulation. Such mechanisms have been identified in the monoaminergic system, the HPA axis, and neurogenesis.

  15. 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.

  16. Molecular mechanics of mineralized collagen fibrils in bone

    PubMed Central

    Nair, Arun K.; Gautieri, Alfonso; Chang, Shu-Wei; Buehler, Markus J.

    2013-01-01

    Bone is a natural composite of collagen protein and the mineral hydroxyapatite. The structure of bone is known to be important to its load-bearing characteristics, but relatively little is known about this structure or the mechanism that govern deformation at the molecular scale. Here we perform full-atomistic calculations of the three-dimensional molecular structure of a mineralized collagen protein matrix to try to better understand its mechanical characteristics under tensile loading at various mineral densities. We find that as the mineral density increases, the tensile modulus of the network increases monotonically and well beyond that of pure collagen fibrils. Our results suggest that the mineral crystals within this network bears up to four times the stress of the collagen fibrils, whereas the collagen is predominantly responsible for the material’s deformation response. These findings reveal the mechanism by which bone is able to achieve superior energy dissipation and fracture resistance characteristics beyond its individual constituents. PMID:23591891

  17. Adaptive molecular resolution approach in Hamiltonian form: An asymptotic analysis.

    PubMed

    Zhu, Jinglong; Klein, Rupert; Delle Site, Luigi

    2016-10-01

    Adaptive molecular resolution approaches in molecular dynamics are becoming relevant tools for the analysis of molecular liquids characterized by the interplay of different physical scales. The essential difference among these methods is in the way the change of molecular resolution is made in a buffer (transition) region. In particular a central question concerns the possibility of the existence of a global Hamiltonian which, by describing the change of resolution, is at the same time physically consistent, mathematically well defined, and numerically accurate. In this paper we present an asymptotic analysis of the adaptive process complemented by numerical results and show that under certain mathematical conditions a Hamiltonian, which is physically consistent and numerically accurate, may exist. Such conditions show that molecular simulations in the current computational implementation require systems of large size, and thus a Hamiltonian approach such as the one proposed, at this stage, would not be practical from the numerical point of view. However, the Hamiltonian proposed provides the basis for a simplification and generalization of the numerical implementation of adaptive resolution algorithms to other molecular dynamics codes.

  18. Submillisecond Elastic Recoil Reveals Molecular Origins of Fibrin Fiber Mechanics

    PubMed Central

    Hudson, Nathan E.; Ding, Feng; Bucay, Igal; O’Brien, E. Timothy; Gorkun, Oleg V.; Superfine, Richard; Lord, Susan T.; Dokholyan, Nikolay V.; Falvo, Michael R.

    2013-01-01

    Fibrin fibers form the structural scaffold of blood clots. Thus, their mechanical properties are of central importance to understanding hemostasis and thrombotic disease. Recent studies have revealed that fibrin fibers are elastomeric despite their high degree of molecular ordering. These results have inspired a variety of molecular models for fibrin’s elasticity, ranging from reversible protein unfolding to rubber-like elasticity. An important property that has not been explored is the timescale of elastic recoil, a parameter that is critical for fibrin’s mechanical function and places a temporal constraint on molecular models of fiber elasticity. Using high-frame-rate imaging and atomic force microscopy-based nanomanipulation, we measured the recoil dynamics of individual fibrin fibers and found that the recoil was orders of magnitude faster than anticipated from models involving protein refolding. We also performed steered discrete molecular-dynamics simulations to investigate the molecular origins of the observed recoil. Our results point to the unstructured αC regions of the otherwise structured fibrin molecule as being responsible for the elastic recoil of the fibers. PMID:23790375

  19. 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

  20. Molecular mechanisms involved in mammalian primary sex determination.

    PubMed

    She, Zhen-Yu; Yang, Wan-Xi

    2014-08-01

    Sex determination refers to the developmental decision that directs the bipotential genital ridge to develop as a testis or an ovary. Genetic studies on mice and humans have led to crucial advances in understanding the molecular fundamentals of sex determination and the mutually antagonistic signaling pathway. In this review, we summarize the current molecular mechanisms of sex determination by focusing on the known critical sex determining genes and their related signaling pathways in mammalian vertebrates from mice to humans. We also discuss the underlying delicate balance between testis and ovary sex determination pathways, concentrating on the antagonisms between major sex determining genes.

  1. Dissecting molecular mechanisms in the living brain of dementia patients.

    PubMed

    Barrio, Jorge R; Satyamurthy, Nagichettiar; Huang, Sung-Cheng; Petric, Andrej; Small, Gary W; Kepe, Vladimir

    2009-07-21

    Understanding the molecular mechanisms associated with the development of dementia is essential for designing successful interventions. Dementia, like cancer and cardiovascular disease, requires early detection to potentially arrest or prevent further disease progression. By the time a neurologist begins to manage clinical symptoms, the disease has often damaged the brain significantly. Because successful treatment is the logical goal, detecting the disease when brain damage is still limited is of the essence. The role of chemistry in this discovery process is critical. With the advent of molecular imaging, the understanding of molecular mechanisms in human neurodegenerative diseases has exploded. Traditionally, knowledge of enzyme and neurotransmitter function in humans has been extrapolated from animal studies, but now we can acquire data directly from both healthy and diseased human subjects. In this Account, we describe the use of molecular imaging probes to elucidate the biochemical and cellular bases of dementia (e.g., Alzheimer's disease) and the application of these discoveries to the design of successful therapeutic interventions. Molecular imaging permits observation and evaluation of the basic molecular mechanisms of disease progression in the living brains of patients. 2-Deoxy-2-[(18)F]fluoro-d-glucose is used to assess the effect of Alzheimer's disease progression on neuronal circuits projecting from and to the temporal lobe (one of the earliest metabolic signs of the disease). Recently, we have developed imaging probes for detection of amyloid neuropathology (both tau and beta-amyloid peptide deposits) and neuronal losses. These probes allow us to visualize the development of pathology in the living brain of dementia patients and its consequences, such as losses of critical neurons associated with memory deficits and other neuropsychiatric impairments. Because inflammatory processes are tightly connected to the brain degenerative processes

  2. New cellular and molecular approaches to ageing brain.

    PubMed

    Tripathi, Anurag

    2012-10-01

    The last decade has witnessed a mammoth progress in the area of brain ageing. Recent gene profiling and brain imaging techniques have made it possible to explore the dark areas of ageing neurons in a new molecular perspective. Many conserved pathways and cellular and molecular mechanisms particularly nuclear mitochondrial molecular interactions are known now. Disruptions in mitochondrial function and reduction in cellular antioxidative and immunoproteins contribute to generation of reactive oxygen species (ROS) which leads to deteriorated adult neurogenesis, reduced white matter and compromised neural plasticity. The overall deteriorated structure and function of neurons is manifested in form of cognitive decline and prolonged neurodegenerative disorders. Dietary restrictions (DR), physical and mental activities however have been shown to counter these ailments. However more precise molecular dynamics at protein levels is still debatable which is the future task for neuroscientists.

  3. 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.

  4. Stability Mechanisms of a Thermophilic Laccase Probed by Molecular Dynamics

    PubMed Central

    Christensen, Niels J.; Kepp, Kasper P.

    2013-01-01

    Laccases are highly stable, industrially important enzymes capable of oxidizing a large range of substrates. Causes for their stability are, as for other proteins, poorly understood. In this work, multiple-seed molecular dynamics (MD) was applied to a Trametes versicolor laccase in response to variable ionic strengths, temperatures, and glycosylation status. Near-physiological conditions provided excellent agreement with the crystal structure (average RMSD ∼0.92 Å) and residual agreement with experimental B-factors. The persistence of backbone hydrogen bonds was identified as a key descriptor of structural response to environment, whereas solvent-accessibility, radius of gyration, and fluctuations were only locally relevant. Backbone hydrogen bonds decreased systematically with temperature in all simulations (∼9 per 50 K), probing structural changes associated with enthalpy-entropy compensation. Approaching Topt (∼350 K) from 300 K, this change correlated with a beginning “unzipping” of critical β-sheets. 0 M ionic strength triggered partial denucleation of the C-terminal (known experimentally to be sensitive) at 400 K, suggesting a general salt stabilization effect. In contrast, F− (but not Cl−) specifically impaired secondary structure by formation of strong hydrogen bonds with backbone NH, providing a mechanism for experimentally observed small anion destabilization, potentially remedied by site-directed mutagenesis at critical intrusion sites. N-glycosylation was found to support structural integrity by increasing persistent backbone hydrogen bonds by ∼4 across simulations, mainly via prevention of F− intrusion. Hydrogen-bond loss in distinct loop regions and ends of critical β-sheets suggest potential strategies for laboratory optimization of these industrially important enzymes. PMID:23658618

  5. Unveiling the Pathogenic Molecular Mechanisms of the Most Common Variant (p.K329E) in Medium-Chain Acyl-CoA Dehydrogenase Deficiency by in Vitro and in Silico Approaches.

    PubMed

    Bonito, Cátia A; Nunes, Joana; Leandro, João; Louro, Filipa; Leandro, Paula; Ventura, Fátima V; Guedes, Rita C

    2016-12-27

    Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common genetic disorder affecting the mitochondrial fatty acid β-oxidation pathway. The mature and functional form of human MCAD (hMCAD) is a homotetramer assembled as a dimer of dimers (monomers A/B and C/D). Each monomer binds a FAD cofactor, necessary for the enzyme's activity. The most frequent mutation in MCADD results from the substitution of a lysine with a glutamate in position 304 of mature hMCAD (p.K329E in the precursor protein). Here, we combined in vitro and in silico approaches to assess the impact of the p.K329E mutation on the protein's structure and function. Our in silico results demonstrated for the first time that the p.K329E mutation, despite lying at the dimer-dimer interface and being deeply buried inside the tetrameric core, seems to affect the tetramer surface, especially the β-domain that forms part of the catalytic pocket wall. Additionally, the molecular dynamics data indicate a stronger impact of the mutation on the protein's motions in dimer A/B, while dimer C/D remains similar to the wild type. For dimer A/B, severe disruptions in the architecture of the pockets and in the FAD and octanoyl-CoA binding affinities were also observed. The presence of unaffected pockets (C/D) in the in silico studies may explain the decreased enzymatic activity determined for the variant protein (46% residual activity). Moreover, the in silico structural changes observed for the p.K329E variant protein provide an explanation for the structural instability observed experimentally, namely, the disturbed oligomeric profile, thermal stability, and conformational flexibility, with respect to the wild-type.

  6. 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.

  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. Inactivation mechanism of glycerol dehydration by diol dehydratase from combined quantum mechanical/molecular mechanical calculations.

    PubMed

    Doitomi, Kazuki; Kamachi, Takashi; Toraya, Tetsuo; Yoshizawa, Kazunari

    2012-11-13

    Inactivation of diol dehydratase during the glycerol dehydration reaction is studied on the basis of quantum mechanical/molecular mechanical calculations. Glycerol is not a chiral compound but contains a prochiral carbon atom. Once it is bound to the active site, the enzyme adopts two binding conformations. One is predominantly responsible for the product-forming reaction (G(R) conformation), and the other primarily contributes to inactivation (G(S) conformation). Reactant radical is converted into a product and byproduct in the product-forming reaction and inactivation, respectively. The OH group migrates from C2 to C1 in the product-forming reaction, whereas the transfer of a hydrogen from the 3-OH group of glycerol to C1 takes place during the inactivation. The activation barrier of the hydrogen transfer does not depend on the substrate-binding conformation. On the other hand, the activation barrier of OH group migration is sensitive to conformation and is 4.5 kcal/mol lower in the G(R) conformation than in the G(S) conformation. In the OH group migration, Glu170 plays a critical role in stabilizing the reactant radical in the G(S) conformation. Moreover, the hydrogen bonding interaction between Ser301 and the 3-OH group of glycerol lowers the activation barrier in G(R)-TS2. As a result, the difference in energy between the hydrogen transfer and the OH group migration is reduced in the G(S) conformation, which shows that the inactivation is favored in the G(S) conformation.

  9. Theory of molecular conductance using a modular approach

    NASA Astrophysics Data System (ADS)

    Hsu, Liang-Yan; Rabitz, Herschel

    2016-12-01

    This study probes the correlation between the conductance of a molecular wire (the property of a whole system) and its constituent backbone units (modules). By using a tight-binding Hamiltonian combined with single-particle Green's functions, we develop an approach that enables an estimate of a conductance decay constant in terms of the Hamiltonians of molecular backbone units and the couplings between two nearest-neighbor units in the off-resonant tunneling regime. For demonstration, we examine several representative molecular systems in a framework of the Hückel model (the simplest atomistic-level model). The Hückel model can be reduced to a single-orbital-per-site formulation [A. Nitzan, Annu. Rev. Phys. Chem. 52, 681 (2001)], and each energy level in the single-orbital-per-site picture can be expressed in an explicit form including the synergistic effect of all molecular orbitals of a molecular backbone unit. Based on the proposed approach, we show the correspondence between the complete destructive quantum interference and an infinite injection gap and derive the preconditions of the modified Simmons equation and the rule of intramolecular series circuits.

  10. Molecular imaging. A new approach to nuclear cardiology.

    PubMed

    Dobrucki, L W; Sinusas, A J

    2005-03-01

    Nuclear cardiology has historically played an important role in detection of cardiovascular disease as well as risk stratification. With the growth of molecular biology have come new therapeutic interventions and the requirement for new diagnostic imaging approaches. Noninvasive targeted radiotracer based as well as transporter gene imaging strategies are evolving to meet these new needs, but require the development of an interdisciplinary approach which focuses on molecular processes, as well as the pathogenesis and progression of disease. This progress has been made possible with the availability of transgenic animal models along with many technological advances. Future adaptations of the developing experimental procedures and instrumentation will allow for the smooth translation and application to clinical practice. This review is intended as a brief overview on the subject molecular imaging. Basic concepts and historical perspective of molecular imaging will be reviewed first, followed by description of current technology, and concluding with current applications in cardiology. The emphasis will be on the use of both single photon emission computed tomography (SPECT) and positron emission tomography (PET) radiotracers, although other imaging modalities will be also briefly discussed. The specific approaches presented here will include receptor-based and reporter gene imaging of natural and therapeutic angiogenesis.

  11. Self-renewal molecular mechanisms of colorectal cancer stem cells

    PubMed Central

    Pan, Tianhui; Xu, Jinghong; Zhu, Yongliang

    2017-01-01

    Colorectal cancer stem cells (CCSCs) represent a small fraction of the colorectal cancer cell population that possess self-renewal and multi-lineage differentiation potential and drive tumorigenicity. Self-renewal is essential for the malignant biological behaviors of colorectal cancer stem cells. While the self-renewal molecular mechanisms of colorectal cancer stem cells are not yet fully understood, the aberrant activation of signaling pathways, such as Wnt, Notch, transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) and Hedgehog-Gli (HH-GLI), specific roles mediated by cell surface markers and micro-environmental factors are involved in the regulation of self-renewal. The elucidation of the molecular mechanisms behind self-renewal may lead to the development of novel targeted interventions for the treatment of colorectal cancer. PMID:27909729

  12. 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

  13. Molecular mechanisms of sound amplification in the mammalian cochlea.

    PubMed

    Ashmore, J F; Géléoc, G S; Harbott, L

    2000-10-24

    Mammalian hearing depends on the enhanced mechanical properties of the basilar membrane within the cochlear duct. The enhancement arises through the action of outer hair cells that act like force generators within the organ of Corti. Simple considerations show that underlying mechanism of somatic motility depends on local area changes within the lateral membrane of the cell. The molecular basis for this phenomenon is a dense array of particles that are inserted into the basolateral membrane and that are capable of sensing membrane potential field. We show here that outer hair cells selectively take up fructose, at rates high enough to suggest that a sugar transporter may be part of the motor complex. The relation of these findings to a recent candidate for the molecular motor is also discussed.

  14. Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy

    PubMed Central

    2010-01-01

    In recent years, tyrosine kinases (TKs) have been recognized as central players and regulators of cancer cell proliferation, apoptosis, and angiogenesis, and are therefore considered suitable potential targets for anti-cancer therapies. Several strategies for targeting TKs have been developed, the most successful being monoclonal antibodies and small molecule tyrosine kinase inhibitors. However, increasing evidence of acquired resistance to these drugs has been documented, and extensive preclinical studies are ongoing to try to understand the molecular mechanisms by which cancer cells are able to bypass their inhibitory activity. This review intends to present the most recently identified molecular mechanisms that mediate acquired resistance to tyrosine kinase inhibitors, identified through the use of in vitro models or the analysis of patient samples. The knowledge obtained from these studies will help to design better therapies that prevent and overcome resistance to treatment in cancer patients. PMID:20385023

  15. Separating Mechanical and Chemical Contributions to Molecular-Level Friction

    SciTech Connect

    KIM,HYUN I.; HOUSTON,JACK E.

    2000-08-14

    The authors use force-probe microscopy to study the friction force and the adhesive interaction for molecular monolayer self-assembled on both Au probe tips and substrate surfaces. By systematically varying the chemical nature of the end groups on these monolayers the authors have, for the first time, delineated the mechanical and chemical origins of molecular-level friction. They use chemically inert {double_bond}CH{sub 3} groups on both interracial surfaces to establish the purely mechanical component of the friction and contrast the results with the findings for chemically active {double_bond}COOH end-groups. In addition, by using odd or even numbers of methylene groups in the alkyl backbones of the molecules they are able to determine the levels of inter-film and intra-film hydrogen bonding.

  16. 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.

  17. Molecular interaction mechanisms in reverse micellar extraction of microbial transglutaminase.

    PubMed

    Yu, Tingting; Lin, Mingxiang; Wan, Junfen; Cao, Xuejun

    2017-08-18

    Reverse micellar extraction is an efficient and economical alternative for protein purification. In this study, microbial transglutaminase (MTGase) from crude materials was purified using reverse micellar extraction, and the molecular interaction mechanism in reverse micellar extraction of MTGase was explored. By using a molecular simulation study, the interaction mechanism of forward extraction was investigated. The molecular simulation results reveal the interaction of MTGase-water-surfactant is the major driving force for the forward extraction. Further, the effect of ionic strength on molecular interactions in backward extraction was investigated using 1H low-field nuclear magnetic resonance (LF-NMR) and circular dichroism (CD) spectra. In backward extraction, the interactions between water and the other two molecules (MTGase and surfactant molecules) are enhanced while the interactions between target molecules (MTGase) and the other two molecules (water and surfactant molecules) are weakened as the ionic strength increases. Moreover, the effect of size exclusion on backward extraction was also investigated. The results demonstrate size exclusion has limit effect at high ionic strength, and the weakened interaction of MTGase-water-surfactant is the main reason causing the release of the target molecules in backward extraction. This work might provide valuable reference to the MTGase purification and downstream processing. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. How insects survive the cold: molecular mechanisms-a review.

    PubMed

    Clark, Melody S; Worland, M Roger

    2008-11-01

    Insects vary considerably in their ability to survive low temperatures. The tractability of these organisms to experimentation has lead to considerable physiology-based work investigating both the variability between species and the actual mechanisms themselves. This has highlighted a range of strategies including freeze tolerance, freeze avoidance, protective dehydration and rapid cold hardening, which are often associated with the production of specific chemicals such as antifreezes and polyol cryoprotectants. But we are still far from identifying the critical elements behind over-wintering success and how some species can regularly survive temperatures below -20 degrees C. Molecular biology is the most recent tool to be added to the insect physiologist's armoury. With the public availability of the genome sequence of model insects such as Drosophila and the production of custom-made molecular resources, such as EST libraries and microarrays, we are now in a position to start dissecting the molecular mechanisms behind some of these well-characterised physiological responses. This review aims to provide a state-of-the-art snapshot of the molecular work currently being conducted into insect cold tolerance and the very interesting preliminary results from such studies, which provide great promise for the future.

  19. 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.

  20. Molecular mechanism of interaction between norfloxacin and trypsin studied by molecular spectroscopy and modeling

    NASA Astrophysics Data System (ADS)

    Lu, Yan; Wang, Gongke; Lu, Xiumin; Lv, Juan; Xu, Meihua; Zhang, Weiwei

    2010-01-01

    The molecular mechanism of the binding of norfloxacin (NRF) to trypsin was investigated by fluorescence, synchronous fluorescence and UV-vis absorbance spectroscopy and molecular modeling at physiological conditions. The quenching mechanism and the binding mode were investigated in terms of the association constants and basic thermodynamic parameters. The results of spectroscopic measurements suggested that NRF have a strong ability to quench the intrinsic fluorescence of trypsin through static quenching procedure. Moreover, fluorescence experiments were also performed at different values of pH to elucidate the effect of pH on the binding. The NRF-trypsin complex was stabilized by hydrophobic forces and hydrogen bonding, via tryptophan residue as indicated from the thermodynamic parameters, which was consistent with the results of molecular docking and accessible surface area calculations.

  1. 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

  2. Molecular mechanism of Ca(2+)-catalyzed fusion of phospholipid micelles.

    PubMed

    Tsai, Hui-Hsu Gavin; Juang, Wei-Fu; Chang, Che-Ming; Hou, Tsai-Yi; Lee, Jian-Bin

    2013-11-01

    Although membrane fusion plays key roles in intracellular trafficking, neurotransmitter release, and viral infection, its underlying molecular mechanism and its energy landscape are not well understood. In this study, we employed all-atom molecular dynamics simulations to investigate the fusion mechanism, catalyzed by Ca(2+) ions, of two highly hydrated 1-palmitoyl-2-oleoyl-sn-3-phosphoethanolamine (POPE) micelles. This simulation system mimics the small contact zone between two large vesicles at which the fusion is initiated. Our simulations revealed that Ca(2+) ions are capable of catalyzing the fusion of POPE micelles; in contrast, we did not observe close contact of the two micelles in the presence of only Na(+) or Mg(2+) ions. Determining the free energy landscape of fusion allowed us to characterize the underlying molecular mechanism. The Ca(2+) ions play a key role in catalyzing the micelle fusion in three aspects: creating a more-hydrophobic surface on the micelles, binding two micelles together, and enhancing the formation of the pre-stalk state. In contrast, Na(+) or Mg(2+) ions have relatively limited effects. Effective fusion proceeds through sequential formation of pre-stalk, stalk, hemifused-like, and fused states. The pre-stalk state is the state featuring lipid tails exposed to the inter-micellar space; its formation is the rate-limiting step. The stalk state is the state where a localized hydrophobic core is formed connecting two micelles; its formation occurs in conjunction with water expulsion from the inter-micellar space. This study provides insight into the molecular mechanism of fusion from the points of view of energetics, structure, and dynamics. © 2013 Elsevier B.V. All rights reserved.

  3. Molecular mechanisms of metabolic regulation by insulin in Drosophila.

    PubMed

    Teleman, Aurelio A

    2009-12-14

    The insulin signalling pathway is highly conserved from mammals to Drosophila. Insulin signalling in the fly, as in mammals, regulates a number of physiological functions, including carbohydrate and lipid metabolism, tissue growth and longevity. In the present review, I discuss the molecular mechanisms by which insulin signalling regulates metabolism in Drosophila, comparing and contrasting with the mammalian system. I discuss both the intracellular signalling network, as well as the communication between organs in the fly.

  4. Molecular Transport Mechanisms for Associating and Solvating Penetrant in Polymers

    DTIC Science & Technology

    2007-11-02

    PIB ) at different vapor activities in order to understand complex diffusion mechanisms and probe molecular structures above the glass tranisition. The...the individual diffusion coefficients can be separated and that they are equal to each other for the acetic acid/ PIB system. The values of the...BOH) mixtures in polyisobutylene ( PIB ) was studied at varying mixture compositions. Diffusion coefficients and hydrogen bonding interactions were

  5. Molecular Mechanism of hTERT Function in Mitochondria

    DTIC Science & Technology

    2016-10-20

    Molecular mechanism of hTERT function in mitochondria (x) Material has been given an OPSEC review and it has been determined to be non sensitive and...transcriptase (hTERT) is localized to mitochondria , as well as the nucleus, but details about its biology and function in the organelle remain largely...demonstrate the canonical nuclear RNA [human telomerase RNA (hTR)] is not present in human mitochondria and not required for the mitochondrial

  6. Rattlesnake Neurotoxin Structure, Mechanism of Action, Immunology and Molecular Biology

    DTIC Science & Technology

    1992-09-10

    Aird, S. D., and Kaiser, I. I. (1988) Physiological and immunological properties of small myotoxins from -Zhe venom of the midget faded rattlesnake ...AD-A258 669 AD RATTLESNAKE NEUROTOXIN STRUCTURE, MECHANISM OF ACTION, IMMUNOLOGY AND MOLECULAR BIOLOGY FINAL REPORT D TIC IVAN I. KAISER ELECTE S DEC...u m_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 6 2 7 8 7 A I 6 2 7 8 7 A 8 7 7 I A A [ ~A 3 1 7 8 2 1 (u) Rattlesnake neurotoxin structure

  7. Rattlesnake Neurotoxin Structure, Mechanism of Action, Immunology and Molecular Biology

    DTIC Science & Technology

    1990-09-01

    from the venom of the midget faded . rattlesnake (Crotalus viridis concolor . Toxicon 2&, 319- 323. Rehm, H. and Betz, H. (1982) Binding of B...8217determined. It was shown to have great similarity to the basic subunits of related toxins from the venoms of the South American and midget faded ...AD-A228 003 CONTRACT NO.: DAMD17-89-C-9007 TITLE: RATTLESNAKE NEUROTOXIN STRUCTURE, MECHANISM OF ACTION, IMMUNOLOGY AND MOLECULAR BIOLOGY PRINCIPAL

  8. Unraveling the mechanism of molecular doping in organic semiconductors.

    PubMed

    Mityashin, Alexander; Olivier, Yoann; Van Regemorter, Tanguy; Rolin, Cedric; Verlaak, Stijn; Martinelli, Nicolas G; Beljonne, David; Cornil, Jérôme; Genoe, Jan; Heremans, Paul

    2012-03-22

    The mechanism by which molecular dopants donate free charge carriers to the host organic semiconductor is investigated and is found to be quite different from the one in inorganic semiconductors. In organics, a strong correlation between the doping concentration and its charge donation efficiency is demonstrated. Moreover, there is a threshold doping level below which doping simply has no electrical effect. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Water Exchange Rates and Molecular Mechanism around Aqueous Halide Ions

    SciTech Connect

    Annapureddy, Harsha V.; Dang, Liem X.

    2014-07-17

    Molecular dynamics simulations were performed to systematically study the water-exchange mechanism around aqueous chloride, bromide, and iodide ions. Transition state theory, Grote-Hynes theory, and the reactive flux method were employed to compute water exchange rates. We computed the pressure dependence of rate constants and the corresponding activation volumes to investigate the mechanism of the solvent exchange event. The activation volumes obtained using the transition state theory rate constants are negative for all the three anions, thus indicating an associative mechanism. Contrary to the transition state theory results, activation volumes obtained using rate constants from Grote-Hynes theory and the reactive flux method are positive, thus indicating a dissociative mechanism. The Division of Chemical Sciences, Geosciences, and Biosciences, Office of Basic Energy Sciences (BES), of the U.S. Department of Energy (DOE) funded this work. Battelle operates Pacific Northwest National Laboratory for DOE. The calculations were carried out using computer resources provided by BES.

  10. Kainate receptor trafficking: physiological roles and molecular mechanisms.

    PubMed

    Isaac, John T R; Mellor, Jack; Hurtado, David; Roche, Katherine W

    2004-12-01

    Recently, there has been intense interest in the mechanisms regulating the trafficking and synaptic targeting of kainate receptors in neurons. This topic is still in its infancy when compared with studies of trafficking of other ionotropic glutamate receptors; however, it is already clear that mechanisms exist for subunit- and splice variant-specific trafficking of kainate receptors. There is also enormous diversity of kainate receptor targeting, with the best-studied neurons in this regard being hippocampal CA3 pyramidal neurons and CA1 GABAergic interneurons. This review summarizes the current state of knowledge on this topic, focusing on the molecular mechanisms of kainate receptor trafficking and the potential for these mechanisms to regulate neuronal kainate receptor function.

  11. Mechanical instability of α-quartz: A molecular dynamics study

    NASA Astrophysics Data System (ADS)

    Tse, John S.; Klug, Dennis D.

    1991-12-01

    Pressure-induced amorphization in α-quartz has been investigated using constant-pressure molecular-dynamics calculations with the two-body potential of van Beest, Kramer, and van Santen. Both the static properties and the crystalline-to-amorphous phase transition were very well reproduced. Through an analysis of the elastic moduli, the mechanism for the transformation is shown to be a mechanical instability driven mainly by a cooperative twisting and compression of the helical tetrahedral silicate units with an abrupt decrease in the C12, C23, C13, C14, and C33 elastic moduli.

  12. Molecular Mechanisms Regulating TGF-β-Induced Foxp3 Expression

    PubMed Central

    Xu, Lili; Kitani, Atsushi; Strober, Warren

    2013-01-01

    Molecular mechanisms regulating TGF-β induction of Foxp3 expression and thus induction of iTregs has been the focus of a great deal of study in recent years. It has become clear that this process is influenced by a number of factors as perhaps might be predicted by the fact that there is an overarching need of the immune system to fine-tune response to environmental antigens. In this review we discuss these mechanisms, with the aim of presenting a broad picture of how the various observations fit together to form an integrated regulatory regime. PMID:20404810

  13. Molecular and Cellular Mechanics (Part I): A moderated discussion

    NASA Astrophysics Data System (ADS)

    Corey, David P.; Martin, Pascal

    2015-12-01

    The following is an edited transcript of a recorded discussion session on the topic of "Molecular and Cellular Mechanics". The discussion, moderated by the authors, took place at the 12th International Workshop on the Mechanics of Hearing held at Cape Sounio, Greece, in June 2014. All participants knew that the session was being recorded. In view of both the spontaneous nature of the discussion and the editing, however, this transcript may not represent the considered or final views of the participants, and may not represent a consensus of experts in the field. The reader is advised to consult additional independent publications.

  14. Molecular and Cellular Mechanics (Part II): A moderated discussion

    NASA Astrophysics Data System (ADS)

    Santos-Sacchi, Joseph

    2015-12-01

    The following is an edited transcript of a recorded discussion session on the topic of "Molecular and Cellular Mechanics". The discussion, moderated by the author, took place at the 12th International Workshop on the Mechanics of Hearing held at Cape Sounio, Greece, in June 2014. All participants knew that the session was being recorded. In view of both the spontaneous nature of the discussion and the editing, however, this transcript may not represent the considered or final views of the participants, and may not represent a consensus of experts in the field. The reader is advised to consult additional independent publications.

  15. Molecular mechanisms of heavy metal hyperaccumulation and phytoremediation.

    PubMed

    Yang, Xiaoe; Feng, Ying; He, Zhenli; Stoffella, Peter J

    2005-01-01

    A relatively small group of hyperaccumulator plants is capable of sequestering heavy metals in their shoot tissues at high concentrations. In recent years, major scientific progress has been made in understanding the physiological mechanisms of metal uptake and transport in these plants. However, relatively little is known about the molecular bases of hyperaccumulation. In this paper, current progresses on understanding cellular/molecular mechanisms of metal tolerance/hyperaccumulation by plants are reviewed. The major processes involved in hyperaccumulation of trace metals from the soil to the shoots by hyperaccumulators include: (a) bioactivation of metals in the rhizosphere through root-microbe interaction; (b) enhanced uptake by metal transporters in the plasma membranes; (c) detoxification of metals by distributing to the apoplasts like binding to cell walls and chelation of metals in the cytoplasm with various ligands, such as phytochelatins, metallothioneins, metal-binding proteins; (d) sequestration of metals into the vacuole by tonoplast-located transporters. The growing application of molecular-genetic technologies led to the well understanding of mechanisms of heavy metal tolerance/accumulation in plants, and subsequently many transgenic plants with increased resistance and uptake of heavy metals were developed for the purpose of phytoremediation. Once the rate-limiting steps for uptake, translocation, and detoxification of metals in hyperaccumulating plants are identified, more informed construction of transgenic plants would result in improved applicability of the phytoremediation technology.

  16. [Ethanol tolerance in yeast: molecular mechanisms and genetic engineering].

    PubMed

    Zhang, Qiumei; Zhao, Xinqing; Jiang, Rujiao; Li, Qian; Bai, Fengwu

    2009-04-01

    Improvement of stress tolerance to various adverse environmental conditions (such as toxic products, high temperature) of the industrial microorganisms is important for industrial applications. Ethanol produced by yeast fermentation is inhibitory to both yeast cell growth and metabolisms, and consequently is one of the key stress elements of brewer's yeast. Research on the biochemical and molecular mechanism of the tolerance of yeast can provide basis for breeding of yeast strain with improved ethanol tolerance. In recent years, employing global gene transcriptional analysis and functional analysis, new knowledge on the biochemical and molecular mechanisms of yeast ethanol tolerance has been accumulated, and novel genes and biochemical parameters related to ethanol tolerance have been revealed. Based on these studies, the overexpression and/or disruption of the related genes have successfully resulted in the breeding of new yeast strains with improved ethanol tolerance. This paper reviewed the recent research progress on the molecular mechanism of yeast ethanol tolerance, as well as the genetic engineering manipulations to improve yeast ethanol tolerance. The studies reviewed here not only deepened our knowledge on yeast ethanol tolerance, but also provided basis for more efficient bioconversion for bio-energy production.

  17. 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.

  18. Molecular Mechanism of Isocupressic Acid Supresses MA-10 Cell Steroidogenesis

    PubMed Central

    Tsui, Kuan-Hao; Wang, Jyun-Yuan; Wu, Leang-Shin; Chiu, Chih-Hsien

    2012-01-01

    Consumption of ponderosa pine needles causes late-term abortions in cattle and is a serious poisonous plant problem in foothill and mountain rangelands. Isocupressic acid (IA) is the component of pine needles responsible for the abortifacient effect, its abortifacient effect may be due to inhibition of steroidogenesis. To investigate the more detail molecular mechanism, we used MA-10 cell, which is wild used to investigate molecular mechanism of steroidogenesis, to characterize the molecular mechanisms underlying the actions of IA in more detail. In this report, we focus on the function of IA on important steroidogenic genes, including steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage (P450scc), and 3β-hydroxysteroid dehydrogenase (3β-HSD). We found that IA does not affect enzyme activities of these genes but inhibits transcription of P450scc and translation of StAR and P450scc through attenuating cAMP-PKA signaling. Thus, steroid productions of cells were suppressed. PMID:22666287

  19. Molecular Mechanism of Isocupressic Acid Supresses MA-10 Cell Steroidogenesis.

    PubMed

    Tsui, Kuan-Hao; Wang, Jyun-Yuan; Wu, Leang-Shin; Chiu, Chih-Hsien

    2012-01-01

    Consumption of ponderosa pine needles causes late-term abortions in cattle and is a serious poisonous plant problem in foothill and mountain rangelands. Isocupressic acid (IA) is the component of pine needles responsible for the abortifacient effect, its abortifacient effect may be due to inhibition of steroidogenesis. To investigate the more detail molecular mechanism, we used MA-10 cell, which is wild used to investigate molecular mechanism of steroidogenesis, to characterize the molecular mechanisms underlying the actions of IA in more detail. In this report, we focus on the function of IA on important steroidogenic genes, including steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage (P450scc), and 3β-hydroxysteroid dehydrogenase (3β-HSD). We found that IA does not affect enzyme activities of these genes but inhibits transcription of P450scc and translation of StAR and P450scc through attenuating cAMP-PKA signaling. Thus, steroid productions of cells were suppressed.

  20. Molecular and cellular mechanisms of cognitive function: implications for psychiatric disorders.

    PubMed

    Silva, A J; Elgersma, Y; Costa, R M

    2000-02-01

    Recent studies on the molecular and cellular basis of learning and memory have brought us closer than ever to understanding the mechanisms of synaptic plasticity and their relevance to memory formation. Genetic approaches have played a central role in these new findings because the same mutant mice can be studied with molecular, cellular, circuit, and behavioral tools. Therefore, the results can be used to construct models that cut across levels of analytical complexity, forging connections from the biochemistry of the modified protein to the behavior of the mutant mice. These findings are not only improving our understanding of learning and memory, they are also enriching our understanding of cognitive disorders, such as neurofibromatosis type I. Mechanisms underlying long-term changes in synaptic function are likely to be at the heart of many cognitive and emotional processes in humans. Therefore, molecular and cellular insights into learning and memory undoubtedly will have a profound impact on the understanding and treatment of psychiatric disorders.